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| Boilerpipe Text | Antidepressant
Drug class
Venlafaxine
(brand name Effexor), an antidepressant acting as a
serotonin–norepinephrine reuptake inhibitor
(SNRI).
Class identifiers
Synonyms
Psychic energizer; Mood elevator; Thymoleptic; Depression pill
Use
Depressive disorders
,
anxiety disorders
,
chronic pain
, and
addiction
ATC code
N06A
Mechanism of action
Varies
Chemical class
Varies
Clinical data
Drugs.com
Drug Classes
Consumer Reports
Best Buy Drugs
WebMD
MedicineNet
RxList
External links
MeSH
D000928
Legal status
In Wikidata
Antidepressants
, also known in the past as
psychic energizers
,
[
1
]
are a class of
medications
used to treat
major depressive disorder
,
anxiety disorders
,
chronic pain
, and
addiction
.
[
2
]
Common
side effects
of antidepressants include
dry mouth
,
weight gain
,
dizziness
,
headaches
,
akathisia
,
[
3
]
sexual dysfunction
,
[
4
]
[
5
]
[
6
]
[
7
]
[
8
]
and
emotional blunting
.
[
9
]
[
10
]
[
11
]
There is an increased risk of
suicidal thinking
and
behavior
when taken by children, adolescents, and young adults.
[
12
]
Discontinuation syndrome
, which resembles recurrent
depression
in the case of the
SSRI
class, may occur after stopping the intake of any antidepressant, having effects which may be permanent and irreversible.
Tapering
off medications gradually is shown to reduce the risk of
withdrawal
complications.
[
13
]
[
14
]
The effectiveness of antidepressants for treating depression in adults has strong support, though studies also highlight potential risks and limitations.
[
15
]
[
16
]
In children and adolescents, evidence of efficacy is more limited, despite a marked increase in antidepressant prescriptions for these age groups since the 2000s.
[
17
]
[
18
]
[
19
]
A 2018 meta-analysis reported that the 21 most commonly prescribed antidepressants were found in all studies to be more effective than
placebos
for the short-term treatment of
major depressive disorder
in adults. However, other research suggests that some benefits may be attributable to the placebo effect. Response to antidepressants is highly variable, and medications that are effective for certain patients may have no effect or a negative effect for others. Research into the factors that influence individual responses to antidepressants is ongoing.
[
20
]
[
21
]
[
22
]
[
23
]
[
24
]
Antidepressants are prescribed to treat
major depressive disorder
(MDD),
anxiety disorders
,
chronic pain
, and some addictions. Antidepressants are often used in combination with one another.
[
2
]
Despite its longstanding prominence in pharmaceutical advertising, the idea that low serotonin levels cause depression is not supported by scientific evidence.
[
25
]
[
26
]
[
27
]
Proponents of the
monoamine hypothesis of depression
recommend choosing an antidepressant which impacts the most prominent symptoms. Under this practice, for example, a person with MDD who is also anxious or irritable would be treated with
selective serotonin reuptake inhibitors
(SSRIs) or
norepinephrine reuptake inhibitors
, while a person suffering from loss of energy and enjoyment of life would take a
norepinephrine–dopamine reuptake inhibitor
.
[
28
]
Major depressive disorder
[
edit
]
The UK
National Institute for Health and Care Excellence
(NICE)'s 2022 guidelines indicate that antidepressants should not be routinely used for the initial treatment of mild depression, "unless that is the person's preference".
[
29
]
The guidelines recommended that antidepressant treatment be considered:
For people with a history of moderate or severe depression.
For people with mild depression that has been present for an extended period.
As a first-line treatment for moderate to severe depression.
As a second-line treatment for mild depression that persists after other interventions.
The guidelines further note that in most cases, antidepressants should be used in combination with psychosocial interventions and should be continued for at least six months to reduce the risk of relapse and that SSRIs are typically better tolerated than other antidepressants.
[
29
]
American Psychiatric Association
(APA) treatment guidelines recommend that initial treatment be individually tailored based on factors including the severity of symptoms, co-existing disorders, prior treatment experience, and the person's preference. Options may include antidepressants,
psychotherapy
,
electroconvulsive therapy
(ECT),
transcranial magnetic stimulation
(TMS), or
light therapy
. The APA recommends antidepressant medication as an initial treatment choice in people with mild, moderate, or severe major depression, and that should be given to all people with severe depression unless ECT is planned.
[
30
]
Reviews of antidepressants generally find that they benefit adults with depression.
[
21
]
[
15
]
On the other hand, some contend that most studies on antidepressant medication are confounded by several biases: the lack of an
active placebo
, which means that many people in the placebo arm of a
double-blind study
may deduce that they are not getting any true treatment, thus destroying double-blindness; a short follow up after termination of treatment; non-systematic recording of adverse effects; very strict exclusion criteria in samples of patients; studies being paid for by the industry; selective publication of results. This means that the small beneficial effects that are found may not be statistically significant.
[
31
]
[
32
]
[
33
]
[
34
]
[
16
]
Among the 21 most commonly prescribed antidepressants, the most effective and well-tolerated are
escitalopram
,
paroxetine
,
sertraline
,
agomelatine
, and
mirtazapine
.
[
20
]
[
21
]
For children and adolescents with moderate to severe depressive disorder, some evidence suggests
fluoxetine
(either with or without
cognitive behavioral therapy
) is the best treatment, but more research is needed to be certain.
[
35
]
[
36
]
[
37
]
[
38
]
Sertraline, escitalopram, and
duloxetine
may also help reduce symptoms.
[
38
]
A 2023
systematic review
and
meta-analysis
of
randomized controlled trials
of antidepressants for major depressive disorder found that the medications provided only small or doubtful benefits in terms of
quality of life
.
[
39
]
Likewise, a 2022 systematic review and meta-analysis of randomized controlled trials of antidepressants for major depressive disorder in children and adolescents found small improvements in quality of life.
[
40
]
Quality of life as an outcome measure is often selectively reported in trials of antidepressants.
[
41
]
For children and adolescents,
fluvoxamine
and
escitalopram
are effective in treating a range of anxiety disorders.
[
42
]
[
37
]
[
43
]
Fluoxetine, sertraline, and paroxetine can also help with managing various forms of anxiety in children and adolescents.
[
42
]
[
37
]
[
43
]
Meta-analyses of published and unpublished trials have found that antidepressants have a
placebo
-subtracted
effect size
(
standardized mean difference
or SMD) in the treatment of anxiety disorders of around 0.3, which equates to a small improvement and is roughly the same magnitude of benefit as their effectiveness in the treatment of depression.
[
44
]
The effect size (SMD) for improvement with placebo in trials of antidepressants for anxiety disorders is approximately 1.0, which is a large improvement in terms of effect size definitions.
[
45
]
In relation to this, most of the benefit of antidepressants for anxiety disorders is attributable to placebo responses rather than to the effects of the antidepressants themselves.
[
44
]
[
45
]
Generalized anxiety disorder
[
edit
]
Antidepressants are recommended by the National Institute for Health and Care Excellence (NICE) for the treatment of
generalized anxiety disorder
(GAD) that has failed to respond to conservative measures such as education and self-help activities. GAD is a common disorder in which the central feature is excessively worrying about numerous events. Key symptoms include excessive anxiety about events and issues going on around them and difficulty controlling worrisome thoughts that persists for at least 6 months.
Antidepressants provide a modest to moderate reduction in anxiety in GAD.
[
46
]
The efficacy of different antidepressants is similar.
[
46
]
Some antidepressants are used as a treatment for
social anxiety disorder
, but their efficacy is not entirely convincing, as only a small proportion of antidepressants showed some effectiveness for this condition. Paroxetine was the first drug to be FDA-approved for this disorder. Its efficacy is considered beneficial, although not everyone responds favorably to the drug. Sertraline and fluvoxamine extended-release were later approved for it as well, while escitalopram is used
off-label
with acceptable efficiency. However, there is not enough evidence to support
citalopram
for treating social anxiety disorder, and fluoxetine was no better than a placebo in clinical trials.
Vortioxetine
may be of benefit.
SSRIs
are used as a first-line treatment for social anxiety, but they do not work for everyone. One alternative would be
venlafaxine
, an
SNRI
, which has shown benefits for social phobia in five clinical trials against a placebo, while the other SNRIs are not considered particularly useful for this disorder as many of them did not undergo testing for it. As of 2008
, it is unclear if duloxetine and
desvenlafaxine
can provide benefits for people with social anxiety. However, another class of antidepressants called
MAOIs
are considered effective for social anxiety, but they come with many unwanted side effects and are rarely used.
Phenelzine
was shown to be a good treatment option, but its use is limited by dietary restrictions.
Moclobemide
is a
RIMA
and showed mixed results, but still received approval in some European countries for social anxiety disorder.
TCA antidepressants
, such as
clomipramine
and
imipramine
, are not considered effective for this anxiety disorder in particular. This leaves out SSRIs such as paroxetine, sertraline, and fluvoxamine CR as acceptable and tolerated treatment options for this disorder.
[
47
]
[
48
]
Obsessive–compulsive disorder
[
edit
]
SSRIs are a
second-line
treatment for adult
obsessive–compulsive disorder
(OCD) with mild functional impairment, and a first-line treatment for those with moderate or severe impairment.
[
49
]
[
50
]
[
51
]
[
52
]
In children, SSRIs are considered as a second-line therapy in those with moderate-to-severe impairment, with close monitoring for psychiatric adverse effects.
[
53
]
Sertraline and fluoxetine are effective in treating OCD for children and adolescents.
[
42
]
[
37
]
[
43
]
Clomipramine
, a TCA drug, is considered effective and useful for OCD.
[
54
]
However, it is used as a second-line treatment because it is less well-tolerated than SSRIs. Despite this, it has not shown superiority to fluvoxamine in trials. All SSRIs can be used effectively for OCD. SNRI use may also be attempted, though no SNRIs have been approved for the treatment of OCD. Despite these treatment options, many patients remain symptomatic after initiating the medication, and less than half achieve
remission
.
[
55
]
Placebo responses are a large component of the benefit of antidepressants in the treatment of depression and anxiety.
[
44
]
[
45
]
However, placebo responses with antidepressants are lower in magnitude in the treatment of OCD compared to depression and anxiety.
[
45
]
[
56
]
A 2019 meta-analysis found placebo improvement effect sizes (SMD) of about 1.2 for depression, 1.0 for anxiety disorders, and 0.6 for OCD with antidepressants.
[
45
]
Post–traumatic stress disorder
[
edit
]
Antidepressants are one of the treatment options for
PTSD
. However, their efficacy is not well established. Paroxetine and sertraline have been FDA approved for the treatment of PTSD. Paroxetine has slightly higher response and remission rates than sertraline for this condition. However, neither drug is considered very helpful for a broad patient demographic. Fluoxetine and venlafaxine are used off-label. Fluoxetine has produced unsatisfactory mixed results. Venlafaxine showed response rates of 78%, which is significantly higher than what paroxetine and sertraline achieved. However, it did not address as many symptoms of PTSD as paroxetine and sertraline, in part due to the fact that venlafaxine is an
SNRI
. This class of drugs inhibits the reuptake of norepinephrine, which may cause anxiety in some patients. Fluvoxamine, escitalopram, and citalopram were not well-tested for this disorder.
MAOIs
, while some of them may be helpful, are not used much because of their unwanted side effects. This leaves paroxetine and sertraline as acceptable treatment options for some people, although more effective antidepressants are needed.
[
57
]
Panic disorder
is treated relatively well with medications compared to other disorders. Several classes of antidepressants have shown efficacy for this disorder, with SSRIs and SNRIs used first-line. Paroxetine, sertraline, and fluoxetine are FDA-approved for panic disorder, while fluvoxamine, escitalopram, and citalopram are also considered effective for them. SNRI venlafaxine is also approved for this condition. Unlike
social anxiety
and
PTSD
, some
TCAs antidepressants
, like clomipramine and imipramine, have shown efficacy for panic disorder. Moreover, the
MAOI
phenelzine
is also considered useful. Panic disorder has many drugs for its treatment. However, the starting dose must be lower than the one used for major depressive disorder because people have reported an increase in anxiety as a result of starting the medication. In conclusion, while panic disorder's treatment options seem acceptable and useful for this condition, many people are still symptomatic after treatment with residual symptoms.
[
58
]
[
59
]
[
60
]
Antidepressants are recommended as an alternative or additional first step to self-help programs in the treatment of
bulimia nervosa
.
[
61
]
SSRIs (fluoxetine in particular) are preferred over other antidepressants due to their acceptability, tolerability, and superior reduction of symptoms in short-term trials. Long-term efficacy remains poorly characterized.
Bupropion
is not recommended for the treatment of eating disorders, due to an increased risk of seizure.
[
62
]
Similar recommendations apply to
binge eating disorder
.
[
61
]
SSRIs provide short-term reductions in binge eating behavior, but have not been associated with significant weight loss.
[
63
]
Clinical trials have generated mostly negative results for the use of SSRIs in the treatment of
anorexia nervosa
.
[
64
]
Treatment guidelines from the National Institute of Health and Care Excellence (NICE)
[
61
]
recommend against the use of SSRIs in this disorder. Those from the American Psychiatric Association (APA) note that SSRIs confer no advantage regarding weight gain, but may be used for the treatment of co-existing depressive, anxiety, or obsessive–compulsive disorders.
[
63
]
A 2012
meta-analysis
concluded that antidepressant treatment favorably affects pain, health-related quality of life, depression, and sleep in
fibromyalgia
syndrome.
Tricyclics
appear to be the most effective class, with moderate effects on pain and sleep, and small effects on fatigue and health-related quality of life. The fraction of people experiencing a 30% pain reduction on tricyclics was 48%, versus 28% on placebo. For SSRIs and SNRIs, the fractions of people experiencing a 30% pain reduction were 36% (20% in the placebo comparator arms) and 42% (32% in the corresponding placebo comparator arms) respectively. Discontinuation of treatment due to side effects was common.
[
65
]
Antidepressants including
amitriptyline
,
duloxetine
,
milnacipran
,
moclobemide
, and
pirlindole
are recommended by the European League Against Rheumatism (EULAR) for the treatment of fibromyalgia based on "limited evidence".
[
66
]
A 2014 meta-analysis from the
Cochrane Collaboration
found the antidepressant duloxetine to be effective for the treatment of pain resulting from
diabetic neuropathy
.
[
67
]
The same group reviewed data for amitriptyline in the treatment of
neuropathic pain
and found limited useful randomized clinical trial data. They concluded that the long history of successful use in the community for the treatment of fibromyalgia and neuropathic pain justified its continued use.
[
68
]
The group was concerned about the potential overestimation of the amount of pain relief provided by amitriptyline, and highlighted that only a small number of people will experience significant pain relief by taking this medication.
[
68
]
Antidepressants may be modestly helpful for treating people who have both depression and
alcohol dependence
, however, the evidence supporting this association is of low quality.
[
69
]
Bupropion is used to help people
stop smoking
. Antidepressants are also used to control some symptoms of
narcolepsy
.
[
70
]
Antidepressants may be used to relieve pain in people with active
rheumatoid arthritis
. However, further research is required.
[
71
]
Antidepressants have been shown to be superior to placebo in treating depression in individuals with physical illness, although reporting bias may have exaggerated this finding.
[
72
]
Antidepressants have been shown to improve some parts of cognitive functioning for depressed users, such as memory, attention, and processing speed.
[
73
]
Certain antidepressants acting as serotonin 5-HT
2A
receptor antagonists, such as
trazodone
and
mirtazapine
, have been used as
hallucinogen antidotes or "trip killers"
to block the effects of
serotonergic psychedelics
like
psilocybin
and
lysergic acid diethylamide
(LSD).
[
74
]
[
75
]
[
76
]
Limitations and strategies
[
edit
]
Among individuals treated with a given antidepressant, between 30% and 50% do not show a response.
[
77
]
[
78
]
Approximately one-third of people achieve a full
remission
, one-third experience a response, and one-third are non-responders. Partial remission is characterized by the presence of poorly defined residual symptoms. These symptoms typically include depressed mood, anxiety, sleep disturbance, fatigue, and diminished interest or pleasure. It is currently unclear which factors predict partial remission. However, it is clear that residual symptoms are powerful predictors of relapse, with relapse rates three to six times higher in people with residual symptoms than in those, who experience full remission.
[
79
]
In addition, antidepressant drugs tend to lose efficacy throughout long-term
maintenance therapy
.
[
80
]
According to data from the
Centers for Disease Control and Prevention
, less than one-third of Americans taking one antidepressant medication have seen a mental health professional in the previous year.
[
81
]
Several strategies are used in clinical practice to try to overcome these limits and variations.
[
82
]
They include switching medication, augmentation, and combination.
There is controversy amongst researchers regarding the efficacy and risk-benefit ratio of antidepressants.
[
83
]
[
84
]
Although antidepressants consistently out-perform a placebo in meta-analyses, the difference is modest and it is not clear that their statistical superiority results in clinical efficacy.
[
21
]
[
85
]
[
86
]
[
87
]
The aggregate effect of antidepressants typically results in changes below the threshold of clinical significance on depression rating scales.
[
88
]
[
89
]
Proponents of antidepressants counter that the most common scale, the
HDRS
, is not suitable for assessing drug action, that the threshold for clinical significance is arbitrary, and that antidepressants consistently result in significantly raised scores on the mood item of the scale.
[
90
]
Assessments of antidepressants using alternative, more sensitive scales, such as the
MADRS
, do not result in marked difference from the HDRS and likewise only find a marginal clinical benefit.
[
91
]
Another hypothesis proposed to explain the poor performance of antidepressants in clinical trials is a high treatment response heterogeneity. Some patients, that differ strongly in their response to antidepressants, could influence the average response, while the heterogeneity could itself be obscured by the averaging. Studies have not supported this hypothesis, but it is very difficult to measure treatment effect heterogeneity.
[
92
]
Poor and complex clinical trial design might also account for the small effects seen for antidepressants.
[
93
]
[
94
]
The randomized controlled trials used to approve drugs are short, and may not capture the full effect of antidepressants.
[
94
]
Additionally, the placebo effect might be inflated in these trials by frequent clinical consultation, lowering the comparative performance of antidepressants.
[
94
]
Critics agree that current clinical trials are poorly-designed, which limits the knowledge on antidepressants.
[
95
]
More naturalistic studies, such as
STAR*D
, have produced results, which suggest that antidepressants may be less effective in clinical practice than in randomized controlled trials.
[
96
]
[
97
]
Critics of antidepressants maintain that the superiority of antidepressants over placebo is the result of systemic flaws in clinical trials and the research literature.
[
96
]
[
88
]
Trials conducted with industry involvement tend to produce more favorable results, and accordingly many of the trials included in meta-analyses are at high risk of bias.
[
98
]
[
88
]
Additionally, meta-analyses co-authored by industry employees find more favorable results for antidepressants.
[
88
]
The results of antidepressant trials are significantly more likely to be published if they are favorable, and unfavorable results are very often left unpublished or misreported, a phenomenon called
publication bias
or selective publication.
[
99
]
Although this issue has diminished with time, it remains an obstacle to accurately assessing the efficacy of antidepressants.
[
100
]
Misreporting of clinical trial outcomes and of serious adverse events, such as suicide, is common.
[
101
]
[
98
]
[
102
]
Ghostwriting
of antidepressant trials is widespread, a practice in which prominent researchers, or so-called key opinion leaders, attach their names to studies actually written by pharmaceutical company employees or consultants.
[
102
]
A particular concern is that the psychoactive effects of antidepressants may lead to the unblinding of participants or researchers, enhancing the placebo effect and biasing results.
[
44
]
[
103
]
[
98
]
Some have therefore maintained that antidepressants may only be active placebos.
[
96
]
[
88
]
When these and other flaws in the research literature are not taken into account, meta-analyses may find inflated results on the basis of poor evidence.
[
98
]
Critics contend that antidepressants have not been proven sufficiently effective by RCTs or in clinical practice and that the widespread use of antidepressants is not evidence-based.
[
96
]
[
88
]
They also note that adverse effects, including withdrawal difficulties, are likely underreported, skewing clinicians' ability to make risk-benefit judgements.
[
84
]
[
104
]
[
105
]
[
96
]
Accordingly, they believe antidepressants are overused, particularly for non-severe depression and conditions in which they are not indicated.
[
84
]
[
106
]
Critics charge that the widespread use and public acceptance of antidepressants is the result of pharmaceutical advertising, research manipulation, and misinformation.
[
107
]
[
108
]
[
109
]
[
110
]
Current mainstream psychiatric opinion recognizes the limitations of antidepressants but recommends their use in adults with more severe depression as a first-line treatment.
[
111
]
[
112
]
Switching antidepressants
[
edit
]
The
American Psychiatric Association
2000 Practice Guideline advises that where no response is achieved within the following six to eight weeks of treatment with an antidepressant, switch to an antidepressant in the same class, and then to a different class. A 2006 meta-analysis review found wide variation in the findings of prior studies: for people who had failed to respond to an SSRI antidepressant, between 12% and 86% showed a response to a new drug. However, the more antidepressants an individual had previously tried, the less likely they were to benefit from a new antidepressant trial.
[
78
]
However, a later meta-analysis found no difference between switching to a new drug and staying on the old medication: although 34% of
treatment-resistant
people responded when switched to the new drug, 40% responded without being switched.
[
113
]
Augmentation and combination
[
edit
]
For a partial response, the American Psychiatric Association (APA) guidelines suggest
augmentation
or adding a drug from a different class. These include
lithium
and
thyroid
augmentation,
dopamine agonists
,
sex steroids
,
NRIs
,
glucocorticoid
-specific agents, or the newer
anticonvulsants
.
[
114
]
A combination strategy involves adding another antidepressant, usually from a different class to affect other mechanisms. Although this may be used in clinical practice, there is little evidence for the relative efficacy or adverse effects of this strategy.
[
115
]
Other tests conducted include the use of
psychostimulants
as an augmentation therapy. Several studies have shown the efficacy of combining
modafinil
for treatment-resistant people. It has been used to help combat SSRI-associated fatigue.
[
116
]
Long-term use and stopping
[
edit
]
The effects of antidepressants typically do not continue once the course of medication ends. This results in a high rate of
relapse
. In 2003, a
meta-analysis
found that 18% of people who had responded to an antidepressant relapsed while still taking it, compared to 41% whose antidepressant was switched for a
placebo
.
[
117
]
A gradual loss of therapeutic benefit occurs in a minority of people during the course of treatment.
[
118
]
[
119
]
A strategy involving the use of
pharmacotherapy
in the treatment of the acute episode, followed by psychotherapy in its residual phase, has been suggested by some studies.
[
120
]
[
121
]
For patients who wish to stop their antidepressants, engaging in brief psychological interventions such as Preventive Cognitive Therapy
[
122
]
or
mindfulness-based cognitive therapy
while
tapering
down has been found to diminish the risk for
relapse
.
[
123
]
Antidepressants can cause various
adverse effects
, depending on the individual and the drug in question.
[
124
]
Almost any medication involved with serotonin regulation has the potential to cause
serotonin toxicity
(also known as
serotonin syndrome
) – an excess of serotonin that can induce mania, restlessness, agitation,
emotional lability
, insomnia, and confusion as its primary symptoms.
[
125
]
[
126
]
Although the condition is serious, it is not particularly common, generally only appearing at high doses or while on other medications. Assuming proper medical intervention has been taken (within about 24 hours) it is rarely fatal.
[
127
]
[
128
]
Antidepressants appear to increase the risk of
diabetes
by about 1.3-fold.
[
129
]
MAOIs
tend to have pronounced (sometimes fatal) interactions with a wide variety of medications and
over-the-counter drugs
. If taken with foods that contain very high levels of
tyramine
(e.g., mature cheese, cured meats, or yeast extracts), they may cause a potentially lethal
hypertensive crisis
. At lower doses, the person may only experience a headache due to an increase in blood pressure.
[
130
]
In response to these adverse effects, a different type of MAOI, the class of
reversible inhibitor of monoamine oxidase A
(RIMA), has been developed. The primary advantage of RIMAs is that they do not require the person to follow a special diet while being purportedly effective as SSRIs and tricyclics in treating depressive disorders.
[
131
]
Tricyclics and SSRI can cause the so-called
drug-induced QT prolongation
, especially in older adults;
[
132
]
this condition can degenerate into a specific type of
abnormal heart rhythm
called
torsades de pointes
, which can potentially lead to
sudden cardiac arrest
.
[
133
]
Some antidepressants are also believed to increase thoughts of
suicidal ideation
.
Antidepressants have been associated with an increased risk of
dementia
in older adults.
[
134
]
Researchers have developed a tool that allows people to rate their concern about common side effects of antidepressants. The tool ranks potential treatment options in a visual display that highlights the drugs with side effects of least concern to an individual.
[
135
]
[
136
]
SSRI use in pregnancy has been associated with a variety of risks with varying degrees of proof of causation. As depression is independently associated with negative pregnancy outcomes, determining the extent to which observed associations between antidepressant use and specific adverse outcomes reflect a causative relationship has been difficult in some cases.
[
137
]
In other cases, the attribution of adverse outcomes to antidepressant exposure seems fairly clear.
SSRI use in pregnancy is associated with an increased risk of spontaneous abortion of about 1.7-fold,
[
138
]
[
139
]
and is associated with preterm birth and low birth weight.
[
140
]
A systematic review of the risk of major birth defects in antidepressant-exposed pregnancies found a small increase (3% to 24%) in the risk of major malformations and a risk of cardiovascular birth defects that did not differ from non-exposed pregnancies.
[
141
]
A study of fluoxetine-exposed pregnancies found a 12% increase in the risk of major malformations that did not reach statistical significance.
[
142
]
Other studies have found an increased risk of cardiovascular birth defects among depressed mothers not undergoing SSRI treatment, suggesting the possibility of ascertainment bias, e.g. that worried mothers may pursue more aggressive testing of their infants.
[
143
]
Another study found no increase in cardiovascular birth defects and a 27% increased risk of major malformations in SSRI exposed pregnancies.
[
139
]
The FDA advises for the risk of birth defects with the use of paroxetine
[
144
]
and the MAOI should be avoided.
A 2013 systematic review and meta-analysis found that antidepressant use during pregnancy was statistically significantly associated with some pregnancy outcomes, such as gestational age and preterm birth, but not with other outcomes. The same review cautioned that because differences between the exposed and unexposed groups were small, it was doubtful whether they were clinically significant.
[
145
]
A
neonate
(infant less than 28 days old) may experience a
withdrawal syndrome
from abrupt discontinuation of the antidepressant at birth. Antidepressants can be present in varying amounts in breast milk, but their effects on infants are currently unknown.
[
146
]
Moreover, SSRIs inhibit nitric oxide synthesis, which plays an important role in setting the vascular tone. Several studies have pointed to an increased risk of prematurity associated with SSRI use, and this association may be due to an increased risk of
pre-eclampsia
during pregnancy.
[
147
]
Antidepressant-induced mania
[
edit
]
Another possible problem with antidepressants is the chance of antidepressant-induced
mania
or
hypomania
in people with or without a diagnosis of
bipolar disorder
. Many cases of bipolar depression are very similar to those of unipolar depression. Therefore, the person can be misdiagnosed with unipolar depression and be given antidepressants. Studies have shown that antidepressant-induced mania can occur in 20–40% of people with bipolar disorder.
[
148
]
For bipolar depression, antidepressants (most frequently SSRIs) can exacerbate or trigger symptoms of hypomania and mania.
[
149
]
Bupropion
has been associated with a lower risk of mood switch than other antidepressants.
[
150
]
Studies have shown that the use of antidepressants is correlated with an increased risk of suicidal behavior and thinking (suicidality) in those aged under 25 years old.
[
151
]
This problem has been serious enough to warrant government intervention by the US Food and Drug Administration (FDA) to warn of the increased risk of suicidality during antidepressant treatment.
[
152
]
According to the FDA, the heightened risk of suicidality occurs within the first one to two months of treatment.
[
153
]
[
154
]
The National Institute for Health and Care Excellence (NICE) places the excess risk in the "early stages of treatment".
[
155
]
A
meta-analysis
suggests that the relationship between antidepressant use and suicidal behavior or thoughts is age-dependent.
[
151
]
Compared with placebo, the use of antidepressants is associated with an increase in suicidal behavior or thoughts among those 25 years old or younger (
OR
=1.62). A review of RCTs and epidemiological studies by Healy and Whitaker found an increase in suicidal acts by a factor of 2.4.
[
156
]
There is no effect or possibly a mild protective effect among those aged 25 to 64 (OR=0.79). Antidepressant treatment has a protective effect against suicidality among those aged 65 and over (OR=0.37).
[
151
]
[
157
]
Sexual side effects are common with SSRIs, such as loss of
sexual drive
,
failure to reach orgasm
, and
erectile dysfunction
.
[
158
]
Although usually reversible, these sexual side-effects can, in rare cases, continue after the drug has been completely withdrawn.
[
159
]
[
160
]
In a study of 1,022 outpatients, overall sexual dysfunction with all antidepressants averaged 59.1%
[
161
]
with SSRI values between 57% and 73%, mirtazapine 24%, nefazodone 8%, amineptine 7%, and
moclobemide
4%. Moclobemide, a selective reversible MAO-A inhibitor, does not cause sexual dysfunction
[
162
]
and can lead to an improvement in all aspects of sexual function.
[
163
]
Biochemical mechanisms suggested as causative include increased serotonin, particularly affecting
5-HT
2
and
5-HT
3
receptors
; decreased
dopamine
; decreased
norepinephrine
; blockade of
cholinergic
and
α
1
adrenergic receptors
; inhibition of
nitric oxide synthetase
; and elevation of
prolactin
levels.
[
164
]
Mirtazapine
is reported to have fewer sexual side effects, most likely because it antagonizes 5-HT
2
and 5-HT
3
receptors and may, in some cases, reverse sexual dysfunction induced by SSRIs by the same mechanism.
[
165
]
Bupropion
, a weak NDRI and nicotinic antagonist, may be useful in treating reduced libido as a result of
SSRI
treatment.
[
166
]
Certain antidepressants may cause
emotional blunting
, characterized by a reduced intensity of both positive and negative emotions as well as symptoms of
apathy
,
indifference
, and
amotivation
.
[
167
]
[
168
]
[
169
]
[
170
]
[
171
]
[
172
]
[
173
]
[
174
]
[
175
]
[
excessive citations
]
It may be experienced as either beneficial or detrimental depending on the situation.
[
176
]
This side effect has been particularly associated with serotonergic antidepressants like SSRIs and SNRIs but may be less with atypical antidepressants like bupropion,
agomelatine
, and
vortioxetine
.
[
168
]
[
174
]
[
177
]
[
178
]
In addition, it is not associated with the
serotonergic psychedelic
psilocybin
.
[
179
]
Higher doses of antidepressants seem to be more likely to produce emotional blunting than lower doses.
[
168
]
Emotional blunting can be decreased by reducing dosage, discontinuing the medication, or switching to a different antidepressant that may have less propensity for causing this side effect.
[
168
]
Changes in appetite or weight are common among antidepressants but are largely drug-dependent and related to which neurotransmitters they affect. Mirtazapine and
paroxetine
, for example, may be associated with weight gain and/or increased appetite,
[
180
]
[
181
]
[
182
]
while others (such as bupropion and
venlafaxine
) achieve the opposite effect.
[
183
]
[
184
]
The
antihistaminic
properties of certain TCA- and TeCA-class antidepressants have been shown to contribute to the common side effects of increased appetite and weight gain associated with these classes of medication.
A 2021 nationwide
cohort study
in South Korea observed a link between SSRI use and bone loss, particularly in recent users. The study also stressed the need of further research to better understand these effects.
[
185
]
A 2012 review found that SSRIs along with tricyclic antidepressants were associated with a significant increase in the risk of osteoporotic fractures, peaking in the months after initiation, and moving back towards baseline during the year after treatment was stopped. These effects exhibited a
dose–response relationship
within SSRIs which varied between different drugs of that class.
[
186
]
A 2018 meta-analysis of 11 small studies found a reduction in bone density of the lumbar spine in SSRI users which affected older people the most.
[
187
]
A 2017
meta-analysis
found that antidepressants were associated with a significantly increased
risk of death
(+33%) and new
cardiovascular complications
(+14%) in the general population.
[
188
]
Conversely, risks were not greater in people with existing
cardiovascular disease
.
[
188
]
Discontinuation syndrome
[
edit
]
Antidepressant discontinuation syndrome, also called antidepressant withdrawal syndrome, is a condition that can occur following the interruption, reduction, or
discontinuation
of antidepressant medication.
[
189
]
The symptoms may include
flu-like symptoms
, trouble sleeping, nausea, poor balance, sensory changes, and
anxiety
.
[
189
]
[
14
]
[
190
]
The problem usually begins within three days and may last for several months.
[
189
]
[
190
]
Rarely
psychosis
may occur.
[
189
]
A discontinuation syndrome can occur after stopping any antidepressant including
selective serotonin reuptake inhibitors
(SSRIs),
serotonin–norepinephrine reuptake inhibitors
(SNRIs), and
tricyclic antidepressants
(TCAs).
[
189
]
[
14
]
The risk is greater among those who have taken the medication for longer and when the medication in question has a short
half-life
.
[
189
]
The underlying reason for its occurrence is unclear.
[
189
]
The diagnosis is based on the symptoms.
[
189
]
Methods of prevention include gradually decreasing the dose (
tapering
) among those who wish to stop, though it is possible for symptoms to occur with tapering.
[
189
]
[
13
]
[
190
]
Treatment may include restarting the medication and slowly decreasing the dose.
[
189
]
People may also be switched to the long-acting antidepressant
fluoxetine
, which can then be gradually decreased.
[
13
]
Approximately 20–50% of people who suddenly stop an antidepressant develop an antidepressant discontinuation syndrome.
[
189
]
[
14
]
[
190
]
The condition is generally not serious,
[
189
]
though about half of people with symptoms describe them as severe.
[
190
]
Some restart antidepressants due to the severity of the symptoms.
[
190
]
Antidepressants act via a large number of different
mechanisms of action
.
[
191
]
[
192
]
[
193
]
This includes
serotonin reuptake inhibition
(SSRIs, SNRIs, TCAs, vilazodone, vortioxetine),
norepinephrine reuptake inhibition
(NRIs, SNRIs, TCAs),
dopamine reuptake inhibition
(bupropion, amineptine, nomifensine), direct
modulation
of
monoamine receptors
(vilazodone, vortioxetine, SARIs, agomelatine, TCAs, TeCAs, antipsychotics),
monoamine oxidase inhibition
(MAOIs), and
NMDA receptor antagonism
(ketamine, esketamine, dextromethorphan), among others (e.g., brexanolone, tianeptine).
[
191
]
[
192
]
[
193
]
Some antidepressants also have additional actions, like
sigma receptor
modulation (certain SSRIs, TCAs, dextromethorphan) and
antagonism
of
histamine
H
1
and
muscarinic acetylcholine receptors
(TCAs, TeCAs).
[
194
]
[
193
]
Mechanisms of action of major antidepressant classes
[
191
]
[
195
]
Class
Action(s)
Examples
Introduced
Opioids
(mostly no longer used)
[
196
]
[
197
]
μ-Opioid receptor
agonism
Codeine
•
Heroin
•
Morphine
•
Opium
•
Tianeptine
(1983)
1800s
Amphetamine psychostimulants
(mostly no longer used)
[
198
]
[
199
]
[
200
]
[
201
]
Norepinephrine release induction
•
Dopamine release induction
Amphetamine
•
Dextroamphetamine
•
Methamphetamine
1930s
Monoamine oxidase inhibitors
(MAOIs)
Monoamine oxidase
inhibition
• Other actions in some cases
Iproniazid
•
Isocarboxazid
•
Isoniazid
•
Moclobemide
(1989) •
Nialamide
•
Phenelzine
•
Selegiline
(1977/2006) •
Tranylcypromine
1950s
Tricyclic antidepressants
(TCAs)
Serotonin reuptake inhibition
•
Norepinephrine reuptake inhibition
•
Serotonin receptor antagonism
•
Adrenergic receptor antagonism
•
Histamine H
1
receptor antagonism
•
Muscarinic acetylcholine receptor antagonism
• Other actions
Amitriptyline
•
Butriptyline
•
Clomipramine
•
Desipramine
•
Dosulepin (dothiepin)
•
Doxepin
•
Imipramine
•
Iprindole
•
Lofepramine
•
Nortriptyline
•
Protriptyline
•
Trimipramine
1950s
Tetracyclic antidepressants
(TeCAs)
Serotonin reuptake inhibition
•
Norepinephrine reuptake inhibition
•
Serotonin receptor antagonism
•
Adrenergic receptor antagonism
•
Histamine H
1
receptor antagonism
•
Muscarinic acetylcholine receptor antagonism
• Other actions
Amoxapine
•
Maprotiline
•
Mianserin
•
Mirtazapine
•
Setiptiline
1970s
Norepinephrine reuptake inhibitors
(NRIs)
Norepinephrine reuptake inhibition
Atomoxetine
(off-label) •
Teniloxazine
•
Reboxetine
•
Viloxazine
1970s
Norepinephrine–dopamine reuptake inhibitors
(NDRIs)
Norepinephrine reuptake inhibition
•
Dopamine reuptake inhibition
Amineptine
•
Bupropion
•
Methylphenidate
(off-label) •
Nomifensine
1970s
Serotonin antagonists and reuptake inhibitors
(SARIs)
Serotonin receptor antagonism
•
Adrenergic receptor antagonism
• Weak
monoamine reuptake inhibition
• Other actions
Etoperidone
•
Nefazodone
•
Trazodone
1980s
Selective serotonin reuptake inhibitors
(SSRIs)
Serotonin reuptake inhibition
Citalopram
•
Escitalopram
•
Fluoxetine
•
Fluvoxamine
•
Indalpine
•
Paroxetine
•
Sertraline
•
Zimelidine
1980s
Serotonin
5-HT
1A
receptor
agonists
(
azapirones
)
Serotonin
5-HT
1A
receptor
partial agonism
• Other actions
Buspirone
(off-label) •
Gepirone
•
Tandospirone
1980s
Serotonin–norepinephrine reuptake inhibitors
(SNRIs)
Serotonin reuptake inhibition
•
Norepinephrine reuptake inhibition
Desvenlafaxine
•
Duloxetine
•
Levomilnacipran
•
Milnacipran
(off-label) •
Venlafaxine
1990s
Serotonin modulators and stimulators
(SMSs)
Serotonin reuptake inhibition
•
Serotonin receptor
modulation
Vilazodone
•
Vortioxetine
2000s
Atypical antipsychotics
Serotonin receptor
modulation
•
Dopamine receptor
modulation
• Other actions
Amisulpride
•
Aripiprazole
•
Brexpiprazole
•
Lumateperone
•
Lurasidone
•
Olanzapine
•
Quetiapine
•
Risperidone
(off-label) •
Sulpiride
2000s
NMDA receptor antagonists
NMDA receptor antagonism
• Possibly other actions
Dextromethorphan/bupropion
•
Esketamine
•
Ketamine
(off-label)
2010s
Serotonergic psychedelics
[
202
]
[
203
]
[
204
]
[
205
]
Serotonin 5-HT
2A
receptor agonism
Psilocybin
•
LSD
• Others
2010s
Neurosteroid
-type
GABA
A
receptor positive allosteric modulators
GABA
A
receptor positive allosteric modulation
Brexanolone
•
Zuranolone
2010s
Serotonin–norepinephrine–dopamine reuptake inhibitors
Serotonin reuptake inhibition
•
Norepinephrine reuptake inhibition
•
Dopamine reuptake inhibition
Toludesvenlafaxine
2020s
Other agents
Various/mixed actions
α-Methyltryptamine
•
Ademetionine (SAMe)
•
Agomelatine
•
D
-Phenylalanine
•
Etryptamine
•
Hypericum perforatum
(St John's wort)
Indeloxazine
•
Lithium
(off-label) •
Medifoxamine
•
Opipramol
•
Oxaflozane
•
Oxitriptan (5-HTP)
•
Pivagabine
•
Thyroid hormone
(off-label) •
Tiazesim
•
Tofenacin
•
Tryptophan
Various
Notes:
(1) Opioids and amphetamines largely ceased being used by the 1950s with the introduction of modern antidepressants. (2) Some antidepressants can also have alternative classifications, such as
mirtazapine
being a "
noradrenergic and specific serotonergic antidepressant
" (NaSSA) or
moclobemide
being a "
reversible inhibitor of monoamine oxidase A
" (RIMA). (3) See
list of antidepressants
for a complete list of approved/marketed antidepressants. (4) See
list of investigational antidepressants
for an extensive list of modern investigational antidepressants (including discontinued agents).
Monoamine hypothesis
[
edit
]
The earliest and most widely known
scientific theory
of antidepressant action is the
monoamine hypothesis
, which can be traced back to the 1950s and 1960s.
[
206
]
[
207
]
This theory states that depression is due to an imbalance, most often a deficiency, of the
monoamine neurotransmitters
, namely
serotonin
,
norepinephrine
, and/or
dopamine
.
[
206
]
[
207
]
However, serotonin in particular has been implicated, as in the serotonin hypothesis of depression.
[
208
]
The monoamine hypothesis was originally proposed based on observations that
reserpine
, a drug which depletes the monoamine neurotransmitters, produced depressive effects in people,
[
207
]
and that certain
hydrazine
antituberculosis agents
like
iproniazid
, which
prevent the breakdown of monoamine neurotransmitters
, produced apparent antidepressant effects.
[
206
]
Most currently marketed antidepressants, which are
monoaminergic
in their actions, are theoretically consistent with the monoamine hypothesis.
[
206
]
Despite the widespread nature of the monoamine hypothesis, it has a number of limitations: for one, all monoaminergic antidepressants have a delayed onset of action of at least a week; and secondly, many people with depression do not respond to monoaminergic antidepressants.
[
209
]
[
210
]
In 2022, a major systematic
umbrella review
by
Joanna Moncrieff
and colleagues showed that the serotonin theory of depression was not supported by evidence from a wide variety of areas.
[
208
]
The authors concluded that there is no association between serotonin and depression, and that there is no evidence that strongly supports the theory that depression is caused by low serotonin activity or concentrations.
[
208
]
Other literature had described the lack of support for the theory previously.
[
107
]
[
108
]
[
110
]
In many of the expert responses to the review, it was stated that the monoamine hypothesis had already long been abandoned by psychiatry.
[
211
]
[
212
]
This is in spite of about 90% of the general public in Western countries believing the theory to be true and many in the field of psychiatry continuing to promote the theory up to recent times.
[
212
]
[
110
]
In addition to the serotonin umbrella review, reviews have found that
reserpine
, a drug that depletes the monoamine neurotransmitters—including serotonin, norepinephrine, and dopamine—shows no consistent evidence of producing depressive effects.
[
207
]
[
213
]
Instead, findings of reserpine and mood are highly mixed, with similar proportions of studies finding that it has no influence on mood, produces depressive effects, or actually has antidepressant effects.
[
213
]
In relation to this, the general monoamine hypothesis, as opposed to only the serotonin theory of depression, likewise does not appear to be well-supported by evidence.
[
207
]
[
213
]
[
110
]
The serotonin and monoamine hypotheses of depression have been heavily promoted by the
pharmaceutical industry
(e.g., in
advertisements
) and by the psychiatric profession at large despite the lack of evidence in support of them.
[
107
]
[
108
]
[
207
]
[
214
]
[
110
]
[
109
]
In the case of the pharmaceutical industry, this can be attributed to obvious financial incentives, with the theory creating a bias against
non-pharmacological treatments
for depression.
[
109
]
[
107
]
[
108
]
[
207
]
Other biological theories
[
edit
]
Besides the monoamine hypothesis, a number of alternative biological hypotheses of depression and antidepressant action have been proposed, including hypotheses involving
glutamate
,
neurogenesis
,
neuroplasticity
,
epigenetics
,
cortisol
hypersecretion
, and
inflammation
, among others.
[
209
]
[
210
]
[
215
]
[
216
]
[
179
]
An alternative theory for antidepressant action proposed by certain academics such as
Irving Kirsch
and
Joanna Moncrieff
is that they work largely or entirely via
placebo
mechanisms.
[
44
]
[
103
]
[
217
]
[
218
]
This is supported by meta-analyses of
randomized controlled trials
of antidepressants for depression, which consistently show that placebo groups in trials improve about 80 to 90% as much as antidepressant groups on average
[
44
]
[
219
]
and that antidepressants are only marginally more effective for depression than placebos.
[
98
]
[
91
]
[
220
]
[
85
]
[
86
]
The difference between antidepressants and placebo corresponds to an
effect size
(
SMD
) of about 0.3, which in turn equates to about a 2- to 3-point additional improvement on the 0–52-point (
HRSD
) and 0–60-point (
MADRS
)
depression rating scales
used in trials.
[
98
]
[
91
]
[
220
]
[
85
]
[
86
]
Differences in effectiveness between different antidepressants are small and not clinically meaningful.
[
221
]
[
220
]
The small advantage of antidepressants over placebo is often
statistically significant
and is the basis for their regulatory approval, but is sufficiently modest that its
clinical significance
is doubtful.
[
89
]
[
222
]
[
91
]
[
86
]
Moreover, the small advantage of antidepressants over placebo may simply be a
methodological artifact
caused by
unblinding
due to the
psychoactive
effects and
side effects
of antidepressants, in turn resulting in
amplified placebo effects
and apparent antidepressant efficacy.
[
44
]
[
86
]
[
103
]
Placebos have been found to modify the activity of several brain regions and to increase levels of dopamine and
endogenous
opioids
in the
reward pathways
.
[
223
]
[
224
]
[
225
]
It has been argued by Kirsch that although antidepressants may be used efficaciously for depression as
active placebos
, they are limited by significant pharmacological
side effects
and risks, and therefore
non-pharmacological therapies
, such as
psychotherapy
and lifestyle changes, which can have similar efficacy to antidepressants but do not have their adverse effects, ought to be preferred as treatments in people with depression.
[
88
]
The
placebo response
, or the improvement in scores in the placebo group in clinical trials, is not only due to the
placebo effect
, but is also due to other phenomena such as
spontaneous remission
and
regression to the mean
.
[
44
]
[
226
]
Depression tends to have an episodic course, with people eventually recovering even with no medical intervention, and people tend to seek treatment, as well as enroll in clinical trials, when they are feeling their worst.
[
102
]
[
226
]
In meta-analyses of trials of depression therapies, Kirsch estimated based on improvement in untreated waiting-list controls that spontaneous remission and regression to the mean only account for about 25% of the improvement in depression scores with antidepressant therapy.
[
44
]
[
227
]
[
228
]
[
229
]
[
102
]
However, another academic,
Michael P. Hengartner
, has argued and presented evidence that spontaneous remission and regression to the mean might actually account for most of the improvement in depression scores with antidepressants, and that the substantial placebo effect observed in clinical trials might largely be a methodological artifact.
[
226
]
This suggests that antidepressants may be associated with much less genuine treatment benefit, whether due to the placebo effect or to the antidepressant itself, than has been traditionally assumed.
[
226
]
It has been proposed that
psychedelics
used for therapeutic purposes may act as
active
"super placebos".
[
230
]
[
231
]
However, due to issues like the
inverse placebo effect
caused by unblinding, psychedelics may actually be no more effective than traditional antidepressants.
[
232
]
[
233
]
[
234
]
[
235
]
Selective serotonin reuptake inhibitors
[
edit
]
2D chemical structure of Paxil (
Paroxetine
), a
selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitors
(SSRIs) are believed to increase the
extracellular
level of the
neurotransmitter
serotonin by
limiting
its
reabsorption
into the
presynaptic cell
, increasing the level of
serotonin
in the
synaptic cleft
available to bind to the
postsynaptic receptor
. They have varying degrees of selectivity for the other
monoamine transporters
, with pure SSRIs having only weak affinity for the
norepinephrine
and
dopamine transporters
.
SSRIs are the most widely prescribed antidepressants in many countries.
[
236
]
The efficacy of SSRIs in mild or moderate cases of depression has been disputed.
[
237
]
[
238
]
[
239
]
[
240
]
Serotonin–norepinephrine reuptake inhibitors
[
edit
]
The chemical structure of
venlafaxine
(Effexor), an
SNRI
Serotonin–norepinephrine reuptake inhibitors
(SNRIs) are potent inhibitors of the
reuptake
of
serotonin
and
norepinephrine
. These
neurotransmitters
are known to play an important role in mood. SNRIs can be contrasted with the more widely used
selective serotonin reuptake inhibitors
(SSRIs), which act mostly upon serotonin alone.
The human
serotonin transporter
(SERT) and
norepinephrine transporter
(NET) are
membrane proteins
that are responsible for the reuptake of serotonin and norepinephrine. Balanced dual inhibition of
monoamine
reuptake may offer advantages over other antidepressants drugs by treating a wider range of symptoms.
[
241
]
SNRIs are sometimes also used to treat
anxiety disorders
,
obsessive–compulsive disorder
(OCD),
attention deficit hyperactivity disorder
(ADHD), chronic
neuropathic pain
, and
fibromyalgia syndrome
(FMS), and for the relief of
menopausal
symptoms.
Serotonin modulators and stimulators
[
edit
]
Serotonin modulator and stimulators
(SMSs), sometimes referred to more simply as "
serotonin
modulators", are a type of
drug
with a multimodal action specific to the serotonin
neurotransmitter
system. To be precise, SMSs simultaneously modulate one or more
serotonin receptors
and inhibit the
reuptake
of serotonin. The term was coined in reference to the
mechanism of action
of the serotonergic antidepressant
vortioxetine
, which acts as a
serotonin reuptake inhibitor
(SRI), a
partial agonist
of the
5-HT
1A
receptor
, and
antagonist
of the
5-HT
3
and
5-HT
7
receptors
.
[
242
]
[
243
]
[
244
]
However, it can also technically be applied to
vilazodone
, which is an antidepressant as well and acts as an SRI and 5-HT
1A
receptor partial agonist.
[
245
]
An alternative term is serotonin partial agonist/reuptake inhibitor (SPARI), which can be applied only to vilazodone.
[
246
]
Serotonin antagonists and reuptake inhibitors
[
edit
]
Serotonin antagonist and reuptake inhibitors
(SARIs) while mainly used as antidepressants are also
anxiolytics
and
hypnotics
. They act by
antagonizing
serotonin receptors
such as
5-HT
2A
and
inhibiting
the
reuptake
of
serotonin
,
norepinephrine
, and/or
dopamine
. Additionally, most also act as
α
1
-adrenergic receptor
antagonists. The majority of the currently marketed SARIs belong to the
phenylpiperazine
class of compounds. They include
trazodone
and
nefazodone
.
Tricyclic antidepressants
[
edit
]
The majority of the
tricyclic antidepressants
(TCAs) act primarily as
serotonin–norepinephrine reuptake inhibitors
(SNRIs) by blocking the
serotonin transporter
(SERT) and the
norepinephrine transporter
(NET), respectively, which results in an elevation of the
synaptic
concentrations of these
neurotransmitters
, and therefore an enhancement of
neurotransmission
.
[
247
]
[
248
]
Notably, with the sole exception of
amineptine
, the TCAs have weak
affinity
for the
dopamine transporter
(DAT), and therefore have low efficacy as
dopamine reuptake inhibitors
(DRIs).
[
247
]
Although TCAs are sometimes
prescribed
for depressive disorders, they have been largely replaced in clinical use in most parts of the world by newer antidepressants such as
selective serotonin reuptake inhibitors
(SSRIs),
serotonin–norepinephrine reuptake inhibitors
(SNRIs), and
norepinephrine reuptake inhibitors
(NRIs). Adverse effects have been found to be of a similar level between TCAs and SSRIs.
[
249
]
Tetracyclic antidepressants
[
edit
]
Tetracyclic antidepressants
(TeCAs) are a class of antidepressants that were first introduced in the 1970s. They are named after their
chemical structure
, which contains four
rings of atoms
, and are closely related to
tricyclic antidepressants
(TCAs), which contain three rings of atoms.
Monoamine oxidase inhibitors
[
edit
]
Monoamine oxidase inhibitors
(MAOIs) are chemicals that inhibit the activity of the
monoamine oxidase enzyme family
. They have a long history of use as medications prescribed for the treatment of
depression
. They are particularly effective in treating
atypical depression
.
[
250
]
They are also used in the treatment of
Parkinson's disease
and several other disorders.
Because of potentially lethal dietary and drug interactions, MAOIs have historically been reserved as a last line of treatment, used only when other classes of antidepressant drugs (for example
selective serotonin reuptake inhibitors
and
tricyclic antidepressants
) have failed.
[
251
]
MAOIs have been found to be effective in the treatment of
panic disorder
with
agoraphobia
,
[
252
]
social phobia
,
[
253
]
[
254
]
[
255
]
atypical depression
[
256
]
[
257
]
or mixed anxiety and depression,
bulimia
,
[
258
]
[
259
]
[
260
]
[
261
]
and
post-traumatic stress disorder
,
[
262
]
as well as
borderline personality disorder
.
[
263
]
MAOIs appear to be particularly effective in the management of
bipolar depression
according to a retrospective-analysis.
[
264
]
There are reports of MAOI efficacy in
obsessive–compulsive disorder
(OCD),
trichotillomania
,
dysmorphophobia
, and
avoidant personality disorder
, but these reports are from uncontrolled case reports.
[
265
]
MAOIs can also be used in the treatment of Parkinson's disease by targeting MAO-B in particular (therefore affecting
dopaminergic neurons
), as well as providing an alternative for
migraine
prophylaxis
. Inhibition of both MAO-A and MAO-B is used in the treatment of
clinical depression
and
anxiety disorders
.
NMDA receptor antagonists
[
edit
]
NMDA receptor antagonists
like
ketamine
and
esketamine
are
rapid-acting antidepressants
and seem to work via
blockade
of the
ionotropic glutamate
NMDA receptor
.
[
266
]
Other NMDA antagonists may also play a role in treating depression. The combination medication
dextromethorphan/bupropion
(Auvelity), which contains the NMDA receptor antagonist
dextromethorphan
, was approved in the United States in 2022 for treating major depressive disorder.
[
267
]
[
268
]
See the
list of antidepressants
and
management of depression
for other drugs that are not specifically characterized.
Adjunct medications are an umbrella category of substances that increase the potency or "enhance" antidepressants.
[
269
]
They work by affecting variables very close to the antidepressant, sometimes affecting a completely different
mechanism of action
. This may be attempted when depression treatments have not been successful in the past.
Common types of adjunct medication techniques generally fall into the following categories:
Two or more antidepressants taken together, from either the same or different classes (affecting the same area of the brain, often at a much higher level).
An
antipsychotic
combined with an antidepressant, particularly
atypical antipsychotics
such as
aripiprazole
(Abilify),
quetiapine
(Seroquel),
olanzapine
(Zyprexa), and
risperidone
(Risperdal).
[
270
]
It is unknown if undergoing
psychological therapy
at the same time as taking anti-depressants enhances the anti-depressive effect of the medication.
[
271
]
Less common adjuncts
[
edit
]
Lithium
has been used to augment antidepressant therapy in those who have failed to respond to antidepressants alone.
[
272
]
Furthermore, Lithium dramatically decreases the suicide risk in recurrent depression.
[
273
]
In addition to reducing the risk of suicide, lithium also reduces the risk of death from all causes in people with mood disorders.
[
274
]
There is some evidence for the addition of a thyroid hormone,
triiodothyronine
, in patients with normal thyroid function.
[
275
]
Psychopharmacologists have also tried adding a
stimulant
, in particular,
D-amphetamine
.
[
276
]
However, the use of stimulants in cases of treatment-resistant depression is relatively controversial.
[
277
]
[
278
]
A review article published in 2007 found psychostimulants may be effective in treatment-resistant depression with concomitant antidepressant therapy, but a more certain conclusion could not be drawn due to substantial deficiencies in the studies available for consideration, and the somewhat contradictory nature of their results.
[
278
]
St John's wort
The idea of an antidepressant, if
melancholy
is thought synonymous with depression, existed at least as early as the 1599 pamphlet
A pil to purge melancholie or, A preparative to a pvrgation: or, Topping, copping, and capping: take either or whether: or, Mash them, and squash them, and dash them, and diddle come derrie come daw them, all together..
.
Thomas d'Urfey
's
Wit and Mirth: Or
Pills to Purge Melancholy
, the title of a large collection of songs, was published between 1698 and 1720.
Before the 1950s,
opioids
and
amphetamines
were commonly used as antidepressants.
[
279
]
[
280
]
[
198
]
Amphetamine
has been described as the first antidepressant.
[
198
]
Use of opioids and amphetamines for depression was later restricted due to their addictive nature and side effects.
[
279
]
[
198
]
Extracts from the herb
St John's wort
have been used as a "nerve tonic" to alleviate depression.
[
281
]
St John's wort
fell out of favor in most countries through the 19th and 20th centuries, except in
Germany
, where
Hypericum
extracts were eventually licensed, packaged, and prescribed. Small-scale efficacy trials were carried out in the 1970s and 1980s, and attention grew in the 1990s following a
meta-analysis
.
[
282
]
It remains an
over-the-counter
(OTC) supplement in most countries. Lead contamination associated with its usage has been seen as concerning, as lead levels in women in the United States taking St. John's wort are elevated by about 20% on average.
[
283
]
Research continues to investigate its active component
hyperforin
, and to further understand its mode of action.
[
284
]
[
285
]
Isoniazid, iproniazid, and imipramine
[
edit
]
In 1951,
Irving Selikoff
and Edward H. Robitzek, working out of
Sea View Hospital
on
Staten Island
, began clinical trials on two new
anti-tuberculosis
agents developed by Hoffman-LaRoche,
isoniazid
, and
iproniazid
. Only patients with a poor
prognosis
were initially treated. Nevertheless, their condition improved dramatically. Selikoff and Robitzek noted "a subtle general stimulation ... the patients exhibited renewed vigor and indeed this occasionally served to introduce disciplinary problems."
[
286
]
The promise of a cure for tuberculosis in the Sea View Hospital trials was excitedly discussed in the mainstream press.
In 1952, learning of the stimulating side effects of isoniazid, the Cincinnati psychiatrist Max Lurie tried it on his patients. In the following year, he and Harry Salzer reported that isoniazid improved depression in two-thirds of their patients, so they then coined the term
antidepressant
to refer to its action.
[
287
]
A similar incident took place in Paris, where
Jean Delay
, head of psychiatry at Sainte-Anne Hospital, heard of this effect from his
pulmonology
colleagues at Cochin Hospital. In 1952 (before Lurie and Salzer), Delay, with the resident Jean-Francois Buisson, reported the positive effect of isoniazid on depressed patients.
[
288
]
The mode of antidepressant action of isoniazid is still unclear. It is speculated that its effect is due to the inhibition of
diamine oxidase
, coupled with a weak inhibition of
monoamine oxidase A
.
[
289
]
Selikoff and Robitzek also experimented with another anti-tuberculosis drug,
iproniazid
; it showed a greater psychostimulant effect, but more pronounced toxicity.
[
290
]
Later, Jackson Smith, Gordon Kamman, George E. Crane, and
Frank Ayd
, described the psychiatric applications of iproniazid.
Ernst Zeller
found iproniazid to be a potent
monoamine oxidase inhibitor
.
[
291
]
Nevertheless, iproniazid remained relatively obscure until
Nathan S. Kline
, the influential head of research at
Rockland State Hospital
, began to popularize it in the medical and popular press as a "psychic energizer".
[
291
]
[
292
]
Roche put a significant marketing effort behind iproniazid.
[
291
]
Its sales grew until it was recalled in 1961, due to reports of lethal
hepatotoxicity
.
[
291
]
The antidepressant effect of a
tricyclic antidepressant
, a three-ringed compound, was first discovered in 1957 by
Roland Kuhn
in a Swiss
psychiatric hospital
.
Antihistamine
derivatives were used to treat surgical shock and later as
neuroleptics
. Although in 1955,
reserpine
was shown to be more effective than a placebo in alleviating anxious depression, neuroleptics were being developed as
sedatives
and
antipsychotics
.
[
medical citation needed
]
Attempting to improve the effectiveness of
chlorpromazine
, Kuhn — in conjunction with the
Geigy
Pharmaceutical Company — discovered the compound "G 22355", later renamed
imipramine
. Imipramine had a beneficial effect on patients with depression who showed mental and
motor retardation
. Kuhn described his new compound as a "thymoleptic" "taking hold of the emotions," in contrast with neuroleptics, "taking hold of the nerves" in 1955–56. These gradually became established, resulting in the patent and manufacture in the US in 1951 by Häfliger and SchinderA.
[
293
]
Antidepressants became
prescription drugs
in the 1950s. It was estimated that no more than fifty to one hundred individuals per million had the kind of depression that these new drugs would treat, and pharmaceutical companies were not enthusiastic about marketing for this small market. Sales through the 1960s remained poor compared to the sales of tranquilizers,
[
294
]
[
unreliable medical source?
]
which were being marketed for different uses.
[
295
]
Imipramine remained in common use and numerous successors were introduced. The use of monoamine oxidase inhibitors (MAOI) increased after the development and introduction of "reversible" forms affecting only the MAO-A subtype of inhibitors, making this drug safer to use.
[
295
]
[
296
]
By the 1960s, it was thought that the mode of action of tricyclics was to inhibit norepinephrine reuptake. However, norepinephrine reuptake became associated with stimulating effects. Later tricyclics were thought to affect
serotonin
as proposed in 1969 by Carlsson and Lindqvist as well as Lapin and Oxenkrug.
[
medical citation needed
]
Second-generation antidepressants
[
edit
]
Researchers began a process of
rational drug design
to isolate antihistamine-derived compounds that would selectively target these systems. The first such compound to be patented was
zimelidine
in 1971, while the first released clinically was
indalpine
.
Fluoxetine
was approved for commercial use by the US
Food and Drug Administration
(FDA) in 1988, becoming the first
blockbuster
SSRI. Fluoxetine was developed at
Eli Lilly and Company
in the early 1970s by
Bryan Molloy
,
Klaus Schmiegel
,
David T. Wong
, and others.
[
297
]
[
298
]
SSRIs became known as "novel antidepressants" along with other newer drugs such as SNRIs and
NRIs
with various selective effects.
[
299
]
Rapid-acting antidepressants
[
edit
]
Esketamine
(brand name Spravato), the first rapid-acting antidepressant to be approved for clinical treatment of depression, was introduced for this indication in March 2019 in the United States.
[
266
]
A 2016
randomized controlled trial
evaluated the
rapid antidepressant
effects of the psychedelic
Ayahuasca
in treatment-resistant depression with a positive outcome.
[
300
]
[
301
]
In 2018, the FDA granted Breakthrough Therapy Designation for
psilocybin
-assisted therapy for treatment-resistant depression and in 2019, the FDA granted Breakthrough Therapy Designation for psilocybin therapy treating major depressive disorder.
[
302
]
Publication bias and aged research
[
edit
]
A 2018 systematic review published in
The Lancet
comparing the efficacy of 21 different first and second generation antidepressants found that antidepressant drugs tended to perform better and cause less adverse events when they were novel or experimental treatments compared to when they were evaluated again years later.
[
36
]
Unpublished data was also associated with smaller positive effect sizes. However, the review did not find evidence of bias associated with industry funded research.
Society and culture
[
edit
]
Prescription trends
[
edit
]
In the UK, figures reported in 2010 indicated that the number of antidepressants prescribed by the
National Health Service
(NHS) almost doubled over a decade.
[
303
]
Further analysis published in 2014 showed that number of antidepressants dispensed annually in the community went up by 25 million in the 14 years between 1998 and 2012, rising from 15 million to 40 million. Nearly 50% of this rise occurred in the four years after the
Great Recession
, during which time the annual increase in prescriptions rose from 6.7% to 8.5%.
[
304
]
These sources also suggest that aside from the recession, other factors that may influence changes in prescribing rates may include: improvements in diagnosis, a reduction of the
stigma
surrounding mental health, broader prescribing trends, GP characteristics, geographical location, and housing status. Another factor that may contribute to increasing consumption of antidepressants is the fact that these medications now are used for other conditions including
social anxiety
and
post-traumatic stress disorder
.
Between 2005 and 2017, the number of adolescents (12 to 17 years) in England who were prescribed antidepressants has doubled. On the other hand, antidepressant prescriptions for children aged 5–11 in England decreased between 1999 and 2017.
[
305
]
[
306
]
From April 2015, prescriptions increased for both age groups (for people aged 0 to 17) and peaked during the first COVID lockdown in March 2020.
[
307
]
According to
National Institute for Health and Care Excellence
(NICE) guidelines, antidepressants for children and adolescents with depression and obsessive-compulsive disorder (OCD) should be prescribed together with therapy and after being assessed by a
child and adolescent psychiatrist
. However, between 2006 and 2017, only 1 in 4 of 12–17 year-olds who were prescribed an SSRI by their GP had seen a specialist psychiatrist and 1 in 6 has seen a pediatrician. Half of these prescriptions were for depression and 16% for anxiety, the latter not being licensed for treatment with antidepressants.
[
42
]
[
308
]
Among the suggested possible reasons why GPs are not following the guidelines are the difficulties of accessing talking therapies, long waiting lists, and the urgency of treatment.
[
42
]
[
309
]
According to some researchers, strict adherence to treatment guidelines would limit access to effective medication for young people with mental health problems.
[
310
]
In the United States, antidepressants were the most commonly prescribed medication in 2013.
[
311
]
Of the estimated 16 million "long term" (over 24 months) users, roughly 70 percent are female.
[
311
]
As of 2017
, about 16.5% of white people in the United States took antidepressants compared with 5.6% of black people in the United States.
[
312
]
Structural formula of the SSRI
sertraline
United States:
The most commonly prescribed antidepressants in the US retail market in 2010 were:
[
313
]
Drug name
Drug class
Total prescriptions
Sertraline
SSRI
33,409,838
Citalopram
SSRI
27,993,635
Fluoxetine
SSRI
24,473,994
Escitalopram
SSRI
23,000,456
Trazodone
SARI
18,786,495
Venlafaxine
(all formulations)
SNRI
16,110,606
Bupropion
(all formulations)
NDRI
15,792,653
Duloxetine
SNRI
14,591,949
Paroxetine
SSRI
12,979,366
Amitriptyline
TCA
12,611,254
Venlafaxine
XR
SNRI
7,603,949
Bupropion
XL
NDRI
7,317,814
Mirtazapine
TeCA
6,308,288
Venlafaxine
ER
SNRI
5,526,132
Bupropion
SR
NDRI
4,588,996
Desvenlafaxine
SNRI
3,412,354
Nortriptyline
TCA
3,210,476
Bupropion
ER
NDRI
3,132,327
Venlafaxine
SNRI
2,980,525
Bupropion
NDRI
753,516
Netherlands:
In the Netherlands,
paroxetine
is the most prescribed antidepressant, followed by
amitriptyline
,
citalopram
and
venlafaxine
.
[
314
]
As of 2003
, worldwide, 30% to 60% of people did not follow their practitioner's instructions about taking their antidepressants,
[
315
]
and as of 2013
in the US, it appeared that around 50% of people did not take their antidepressants as directed by their practitioner.
[
316
]
When people fail to take their antidepressants, there is a greater risk that the drug will not help, that symptoms get worse, that they miss work or are less productive at work, and that the person may be hospitalized.
[
317
]
Some academics
[
who?
]
have highlighted the need to examine the use of antidepressants and other medical treatments in cross-cultural terms, because various cultures prescribe and observe different manifestations, symptoms, meanings, and associations of depression and other medical conditions within their populations.
[
318
]
[
319
]
These cross-cultural discrepancies, it has been argued, then have implications on the perceived efficacy and use of antidepressants and other strategies in the treatment of depression in these different cultures.
[
318
]
[
319
]
In India, antidepressants are largely seen as tools to combat marginality, promising the individual the ability to reintegrate into society through their use—a view and association not observed in the West.
[
318
]
Environmental impacts
[
edit
]
Because most antidepressants function by inhibiting the reuptake of neurotransmitters serotonin, dopamine, and norepinephrine
[
320
]
these drugs can interfere with natural neurotransmitter levels in other organisms impacted by indirect exposure.
[
321
]
Antidepressants fluoxetine and sertraline have been detected in aquatic organisms residing in effluent-dominated streams.
[
322
]
The presence of antidepressants in surface waters and aquatic organisms has caused concern because ecotoxicological effects on aquatic organisms due to fluoxetine exposure have been demonstrated.
[
323
]
Coral reef fish have been demonstrated to modulate aggressive behavior through serotonin.
[
324
]
Artificially increasing serotonin levels in crustaceans can temporarily reverse social status and turn subordinates into aggressive and territorial dominant males.
[
325
]
Exposure to Fluoxetine has been demonstrated to increase serotonergic activity in fish, subsequently reducing aggressive behavior.
[
326
]
Perinatal exposure to Fluoxetine at relevant environmental concentrations has been shown to lead to significant modifications of memory processing in 1-month-old cuttlefish.
[
327
]
This impairment may disadvantage cuttlefish and decrease their survival. Somewhat less than 10% of orally administered Fluoxetine is excreted from humans unchanged or as
glucuronide
.
[
328
]
[
329
]
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Atypical antidepressant
Depression and natural therapies
Depression in childhood and adolescence
List of antidepressants
Management of depression
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## Contents
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- [(Top)](https://en.wikipedia.org/wiki/Antidepressant)
- [1 Medical uses](https://en.wikipedia.org/wiki/Antidepressant#Medical_uses)
Toggle Medical uses subsection
- [1\.1 Major depressive disorder](https://en.wikipedia.org/wiki/Antidepressant#Major_depressive_disorder)
- [1\.2 Anxiety disorders](https://en.wikipedia.org/wiki/Antidepressant#Anxiety_disorders)
- [1\.2.1 Generalized anxiety disorder](https://en.wikipedia.org/wiki/Antidepressant#Generalized_anxiety_disorder)
- [1\.2.2 Social anxiety disorder](https://en.wikipedia.org/wiki/Antidepressant#Social_anxiety_disorder)
- [1\.2.3 Obsessive–compulsive disorder](https://en.wikipedia.org/wiki/Antidepressant#Obsessive%E2%80%93compulsive_disorder)
- [1\.2.4 Post–traumatic stress disorder](https://en.wikipedia.org/wiki/Antidepressant#Post%E2%80%93traumatic_stress_disorder)
- [1\.2.5 Panic disorder](https://en.wikipedia.org/wiki/Antidepressant#Panic_disorder)
- [1\.3 Eating disorders](https://en.wikipedia.org/wiki/Antidepressant#Eating_disorders)
- [1\.4 Pain](https://en.wikipedia.org/wiki/Antidepressant#Pain)
- [1\.4.1 Fibromyalgia](https://en.wikipedia.org/wiki/Antidepressant#Fibromyalgia)
- [1\.4.2 Neuropathic pain](https://en.wikipedia.org/wiki/Antidepressant#Neuropathic_pain)
- [1\.5 Other uses](https://en.wikipedia.org/wiki/Antidepressant#Other_uses)
- [1\.6 Limitations and strategies](https://en.wikipedia.org/wiki/Antidepressant#Limitations_and_strategies)
- [1\.7 Switching antidepressants](https://en.wikipedia.org/wiki/Antidepressant#Switching_antidepressants)
- [1\.8 Augmentation and combination](https://en.wikipedia.org/wiki/Antidepressant#Augmentation_and_combination)
- [1\.9 Long-term use and stopping](https://en.wikipedia.org/wiki/Antidepressant#Long-term_use_and_stopping)
- [2 Adverse effects](https://en.wikipedia.org/wiki/Antidepressant#Adverse_effects)
Toggle Adverse effects subsection
- [2\.1 Pregnancy](https://en.wikipedia.org/wiki/Antidepressant#Pregnancy)
- [2\.2 Antidepressant-induced mania](https://en.wikipedia.org/wiki/Antidepressant#Antidepressant-induced_mania)
- [2\.3 Suicide](https://en.wikipedia.org/wiki/Antidepressant#Suicide)
- [2\.4 Sexual dysfunction](https://en.wikipedia.org/wiki/Antidepressant#Sexual_dysfunction)
- [2\.5 Emotional blunting](https://en.wikipedia.org/wiki/Antidepressant#Emotional_blunting)
- [2\.6 Changes in weight](https://en.wikipedia.org/wiki/Antidepressant#Changes_in_weight)
- [2\.7 Bone loss](https://en.wikipedia.org/wiki/Antidepressant#Bone_loss)
- [2\.8 Risk of death](https://en.wikipedia.org/wiki/Antidepressant#Risk_of_death)
- [2\.9 Discontinuation syndrome](https://en.wikipedia.org/wiki/Antidepressant#Discontinuation_syndrome)
- [3 Pharmacology](https://en.wikipedia.org/wiki/Antidepressant#Pharmacology)
Toggle Pharmacology subsection
- [3\.1 Monoamine hypothesis](https://en.wikipedia.org/wiki/Antidepressant#Monoamine_hypothesis)
- [3\.2 Other biological theories](https://en.wikipedia.org/wiki/Antidepressant#Other_biological_theories)
- [3\.3 Placebo mechanisms](https://en.wikipedia.org/wiki/Antidepressant#Placebo_mechanisms)
- [4 Types](https://en.wikipedia.org/wiki/Antidepressant#Types)
Toggle Types subsection
- [4\.1 Selective serotonin reuptake inhibitors](https://en.wikipedia.org/wiki/Antidepressant#Selective_serotonin_reuptake_inhibitors)
- [4\.2 Serotonin–norepinephrine reuptake inhibitors](https://en.wikipedia.org/wiki/Antidepressant#Serotonin%E2%80%93norepinephrine_reuptake_inhibitors)
- [4\.3 Serotonin modulators and stimulators](https://en.wikipedia.org/wiki/Antidepressant#Serotonin_modulators_and_stimulators)
- [4\.4 Serotonin antagonists and reuptake inhibitors](https://en.wikipedia.org/wiki/Antidepressant#Serotonin_antagonists_and_reuptake_inhibitors)
- [4\.5 Tricyclic antidepressants](https://en.wikipedia.org/wiki/Antidepressant#Tricyclic_antidepressants)
- [4\.6 Tetracyclic antidepressants](https://en.wikipedia.org/wiki/Antidepressant#Tetracyclic_antidepressants)
- [4\.7 Monoamine oxidase inhibitors](https://en.wikipedia.org/wiki/Antidepressant#Monoamine_oxidase_inhibitors)
- [4\.8 NMDA receptor antagonists](https://en.wikipedia.org/wiki/Antidepressant#NMDA_receptor_antagonists)
- [4\.9 Others](https://en.wikipedia.org/wiki/Antidepressant#Others)
- [5 Adjuncts](https://en.wikipedia.org/wiki/Antidepressant#Adjuncts)
Toggle Adjuncts subsection
- [5\.1 Less common adjuncts](https://en.wikipedia.org/wiki/Antidepressant#Less_common_adjuncts)
- [6 History](https://en.wikipedia.org/wiki/Antidepressant#History)
Toggle History subsection
- [6\.1 Isoniazid, iproniazid, and imipramine](https://en.wikipedia.org/wiki/Antidepressant#Isoniazid,_iproniazid,_and_imipramine)
- [6\.2 Second-generation antidepressants](https://en.wikipedia.org/wiki/Antidepressant#Second-generation_antidepressants)
- [6\.3 Rapid-acting antidepressants](https://en.wikipedia.org/wiki/Antidepressant#Rapid-acting_antidepressants)
- [6\.3.1 Research](https://en.wikipedia.org/wiki/Antidepressant#Research)
- [6\.4 Publication bias and aged research](https://en.wikipedia.org/wiki/Antidepressant#Publication_bias_and_aged_research)
- [7 Society and culture](https://en.wikipedia.org/wiki/Antidepressant#Society_and_culture)
Toggle Society and culture subsection
- [7\.1 Prescription trends](https://en.wikipedia.org/wiki/Antidepressant#Prescription_trends)
- [7\.1.1 United Kingdom](https://en.wikipedia.org/wiki/Antidepressant#United_Kingdom)
- [7\.1.2 United States](https://en.wikipedia.org/wiki/Antidepressant#United_States)
- [7\.2 Adherence](https://en.wikipedia.org/wiki/Antidepressant#Adherence)
- [7\.3 Social science perspective](https://en.wikipedia.org/wiki/Antidepressant#Social_science_perspective)
- [7\.4 Environmental impacts](https://en.wikipedia.org/wiki/Antidepressant#Environmental_impacts)
- [8 See also](https://en.wikipedia.org/wiki/Antidepressant#See_also)
- [9 References](https://en.wikipedia.org/wiki/Antidepressant#References)
- [10 Further reading](https://en.wikipedia.org/wiki/Antidepressant#Further_reading)
- [11 External links](https://en.wikipedia.org/wiki/Antidepressant#External_links)
Toggle the table of contents
# Antidepressant
60 languages
- [Afrikaans](https://af.wikipedia.org/wiki/Antidepressant "Antidepressant – Afrikaans")
- [العربية](https://ar.wikipedia.org/wiki/%D9%85%D8%B6%D8%A7%D8%AF_%D8%A7%D9%83%D8%AA%D8%A6%D8%A7%D8%A8 "مضاد اكتئاب – Arabic")
- [Azərbaycanca](https://az.wikipedia.org/wiki/Antidepressant "Antidepressant – Azerbaijani")
- [Беларуская](https://be.wikipedia.org/wiki/%D0%90%D0%BD%D1%82%D1%8B%D0%B4%D1%8D%D0%BF%D1%80%D1%8D%D1%81%D0%B0%D0%BD%D1%82%D1%8B "Антыдэпрэсанты – Belarusian")
- [Български](https://bg.wikipedia.org/wiki/%D0%90%D0%BD%D1%82%D0%B8%D0%B4%D0%B5%D0%BF%D1%80%D0%B5%D1%81%D0%B0%D0%BD%D1%82 "Антидепресант – Bulgarian")
- [Bosanski](https://bs.wikipedia.org/wiki/Antidepresiv "Antidepresiv – Bosnian")
- [Català](https://ca.wikipedia.org/wiki/Antidepressiu "Antidepressiu – Catalan")
- [Čeština](https://cs.wikipedia.org/wiki/Antidepresivum "Antidepresivum – Czech")
- [Cymraeg](https://cy.wikipedia.org/wiki/Cyffur_gwrthiselder "Cyffur gwrthiselder – Welsh")
- [Dansk](https://da.wikipedia.org/wiki/Antidepressivum "Antidepressivum – Danish")
- [Deutsch](https://de.wikipedia.org/wiki/Antidepressivum "Antidepressivum – German")
- [Ελληνικά](https://el.wikipedia.org/wiki/%CE%91%CE%BD%CF%84%CE%B9%CE%BA%CE%B1%CF%84%CE%B1%CE%B8%CE%BB%CE%B9%CF%80%CF%84%CE%B9%CE%BA%CF%8C "Αντικαταθλιπτικό – Greek")
- [Esperanto](https://eo.wikipedia.org/wiki/Kontra%C5%ADdeprimilo "Kontraŭdeprimilo – Esperanto")
- [Español](https://es.wikipedia.org/wiki/Antidepresivo "Antidepresivo – Spanish")
- [Eesti](https://et.wikipedia.org/wiki/Antidepressandid "Antidepressandid – Estonian")
- [Euskara](https://eu.wikipedia.org/wiki/Antidepresibo "Antidepresibo – Basque")
- [فارسی](https://fa.wikipedia.org/wiki/%D8%AF%D8%A7%D8%B1%D9%88%D9%87%D8%A7%DB%8C_%D8%B6%D8%AF%D8%A7%D9%81%D8%B3%D8%B1%D8%AF%DA%AF%DB%8C "داروهای ضدافسردگی – Persian")
- [Suomi](https://fi.wikipedia.org/wiki/Masennusl%C3%A4%C3%A4kkeet "Masennuslääkkeet – Finnish")
- [Français](https://fr.wikipedia.org/wiki/Antid%C3%A9presseur "Antidépresseur – French")
- [Gaeilge](https://ga.wikipedia.org/wiki/Frithdh%C3%BAlagr%C3%A1n "Frithdhúlagrán – Irish")
- [Galego](https://gl.wikipedia.org/wiki/Antidepresivo "Antidepresivo – Galician")
- [עברית](https://he.wikipedia.org/wiki/%D7%AA%D7%A8%D7%95%D7%A4%D7%95%D7%AA_%D7%A0%D7%95%D7%92%D7%93%D7%95%D7%AA_%D7%93%D7%99%D7%9B%D7%90%D7%95%D7%9F "תרופות נוגדות דיכאון – Hebrew")
- [Hrvatski](https://hr.wikipedia.org/wiki/Antidepresivi "Antidepresivi – Croatian")
- [Magyar](https://hu.wikipedia.org/wiki/Antidepressz%C3%A1ns "Antidepresszáns – Hungarian")
- [Հայերեն](https://hy.wikipedia.org/wiki/%D5%80%D5%A1%D5%AF%D5%A1%D5%A4%D5%A5%D5%BA%D6%80%D5%A5%D5%BD%D5%A1%D5%B6%D5%BF%D5%B6%D5%A5%D6%80 "Հակադեպրեսանտներ – Armenian")
- [Bahasa Indonesia](https://id.wikipedia.org/wiki/Antidepresan "Antidepresan – Indonesian")
- [Íslenska](https://is.wikipedia.org/wiki/%C3%9Eunglyndislyf "Þunglyndislyf – Icelandic")
- [Italiano](https://it.wikipedia.org/wiki/Antidepressivo "Antidepressivo – Italian")
- [日本語](https://ja.wikipedia.org/wiki/%E6%8A%97%E3%81%86%E3%81%A4%E8%96%AC "抗うつ薬 – Japanese")
- [ქართული](https://ka.wikipedia.org/wiki/%E1%83%90%E1%83%9C%E1%83%A2%E1%83%98%E1%83%93%E1%83%94%E1%83%9E%E1%83%A0%E1%83%94%E1%83%A1%E1%83%90%E1%83%9C%E1%83%A2%E1%83%98 "ანტიდეპრესანტი – Georgian")
- [ಕನ್ನಡ](https://kn.wikipedia.org/wiki/%E0%B2%96%E0%B2%BF%E0%B2%A8%E0%B3%8D%E0%B2%A8%E0%B2%A4%E0%B3%86-%E0%B2%B6%E0%B2%AE%E0%B2%A8%E0%B2%95%E0%B2%BE%E0%B2%B0%E0%B2%BF\(%E0%B2%86%E0%B2%82%E0%B2%9F%E0%B2%BF-%E0%B2%A1%E0%B2%BF%E0%B2%AA%E0%B3%8D%E0%B2%B0%E0%B3%86%E0%B2%B8%E0%B3%86%E0%B2%82%E0%B2%9F%E0%B3%8D\) "ಖಿನ್ನತೆ-ಶಮನಕಾರಿ(ಆಂಟಿ-ಡಿಪ್ರೆಸೆಂಟ್) – Kannada")
- [한국어](https://ko.wikipedia.org/wiki/%ED%95%AD%EC%9A%B0%EC%9A%B8%EC%A0%9C "항우울제 – Korean")
- [Kurdî](https://ku.wikipedia.org/wiki/Ant%C3%AEdepresan "Antîdepresan – Kurdish")
- [Latina](https://la.wikipedia.org/wiki/Antidepressivum "Antidepressivum – Latin")
- [Lietuvių](https://lt.wikipedia.org/wiki/Antidepresantas "Antidepresantas – Lithuanian")
- [Latviešu](https://lv.wikipedia.org/wiki/Antidepresanti "Antidepresanti – Latvian")
- [Nederlands](https://nl.wikipedia.org/wiki/Antidepressiva "Antidepressiva – Dutch")
- [Norsk nynorsk](https://nn.wikipedia.org/wiki/Antidepressiva "Antidepressiva – Norwegian Nynorsk")
- [Norsk bokmål](https://no.wikipedia.org/wiki/Antidepressivum "Antidepressivum – Norwegian Bokmål")
- [Papiamentu](https://pap.wikipedia.org/wiki/Antidepresivo "Antidepresivo – Papiamento")
- [Polski](https://pl.wikipedia.org/wiki/Leki_przeciwdepresyjne "Leki przeciwdepresyjne – Polish")
- [Português](https://pt.wikipedia.org/wiki/Antidepressivo "Antidepressivo – Portuguese")
- [Română](https://ro.wikipedia.org/wiki/Antidepresiv "Antidepresiv – Romanian")
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From Wikipedia, the free encyclopedia
Class of medication used to treat depression and other conditions
For the 2025 Suede album, see [Antidepressants (album)](https://en.wikipedia.org/wiki/Antidepressants_\(album\) "Antidepressants (album)"). For the 2006 Lloyd Cole album, see [Antidepressant (album)](https://en.wikipedia.org/wiki/Antidepressant_\(album\) "Antidepressant (album)").
| Antidepressant | |
|---|---|
| *[Drug class](https://en.wikipedia.org/wiki/Drug_class "Drug class")* | |
| [](https://en.wikipedia.org/wiki/File:Venlafaxine_structure.svg)[Venlafaxine](https://en.wikipedia.org/wiki/Venlafaxine "Venlafaxine") (brand name Effexor), an antidepressant acting as a [serotonin–norepinephrine reuptake inhibitor](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") (SNRI). | |
| Class identifiers | |
| [Synonyms](https://en.wikipedia.org/wiki/Synonym "Synonym") | Psychic energizer; Mood elevator; Thymoleptic; Depression pill |
| Use | [Depressive disorders](https://en.wikipedia.org/wiki/Mood_disorder#Depressive_disorders "Mood disorder"), [anxiety disorders](https://en.wikipedia.org/wiki/Anxiety_disorders "Anxiety disorders"), [chronic pain](https://en.wikipedia.org/wiki/Chronic_pain "Chronic pain"), and [addiction](https://en.wikipedia.org/wiki/Addiction "Addiction") |
| [ATC code](https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System "Anatomical Therapeutic Chemical Classification System") | [N06A](https://en.wikipedia.org/wiki/ATC_code_N06A "ATC code N06A") |
| [Mechanism of action](https://en.wikipedia.org/wiki/Mechanism_of_action "Mechanism of action") | Varies |
| [Chemical class](https://en.wikipedia.org/wiki/Chemical_classification "Chemical classification") | Varies |
| Clinical data | |
| [Drugs.com](https://en.wikipedia.org/wiki/Drugs.com "Drugs.com") | [Drug Classes](https://www.drugs.com/drug-class/antidepressants.html) |
| [Consumer Reports](https://en.wikipedia.org/wiki/Consumer_Reports "Consumer Reports") | [Best Buy Drugs](http://www.consumerreports.org/health/best-buy-drugs/antidepressants.htm) |
| [WebMD](https://en.wikipedia.org/wiki/WebMD "WebMD") | [MedicineNet](http://www.medicinenet.com/antidepressants/article.htm) [RxList](http://www.rxlist.com/script/main/art.asp?articlekey=100734) |
| External links | |
| [MeSH](https://en.wikipedia.org/wiki/Medical_Subject_Headings "Medical Subject Headings") | [D000928](https://meshb.nlm.nih.gov/record/ui?ui=D000928) |
| Legal status | |
| [In Wikidata](https://www.wikidata.org/wiki/Q76560 "d:Q76560") | |
**Antidepressants**, also known in the past as **psychic energizers**,[\[1\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Ghaemi2015-1) are a class of [medications](https://en.wikipedia.org/wiki/Medication "Medication") used to treat [major depressive disorder](https://en.wikipedia.org/wiki/Major_depressive_disorder "Major depressive disorder"), [anxiety disorders](https://en.wikipedia.org/wiki/Anxiety_disorder "Anxiety disorder"), [chronic pain](https://en.wikipedia.org/wiki/Chronic_pain "Chronic pain"), and [addiction](https://en.wikipedia.org/wiki/Addiction "Addiction").[\[2\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Jennings2018-2)
Common [side effects](https://en.wikipedia.org/wiki/Side_effect "Side effect") of antidepressants include [dry mouth](https://en.wikipedia.org/wiki/Xerostomia "Xerostomia"), [weight gain](https://en.wikipedia.org/wiki/Weight_gain "Weight gain"), [dizziness](https://en.wikipedia.org/wiki/Dizziness "Dizziness"), [headaches](https://en.wikipedia.org/wiki/Headache "Headache"), [akathisia](https://en.wikipedia.org/wiki/Akathisia "Akathisia"),[\[3\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-3) [sexual dysfunction](https://en.wikipedia.org/wiki/Sexual_dysfunction "Sexual dysfunction"),[\[4\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-4)[\[5\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Bahrick-5)[\[6\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-6)[\[7\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-7)[\[8\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-8) and [emotional blunting](https://en.wikipedia.org/wiki/Emotional_blunting "Emotional blunting").[\[9\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-9)[\[10\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-10)[\[11\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-11) There is an increased risk of [suicidal thinking](https://en.wikipedia.org/wiki/Suicidal_ideation "Suicidal ideation") and [behavior](https://en.wikipedia.org/wiki/Suicide "Suicide") when taken by children, adolescents, and young adults.[\[12\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-12) [Discontinuation syndrome](https://en.wikipedia.org/wiki/Antidepressant_discontinuation_syndrome "Antidepressant discontinuation syndrome"), which resembles recurrent [depression](https://en.wikipedia.org/wiki/Depression_\(mood\) "Depression (mood)") in the case of the [SSRI](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor "Selective serotonin reuptake inhibitor") class, may occur after stopping the intake of any antidepressant, having effects which may be permanent and irreversible. [Tapering](https://en.wikipedia.org/wiki/Tapering_\(medicine\) "Tapering (medicine)") off medications gradually is shown to reduce the risk of [withdrawal](https://en.wikipedia.org/wiki/Antidepressant_discontinuation_syndrome "Antidepressant discontinuation syndrome") complications.[\[13\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Wil2015-13)[\[14\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Gab2017-14)
The effectiveness of antidepressants for treating depression in adults has strong support, though studies also highlight potential risks and limitations.[\[15\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-BarthKriston2018-15)[\[16\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-BMJ2019-16) In children and adolescents, evidence of efficacy is more limited, despite a marked increase in antidepressant prescriptions for these age groups since the 2000s.[\[17\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-CiprianiZhou2016-17)[\[18\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-18)[\[19\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-19) A 2018 meta-analysis reported that the 21 most commonly prescribed antidepressants were found in all studies to be more effective than [placebos](https://en.wikipedia.org/wiki/Placebo "Placebo") for the short-term treatment of [major depressive disorder](https://en.wikipedia.org/wiki/Major_depressive_disorder "Major depressive disorder") in adults. However, other research suggests that some benefits may be attributable to the placebo effect. Response to antidepressants is highly variable, and medications that are effective for certain patients may have no effect or a negative effect for others. Research into the factors that influence individual responses to antidepressants is ongoing.[\[20\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NIHR-2018-20)[\[21\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-CiprianiFurukawa2018-21)[\[22\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-22)[\[23\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-TurnerRosenthal2008-23)[\[24\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-24)
## Medical uses
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=1 "Edit section: Medical uses")\]
Antidepressants are prescribed to treat [major depressive disorder](https://en.wikipedia.org/wiki/Major_depressive_disorder "Major depressive disorder") (MDD), [anxiety disorders](https://en.wikipedia.org/wiki/Anxiety_disorder "Anxiety disorder"), [chronic pain](https://en.wikipedia.org/wiki/Chronic_pain "Chronic pain"), and some addictions. Antidepressants are often used in combination with one another.[\[2\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Jennings2018-2)
Despite its longstanding prominence in pharmaceutical advertising, the idea that low serotonin levels cause depression is not supported by scientific evidence.[\[25\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-25)[\[26\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-26)[\[27\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-27) Proponents of the [monoamine hypothesis of depression](https://en.wikipedia.org/wiki/Biology_of_depression "Biology of depression") recommend choosing an antidepressant which impacts the most prominent symptoms. Under this practice, for example, a person with MDD who is also anxious or irritable would be treated with [selective serotonin reuptake inhibitors](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor "Selective serotonin reuptake inhibitor") (SSRIs) or [norepinephrine reuptake inhibitors](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitor "Norepinephrine reuptake inhibitor"), while a person suffering from loss of energy and enjoyment of life would take a [norepinephrine–dopamine reuptake inhibitor](https://en.wikipedia.org/wiki/Norepinephrine%E2%80%93dopamine_reuptake_inhibitor "Norepinephrine–dopamine reuptake inhibitor").[\[28\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid18494537-28)
### Major depressive disorder
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=2 "Edit section: Major depressive disorder")\]
The UK [National Institute for Health and Care Excellence](https://en.wikipedia.org/wiki/National_Institute_for_Health_and_Care_Excellence "National Institute for Health and Care Excellence") (NICE)'s 2022 guidelines indicate that antidepressants should not be routinely used for the initial treatment of mild depression, "unless that is the person's preference".[\[29\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NIHCE-2022-29) The guidelines recommended that antidepressant treatment be considered:
- For people with a history of moderate or severe depression.
- For people with mild depression that has been present for an extended period.
- As a first-line treatment for moderate to severe depression.
- As a second-line treatment for mild depression that persists after other interventions.
The guidelines further note that in most cases, antidepressants should be used in combination with psychosocial interventions and should be continued for at least six months to reduce the risk of relapse and that SSRIs are typically better tolerated than other antidepressants.[\[29\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NIHCE-2022-29)
[American Psychiatric Association](https://en.wikipedia.org/wiki/American_Psychiatric_Association "American Psychiatric Association") (APA) treatment guidelines recommend that initial treatment be individually tailored based on factors including the severity of symptoms, co-existing disorders, prior treatment experience, and the person's preference. Options may include antidepressants, [psychotherapy](https://en.wikipedia.org/wiki/Psychotherapy "Psychotherapy"), [electroconvulsive therapy](https://en.wikipedia.org/wiki/Electroconvulsive_therapy "Electroconvulsive therapy") (ECT), [transcranial magnetic stimulation](https://en.wikipedia.org/wiki/Transcranial_magnetic_stimulation "Transcranial magnetic stimulation") (TMS), or [light therapy](https://en.wikipedia.org/wiki/Light_therapy "Light therapy"). The APA recommends antidepressant medication as an initial treatment choice in people with mild, moderate, or severe major depression, and that should be given to all people with severe depression unless ECT is planned.[\[30\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-30)
Reviews of antidepressants generally find that they benefit adults with depression.[\[21\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-CiprianiFurukawa2018-21)[\[15\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-BarthKriston2018-15) On the other hand, some contend that most studies on antidepressant medication are confounded by several biases: the lack of an [active placebo](https://en.wikipedia.org/wiki/Active_placebo "Active placebo"), which means that many people in the placebo arm of a [double-blind study](https://en.wikipedia.org/wiki/Randomized_controlled_trial "Randomized controlled trial") may deduce that they are not getting any true treatment, thus destroying double-blindness; a short follow up after termination of treatment; non-systematic recording of adverse effects; very strict exclusion criteria in samples of patients; studies being paid for by the industry; selective publication of results. This means that the small beneficial effects that are found may not be statistically significant.[\[31\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-31)[\[32\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-32)[\[33\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-33)[\[34\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-34)[\[16\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-BMJ2019-16)
Among the 21 most commonly prescribed antidepressants, the most effective and well-tolerated are [escitalopram](https://en.wikipedia.org/wiki/Escitalopram "Escitalopram"), [paroxetine](https://en.wikipedia.org/wiki/Paroxetine "Paroxetine"), [sertraline](https://en.wikipedia.org/wiki/Sertraline "Sertraline"), [agomelatine](https://en.wikipedia.org/wiki/Agomelatine "Agomelatine"), and [mirtazapine](https://en.wikipedia.org/wiki/Mirtazapine "Mirtazapine").[\[20\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NIHR-2018-20)[\[21\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-CiprianiFurukawa2018-21) For children and adolescents with moderate to severe depressive disorder, some evidence suggests [fluoxetine](https://en.wikipedia.org/wiki/Fluoxetine "Fluoxetine") (either with or without [cognitive behavioral therapy](https://en.wikipedia.org/wiki/Cognitive_behavioral_therapy "Cognitive behavioral therapy")) is the best treatment, but more research is needed to be certain.[\[35\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Evidence-2020-35)[\[36\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Zhou-2020-36)[\[37\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Boaden-2020-37)[\[38\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Hetrick-2021-38) Sertraline, escitalopram, and [duloxetine](https://en.wikipedia.org/wiki/Duloxetine "Duloxetine") may also help reduce symptoms.[\[38\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Hetrick-2021-38)
A 2023 [systematic review](https://en.wikipedia.org/wiki/Systematic_review "Systematic review") and [meta-analysis](https://en.wikipedia.org/wiki/Meta-analysis "Meta-analysis") of [randomized controlled trials](https://en.wikipedia.org/wiki/Randomized_controlled_trial "Randomized controlled trial") of antidepressants for major depressive disorder found that the medications provided only small or doubtful benefits in terms of [quality of life](https://en.wikipedia.org/wiki/Quality_of_life "Quality of life").[\[39\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid36905396-39) Likewise, a 2022 systematic review and meta-analysis of randomized controlled trials of antidepressants for major depressive disorder in children and adolescents found small improvements in quality of life.[\[40\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35508443-40) Quality of life as an outcome measure is often selectively reported in trials of antidepressants.[\[41\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Paludan-M%C3%BCller_2021-41)
### Anxiety disorders
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=3 "Edit section: Anxiety disorders")\]
For children and adolescents, [fluvoxamine](https://en.wikipedia.org/wiki/Fluvoxamine "Fluvoxamine") and [escitalopram](https://en.wikipedia.org/wiki/Escitalopram "Escitalopram") are effective in treating a range of anxiety disorders.[\[42\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NIHR-2022-42)[\[37\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Boaden-2020-37)[\[43\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Correll-2021-43) Fluoxetine, sertraline, and paroxetine can also help with managing various forms of anxiety in children and adolescents.[\[42\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NIHR-2022-42)[\[37\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Boaden-2020-37)[\[43\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Correll-2021-43)
Meta-analyses of published and unpublished trials have found that antidepressants have a [placebo](https://en.wikipedia.org/wiki/Placebo_group "Placebo group")\-subtracted [effect size](https://en.wikipedia.org/wiki/Effect_size "Effect size") ([standardized mean difference](https://en.wikipedia.org/wiki/Standardized_mean_difference "Standardized mean difference") or SMD) in the treatment of anxiety disorders of around 0.3, which equates to a small improvement and is roughly the same magnitude of benefit as their effectiveness in the treatment of depression.[\[44\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31249537-44) The effect size (SMD) for improvement with placebo in trials of antidepressants for anxiety disorders is approximately 1.0, which is a large improvement in terms of effect size definitions.[\[45\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31573058-45) In relation to this, most of the benefit of antidepressants for anxiety disorders is attributable to placebo responses rather than to the effects of the antidepressants themselves.[\[44\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31249537-44)[\[45\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31573058-45)
#### Generalized anxiety disorder
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=4 "Edit section: Generalized anxiety disorder")\]
Antidepressants are recommended by the National Institute for Health and Care Excellence (NICE) for the treatment of [generalized anxiety disorder](https://en.wikipedia.org/wiki/Generalized_anxiety_disorder "Generalized anxiety disorder") (GAD) that has failed to respond to conservative measures such as education and self-help activities. GAD is a common disorder in which the central feature is excessively worrying about numerous events. Key symptoms include excessive anxiety about events and issues going on around them and difficulty controlling worrisome thoughts that persists for at least 6 months.
Antidepressants provide a modest to moderate reduction in anxiety in GAD.[\[46\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-urlwww.nice.org.uk-46) The efficacy of different antidepressants is similar.[\[46\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-urlwww.nice.org.uk-46)
#### Social anxiety disorder
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=5 "Edit section: Social anxiety disorder")\]
Some antidepressants are used as a treatment for [social anxiety disorder](https://en.wikipedia.org/wiki/Social_anxiety_disorder "Social anxiety disorder"), but their efficacy is not entirely convincing, as only a small proportion of antidepressants showed some effectiveness for this condition. Paroxetine was the first drug to be FDA-approved for this disorder. Its efficacy is considered beneficial, although not everyone responds favorably to the drug. Sertraline and fluvoxamine extended-release were later approved for it as well, while escitalopram is used [off-label](https://en.wikipedia.org/wiki/Off-label_use "Off-label use") with acceptable efficiency. However, there is not enough evidence to support [citalopram](https://en.wikipedia.org/wiki/Citalopram "Citalopram") for treating social anxiety disorder, and fluoxetine was no better than a placebo in clinical trials. [Vortioxetine](https://en.wikipedia.org/wiki/Vortioxetine "Vortioxetine") may be of benefit. [SSRIs](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor "Selective serotonin reuptake inhibitor") are used as a first-line treatment for social anxiety, but they do not work for everyone. One alternative would be [venlafaxine](https://en.wikipedia.org/wiki/Venlafaxine "Venlafaxine"), an [SNRI](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor"), which has shown benefits for social phobia in five clinical trials against a placebo, while the other SNRIs are not considered particularly useful for this disorder as many of them did not undergo testing for it. As of 2008[\[update\]](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit), it is unclear if duloxetine and [desvenlafaxine](https://en.wikipedia.org/wiki/Desvenlafaxine "Desvenlafaxine") can provide benefits for people with social anxiety. However, another class of antidepressants called [MAOIs](https://en.wikipedia.org/wiki/Monoamine_oxidase_inhibitor "Monoamine oxidase inhibitor") are considered effective for social anxiety, but they come with many unwanted side effects and are rarely used. [Phenelzine](https://en.wikipedia.org/wiki/Phenelzine "Phenelzine") was shown to be a good treatment option, but its use is limited by dietary restrictions. [Moclobemide](https://en.wikipedia.org/wiki/Moclobemide "Moclobemide") is a [RIMA](https://en.wikipedia.org/wiki/Reversible_inhibitor_of_MAO-A "Reversible inhibitor of MAO-A") and showed mixed results, but still received approval in some European countries for social anxiety disorder. [TCA antidepressants](https://en.wikipedia.org/wiki/Tricyclic_antidepressant "Tricyclic antidepressant"), such as [clomipramine](https://en.wikipedia.org/wiki/Clomipramine "Clomipramine") and [imipramine](https://en.wikipedia.org/wiki/Imipramine "Imipramine"), are not considered effective for this anxiety disorder in particular. This leaves out SSRIs such as paroxetine, sertraline, and fluvoxamine CR as acceptable and tolerated treatment options for this disorder.[\[47\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-47)[\[48\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-48)
#### Obsessive–compulsive disorder
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=6 "Edit section: Obsessive–compulsive disorder")\]
SSRIs are a [second-line](https://en.wikipedia.org/wiki/Second-line_medication "Second-line medication") treatment for adult [obsessive–compulsive disorder](https://en.wikipedia.org/wiki/Obsessive%E2%80%93compulsive_disorder "Obsessive–compulsive disorder") (OCD) with mild functional impairment, and a first-line treatment for those with moderate or severe impairment.[\[49\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-49)[\[50\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-50)[\[51\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-51)[\[52\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-52)
In children, SSRIs are considered as a second-line therapy in those with moderate-to-severe impairment, with close monitoring for psychiatric adverse effects.[\[53\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-53) Sertraline and fluoxetine are effective in treating OCD for children and adolescents.[\[42\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NIHR-2022-42)[\[37\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Boaden-2020-37)[\[43\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Correll-2021-43)
[Clomipramine](https://en.wikipedia.org/wiki/Clomipramine "Clomipramine"), a TCA drug, is considered effective and useful for OCD.[\[54\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-54) However, it is used as a second-line treatment because it is less well-tolerated than SSRIs. Despite this, it has not shown superiority to fluvoxamine in trials. All SSRIs can be used effectively for OCD. SNRI use may also be attempted, though no SNRIs have been approved for the treatment of OCD. Despite these treatment options, many patients remain symptomatic after initiating the medication, and less than half achieve [remission](https://en.wikipedia.org/wiki/Remission_\(medicine\) "Remission (medicine)").[\[55\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-55)
Placebo responses are a large component of the benefit of antidepressants in the treatment of depression and anxiety.[\[44\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31249537-44)[\[45\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31573058-45) However, placebo responses with antidepressants are lower in magnitude in the treatment of OCD compared to depression and anxiety.[\[45\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31573058-45)[\[56\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid28477500-56) A 2019 meta-analysis found placebo improvement effect sizes (SMD) of about 1.2 for depression, 1.0 for anxiety disorders, and 0.6 for OCD with antidepressants.[\[45\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31573058-45)
#### Post–traumatic stress disorder
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=7 "Edit section: Post–traumatic stress disorder")\]
Antidepressants are one of the treatment options for [PTSD](https://en.wikipedia.org/wiki/Post-traumatic_stress_disorder "Post-traumatic stress disorder"). However, their efficacy is not well established. Paroxetine and sertraline have been FDA approved for the treatment of PTSD. Paroxetine has slightly higher response and remission rates than sertraline for this condition. However, neither drug is considered very helpful for a broad patient demographic. Fluoxetine and venlafaxine are used off-label. Fluoxetine has produced unsatisfactory mixed results. Venlafaxine showed response rates of 78%, which is significantly higher than what paroxetine and sertraline achieved. However, it did not address as many symptoms of PTSD as paroxetine and sertraline, in part due to the fact that venlafaxine is an [SNRI](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor"). This class of drugs inhibits the reuptake of norepinephrine, which may cause anxiety in some patients. Fluvoxamine, escitalopram, and citalopram were not well-tested for this disorder. [MAOIs](https://en.wikipedia.org/wiki/Monoamine_oxidase_inhibitor "Monoamine oxidase inhibitor"), while some of them may be helpful, are not used much because of their unwanted side effects. This leaves paroxetine and sertraline as acceptable treatment options for some people, although more effective antidepressants are needed.[\[57\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-57)
#### Panic disorder
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=8 "Edit section: Panic disorder")\]
[Panic disorder](https://en.wikipedia.org/wiki/Panic_disorder "Panic disorder") is treated relatively well with medications compared to other disorders. Several classes of antidepressants have shown efficacy for this disorder, with SSRIs and SNRIs used first-line. Paroxetine, sertraline, and fluoxetine are FDA-approved for panic disorder, while fluvoxamine, escitalopram, and citalopram are also considered effective for them. SNRI venlafaxine is also approved for this condition. Unlike [social anxiety](https://en.wikipedia.org/wiki/Social_anxiety "Social anxiety") and [PTSD](https://en.wikipedia.org/wiki/Post-traumatic_stress_disorder "Post-traumatic stress disorder"), some [TCAs antidepressants](https://en.wikipedia.org/wiki/Tricyclic_antidepressant "Tricyclic antidepressant"), like clomipramine and imipramine, have shown efficacy for panic disorder. Moreover, the [MAOI](https://en.wikipedia.org/wiki/Monoamine_oxidase_inhibitor "Monoamine oxidase inhibitor") [phenelzine](https://en.wikipedia.org/wiki/Phenelzine "Phenelzine") is also considered useful. Panic disorder has many drugs for its treatment. However, the starting dose must be lower than the one used for major depressive disorder because people have reported an increase in anxiety as a result of starting the medication. In conclusion, while panic disorder's treatment options seem acceptable and useful for this condition, many people are still symptomatic after treatment with residual symptoms.[\[58\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-58)[\[59\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-59)[\[60\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-60)
### Eating disorders
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=9 "Edit section: Eating disorders")\]
Antidepressants are recommended as an alternative or additional first step to self-help programs in the treatment of [bulimia nervosa](https://en.wikipedia.org/wiki/Bulimia_nervosa "Bulimia nervosa").[\[61\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-urlwww.nice.org.uk2-61) SSRIs (fluoxetine in particular) are preferred over other antidepressants due to their acceptability, tolerability, and superior reduction of symptoms in short-term trials. Long-term efficacy remains poorly characterized. [Bupropion](https://en.wikipedia.org/wiki/Bupropion "Bupropion") is not recommended for the treatment of eating disorders, due to an increased risk of seizure.[\[62\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-62)
Similar recommendations apply to [binge eating disorder](https://en.wikipedia.org/wiki/Binge_eating_disorder "Binge eating disorder").[\[61\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-urlwww.nice.org.uk2-61) SSRIs provide short-term reductions in binge eating behavior, but have not been associated with significant weight loss.[\[63\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-urlNational_Guideline_Clearinghouse_|_Practice_guideline_for_the_treatment_of_patients_with_eating_disorders.-63)
Clinical trials have generated mostly negative results for the use of SSRIs in the treatment of [anorexia nervosa](https://en.wikipedia.org/wiki/Anorexia_nervosa "Anorexia nervosa").[\[64\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid21414249-64) Treatment guidelines from the National Institute of Health and Care Excellence (NICE)[\[61\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-urlwww.nice.org.uk2-61) recommend against the use of SSRIs in this disorder. Those from the American Psychiatric Association (APA) note that SSRIs confer no advantage regarding weight gain, but may be used for the treatment of co-existing depressive, anxiety, or obsessive–compulsive disorders.[\[63\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-urlNational_Guideline_Clearinghouse_|_Practice_guideline_for_the_treatment_of_patients_with_eating_disorders.-63)
### Pain
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=10 "Edit section: Pain")\]
#### Fibromyalgia
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=11 "Edit section: Fibromyalgia")\]
A 2012 [meta-analysis](https://en.wikipedia.org/wiki/Meta-analysis "Meta-analysis") concluded that antidepressant treatment favorably affects pain, health-related quality of life, depression, and sleep in [fibromyalgia](https://en.wikipedia.org/wiki/Fibromyalgia "Fibromyalgia") syndrome. [Tricyclics](https://en.wikipedia.org/wiki/Tricyclic_antidepressant "Tricyclic antidepressant") appear to be the most effective class, with moderate effects on pain and sleep, and small effects on fatigue and health-related quality of life. The fraction of people experiencing a 30% pain reduction on tricyclics was 48%, versus 28% on placebo. For SSRIs and SNRIs, the fractions of people experiencing a 30% pain reduction were 36% (20% in the placebo comparator arms) and 42% (32% in the corresponding placebo comparator arms) respectively. Discontinuation of treatment due to side effects was common.[\[65\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-65) Antidepressants including [amitriptyline](https://en.wikipedia.org/wiki/Amitriptyline "Amitriptyline"), [duloxetine](https://en.wikipedia.org/wiki/Duloxetine "Duloxetine"), [milnacipran](https://en.wikipedia.org/wiki/Milnacipran "Milnacipran"), [moclobemide](https://en.wikipedia.org/wiki/Moclobemide "Moclobemide"), and [pirlindole](https://en.wikipedia.org/wiki/Pirlindole "Pirlindole") are recommended by the European League Against Rheumatism (EULAR) for the treatment of fibromyalgia based on "limited evidence".[\[66\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid17644548-66)
#### Neuropathic pain
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=12 "Edit section: Neuropathic pain")\]
A 2014 meta-analysis from the [Cochrane Collaboration](https://en.wikipedia.org/wiki/Cochrane_Collaboration "Cochrane Collaboration") found the antidepressant duloxetine to be effective for the treatment of pain resulting from [diabetic neuropathy](https://en.wikipedia.org/wiki/Diabetic_neuropathy "Diabetic neuropathy").[\[67\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-67) The same group reviewed data for amitriptyline in the treatment of [neuropathic pain](https://en.wikipedia.org/wiki/Neuropathic_pain "Neuropathic pain") and found limited useful randomized clinical trial data. They concluded that the long history of successful use in the community for the treatment of fibromyalgia and neuropathic pain justified its continued use.[\[68\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Moore2015-68) The group was concerned about the potential overestimation of the amount of pain relief provided by amitriptyline, and highlighted that only a small number of people will experience significant pain relief by taking this medication.[\[68\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Moore2015-68)
### Other uses
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=13 "Edit section: Other uses")\]
Antidepressants may be modestly helpful for treating people who have both depression and [alcohol dependence](https://en.wikipedia.org/wiki/Alcohol_dependence "Alcohol dependence"), however, the evidence supporting this association is of low quality.[\[69\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-69) Bupropion is used to help people [stop smoking](https://en.wikipedia.org/wiki/Smoking_cessation "Smoking cessation"). Antidepressants are also used to control some symptoms of [narcolepsy](https://en.wikipedia.org/wiki/Narcolepsy "Narcolepsy").[\[70\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-70) Antidepressants may be used to relieve pain in people with active [rheumatoid arthritis](https://en.wikipedia.org/wiki/Rheumatoid_arthritis "Rheumatoid arthritis"). However, further research is required.[\[71\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-71) Antidepressants have been shown to be superior to placebo in treating depression in individuals with physical illness, although reporting bias may have exaggerated this finding.[\[72\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-72) Antidepressants have been shown to improve some parts of cognitive functioning for depressed users, such as memory, attention, and processing speed.[\[73\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-73)
Certain antidepressants acting as serotonin 5-HT2A receptor antagonists, such as [trazodone](https://en.wikipedia.org/wiki/Trazodone "Trazodone") and [mirtazapine](https://en.wikipedia.org/wiki/Mirtazapine "Mirtazapine"), have been used as [hallucinogen antidotes or "trip killers"](https://en.wikipedia.org/wiki/Trip_killer "Trip killer") to block the effects of [serotonergic psychedelics](https://en.wikipedia.org/wiki/Serotonergic_psychedelic "Serotonergic psychedelic") like [psilocybin](https://en.wikipedia.org/wiki/Psilocybin "Psilocybin") and [lysergic acid diethylamide](https://en.wikipedia.org/wiki/Lysergic_acid_diethylamide "Lysergic acid diethylamide") (LSD).[\[74\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-HalmanKongSarris2024-74)[\[75\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-YatesMelon2024-75)[\[76\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Suran2024-76)
### Limitations and strategies
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=14 "Edit section: Limitations and strategies")\]
Among individuals treated with a given antidepressant, between 30% and 50% do not show a response.[\[77\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-77)[\[78\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-SSRIswitch-78) Approximately one-third of people achieve a full [remission](https://en.wikipedia.org/wiki/Remission_\(medicine\) "Remission (medicine)"), one-third experience a response, and one-third are non-responders. Partial remission is characterized by the presence of poorly defined residual symptoms. These symptoms typically include depressed mood, anxiety, sleep disturbance, fatigue, and diminished interest or pleasure. It is currently unclear which factors predict partial remission. However, it is clear that residual symptoms are powerful predictors of relapse, with relapse rates three to six times higher in people with residual symptoms than in those, who experience full remission.[\[79\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-79) In addition, antidepressant drugs tend to lose efficacy throughout long-term [maintenance therapy](https://en.wikipedia.org/wiki/Maintenance_therapy "Maintenance therapy").[\[80\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-80) According to data from the [Centers for Disease Control and Prevention](https://en.wikipedia.org/wiki/Centers_for_Disease_Control_and_Prevention "Centers for Disease Control and Prevention"), less than one-third of Americans taking one antidepressant medication have seen a mental health professional in the previous year.[\[81\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-81) Several strategies are used in clinical practice to try to overcome these limits and variations.[\[82\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-82) They include switching medication, augmentation, and combination.
There is controversy amongst researchers regarding the efficacy and risk-benefit ratio of antidepressants.[\[83\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Wilson2018-83)[\[84\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Warren2020-84) Although antidepressants consistently out-perform a placebo in meta-analyses, the difference is modest and it is not clear that their statistical superiority results in clinical efficacy.[\[21\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-CiprianiFurukawa2018-21)[\[85\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35918097-85)[\[86\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid30386270-86)[\[87\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-McCormack2018-87) The aggregate effect of antidepressants typically results in changes below the threshold of clinical significance on depression rating scales.[\[88\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31554608-88)[\[89\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid25979317-89) Proponents of antidepressants counter that the most common scale, the [HDRS](https://en.wikipedia.org/wiki/HDRS "HDRS"), is not suitable for assessing drug action, that the threshold for clinical significance is arbitrary, and that antidepressants consistently result in significantly raised scores on the mood item of the scale.[\[90\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Pariante2022-90) Assessments of antidepressants using alternative, more sensitive scales, such as the [MADRS](https://en.wikipedia.org/wiki/Montgomery%E2%80%93%C3%85sberg_Depression_Rating_Scale "Montgomery–Åsberg Depression Rating Scale"), do not result in marked difference from the HDRS and likewise only find a marginal clinical benefit.[\[91\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid32101579-91) Another hypothesis proposed to explain the poor performance of antidepressants in clinical trials is a high treatment response heterogeneity. Some patients, that differ strongly in their response to antidepressants, could influence the average response, while the heterogeneity could itself be obscured by the averaging. Studies have not supported this hypothesis, but it is very difficult to measure treatment effect heterogeneity.[\[92\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Luedtke2021-92) Poor and complex clinical trial design might also account for the small effects seen for antidepressants.[\[93\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Khan2015-93)[\[94\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Nutt2008-94) The randomized controlled trials used to approve drugs are short, and may not capture the full effect of antidepressants.[\[94\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Nutt2008-94) Additionally, the placebo effect might be inflated in these trials by frequent clinical consultation, lowering the comparative performance of antidepressants.[\[94\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Nutt2008-94) Critics agree that current clinical trials are poorly-designed, which limits the knowledge on antidepressants.[\[95\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Boesen2021-95) More naturalistic studies, such as [STAR\*D](https://en.wikipedia.org/wiki/STAR*D "STAR*D"), have produced results, which suggest that antidepressants may be less effective in clinical practice than in randomized controlled trials.[\[96\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Read2022-96)[\[97\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-97)
Critics of antidepressants maintain that the superiority of antidepressants over placebo is the result of systemic flaws in clinical trials and the research literature.[\[96\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Read2022-96)[\[88\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31554608-88) Trials conducted with industry involvement tend to produce more favorable results, and accordingly many of the trials included in meta-analyses are at high risk of bias.[\[98\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31248914-98)[\[88\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31554608-88) Additionally, meta-analyses co-authored by industry employees find more favorable results for antidepressants.[\[88\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31554608-88) The results of antidepressant trials are significantly more likely to be published if they are favorable, and unfavorable results are very often left unpublished or misreported, a phenomenon called [publication bias](https://en.wikipedia.org/wiki/Publication_bias "Publication bias") or selective publication.[\[99\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Turner2008-99) Although this issue has diminished with time, it remains an obstacle to accurately assessing the efficacy of antidepressants.[\[100\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Turner2022-100) Misreporting of clinical trial outcomes and of serious adverse events, such as suicide, is common.[\[101\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Hughes2014-101)[\[98\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31248914-98)[\[102\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Hengartner2022-102) [Ghostwriting](https://en.wikipedia.org/wiki/Ghostwriting "Ghostwriting") of antidepressant trials is widespread, a practice in which prominent researchers, or so-called key opinion leaders, attach their names to studies actually written by pharmaceutical company employees or consultants.[\[102\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Hengartner2022-102) A particular concern is that the psychoactive effects of antidepressants may lead to the unblinding of participants or researchers, enhancing the placebo effect and biasing results.[\[44\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31249537-44)[\[103\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Kirsch2014-103)[\[98\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31248914-98) Some have therefore maintained that antidepressants may only be active placebos.[\[96\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Read2022-96)[\[88\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31554608-88) When these and other flaws in the research literature are not taken into account, meta-analyses may find inflated results on the basis of poor evidence.[\[98\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31248914-98)
Critics contend that antidepressants have not been proven sufficiently effective by RCTs or in clinical practice and that the widespread use of antidepressants is not evidence-based.[\[96\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Read2022-96)[\[88\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31554608-88) They also note that adverse effects, including withdrawal difficulties, are likely underreported, skewing clinicians' ability to make risk-benefit judgements.[\[84\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Warren2020-84)[\[104\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Sharma2016-104)[\[105\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Bielefeldt2016-105)[\[96\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Read2022-96) Accordingly, they believe antidepressants are overused, particularly for non-severe depression and conditions in which they are not indicated.[\[84\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Warren2020-84)[\[106\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Fava2014-106) Critics charge that the widespread use and public acceptance of antidepressants is the result of pharmaceutical advertising, research manipulation, and misinformation.[\[107\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid16268734-107)[\[108\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-LacasseLeo2015-108)[\[109\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Lacasse2005-109)[\[110\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-AngHorowitzMoncrieff2022-110)
Current mainstream psychiatric opinion recognizes the limitations of antidepressants but recommends their use in adults with more severe depression as a first-line treatment.[\[111\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-nrdp2016-111)[\[112\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NICE2022-112)
### Switching antidepressants
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=15 "Edit section: Switching antidepressants")\]
See also: [Treatment-resistant depression § Switching antidepressants](https://en.wikipedia.org/wiki/Treatment-resistant_depression#Switching_antidepressants "Treatment-resistant depression")
The [American Psychiatric Association](https://en.wikipedia.org/wiki/American_Psychiatric_Association "American Psychiatric Association") 2000 Practice Guideline advises that where no response is achieved within the following six to eight weeks of treatment with an antidepressant, switch to an antidepressant in the same class, and then to a different class. A 2006 meta-analysis review found wide variation in the findings of prior studies: for people who had failed to respond to an SSRI antidepressant, between 12% and 86% showed a response to a new drug. However, the more antidepressants an individual had previously tried, the less likely they were to benefit from a new antidepressant trial.[\[78\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-SSRIswitch-78) However, a later meta-analysis found no difference between switching to a new drug and staying on the old medication: although 34% of [treatment-resistant](https://en.wikipedia.org/wiki/Treatment-resistant_depression "Treatment-resistant depression") people responded when switched to the new drug, 40% responded without being switched.[\[113\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-113)
### Augmentation and combination
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=16 "Edit section: Augmentation and combination")\]
For a partial response, the American Psychiatric Association (APA) guidelines suggest [augmentation](https://en.wikipedia.org/wiki/Augmentation_\(pharmacology\) "Augmentation (pharmacology)") or adding a drug from a different class. These include [lithium](https://en.wikipedia.org/wiki/Lithium_\(medication\) "Lithium (medication)") and [thyroid](https://en.wikipedia.org/wiki/Thyroid "Thyroid") augmentation, [dopamine agonists](https://en.wikipedia.org/wiki/Dopamine_agonist "Dopamine agonist"), [sex steroids](https://en.wikipedia.org/wiki/Sex_steroid "Sex steroid"), [NRIs](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitor "Norepinephrine reuptake inhibitor"), [glucocorticoid](https://en.wikipedia.org/wiki/Glucocorticoid "Glucocorticoid")\-specific agents, or the newer [anticonvulsants](https://en.wikipedia.org/wiki/Anticonvulsant "Anticonvulsant").[\[114\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-augment-114)
A combination strategy involves adding another antidepressant, usually from a different class to affect other mechanisms. Although this may be used in clinical practice, there is little evidence for the relative efficacy or adverse effects of this strategy.[\[115\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-115) Other tests conducted include the use of [psychostimulants](https://en.wikipedia.org/wiki/Psychostimulant "Psychostimulant") as an augmentation therapy. Several studies have shown the efficacy of combining [modafinil](https://en.wikipedia.org/wiki/Modafinil "Modafinil") for treatment-resistant people. It has been used to help combat SSRI-associated fatigue.[\[116\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-116)
### Long-term use and stopping
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=17 "Edit section: Long-term use and stopping")\]
The effects of antidepressants typically do not continue once the course of medication ends. This results in a high rate of [relapse](https://en.wikipedia.org/wiki/Relapse "Relapse"). In 2003, a [meta-analysis](https://en.wikipedia.org/wiki/Meta-analysis "Meta-analysis") found that 18% of people who had responded to an antidepressant relapsed while still taking it, compared to 41% whose antidepressant was switched for a [placebo](https://en.wikipedia.org/wiki/Placebo "Placebo").[\[117\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-117)
A gradual loss of therapeutic benefit occurs in a minority of people during the course of treatment.[\[118\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-118)[\[119\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-fava-119) A strategy involving the use of [pharmacotherapy](https://en.wikipedia.org/wiki/Pharmacotherapy "Pharmacotherapy") in the treatment of the acute episode, followed by psychotherapy in its residual phase, has been suggested by some studies.[\[120\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-120)[\[121\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-121) For patients who wish to stop their antidepressants, engaging in brief psychological interventions such as Preventive Cognitive Therapy[\[122\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-122) or [mindfulness-based cognitive therapy](https://en.wikipedia.org/wiki/Mindfulness-based_cognitive_therapy "Mindfulness-based cognitive therapy") while [tapering](https://en.wikipedia.org/wiki/Tapering_\(medicine\) "Tapering (medicine)") down has been found to diminish the risk for [relapse](https://en.wikipedia.org/wiki/Relapse_prevention "Relapse prevention").[\[123\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-123)
## Adverse effects
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=18 "Edit section: Adverse effects")\]
Antidepressants can cause various [adverse effects](https://en.wikipedia.org/wiki/Adverse_effects "Adverse effects"), depending on the individual and the drug in question.[\[124\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-124)
Almost any medication involved with serotonin regulation has the potential to cause [serotonin toxicity](https://en.wikipedia.org/wiki/Serotonin_syndrome "Serotonin syndrome") (also known as *serotonin syndrome*) – an excess of serotonin that can induce mania, restlessness, agitation, [emotional lability](https://en.wikipedia.org/wiki/Emotional_lability "Emotional lability"), insomnia, and confusion as its primary symptoms.[\[125\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid12771076-125)[\[126\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid15784664-126) Although the condition is serious, it is not particularly common, generally only appearing at high doses or while on other medications. Assuming proper medical intervention has been taken (within about 24 hours) it is rarely fatal.[\[127\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid10941349-127)[\[128\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid10818648-128) Antidepressants appear to increase the risk of [diabetes](https://en.wikipedia.org/wiki/Diabetes "Diabetes") by about 1.3-fold.[\[129\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Salvi_2017-129)
[MAOIs](https://en.wikipedia.org/wiki/MAOIs "MAOIs") tend to have pronounced (sometimes fatal) interactions with a wide variety of medications and [over-the-counter drugs](https://en.wikipedia.org/wiki/Over-the-counter_drug "Over-the-counter drug"). If taken with foods that contain very high levels of [tyramine](https://en.wikipedia.org/wiki/Tyramine "Tyramine") (e.g., mature cheese, cured meats, or yeast extracts), they may cause a potentially lethal [hypertensive crisis](https://en.wikipedia.org/wiki/Hypertensive_crisis "Hypertensive crisis"). At lower doses, the person may only experience a headache due to an increase in blood pressure.[\[130\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid19742203-130)
In response to these adverse effects, a different type of MAOI, the class of [reversible inhibitor of monoamine oxidase A](https://en.wikipedia.org/wiki/Reversible_inhibitor_of_monoamine_oxidase_A "Reversible inhibitor of monoamine oxidase A") (RIMA), has been developed. The primary advantage of RIMAs is that they do not require the person to follow a special diet while being purportedly effective as SSRIs and tricyclics in treating depressive disorders.[\[131\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid7717091-131)
Tricyclics and SSRI can cause the so-called [drug-induced QT prolongation](https://en.wikipedia.org/wiki/Drug-induced_QT_prolongation "Drug-induced QT prolongation"), especially in older adults;[\[132\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-132) this condition can degenerate into a specific type of [abnormal heart rhythm](https://en.wikipedia.org/wiki/Heart_arrhythmia "Heart arrhythmia") called [torsades de pointes](https://en.wikipedia.org/wiki/Torsades_de_pointes "Torsades de pointes"), which can potentially lead to [sudden cardiac arrest](https://en.wikipedia.org/wiki/Cardiac_arrest "Cardiac arrest").[\[133\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-133)
Some antidepressants are also believed to increase thoughts of [suicidal ideation](https://en.wikipedia.org/wiki/Suicidal_ideation "Suicidal ideation").
Antidepressants have been associated with an increased risk of [dementia](https://en.wikipedia.org/wiki/Dementia "Dementia") in older adults.[\[134\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid37834986-134)
Researchers have developed a tool that allows people to rate their concern about common side effects of antidepressants. The tool ranks potential treatment options in a visual display that highlights the drugs with side effects of least concern to an individual.[\[135\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-135)[\[136\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-136)
### Pregnancy
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=19 "Edit section: Pregnancy")\]
SSRI use in pregnancy has been associated with a variety of risks with varying degrees of proof of causation. As depression is independently associated with negative pregnancy outcomes, determining the extent to which observed associations between antidepressant use and specific adverse outcomes reflect a causative relationship has been difficult in some cases.[\[137\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-137) In other cases, the attribution of adverse outcomes to antidepressant exposure seems fairly clear.
SSRI use in pregnancy is associated with an increased risk of spontaneous abortion of about 1.7-fold,[\[138\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-138)[\[139\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid23351929-139) and is associated with preterm birth and low birth weight.[\[140\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-140)
A systematic review of the risk of major birth defects in antidepressant-exposed pregnancies found a small increase (3% to 24%) in the risk of major malformations and a risk of cardiovascular birth defects that did not differ from non-exposed pregnancies.[\[141\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-141) A study of fluoxetine-exposed pregnancies found a 12% increase in the risk of major malformations that did not reach statistical significance.[\[142\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-142) Other studies have found an increased risk of cardiovascular birth defects among depressed mothers not undergoing SSRI treatment, suggesting the possibility of ascertainment bias, e.g. that worried mothers may pursue more aggressive testing of their infants.[\[143\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-143) Another study found no increase in cardiovascular birth defects and a 27% increased risk of major malformations in SSRI exposed pregnancies.[\[139\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid23351929-139) The FDA advises for the risk of birth defects with the use of paroxetine[\[144\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-144) and the MAOI should be avoided.
A 2013 systematic review and meta-analysis found that antidepressant use during pregnancy was statistically significantly associated with some pregnancy outcomes, such as gestational age and preterm birth, but not with other outcomes. The same review cautioned that because differences between the exposed and unexposed groups were small, it was doubtful whether they were clinically significant.[\[145\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-145)
A [neonate](https://en.wikipedia.org/wiki/Neonate "Neonate") (infant less than 28 days old) may experience a [withdrawal syndrome](https://en.wikipedia.org/wiki/Withdrawal_syndrome "Withdrawal syndrome") from abrupt discontinuation of the antidepressant at birth. Antidepressants can be present in varying amounts in breast milk, but their effects on infants are currently unknown.[\[146\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-146)
Moreover, SSRIs inhibit nitric oxide synthesis, which plays an important role in setting the vascular tone. Several studies have pointed to an increased risk of prematurity associated with SSRI use, and this association may be due to an increased risk of [pre-eclampsia](https://en.wikipedia.org/wiki/Pre-eclampsia "Pre-eclampsia") during pregnancy.[\[147\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-147)
### Antidepressant-induced mania
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=20 "Edit section: Antidepressant-induced mania")\]
See also: [Bipolar disorder § Antidepressants](https://en.wikipedia.org/wiki/Bipolar_disorder#Antidepressants "Bipolar disorder")
Another possible problem with antidepressants is the chance of antidepressant-induced [mania](https://en.wikipedia.org/wiki/Mania "Mania") or [hypomania](https://en.wikipedia.org/wiki/Hypomania "Hypomania") in people with or without a diagnosis of [bipolar disorder](https://en.wikipedia.org/wiki/Bipolar_disorder "Bipolar disorder"). Many cases of bipolar depression are very similar to those of unipolar depression. Therefore, the person can be misdiagnosed with unipolar depression and be given antidepressants. Studies have shown that antidepressant-induced mania can occur in 20–40% of people with bipolar disorder.[\[148\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-148) For bipolar depression, antidepressants (most frequently SSRIs) can exacerbate or trigger symptoms of hypomania and mania.[\[149\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid9387089-149) [Bupropion](https://en.wikipedia.org/wiki/Bupropion "Bupropion") has been associated with a lower risk of mood switch than other antidepressants.[\[150\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid37119556-150)
### Suicide
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=21 "Edit section: Suicide")\]
Main article: [Antidepressants and suicide risk](https://en.wikipedia.org/wiki/Antidepressants_and_suicide_risk "Antidepressants and suicide risk")
Studies have shown that the use of antidepressants is correlated with an increased risk of suicidal behavior and thinking (suicidality) in those aged under 25 years old.[\[151\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-StoneETAL-151) This problem has been serious enough to warrant government intervention by the US Food and Drug Administration (FDA) to warn of the increased risk of suicidality during antidepressant treatment.[\[152\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid17485726-152) According to the FDA, the heightened risk of suicidality occurs within the first one to two months of treatment.[\[153\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-153)[\[154\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-154) The National Institute for Health and Care Excellence (NICE) places the excess risk in the "early stages of treatment".[\[155\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-155) A [meta-analysis](https://en.wikipedia.org/wiki/Meta-analysis "Meta-analysis") suggests that the relationship between antidepressant use and suicidal behavior or thoughts is age-dependent.[\[151\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-StoneETAL-151) Compared with placebo, the use of antidepressants is associated with an increase in suicidal behavior or thoughts among those 25 years old or younger ([OR](https://en.wikipedia.org/wiki/Odds_ratio "Odds ratio")\=1.62). A review of RCTs and epidemiological studies by Healy and Whitaker found an increase in suicidal acts by a factor of 2.4.[\[156\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-156) There is no effect or possibly a mild protective effect among those aged 25 to 64 (OR=0.79). Antidepressant treatment has a protective effect against suicidality among those aged 65 and over (OR=0.37).[\[151\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-StoneETAL-151)[\[157\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-dhintrev-157)
### Sexual dysfunction
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=22 "Edit section: Sexual dysfunction")\]
See also: [Selective serotonin reuptake inhibitor § Sexual dysfunction](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor#Sexual_dysfunction "Selective serotonin reuptake inhibitor")
Sexual side effects are common with SSRIs, such as loss of [sexual drive](https://en.wikipedia.org/wiki/Sexual_drive "Sexual drive"), [failure to reach orgasm](https://en.wikipedia.org/wiki/Anorgasmia "Anorgasmia"), and [erectile dysfunction](https://en.wikipedia.org/wiki/Erectile_dysfunction "Erectile dysfunction").[\[158\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-158) Although usually reversible, these sexual side-effects can, in rare cases, continue after the drug has been completely withdrawn.[\[159\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid18173768-159)[\[160\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-160)
In a study of 1,022 outpatients, overall sexual dysfunction with all antidepressants averaged 59.1%[\[161\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid11229449-161) with SSRI values between 57% and 73%, mirtazapine 24%, nefazodone 8%, amineptine 7%, and [moclobemide](https://en.wikipedia.org/wiki/Moclobemide "Moclobemide") 4%. Moclobemide, a selective reversible MAO-A inhibitor, does not cause sexual dysfunction[\[162\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid19440080-162) and can lead to an improvement in all aspects of sexual function.[\[163\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid9696909-163)
Biochemical mechanisms suggested as causative include increased serotonin, particularly affecting [5-HT2](https://en.wikipedia.org/wiki/5-HT2_receptor "5-HT2 receptor") and [5-HT3 receptors](https://en.wikipedia.org/wiki/5HT3_receptor "5HT3 receptor"); decreased [dopamine](https://en.wikipedia.org/wiki/Dopamine "Dopamine"); decreased [norepinephrine](https://en.wikipedia.org/wiki/Norepinephrine "Norepinephrine"); blockade of [cholinergic](https://en.wikipedia.org/wiki/Cholinergic_receptor "Cholinergic receptor") and [α1adrenergic receptors](https://en.wikipedia.org/wiki/Alpha-1_adrenergic_receptor "Alpha-1 adrenergic receptor"); inhibition of [nitric oxide synthetase](https://en.wikipedia.org/wiki/Nitric_oxide_synthase "Nitric oxide synthase"); and elevation of [prolactin](https://en.wikipedia.org/wiki/Prolactin "Prolactin") levels.[\[164\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-164) [Mirtazapine](https://en.wikipedia.org/wiki/Mirtazapine "Mirtazapine") is reported to have fewer sexual side effects, most likely because it antagonizes 5-HT2 and 5-HT3 receptors and may, in some cases, reverse sexual dysfunction induced by SSRIs by the same mechanism.[\[165\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid18278806-165)
[Bupropion](https://en.wikipedia.org/wiki/Bupropion "Bupropion"), a weak NDRI and nicotinic antagonist, may be useful in treating reduced libido as a result of [SSRI](https://en.wikipedia.org/wiki/SSRI "SSRI") treatment.[\[166\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Schwasinger-Schmidt2018-166)
### Emotional blunting
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=23 "Edit section: Emotional blunting")\]
See also: [Selective serotonin reuptake inhibitor § Emotional blunting](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor#Emotional_blunting "Selective serotonin reuptake inhibitor")
Certain antidepressants may cause [emotional blunting](https://en.wikipedia.org/wiki/Emotional_blunting "Emotional blunting"), characterized by a reduced intensity of both positive and negative emotions as well as symptoms of [apathy](https://en.wikipedia.org/wiki/Apathy "Apathy"), [indifference](https://en.wikipedia.org/wiki/Psychological_indifference "Psychological indifference"), and [amotivation](https://en.wikipedia.org/wiki/Amotivational_syndrome "Amotivational syndrome").[\[167\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid34908941-167)[\[168\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid34970173-168)[\[169\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid15330228-169)[\[170\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid21103140-170)[\[171\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid19721109-171)[\[172\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid28628765-172)[\[173\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid29866014-173)[\[174\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35346413-174)[\[175\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid11436958-175)\[*[excessive citations](https://en.wikipedia.org/wiki/Wikipedia:Citing_sources#Bundling_citations "Wikipedia:Citing sources")*\] It may be experienced as either beneficial or detrimental depending on the situation.[\[176\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid26407780-176) This side effect has been particularly associated with serotonergic antidepressants like SSRIs and SNRIs but may be less with atypical antidepressants like bupropion, [agomelatine](https://en.wikipedia.org/wiki/Agomelatine "Agomelatine"), and [vortioxetine](https://en.wikipedia.org/wiki/Vortioxetine "Vortioxetine").[\[168\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid34970173-168)[\[174\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35346413-174)[\[177\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid23823799-177)[\[178\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid33516560-178) In addition, it is not associated with the [serotonergic psychedelic](https://en.wikipedia.org/wiki/Serotonergic_psychedelic "Serotonergic psychedelic") [psilocybin](https://en.wikipedia.org/wiki/Psilocybin "Psilocybin").[\[179\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-SiegelListonNicol2026-179) Higher doses of antidepressants seem to be more likely to produce emotional blunting than lower doses.[\[168\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid34970173-168) Emotional blunting can be decreased by reducing dosage, discontinuing the medication, or switching to a different antidepressant that may have less propensity for causing this side effect.[\[168\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid34970173-168)
### Changes in weight
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=24 "Edit section: Changes in weight")\]
Changes in appetite or weight are common among antidepressants but are largely drug-dependent and related to which neurotransmitters they affect. Mirtazapine and [paroxetine](https://en.wikipedia.org/wiki/Paroxetine "Paroxetine"), for example, may be associated with weight gain and/or increased appetite,[\[180\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Stimmel-180)[\[181\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-181)[\[182\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-autogenerated1032-182) while others (such as bupropion and [venlafaxine](https://en.wikipedia.org/wiki/Venlafaxine "Venlafaxine")) achieve the opposite effect.[\[183\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Bupropion_weight-183)[\[184\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-184)
The [antihistaminic](https://en.wikipedia.org/wiki/Antihistamine "Antihistamine") properties of certain TCA- and TeCA-class antidepressants have been shown to contribute to the common side effects of increased appetite and weight gain associated with these classes of medication.
### Bone loss
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=25 "Edit section: Bone loss")\]
A 2021 nationwide [cohort study](https://en.wikipedia.org/wiki/Cohort_study "Cohort study") in South Korea observed a link between SSRI use and bone loss, particularly in recent users. The study also stressed the need of further research to better understand these effects.[\[185\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-185) A 2012 review found that SSRIs along with tricyclic antidepressants were associated with a significant increase in the risk of osteoporotic fractures, peaking in the months after initiation, and moving back towards baseline during the year after treatment was stopped. These effects exhibited a [dose–response relationship](https://en.wikipedia.org/wiki/Dose%E2%80%93response_relationship "Dose–response relationship") within SSRIs which varied between different drugs of that class.[\[186\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-186) A 2018 meta-analysis of 11 small studies found a reduction in bone density of the lumbar spine in SSRI users which affected older people the most.[\[187\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-187)
### Risk of death
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=26 "Edit section: Risk of death")\]
A 2017 [meta-analysis](https://en.wikipedia.org/wiki/Meta-analysis "Meta-analysis") found that antidepressants were associated with a significantly increased [risk of death](https://en.wikipedia.org/wiki/Mortality_rate "Mortality rate") (+33%) and new [cardiovascular complications](https://en.wikipedia.org/wiki/Cardiovascular_complication "Cardiovascular complication") (+14%) in the general population.[\[188\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid28903117-188) Conversely, risks were not greater in people with existing [cardiovascular disease](https://en.wikipedia.org/wiki/Cardiovascular_disease "Cardiovascular disease").[\[188\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid28903117-188)
### Discontinuation syndrome
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=27 "Edit section: Discontinuation syndrome")\]
Main article: [Antidepressant discontinuation syndrome](https://en.wikipedia.org/wiki/Antidepressant_discontinuation_syndrome "Antidepressant discontinuation syndrome")
Antidepressant discontinuation syndrome, also called antidepressant withdrawal syndrome, is a condition that can occur following the interruption, reduction, or [discontinuation](https://en.wikipedia.org/wiki/Medication_discontinuation "Medication discontinuation") of antidepressant medication.[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189) The symptoms may include [flu-like symptoms](https://en.wikipedia.org/wiki/Flu-like_symptoms "Flu-like symptoms"), trouble sleeping, nausea, poor balance, sensory changes, and [anxiety](https://en.wikipedia.org/wiki/Anxiety "Anxiety").[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189)[\[14\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Gab2017-14)[\[190\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Dav2018-190) The problem usually begins within three days and may last for several months.[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189)[\[190\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Dav2018-190) Rarely [psychosis](https://en.wikipedia.org/wiki/Psychosis "Psychosis") may occur.[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189)
A discontinuation syndrome can occur after stopping any antidepressant including [selective serotonin reuptake inhibitors](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor "Selective serotonin reuptake inhibitor") (SSRIs), [serotonin–norepinephrine reuptake inhibitors](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") (SNRIs), and [tricyclic antidepressants](https://en.wikipedia.org/wiki/Tricyclic_antidepressants "Tricyclic antidepressants") (TCAs).[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189)[\[14\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Gab2017-14) The risk is greater among those who have taken the medication for longer and when the medication in question has a short [half-life](https://en.wikipedia.org/wiki/Half-life "Half-life").[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189) The underlying reason for its occurrence is unclear.[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189) The diagnosis is based on the symptoms.[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189)
Methods of prevention include gradually decreasing the dose ([tapering](https://en.wikipedia.org/wiki/Tapering_\(medicine\) "Tapering (medicine)")) among those who wish to stop, though it is possible for symptoms to occur with tapering.[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189)[\[13\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Wil2015-13)[\[190\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Dav2018-190) Treatment may include restarting the medication and slowly decreasing the dose.[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189) People may also be switched to the long-acting antidepressant [fluoxetine](https://en.wikipedia.org/wiki/Fluoxetine "Fluoxetine"), which can then be gradually decreased.[\[13\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Wil2015-13)
Approximately 20–50% of people who suddenly stop an antidepressant develop an antidepressant discontinuation syndrome.[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189)[\[14\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Gab2017-14)[\[190\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Dav2018-190) The condition is generally not serious,[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189) though about half of people with symptoms describe them as severe.[\[190\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Dav2018-190) Some restart antidepressants due to the severity of the symptoms.[\[190\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Dav2018-190)
## Pharmacology
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=28 "Edit section: Pharmacology")\]
Main article: [Pharmacology of antidepressants](https://en.wikipedia.org/wiki/Pharmacology_of_antidepressants "Pharmacology of antidepressants")
Antidepressants act via a large number of different [mechanisms of action](https://en.wikipedia.org/wiki/Mechanism_of_action "Mechanism of action").[\[191\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Fasipe2018-191)[\[192\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35714379-192)[\[193\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Stahl2020-193) This includes [serotonin reuptake inhibition](https://en.wikipedia.org/wiki/Serotonin_reuptake_inhibition "Serotonin reuptake inhibition") (SSRIs, SNRIs, TCAs, vilazodone, vortioxetine), [norepinephrine reuptake inhibition](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibition "Norepinephrine reuptake inhibition") (NRIs, SNRIs, TCAs), [dopamine reuptake inhibition](https://en.wikipedia.org/wiki/Dopamine_reuptake_inhibition "Dopamine reuptake inhibition") (bupropion, amineptine, nomifensine), direct [modulation](https://en.wikipedia.org/wiki/Receptor_modulation "Receptor modulation") of [monoamine receptors](https://en.wikipedia.org/wiki/Monoamine_receptor "Monoamine receptor") (vilazodone, vortioxetine, SARIs, agomelatine, TCAs, TeCAs, antipsychotics), [monoamine oxidase inhibition](https://en.wikipedia.org/wiki/Monoamine_oxidase_inhibition "Monoamine oxidase inhibition") (MAOIs), and [NMDA receptor antagonism](https://en.wikipedia.org/wiki/NMDA_receptor_antagonism "NMDA receptor antagonism") (ketamine, esketamine, dextromethorphan), among others (e.g., brexanolone, tianeptine).[\[191\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Fasipe2018-191)[\[192\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35714379-192)[\[193\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Stahl2020-193) Some antidepressants also have additional actions, like [sigma receptor](https://en.wikipedia.org/wiki/Sigma_receptor "Sigma receptor") modulation (certain SSRIs, TCAs, dextromethorphan) and [antagonism](https://en.wikipedia.org/wiki/Receptor_antagonism "Receptor antagonism") of [histamine](https://en.wikipedia.org/wiki/Histamine "Histamine") [H1](https://en.wikipedia.org/wiki/H1_receptor "H1 receptor") and [muscarinic acetylcholine receptors](https://en.wikipedia.org/wiki/Muscarinic_acetylcholine_receptor "Muscarinic acetylcholine receptor") (TCAs, TeCAs).[\[194\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-BolandKeller2008-194)[\[193\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Stahl2020-193)
| Class | Action(s) | Examples | Introduced |
|---|---|---|---|
| [Opioids](https://en.wikipedia.org/wiki/Opioid "Opioid") (mostly no longer used)[\[196\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-SaxenaBodkin2019-196)[\[197\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NishioLindsleyBender2024-197) | [μ-Opioid receptor](https://en.wikipedia.org/wiki/%CE%9C-Opioid_receptor "Μ-Opioid receptor") [agonism](https://en.wikipedia.org/wiki/Agonist "Agonist") | [Codeine](https://en.wikipedia.org/wiki/Codeine "Codeine") • [Heroin](https://en.wikipedia.org/wiki/Heroin "Heroin") • [Morphine](https://en.wikipedia.org/wiki/Morphine "Morphine") • [Opium](https://en.wikipedia.org/wiki/Opium "Opium") • [Tianeptine](https://en.wikipedia.org/wiki/Tianeptine "Tianeptine") (1983) | 1800s |
| [Amphetamine psychostimulants](https://en.wikipedia.org/wiki/Amphetamine-type_stimulant "Amphetamine-type stimulant") (mostly no longer used)[\[198\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Rasmussen2006-198)[\[199\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Ciccarone2011-199)[\[200\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Rasmussen2015-200)[\[201\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-HealSmithGosden2013-201) | [Norepinephrine release induction](https://en.wikipedia.org/wiki/Norepinephrine_releasing_agent "Norepinephrine releasing agent") • [Dopamine release induction](https://en.wikipedia.org/wiki/Dopamine_releasing_agent "Dopamine releasing agent") | [Amphetamine](https://en.wikipedia.org/wiki/Amphetamine "Amphetamine") • [Dextroamphetamine](https://en.wikipedia.org/wiki/Dextroamphetamine "Dextroamphetamine") • [Methamphetamine](https://en.wikipedia.org/wiki/Methamphetamine "Methamphetamine") | 1930s |
| [Monoamine oxidase inhibitors](https://en.wikipedia.org/wiki/Monoamine_oxidase_inhibitor "Monoamine oxidase inhibitor") (MAOIs) | [Monoamine oxidase](https://en.wikipedia.org/wiki/Monoamine_oxidase "Monoamine oxidase") [inhibition](https://en.wikipedia.org/wiki/Enzyme_inhibitor "Enzyme inhibitor") • Other actions in some cases | [Iproniazid](https://en.wikipedia.org/wiki/Iproniazid "Iproniazid") • [Isocarboxazid](https://en.wikipedia.org/wiki/Isocarboxazid "Isocarboxazid") • [Isoniazid](https://en.wikipedia.org/wiki/Isoniazid "Isoniazid") • [Moclobemide](https://en.wikipedia.org/wiki/Moclobemide "Moclobemide") (1989) • [Nialamide](https://en.wikipedia.org/wiki/Nialamide "Nialamide") • [Phenelzine](https://en.wikipedia.org/wiki/Phenelzine "Phenelzine") • [Selegiline](https://en.wikipedia.org/wiki/Selegiline "Selegiline") (1977/2006) • [Tranylcypromine](https://en.wikipedia.org/wiki/Tranylcypromine "Tranylcypromine") | 1950s |
| [Tricyclic antidepressants](https://en.wikipedia.org/wiki/Tricyclic_antidepressant "Tricyclic antidepressant") (TCAs) | [Serotonin reuptake inhibition](https://en.wikipedia.org/wiki/Serotonin_reuptake_inhibitor "Serotonin reuptake inhibitor") • [Norepinephrine reuptake inhibition](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitor "Norepinephrine reuptake inhibitor") • [Serotonin receptor antagonism](https://en.wikipedia.org/wiki/Serotonin_receptor_antagonist "Serotonin receptor antagonist") • [Adrenergic receptor antagonism](https://en.wikipedia.org/wiki/Adrenergic_receptor_antagonist "Adrenergic receptor antagonist") • [Histamine H1 receptor antagonism](https://en.wikipedia.org/wiki/H1_antagonist "H1 antagonist") • [Muscarinic acetylcholine receptor antagonism](https://en.wikipedia.org/wiki/Muscarinic_antagonist "Muscarinic antagonist") • Other actions | [Amitriptyline](https://en.wikipedia.org/wiki/Amitriptyline "Amitriptyline") • [Butriptyline](https://en.wikipedia.org/wiki/Butriptyline "Butriptyline") • [Clomipramine](https://en.wikipedia.org/wiki/Clomipramine "Clomipramine") • [Desipramine](https://en.wikipedia.org/wiki/Desipramine "Desipramine") • [Dosulepin (dothiepin)](https://en.wikipedia.org/wiki/Dosulepin "Dosulepin") • [Doxepin](https://en.wikipedia.org/wiki/Doxepin "Doxepin") • [Imipramine](https://en.wikipedia.org/wiki/Imipramine "Imipramine") • [Iprindole](https://en.wikipedia.org/wiki/Iprindole "Iprindole") • [Lofepramine](https://en.wikipedia.org/wiki/Lofepramine "Lofepramine") • [Nortriptyline](https://en.wikipedia.org/wiki/Nortriptyline "Nortriptyline") • [Protriptyline](https://en.wikipedia.org/wiki/Protriptyline "Protriptyline") • [Trimipramine](https://en.wikipedia.org/wiki/Trimipramine "Trimipramine") | 1950s |
| [Tetracyclic antidepressants](https://en.wikipedia.org/wiki/Tetracyclic_antidepressant "Tetracyclic antidepressant") (TeCAs) | [Serotonin reuptake inhibition](https://en.wikipedia.org/wiki/Serotonin_reuptake_inhibitor "Serotonin reuptake inhibitor") • [Norepinephrine reuptake inhibition](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitor "Norepinephrine reuptake inhibitor") • [Serotonin receptor antagonism](https://en.wikipedia.org/wiki/Serotonin_receptor_antagonist "Serotonin receptor antagonist") • [Adrenergic receptor antagonism](https://en.wikipedia.org/wiki/Adrenergic_receptor_antagonist "Adrenergic receptor antagonist") • [Histamine H1 receptor antagonism](https://en.wikipedia.org/wiki/H1_antagonist "H1 antagonist") • [Muscarinic acetylcholine receptor antagonism](https://en.wikipedia.org/wiki/Muscarinic_antagonist "Muscarinic antagonist") • Other actions | [Amoxapine](https://en.wikipedia.org/wiki/Amoxapine "Amoxapine") • [Maprotiline](https://en.wikipedia.org/wiki/Maprotiline "Maprotiline") • [Mianserin](https://en.wikipedia.org/wiki/Mianserin "Mianserin") • [Mirtazapine](https://en.wikipedia.org/wiki/Mirtazapine "Mirtazapine") • [Setiptiline](https://en.wikipedia.org/wiki/Setiptiline "Setiptiline") | 1970s |
| [Norepinephrine reuptake inhibitors](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitor "Norepinephrine reuptake inhibitor") (NRIs) | [Norepinephrine reuptake inhibition](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitor "Norepinephrine reuptake inhibitor") | [Atomoxetine](https://en.wikipedia.org/wiki/Atomoxetine "Atomoxetine") (off-label) • [Teniloxazine](https://en.wikipedia.org/wiki/Teniloxazine "Teniloxazine") • [Reboxetine](https://en.wikipedia.org/wiki/Reboxetine "Reboxetine") • [Viloxazine](https://en.wikipedia.org/wiki/Viloxazine "Viloxazine") | 1970s |
| [Norepinephrine–dopamine reuptake inhibitors](https://en.wikipedia.org/wiki/Norepinephrine%E2%80%93dopamine_reuptake_inhibitor "Norepinephrine–dopamine reuptake inhibitor") (NDRIs) | [Norepinephrine reuptake inhibition](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitor "Norepinephrine reuptake inhibitor") • [Dopamine reuptake inhibition](https://en.wikipedia.org/wiki/Dopamine_reuptake_inhibitor "Dopamine reuptake inhibitor") | [Amineptine](https://en.wikipedia.org/wiki/Amineptine "Amineptine") • [Bupropion](https://en.wikipedia.org/wiki/Bupropion "Bupropion") • [Methylphenidate](https://en.wikipedia.org/wiki/Methylphenidate "Methylphenidate") (off-label) • [Nomifensine](https://en.wikipedia.org/wiki/Nomifensine "Nomifensine") | 1970s |
| [Serotonin antagonists and reuptake inhibitors](https://en.wikipedia.org/wiki/Serotonin_antagonists_and_reuptake_inhibitors "Serotonin antagonists and reuptake inhibitors") (SARIs) | [Serotonin receptor antagonism](https://en.wikipedia.org/wiki/Serotonin_receptor_antagonist "Serotonin receptor antagonist") • [Adrenergic receptor antagonism](https://en.wikipedia.org/wiki/Adrenergic_receptor_antagonist "Adrenergic receptor antagonist") • Weak [monoamine reuptake inhibition](https://en.wikipedia.org/wiki/Monoamine_reuptake_inhibitor "Monoamine reuptake inhibitor") • Other actions | [Etoperidone](https://en.wikipedia.org/wiki/Etoperidone "Etoperidone") • [Nefazodone](https://en.wikipedia.org/wiki/Nefazodone "Nefazodone") • [Trazodone](https://en.wikipedia.org/wiki/Trazodone "Trazodone") | 1980s |
| [Selective serotonin reuptake inhibitors](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor "Selective serotonin reuptake inhibitor") (SSRIs) | [Serotonin reuptake inhibition](https://en.wikipedia.org/wiki/Serotonin_reuptake_inhibitor "Serotonin reuptake inhibitor") | [Citalopram](https://en.wikipedia.org/wiki/Citalopram "Citalopram") • [Escitalopram](https://en.wikipedia.org/wiki/Escitalopram "Escitalopram") • [Fluoxetine](https://en.wikipedia.org/wiki/Fluoxetine "Fluoxetine") • [Fluvoxamine](https://en.wikipedia.org/wiki/Fluvoxamine "Fluvoxamine") • [Indalpine](https://en.wikipedia.org/wiki/Indalpine "Indalpine") • [Paroxetine](https://en.wikipedia.org/wiki/Paroxetine "Paroxetine") • [Sertraline](https://en.wikipedia.org/wiki/Sertraline "Sertraline") • [Zimelidine](https://en.wikipedia.org/wiki/Zimelidine "Zimelidine") | 1980s |
| [Serotonin](https://en.wikipedia.org/wiki/Serotonin "Serotonin") [5-HT1A receptor](https://en.wikipedia.org/wiki/5-HT1A_receptor "5-HT1A receptor") [agonists](https://en.wikipedia.org/wiki/Agonist "Agonist") ([azapirones](https://en.wikipedia.org/wiki/Azapirone "Azapirone")) | [Serotonin](https://en.wikipedia.org/wiki/Serotonin "Serotonin") [5-HT1A receptor](https://en.wikipedia.org/wiki/5-HT1A_receptor "5-HT1A receptor") [partial agonism](https://en.wikipedia.org/wiki/Partial_agonist "Partial agonist") • Other actions | [Buspirone](https://en.wikipedia.org/wiki/Buspirone "Buspirone") (off-label) • [Gepirone](https://en.wikipedia.org/wiki/Gepirone "Gepirone") • [Tandospirone](https://en.wikipedia.org/wiki/Tandospirone "Tandospirone") | 1980s |
| [Serotonin–norepinephrine reuptake inhibitors](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") (SNRIs) | [Serotonin reuptake inhibition](https://en.wikipedia.org/wiki/Serotonin_reuptake_inhibitor "Serotonin reuptake inhibitor") • [Norepinephrine reuptake inhibition](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitor "Norepinephrine reuptake inhibitor") | [Desvenlafaxine](https://en.wikipedia.org/wiki/Desvenlafaxine "Desvenlafaxine") • [Duloxetine](https://en.wikipedia.org/wiki/Duloxetine "Duloxetine") • [Levomilnacipran](https://en.wikipedia.org/wiki/Levomilnacipran "Levomilnacipran") • [Milnacipran](https://en.wikipedia.org/wiki/Milnacipran "Milnacipran") (off-label) • [Venlafaxine](https://en.wikipedia.org/wiki/Venlafaxine "Venlafaxine") | 1990s |
| [Serotonin modulators and stimulators](https://en.wikipedia.org/wiki/Serotonin_modulators_and_stimulators "Serotonin modulators and stimulators") (SMSs) | [Serotonin reuptake inhibition](https://en.wikipedia.org/wiki/Serotonin_reuptake_inhibitor "Serotonin reuptake inhibitor") • [Serotonin receptor](https://en.wikipedia.org/wiki/Serotonin_receptor "Serotonin receptor") [modulation](https://en.wikipedia.org/wiki/Receptor_modulator "Receptor modulator") | [Vilazodone](https://en.wikipedia.org/wiki/Vilazodone "Vilazodone") • [Vortioxetine](https://en.wikipedia.org/wiki/Vortioxetine "Vortioxetine") | 2000s |
| [Atypical antipsychotics](https://en.wikipedia.org/wiki/Atypical_antipsychotic "Atypical antipsychotic") | [Serotonin receptor](https://en.wikipedia.org/wiki/Serotonin_receptor "Serotonin receptor") [modulation](https://en.wikipedia.org/wiki/Receptor_modulation "Receptor modulation") • [Dopamine receptor](https://en.wikipedia.org/wiki/Dopamine_receptor "Dopamine receptor") [modulation](https://en.wikipedia.org/wiki/Receptor_modulator "Receptor modulator") • Other actions | [Amisulpride](https://en.wikipedia.org/wiki/Amisulpride "Amisulpride") • [Aripiprazole](https://en.wikipedia.org/wiki/Aripiprazole "Aripiprazole") • [Brexpiprazole](https://en.wikipedia.org/wiki/Brexpiprazole "Brexpiprazole") • [Lumateperone](https://en.wikipedia.org/wiki/Lumateperone "Lumateperone") • [Lurasidone](https://en.wikipedia.org/wiki/Lurasidone "Lurasidone") • [Olanzapine](https://en.wikipedia.org/wiki/Olanzapine "Olanzapine") • [Quetiapine](https://en.wikipedia.org/wiki/Quetiapine "Quetiapine") • [Risperidone](https://en.wikipedia.org/wiki/Risperidone "Risperidone") (off-label) • [Sulpiride](https://en.wikipedia.org/wiki/Sulpiride "Sulpiride") | 2000s |
| [NMDA receptor antagonists](https://en.wikipedia.org/wiki/NMDA_receptor_antagonist "NMDA receptor antagonist") | [NMDA receptor antagonism](https://en.wikipedia.org/wiki/NMDA_receptor_antagonism "NMDA receptor antagonism") • Possibly other actions | [Dextromethorphan/bupropion](https://en.wikipedia.org/wiki/Dextromethorphan/bupropion "Dextromethorphan/bupropion") • [Esketamine](https://en.wikipedia.org/wiki/Esketamine "Esketamine") • [Ketamine](https://en.wikipedia.org/wiki/Ketamine "Ketamine") (off-label) | 2010s |
| [Serotonergic psychedelics](https://en.wikipedia.org/wiki/Serotonergic_psychedelic "Serotonergic psychedelic")[\[202\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Langlitz2025-202)[\[203\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NuttHuntSchlag2024-203)[\[204\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-AicherM%C3%BCllerGasser2025-204)[\[205\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-LiechtiGasserAicher2025-205) | [Serotonin 5-HT2A receptor agonism](https://en.wikipedia.org/wiki/Serotonin_5-HT2A_receptor_agonist "Serotonin 5-HT2A receptor agonist") | [Psilocybin](https://en.wikipedia.org/wiki/Psilocybin "Psilocybin") • [LSD](https://en.wikipedia.org/wiki/LSD "LSD") • Others | 2010s |
| [Neurosteroid](https://en.wikipedia.org/wiki/Neurosteroid "Neurosteroid")\-type [GABAA receptor positive allosteric modulators](https://en.wikipedia.org/wiki/GABAA_receptor_positive_allosteric_modulator "GABAA receptor positive allosteric modulator") | [GABAA receptor positive allosteric modulation](https://en.wikipedia.org/wiki/GABAA_receptor_positive_allosteric_modulator "GABAA receptor positive allosteric modulator") | [Brexanolone](https://en.wikipedia.org/wiki/Brexanolone "Brexanolone") • [Zuranolone](https://en.wikipedia.org/wiki/Zuranolone "Zuranolone") | 2010s |
| [Serotonin–norepinephrine–dopamine reuptake inhibitors](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine%E2%80%93dopamine_reuptake_inhibitor "Serotonin–norepinephrine–dopamine reuptake inhibitor") | [Serotonin reuptake inhibition](https://en.wikipedia.org/wiki/Serotonin_reuptake_inhibitor "Serotonin reuptake inhibitor") • [Norepinephrine reuptake inhibition](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitor "Norepinephrine reuptake inhibitor") • [Dopamine reuptake inhibition](https://en.wikipedia.org/wiki/Dopamine_reuptake_inhibitor "Dopamine reuptake inhibitor") | [Toludesvenlafaxine](https://en.wikipedia.org/wiki/Toludesvenlafaxine "Toludesvenlafaxine") | 2020s |
| [Other agents](https://en.wikipedia.org/wiki/Atypical_antidepressant "Atypical antidepressant") | Various/mixed actions | [α-Methyltryptamine](https://en.wikipedia.org/wiki/%CE%91-Methyltryptamine "Α-Methyltryptamine") • [Ademetionine (SAMe)](https://en.wikipedia.org/wiki/Ademetionine "Ademetionine") • [Agomelatine](https://en.wikipedia.org/wiki/Agomelatine "Agomelatine") • [D-Phenylalanine](https://en.wikipedia.org/wiki/D-Phenylalanine "D-Phenylalanine") • [Etryptamine](https://en.wikipedia.org/wiki/Etryptamine "Etryptamine") • [*Hypericum perforatum* (St John's wort)](https://en.wikipedia.org/wiki/Hypericum_perforatum "Hypericum perforatum") [Indeloxazine](https://en.wikipedia.org/wiki/Indeloxazine "Indeloxazine") • [Lithium](https://en.wikipedia.org/wiki/Lithium_\(medication\) "Lithium (medication)") (off-label) • [Medifoxamine](https://en.wikipedia.org/wiki/Medifoxamine "Medifoxamine") • [Opipramol](https://en.wikipedia.org/wiki/Opipramol "Opipramol") • [Oxaflozane](https://en.wikipedia.org/wiki/Oxaflozane "Oxaflozane") • [Oxitriptan (5-HTP)](https://en.wikipedia.org/wiki/Oxitriptan "Oxitriptan") • [Pivagabine](https://en.wikipedia.org/wiki/Pivagabine "Pivagabine") • [Thyroid hormone](https://en.wikipedia.org/wiki/Thyroid_hormone "Thyroid hormone") (off-label) • [Tiazesim](https://en.wikipedia.org/wiki/Tiazesim "Tiazesim") • [Tofenacin](https://en.wikipedia.org/wiki/Tofenacin "Tofenacin") • [Tryptophan](https://en.wikipedia.org/wiki/Tryptophan "Tryptophan") | Various |
| **Notes:** (1) Opioids and amphetamines largely ceased being used by the 1950s with the introduction of modern antidepressants. (2) Some antidepressants can also have alternative classifications, such as [mirtazapine](https://en.wikipedia.org/wiki/Mirtazapine "Mirtazapine") being a "[noradrenergic and specific serotonergic antidepressant](https://en.wikipedia.org/wiki/Noradrenergic_and_specific_serotonergic_antidepressant "Noradrenergic and specific serotonergic antidepressant")" (NaSSA) or [moclobemide](https://en.wikipedia.org/wiki/Moclobemide "Moclobemide") being a "[reversible inhibitor of monoamine oxidase A](https://en.wikipedia.org/wiki/Reversible_inhibitor_of_monoamine_oxidase_A "Reversible inhibitor of monoamine oxidase A")" (RIMA). (3) See [list of antidepressants](https://en.wikipedia.org/wiki/List_of_antidepressants "List of antidepressants") for a complete list of approved/marketed antidepressants. (4) See [list of investigational antidepressants](https://en.wikipedia.org/wiki/List_of_investigational_antidepressants "List of investigational antidepressants") for an extensive list of modern investigational antidepressants (including discontinued agents). | | | |
### Monoamine hypothesis
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=29 "Edit section: Monoamine hypothesis")\]
See also: [Biology of depression § Monoamines](https://en.wikipedia.org/wiki/Biology_of_depression#Monoamines "Biology of depression")
The earliest and most widely known [scientific theory](https://en.wikipedia.org/wiki/Scientific_theory "Scientific theory") of antidepressant action is the [monoamine hypothesis](https://en.wikipedia.org/wiki/Monoamine_hypothesis "Monoamine hypothesis"), which can be traced back to the 1950s and 1960s.[\[206\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-GG-206)[\[207\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid12953623-207) This theory states that depression is due to an imbalance, most often a deficiency, of the [monoamine neurotransmitters](https://en.wikipedia.org/wiki/Monoamine_neurotransmitter "Monoamine neurotransmitter"), namely [serotonin](https://en.wikipedia.org/wiki/Serotonin "Serotonin"), [norepinephrine](https://en.wikipedia.org/wiki/Norepinephrine "Norepinephrine"), and/or [dopamine](https://en.wikipedia.org/wiki/Dopamine "Dopamine").[\[206\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-GG-206)[\[207\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid12953623-207) However, serotonin in particular has been implicated, as in the serotonin hypothesis of depression.[\[208\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35854107-208) The monoamine hypothesis was originally proposed based on observations that [reserpine](https://en.wikipedia.org/wiki/Reserpine "Reserpine"), a drug which depletes the monoamine neurotransmitters, produced depressive effects in people,[\[207\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid12953623-207) and that certain [hydrazine](https://en.wikipedia.org/wiki/Hydrazine "Hydrazine") [antituberculosis agents](https://en.wikipedia.org/wiki/Antituberculosis_agent "Antituberculosis agent") like [iproniazid](https://en.wikipedia.org/wiki/Iproniazid "Iproniazid"), which [prevent the breakdown of monoamine neurotransmitters](https://en.wikipedia.org/wiki/Monoamine_oxidase_inhibitor "Monoamine oxidase inhibitor"), produced apparent antidepressant effects.[\[206\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-GG-206) Most currently marketed antidepressants, which are [monoaminergic](https://en.wikipedia.org/wiki/Monoaminergic "Monoaminergic") in their actions, are theoretically consistent with the monoamine hypothesis.[\[206\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-GG-206) Despite the widespread nature of the monoamine hypothesis, it has a number of limitations: for one, all monoaminergic antidepressants have a delayed onset of action of at least a week; and secondly, many people with depression do not respond to monoaminergic antidepressants.[\[209\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Infl-209)[\[210\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-glut-210)
In 2022, a major systematic [umbrella review](https://en.wikipedia.org/wiki/Umbrella_review "Umbrella review") by [Joanna Moncrieff](https://en.wikipedia.org/wiki/Joanna_Moncrieff "Joanna Moncrieff") and colleagues showed that the serotonin theory of depression was not supported by evidence from a wide variety of areas.[\[208\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35854107-208) The authors concluded that there is no association between serotonin and depression, and that there is no evidence that strongly supports the theory that depression is caused by low serotonin activity or concentrations.[\[208\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35854107-208) Other literature had described the lack of support for the theory previously.[\[107\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid16268734-107)[\[108\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-LacasseLeo2015-108)[\[110\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-AngHorowitzMoncrieff2022-110) In many of the expert responses to the review, it was stated that the monoamine hypothesis had already long been abandoned by psychiatry.[\[211\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-ScienceMediaCentre2022-211)[\[212\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-MadInAmerica2022-212) This is in spite of about 90% of the general public in Western countries believing the theory to be true and many in the field of psychiatry continuing to promote the theory up to recent times.[\[212\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-MadInAmerica2022-212)[\[110\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-AngHorowitzMoncrieff2022-110) In addition to the serotonin umbrella review, reviews have found that [reserpine](https://en.wikipedia.org/wiki/Reserpine "Reserpine"), a drug that depletes the monoamine neurotransmitters—including serotonin, norepinephrine, and dopamine—shows no consistent evidence of producing depressive effects.[\[207\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid12953623-207)[\[213\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid36000248-213) Instead, findings of reserpine and mood are highly mixed, with similar proportions of studies finding that it has no influence on mood, produces depressive effects, or actually has antidepressant effects.[\[213\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid36000248-213) In relation to this, the general monoamine hypothesis, as opposed to only the serotonin theory of depression, likewise does not appear to be well-supported by evidence.[\[207\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid12953623-207)[\[213\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid36000248-213)[\[110\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-AngHorowitzMoncrieff2022-110)
The serotonin and monoamine hypotheses of depression have been heavily promoted by the [pharmaceutical industry](https://en.wikipedia.org/wiki/Pharmaceutical_industry "Pharmaceutical industry") (e.g., in [advertisements](https://en.wikipedia.org/wiki/Advertisement "Advertisement")) and by the psychiatric profession at large despite the lack of evidence in support of them.[\[107\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid16268734-107)[\[108\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-LacasseLeo2015-108)[\[207\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid12953623-207)[\[214\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-LeoLacasse2007-214)[\[110\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-AngHorowitzMoncrieff2022-110)[\[109\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Lacasse2005-109) In the case of the pharmaceutical industry, this can be attributed to obvious financial incentives, with the theory creating a bias against [non-pharmacological treatments](https://en.wikipedia.org/wiki/Non-pharmacological_treatment "Non-pharmacological treatment") for depression.[\[109\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Lacasse2005-109)[\[107\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid16268734-107)[\[108\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-LacasseLeo2015-108)[\[207\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid12953623-207)
### Other biological theories
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=30 "Edit section: Other biological theories")\]
Besides the monoamine hypothesis, a number of alternative biological hypotheses of depression and antidepressant action have been proposed, including hypotheses involving [glutamate](https://en.wikipedia.org/wiki/Glutamate "Glutamate"), [neurogenesis](https://en.wikipedia.org/wiki/Neurogenesis "Neurogenesis"), [neuroplasticity](https://en.wikipedia.org/wiki/Neuroplasticity "Neuroplasticity"), [epigenetics](https://en.wikipedia.org/wiki/Epigenetics "Epigenetics"), [cortisol](https://en.wikipedia.org/wiki/Cortisol "Cortisol") [hypersecretion](https://en.wikipedia.org/wiki/Hypersecretion "Hypersecretion"), and [inflammation](https://en.wikipedia.org/wiki/Inflammation "Inflammation"), among others.[\[209\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Infl-209)[\[210\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-glut-210)[\[215\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Epig-215)[\[216\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Epig2-216)[\[179\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-SiegelListonNicol2026-179)
### Placebo mechanisms
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=31 "Edit section: Placebo mechanisms")\]
See also: [Placebo](https://en.wikipedia.org/wiki/Placebo "Placebo") and [Amplified placebo effect](https://en.wikipedia.org/wiki/Amplified_placebo_effect "Amplified placebo effect")
An alternative theory for antidepressant action proposed by certain academics such as [Irving Kirsch](https://en.wikipedia.org/wiki/Irving_Kirsch "Irving Kirsch") and [Joanna Moncrieff](https://en.wikipedia.org/wiki/Joanna_Moncrieff "Joanna Moncrieff") is that they work largely or entirely via [placebo](https://en.wikipedia.org/wiki/Placebo "Placebo") mechanisms.[\[44\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31249537-44)[\[103\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Kirsch2014-103)[\[217\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Kirsch2010-217)[\[218\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35100527-218) This is supported by meta-analyses of [randomized controlled trials](https://en.wikipedia.org/wiki/Randomized_controlled_trial "Randomized controlled trial") of antidepressants for depression, which consistently show that placebo groups in trials improve about 80 to 90% as much as antidepressant groups on average[\[44\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31249537-44)[\[219\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-HengartnerPl%C3%B6derl2018-219) and that antidepressants are only marginally more effective for depression than placebos.[\[98\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31248914-98)[\[91\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid32101579-91)[\[220\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid29477251-220)[\[85\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35918097-85)[\[86\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid30386270-86) The difference between antidepressants and placebo corresponds to an [effect size](https://en.wikipedia.org/wiki/Effect_size "Effect size") ([SMD](https://en.wikipedia.org/wiki/Standardized_mean_difference "Standardized mean difference")) of about 0.3, which in turn equates to about a 2- to 3-point additional improvement on the 0–52-point ([HRSD](https://en.wikipedia.org/wiki/Hamilton_Depression_Rating_Scale "Hamilton Depression Rating Scale")) and 0–60-point ([MADRS](https://en.wikipedia.org/wiki/Montgomery%E2%80%93%C3%85sberg_Depression_Rating_Scale "Montgomery–Åsberg Depression Rating Scale")) [depression rating scales](https://en.wikipedia.org/wiki/Depression_rating_scale "Depression rating scale") used in trials.[\[98\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31248914-98)[\[91\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid32101579-91)[\[220\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid29477251-220)[\[85\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35918097-85)[\[86\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid30386270-86) Differences in effectiveness between different antidepressants are small and not clinically meaningful.[\[221\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid36638223-221)[\[220\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid29477251-220) The small advantage of antidepressants over placebo is often [statistically significant](https://en.wikipedia.org/wiki/Statistically_significant "Statistically significant") and is the basis for their regulatory approval, but is sufficiently modest that its [clinical significance](https://en.wikipedia.org/wiki/Clinical_significance "Clinical significance") is doubtful.[\[89\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid25979317-89)[\[222\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid33593736-222)[\[91\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid32101579-91)[\[86\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid30386270-86) Moreover, the small advantage of antidepressants over placebo may simply be a [methodological artifact](https://en.wikipedia.org/wiki/Methodological_artifact "Methodological artifact") caused by [unblinding](https://en.wikipedia.org/wiki/Unblinding "Unblinding") due to the [psychoactive](https://en.wikipedia.org/wiki/Psychoactive "Psychoactive") effects and [side effects](https://en.wikipedia.org/wiki/Side_effect "Side effect") of antidepressants, in turn resulting in [amplified placebo effects](https://en.wikipedia.org/wiki/Amplified_placebo_effect "Amplified placebo effect") and apparent antidepressant efficacy.[\[44\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31249537-44)[\[86\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid30386270-86)[\[103\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Kirsch2014-103) Placebos have been found to modify the activity of several brain regions and to increase levels of dopamine and [endogenous](https://en.wikipedia.org/wiki/Endogenous "Endogenous") [opioids](https://en.wikipedia.org/wiki/Opioid "Opioid") in the [reward pathways](https://en.wikipedia.org/wiki/Reward_pathway "Reward pathway").[\[223\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35078210-223)[\[224\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid36006479-224)[\[225\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid15874901-225) It has been argued by Kirsch that although antidepressants may be used efficaciously for depression as [active placebos](https://en.wikipedia.org/wiki/Active_placebo "Active placebo"), they are limited by significant pharmacological [side effects](https://en.wikipedia.org/wiki/Side_effect "Side effect") and risks, and therefore [non-pharmacological therapies](https://en.wikipedia.org/wiki/Non-pharmaceutical_intervention "Non-pharmaceutical intervention"), such as [psychotherapy](https://en.wikipedia.org/wiki/Psychotherapy "Psychotherapy") and lifestyle changes, which can have similar efficacy to antidepressants but do not have their adverse effects, ought to be preferred as treatments in people with depression.[\[88\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31554608-88)
The [placebo response](https://en.wikipedia.org/wiki/Placebo_response "Placebo response"), or the improvement in scores in the placebo group in clinical trials, is not only due to the [placebo effect](https://en.wikipedia.org/wiki/Placebo_effect "Placebo effect"), but is also due to other phenomena such as [spontaneous remission](https://en.wikipedia.org/wiki/Spontaneous_remission "Spontaneous remission") and [regression to the mean](https://en.wikipedia.org/wiki/Regression_to_the_mean "Regression to the mean").[\[44\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31249537-44)[\[226\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid30975717-226) Depression tends to have an episodic course, with people eventually recovering even with no medical intervention, and people tend to seek treatment, as well as enroll in clinical trials, when they are feeling their worst.[\[102\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Hengartner2022-102)[\[226\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid30975717-226) In meta-analyses of trials of depression therapies, Kirsch estimated based on improvement in untreated waiting-list controls that spontaneous remission and regression to the mean only account for about 25% of the improvement in depression scores with antidepressant therapy.[\[44\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31249537-44)[\[227\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid22860015-227)[\[228\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-KirschSapirstein1998-228)[\[229\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid20170046-229)[\[102\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Hengartner2022-102) However, another academic, [Michael P. Hengartner](https://en.wikipedia.org/wiki/Michael_P._Hengartner "Michael P. Hengartner"), has argued and presented evidence that spontaneous remission and regression to the mean might actually account for most of the improvement in depression scores with antidepressants, and that the substantial placebo effect observed in clinical trials might largely be a methodological artifact.[\[226\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid30975717-226) This suggests that antidepressants may be associated with much less genuine treatment benefit, whether due to the placebo effect or to the antidepressant itself, than has been traditionally assumed.[\[226\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid30975717-226)
It has been proposed that [psychedelics](https://en.wikipedia.org/wiki/Psychedelic_drug "Psychedelic drug") used for therapeutic purposes may act as [active](https://en.wikipedia.org/wiki/Active_placebo "Active placebo") "super placebos".[\[230\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-DupuisVeissi%C3%A8re2022-230)[\[231\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-vanElkYaden2022-231) However, due to issues like the [inverse placebo effect](https://en.wikipedia.org/wiki/Inverse_placebo_effect "Inverse placebo effect") caused by unblinding, psychedelics may actually be no more effective than traditional antidepressants.[\[232\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-WilliamsBarnettSzigeti2026-232)[\[233\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-AnsariElliottHolmes2026-233)[\[234\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Hamzelou2026-234)[\[235\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Busby2026-235)
## Types
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=32 "Edit section: Types")\]
See also: [List of antidepressants](https://en.wikipedia.org/wiki/List_of_antidepressants "List of antidepressants")
### Selective serotonin reuptake inhibitors
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=33 "Edit section: Selective serotonin reuptake inhibitors")\]
[](https://en.wikipedia.org/wiki/File:Paroxetine-2D-skeletal.svg)
2D chemical structure of Paxil ([Paroxetine](https://en.wikipedia.org/wiki/Paroxetine "Paroxetine")), a [selective serotonin reuptake inhibitor](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor "Selective serotonin reuptake inhibitor")
[Selective serotonin reuptake inhibitors](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor "Selective serotonin reuptake inhibitor") (SSRIs) are believed to increase the [extracellular](https://en.wikipedia.org/wiki/Extracellular "Extracellular") level of the [neurotransmitter](https://en.wikipedia.org/wiki/Neurotransmitter "Neurotransmitter") serotonin by [limiting](https://en.wikipedia.org/wiki/Reuptake_inhibitor "Reuptake inhibitor") its [reabsorption](https://en.wikipedia.org/wiki/Reuptake "Reuptake") into the [presynaptic cell](https://en.wikipedia.org/wiki/Presynaptic_cell "Presynaptic cell"), increasing the level of [serotonin](https://en.wikipedia.org/wiki/Serotonin "Serotonin") in the [synaptic cleft](https://en.wikipedia.org/wiki/Synaptic_cleft "Synaptic cleft") available to bind to the [postsynaptic receptor](https://en.wikipedia.org/wiki/Postsynaptic_receptor "Postsynaptic receptor"). They have varying degrees of selectivity for the other [monoamine transporters](https://en.wikipedia.org/wiki/Monoamine_transporter "Monoamine transporter"), with pure SSRIs having only weak affinity for the [norepinephrine](https://en.wikipedia.org/wiki/Norepinephrine_transporter "Norepinephrine transporter") and [dopamine transporters](https://en.wikipedia.org/wiki/Dopamine_transporter "Dopamine transporter").
SSRIs are the most widely prescribed antidepressants in many countries.[\[236\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-PRESCORN2004-236) The efficacy of SSRIs in mild or moderate cases of depression has been disputed.[\[237\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-JAMA2010-237)[\[238\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Kramer-238)[\[239\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Pies-239)[\[240\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-240)
### Serotonin–norepinephrine reuptake inhibitors
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=34 "Edit section: Serotonin–norepinephrine reuptake inhibitors")\]
[](https://en.wikipedia.org/wiki/File:Venlafaxine-3D-balls.png)
The chemical structure of [venlafaxine](https://en.wikipedia.org/wiki/Venlafaxine "Venlafaxine") (Effexor), an [SNRI](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor")
[Serotonin–norepinephrine reuptake inhibitors](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") (SNRIs) are potent inhibitors of the [reuptake](https://en.wikipedia.org/wiki/Reuptake "Reuptake") of [serotonin](https://en.wikipedia.org/wiki/Serotonin "Serotonin") and [norepinephrine](https://en.wikipedia.org/wiki/Norepinephrine "Norepinephrine"). These [neurotransmitters](https://en.wikipedia.org/wiki/Neurotransmitter "Neurotransmitter") are known to play an important role in mood. SNRIs can be contrasted with the more widely used [selective serotonin reuptake inhibitors](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor "Selective serotonin reuptake inhibitor") (SSRIs), which act mostly upon serotonin alone.
The human [serotonin transporter](https://en.wikipedia.org/wiki/Serotonin_transporter "Serotonin transporter") (SERT) and [norepinephrine transporter](https://en.wikipedia.org/wiki/Norepinephrine_transporter "Norepinephrine transporter") (NET) are [membrane proteins](https://en.wikipedia.org/wiki/Membrane_protein "Membrane protein") that are responsible for the reuptake of serotonin and norepinephrine. Balanced dual inhibition of [monoamine](https://en.wikipedia.org/wiki/Monoamine "Monoamine") reuptake may offer advantages over other antidepressants drugs by treating a wider range of symptoms.[\[241\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid19740668-241)
SNRIs are sometimes also used to treat [anxiety disorders](https://en.wikipedia.org/wiki/Anxiety_disorder "Anxiety disorder"), [obsessive–compulsive disorder](https://en.wikipedia.org/wiki/Obsessive%E2%80%93compulsive_disorder "Obsessive–compulsive disorder") (OCD), [attention deficit hyperactivity disorder](https://en.wikipedia.org/wiki/Attention_deficit_hyperactivity_disorder "Attention deficit hyperactivity disorder") (ADHD), chronic [neuropathic pain](https://en.wikipedia.org/wiki/Neuropathic_pain "Neuropathic pain"), and [fibromyalgia syndrome](https://en.wikipedia.org/wiki/Fibromyalgia_syndrome "Fibromyalgia syndrome") (FMS), and for the relief of [menopausal](https://en.wikipedia.org/wiki/Menopause "Menopause") symptoms.
### Serotonin modulators and stimulators
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=35 "Edit section: Serotonin modulators and stimulators")\]
[Serotonin modulator and stimulators](https://en.wikipedia.org/wiki/Serotonin_modulator_and_stimulator "Serotonin modulator and stimulator") (SMSs), sometimes referred to more simply as "[serotonin](https://en.wikipedia.org/wiki/Serotonin "Serotonin") modulators", are a type of [drug](https://en.wikipedia.org/wiki/Drug "Drug") with a multimodal action specific to the serotonin [neurotransmitter](https://en.wikipedia.org/wiki/Neurotransmitter "Neurotransmitter") system. To be precise, SMSs simultaneously modulate one or more [serotonin receptors](https://en.wikipedia.org/wiki/Serotonin_receptor "Serotonin receptor") and inhibit the [reuptake](https://en.wikipedia.org/wiki/Reuptake "Reuptake") of serotonin. The term was coined in reference to the [mechanism of action](https://en.wikipedia.org/wiki/Mechanism_of_action "Mechanism of action") of the serotonergic antidepressant [vortioxetine](https://en.wikipedia.org/wiki/Vortioxetine "Vortioxetine"), which acts as a [serotonin reuptake inhibitor](https://en.wikipedia.org/wiki/Serotonin_reuptake_inhibitor "Serotonin reuptake inhibitor") (SRI), a [partial agonist](https://en.wikipedia.org/wiki/Partial_agonist "Partial agonist") of the [5-HT1A receptor](https://en.wikipedia.org/wiki/5-HT1A_receptor "5-HT1A receptor"), and [antagonist](https://en.wikipedia.org/wiki/Receptor_antagonist "Receptor antagonist") of the [5-HT3](https://en.wikipedia.org/wiki/5-HT3_receptor "5-HT3 receptor") and [5-HT7 receptors](https://en.wikipedia.org/wiki/5-HT7_receptor "5-HT7 receptor").[\[242\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid24391391-242)[\[243\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-AmerPharmAssoc2013-243)[\[244\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-LATimes2013-244) However, it can also technically be applied to [vilazodone](https://en.wikipedia.org/wiki/Vilazodone "Vilazodone"), which is an antidepressant as well and acts as an SRI and 5-HT1A receptor partial agonist.[\[245\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid15740724-245)
An alternative term is serotonin partial agonist/reuptake inhibitor (SPARI), which can be applied only to vilazodone.[\[246\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-246)
### Serotonin antagonists and reuptake inhibitors
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=36 "Edit section: Serotonin antagonists and reuptake inhibitors")\]
[Serotonin antagonist and reuptake inhibitors](https://en.wikipedia.org/wiki/Serotonin_antagonist_and_reuptake_inhibitors "Serotonin antagonist and reuptake inhibitors") (SARIs) while mainly used as antidepressants are also [anxiolytics](https://en.wikipedia.org/wiki/Anxiolytic "Anxiolytic") and [hypnotics](https://en.wikipedia.org/wiki/Hypnotic "Hypnotic"). They act by [antagonizing](https://en.wikipedia.org/wiki/Receptor_antagonist "Receptor antagonist") [serotonin receptors](https://en.wikipedia.org/wiki/Serotonin_receptor "Serotonin receptor") such as [5-HT2A](https://en.wikipedia.org/wiki/5-HT2A_receptor "5-HT2A receptor") and [inhibiting](https://en.wikipedia.org/wiki/Reuptake_inhibitor "Reuptake inhibitor") the [reuptake](https://en.wikipedia.org/wiki/Reuptake "Reuptake") of [serotonin](https://en.wikipedia.org/wiki/Serotonin "Serotonin"), [norepinephrine](https://en.wikipedia.org/wiki/Norepinephrine "Norepinephrine"), and/or [dopamine](https://en.wikipedia.org/wiki/Dopamine "Dopamine"). Additionally, most also act as [α1\-adrenergic receptor](https://en.wikipedia.org/wiki/Alpha-1_adrenergic_receptor "Alpha-1 adrenergic receptor") antagonists. The majority of the currently marketed SARIs belong to the [phenylpiperazine](https://en.wikipedia.org/wiki/Phenylpiperazine "Phenylpiperazine") class of compounds. They include [trazodone](https://en.wikipedia.org/wiki/Trazodone "Trazodone") and [nefazodone](https://en.wikipedia.org/wiki/Nefazodone "Nefazodone").
### Tricyclic antidepressants
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=37 "Edit section: Tricyclic antidepressants")\]
The majority of the [tricyclic antidepressants](https://en.wikipedia.org/wiki/Tricyclic_antidepressant "Tricyclic antidepressant") (TCAs) act primarily as [serotonin–norepinephrine reuptake inhibitors](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") (SNRIs) by blocking the [serotonin transporter](https://en.wikipedia.org/wiki/Serotonin_transporter "Serotonin transporter") (SERT) and the [norepinephrine transporter](https://en.wikipedia.org/wiki/Norepinephrine_transporter "Norepinephrine transporter") (NET), respectively, which results in an elevation of the [synaptic](https://en.wikipedia.org/wiki/Synapse "Synapse") concentrations of these [neurotransmitters](https://en.wikipedia.org/wiki/Neurotransmitter "Neurotransmitter"), and therefore an enhancement of [neurotransmission](https://en.wikipedia.org/wiki/Neurotransmission "Neurotransmission").[\[247\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid9537821-247)[\[248\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid17471183-248) Notably, with the sole exception of [amineptine](https://en.wikipedia.org/wiki/Amineptine "Amineptine"), the TCAs have weak [affinity](https://en.wikipedia.org/wiki/Affinity_\(pharmacology\) "Affinity (pharmacology)") for the [dopamine transporter](https://en.wikipedia.org/wiki/Dopamine_transporter "Dopamine transporter") (DAT), and therefore have low efficacy as [dopamine reuptake inhibitors](https://en.wikipedia.org/wiki/Dopamine_reuptake_inhibitor "Dopamine reuptake inhibitor") (DRIs).[\[247\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid9537821-247)
Although TCAs are sometimes [prescribed](https://en.wikipedia.org/wiki/Medical_prescription "Medical prescription") for depressive disorders, they have been largely replaced in clinical use in most parts of the world by newer antidepressants such as [selective serotonin reuptake inhibitors](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor "Selective serotonin reuptake inhibitor") (SSRIs), [serotonin–norepinephrine reuptake inhibitors](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") (SNRIs), and [norepinephrine reuptake inhibitors](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitor "Norepinephrine reuptake inhibitor") (NRIs). Adverse effects have been found to be of a similar level between TCAs and SSRIs.[\[249\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-249)
### Tetracyclic antidepressants
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=38 "Edit section: Tetracyclic antidepressants")\]
[Tetracyclic antidepressants](https://en.wikipedia.org/wiki/Tetracyclic_antidepressants "Tetracyclic antidepressants") (TeCAs) are a class of antidepressants that were first introduced in the 1970s. They are named after their [chemical structure](https://en.wikipedia.org/wiki/Chemical_structure "Chemical structure"), which contains four [rings of atoms](https://en.wikipedia.org/wiki/Cyclic_compound "Cyclic compound"), and are closely related to [tricyclic antidepressants](https://en.wikipedia.org/wiki/Tricyclic_antidepressant "Tricyclic antidepressant") (TCAs), which contain three rings of atoms.
### Monoamine oxidase inhibitors
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=39 "Edit section: Monoamine oxidase inhibitors")\]
[Monoamine oxidase inhibitors](https://en.wikipedia.org/wiki/Monoamine_oxidase_inhibitor "Monoamine oxidase inhibitor") (MAOIs) are chemicals that inhibit the activity of the [monoamine oxidase enzyme family](https://en.wikipedia.org/wiki/Monoamine_oxidase "Monoamine oxidase"). They have a long history of use as medications prescribed for the treatment of [depression](https://en.wikipedia.org/wiki/Clinical_depression "Clinical depression"). They are particularly effective in treating [atypical depression](https://en.wikipedia.org/wiki/Atypical_depression "Atypical depression").[\[250\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-250) They are also used in the treatment of [Parkinson's disease](https://en.wikipedia.org/wiki/Parkinson%27s_disease "Parkinson's disease") and several other disorders.
Because of potentially lethal dietary and drug interactions, MAOIs have historically been reserved as a last line of treatment, used only when other classes of antidepressant drugs (for example [selective serotonin reuptake inhibitors](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor "Selective serotonin reuptake inhibitor") and [tricyclic antidepressants](https://en.wikipedia.org/wiki/Tricyclic_antidepressant "Tricyclic antidepressant")) have failed.[\[251\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-251)
MAOIs have been found to be effective in the treatment of [panic disorder](https://en.wikipedia.org/wiki/Panic_disorder "Panic disorder") with [agoraphobia](https://en.wikipedia.org/wiki/Agoraphobia "Agoraphobia"),[\[252\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-252) [social phobia](https://en.wikipedia.org/wiki/Social_phobia "Social phobia"),[\[253\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-253)[\[254\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-254)[\[255\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-255) atypical depression[\[256\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-256)[\[257\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-257) or mixed anxiety and depression, [bulimia](https://en.wikipedia.org/wiki/Bulimia "Bulimia"),[\[258\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-258)[\[259\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-259)[\[260\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-260)[\[261\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-261) and [post-traumatic stress disorder](https://en.wikipedia.org/wiki/Post-traumatic_stress_disorder "Post-traumatic stress disorder"),[\[262\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-262) as well as [borderline personality disorder](https://en.wikipedia.org/wiki/Borderline_personality_disorder "Borderline personality disorder").[\[263\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-263) MAOIs appear to be particularly effective in the management of [bipolar depression](https://en.wikipedia.org/wiki/Bipolar_disorder "Bipolar disorder") according to a retrospective-analysis.[\[264\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-264) There are reports of MAOI efficacy in [obsessive–compulsive disorder](https://en.wikipedia.org/wiki/Obsessive%E2%80%93compulsive_disorder "Obsessive–compulsive disorder") (OCD), [trichotillomania](https://en.wikipedia.org/wiki/Trichotillomania "Trichotillomania"), [dysmorphophobia](https://en.wikipedia.org/wiki/Dysmorphophobia "Dysmorphophobia"), and [avoidant personality disorder](https://en.wikipedia.org/wiki/Avoidant_personality_disorder "Avoidant personality disorder"), but these reports are from uncontrolled case reports.[\[265\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid2248064-265)
MAOIs can also be used in the treatment of Parkinson's disease by targeting MAO-B in particular (therefore affecting [dopaminergic neurons](https://en.wikipedia.org/wiki/Dopaminergic_neuron "Dopaminergic neuron")), as well as providing an alternative for [migraine](https://en.wikipedia.org/wiki/Migraine "Migraine") [prophylaxis](https://en.wikipedia.org/wiki/Prophylaxis "Prophylaxis"). Inhibition of both MAO-A and MAO-B is used in the treatment of [clinical depression](https://en.wikipedia.org/wiki/Clinical_depression "Clinical depression") and [anxiety disorders](https://en.wikipedia.org/wiki/Anxiety_disorder "Anxiety disorder").
### NMDA receptor antagonists
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=40 "Edit section: NMDA receptor antagonists")\]
[NMDA receptor antagonists](https://en.wikipedia.org/wiki/NMDA_receptor_antagonist "NMDA receptor antagonist") like [ketamine](https://en.wikipedia.org/wiki/Ketamine "Ketamine") and [esketamine](https://en.wikipedia.org/wiki/Esketamine "Esketamine") are [rapid-acting antidepressants](https://en.wikipedia.org/wiki/Rapid-acting_antidepressant "Rapid-acting antidepressant") and seem to work via [blockade](https://en.wikipedia.org/wiki/Receptor_antagonist "Receptor antagonist") of the [ionotropic glutamate](https://en.wikipedia.org/wiki/Ionotropic_glutamate_receptor "Ionotropic glutamate receptor") [NMDA receptor](https://en.wikipedia.org/wiki/NMDA_receptor "NMDA receptor").[\[266\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-SpravatoLabel-266) Other NMDA antagonists may also play a role in treating depression. The combination medication [dextromethorphan/bupropion](https://en.wikipedia.org/wiki/Dextromethorphan/bupropion "Dextromethorphan/bupropion") (Auvelity), which contains the NMDA receptor antagonist [dextromethorphan](https://en.wikipedia.org/wiki/Dextromethorphan "Dextromethorphan"), was approved in the United States in 2022 for treating major depressive disorder.[\[267\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid36301443-267)[\[268\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid36943010-268)
### Others
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=41 "Edit section: Others")\]
See the [list of antidepressants](https://en.wikipedia.org/wiki/List_of_antidepressants "List of antidepressants") and [management of depression](https://en.wikipedia.org/wiki/Management_of_depression "Management of depression") for other drugs that are not specifically characterized.
## Adjuncts
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=42 "Edit section: Adjuncts")\]
Adjunct medications are an umbrella category of substances that increase the potency or "enhance" antidepressants.[\[269\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-269) They work by affecting variables very close to the antidepressant, sometimes affecting a completely different [mechanism of action](https://en.wikipedia.org/wiki/Mechanism_of_action "Mechanism of action"). This may be attempted when depression treatments have not been successful in the past.
Common types of adjunct medication techniques generally fall into the following categories:
- Two or more antidepressants taken together, from either the same or different classes (affecting the same area of the brain, often at a much higher level).
- An [antipsychotic](https://en.wikipedia.org/wiki/Antipsychotic "Antipsychotic") combined with an antidepressant, particularly [atypical antipsychotics](https://en.wikipedia.org/wiki/Atypical_antipsychotic "Atypical antipsychotic") such as [aripiprazole](https://en.wikipedia.org/wiki/Aripiprazole "Aripiprazole") (Abilify), [quetiapine](https://en.wikipedia.org/wiki/Quetiapine "Quetiapine") (Seroquel), [olanzapine](https://en.wikipedia.org/wiki/Olanzapine "Olanzapine") (Zyprexa), and [risperidone](https://en.wikipedia.org/wiki/Risperidone "Risperidone") (Risperdal).[\[270\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Maudsley-270)
It is unknown if undergoing [psychological therapy](https://en.wikipedia.org/wiki/Psychological_therapy "Psychological therapy") at the same time as taking anti-depressants enhances the anti-depressive effect of the medication.[\[271\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-271)
### Less common adjuncts
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=43 "Edit section: Less common adjuncts")\]
[Lithium](https://en.wikipedia.org/wiki/Lithium_\(medication\) "Lithium (medication)") has been used to augment antidepressant therapy in those who have failed to respond to antidepressants alone.[\[272\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid10505584-272) Furthermore, Lithium dramatically decreases the suicide risk in recurrent depression.[\[273\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid17388706-273) In addition to reducing the risk of suicide, lithium also reduces the risk of death from all causes in people with mood disorders.[\[274\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-274) There is some evidence for the addition of a thyroid hormone, [triiodothyronine](https://en.wikipedia.org/wiki/Triiodothyronine "Triiodothyronine"), in patients with normal thyroid function.[\[275\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid16946176-275)
Psychopharmacologists have also tried adding a [stimulant](https://en.wikipedia.org/wiki/Psychostimulant "Psychostimulant"), in particular, [D-amphetamine](https://en.wikipedia.org/wiki/D-amphetamine "D-amphetamine").[\[276\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-276) However, the use of stimulants in cases of treatment-resistant depression is relatively controversial.[\[277\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid1411740-277)[\[278\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid17338594-278) A review article published in 2007 found psychostimulants may be effective in treatment-resistant depression with concomitant antidepressant therapy, but a more certain conclusion could not be drawn due to substantial deficiencies in the studies available for consideration, and the somewhat contradictory nature of their results.[\[278\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid17338594-278)
## History
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=44 "Edit section: History")\]
See also: [Discovery and development of dual serotonin and norepinephrine reuptake inhibitors](https://en.wikipedia.org/wiki/Discovery_and_development_of_dual_serotonin_and_norepinephrine_reuptake_inhibitors "Discovery and development of dual serotonin and norepinephrine reuptake inhibitors")
[](https://en.wikipedia.org/wiki/File:Saint_John%27s_wort_flowers.jpg)
[St John's wort](https://en.wikipedia.org/wiki/Hypericum_perforatum "Hypericum perforatum")
The idea of an antidepressant, if [melancholy](https://en.wikipedia.org/wiki/Melancholia "Melancholia") is thought synonymous with depression, existed at least as early as the 1599 pamphlet *A pil to purge melancholie or, A preparative to a pvrgation: or, Topping, copping, and capping: take either or whether: or, Mash them, and squash them, and dash them, and diddle come derrie come daw them, all together..*. [Thomas d'Urfey](https://en.wikipedia.org/wiki/Thomas_d%27Urfey "Thomas d'Urfey")'s *Wit and Mirth: Or [Pills to Purge Melancholy](https://en.wikipedia.org/wiki/Pills_to_Purge_Melancholy "Pills to Purge Melancholy")*, the title of a large collection of songs, was published between 1698 and 1720.
Before the 1950s, [opioids](https://en.wikipedia.org/wiki/Opioid "Opioid") and [amphetamines](https://en.wikipedia.org/wiki/Amphetamine-type_stimulant "Amphetamine-type stimulant") were commonly used as antidepressants.[\[279\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Weber_1988_255%E2%80%9366-279)[\[280\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Amph_Uses_Dex-280)[\[198\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Rasmussen2006-198) [Amphetamine](https://en.wikipedia.org/wiki/Amphetamine "Amphetamine") has been described as the first antidepressant.[\[198\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Rasmussen2006-198) Use of opioids and amphetamines for depression was later restricted due to their addictive nature and side effects.[\[279\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Weber_1988_255%E2%80%9366-279)[\[198\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Rasmussen2006-198) Extracts from the herb [St John's wort](https://en.wikipedia.org/wiki/Hypericum_perforatum "Hypericum perforatum") have been used as a "nerve tonic" to alleviate depression.[\[281\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-281)
[St John's wort](https://en.wikipedia.org/wiki/Hypericum_perforatum "Hypericum perforatum") fell out of favor in most countries through the 19th and 20th centuries, except in [Germany](https://en.wikipedia.org/wiki/Germany "Germany"), where *[Hypericum](https://en.wikipedia.org/wiki/Hypericum "Hypericum")* extracts were eventually licensed, packaged, and prescribed. Small-scale efficacy trials were carried out in the 1970s and 1980s, and attention grew in the 1990s following a [meta-analysis](https://en.wikipedia.org/wiki/Meta-analysis "Meta-analysis").[\[282\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-282) It remains an [over-the-counter](https://en.wikipedia.org/wiki/Over-the-counter_drug "Over-the-counter drug") (OTC) supplement in most countries. Lead contamination associated with its usage has been seen as concerning, as lead levels in women in the United States taking St. John's wort are elevated by about 20% on average.[\[283\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-LeadInHerbs-283) Research continues to investigate its active component [hyperforin](https://en.wikipedia.org/wiki/Hyperforin "Hyperforin"), and to further understand its mode of action.[\[284\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-284)[\[285\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-285)
### Isoniazid, iproniazid, and imipramine
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=45 "Edit section: Isoniazid, iproniazid, and imipramine")\]
In 1951, [Irving Selikoff](https://en.wikipedia.org/wiki/Irving_Selikoff "Irving Selikoff") and Edward H. Robitzek, working out of [Sea View Hospital](https://en.wikipedia.org/wiki/Sea_View_Hospital "Sea View Hospital") on [Staten Island](https://en.wikipedia.org/wiki/Staten_Island "Staten Island"), began clinical trials on two new [anti-tuberculosis](https://en.wikipedia.org/wiki/Tuberculosis "Tuberculosis") agents developed by Hoffman-LaRoche, [isoniazid](https://en.wikipedia.org/wiki/Isoniazid "Isoniazid"), and [iproniazid](https://en.wikipedia.org/wiki/Iproniazid "Iproniazid"). Only patients with a poor [prognosis](https://en.wikipedia.org/wiki/Prognosis "Prognosis") were initially treated. Nevertheless, their condition improved dramatically. Selikoff and Robitzek noted "a subtle general stimulation ... the patients exhibited renewed vigor and indeed this occasionally served to introduce disciplinary problems."[\[286\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid14906149-286) The promise of a cure for tuberculosis in the Sea View Hospital trials was excitedly discussed in the mainstream press.
In 1952, learning of the stimulating side effects of isoniazid, the Cincinnati psychiatrist Max Lurie tried it on his patients. In the following year, he and Harry Salzer reported that isoniazid improved depression in two-thirds of their patients, so they then coined the term *antidepressant* to refer to its action.[\[287\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-isbn0-88048-397-0-287) A similar incident took place in Paris, where [Jean Delay](https://en.wikipedia.org/wiki/Jean_Delay "Jean Delay"), head of psychiatry at Sainte-Anne Hospital, heard of this effect from his [pulmonology](https://en.wikipedia.org/wiki/Pulmonology "Pulmonology") colleagues at Cochin Hospital. In 1952 (before Lurie and Salzer), Delay, with the resident Jean-Francois Buisson, reported the positive effect of isoniazid on depressed patients.[\[288\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Healy96-288) The mode of antidepressant action of isoniazid is still unclear. It is speculated that its effect is due to the inhibition of [diamine oxidase](https://en.wikipedia.org/wiki/Diamine_oxidase "Diamine oxidase"), coupled with a weak inhibition of [monoamine oxidase A](https://en.wikipedia.org/wiki/Monoamine_oxidase_A "Monoamine oxidase A").[\[289\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-isbn1-86036-010-6-289)
Selikoff and Robitzek also experimented with another anti-tuberculosis drug, [iproniazid](https://en.wikipedia.org/wiki/Iproniazid "Iproniazid"); it showed a greater psychostimulant effect, but more pronounced toxicity.[\[290\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid12998444-290) Later, Jackson Smith, Gordon Kamman, George E. Crane, and [Frank Ayd](https://en.wikipedia.org/wiki/Frank_Ayd "Frank Ayd"), described the psychiatric applications of iproniazid. [Ernst Zeller](https://en.wikipedia.org/w/index.php?title=Ernst_Zeller&action=edit&redlink=1 "Ernst Zeller (page does not exist)") found iproniazid to be a potent [monoamine oxidase inhibitor](https://en.wikipedia.org/wiki/Monoamine_oxidase_inhibitor "Monoamine oxidase inhibitor").[\[291\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid18004120-291) Nevertheless, iproniazid remained relatively obscure until [Nathan S. Kline](https://en.wikipedia.org/wiki/Nathan_S._Kline "Nathan S. Kline"), the influential head of research at [Rockland State Hospital](https://en.wikipedia.org/wiki/Rockland_State_Hospital "Rockland State Hospital"), began to popularize it in the medical and popular press as a "psychic energizer".[\[291\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid18004120-291)[\[292\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-292) Roche put a significant marketing effort behind iproniazid.[\[291\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid18004120-291) Its sales grew until it was recalled in 1961, due to reports of lethal [hepatotoxicity](https://en.wikipedia.org/wiki/Hepatotoxicity "Hepatotoxicity").[\[291\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid18004120-291)
The antidepressant effect of a [tricyclic antidepressant](https://en.wikipedia.org/wiki/Tricyclic_antidepressant "Tricyclic antidepressant"), a three-ringed compound, was first discovered in 1957 by [Roland Kuhn](https://en.wikipedia.org/wiki/Roland_Kuhn "Roland Kuhn") in a Swiss [psychiatric hospital](https://en.wikipedia.org/wiki/Psychiatric_hospital "Psychiatric hospital"). [Antihistamine](https://en.wikipedia.org/wiki/Antihistamine "Antihistamine") derivatives were used to treat surgical shock and later as [neuroleptics](https://en.wikipedia.org/wiki/Neuroleptics "Neuroleptics"). Although in 1955, [reserpine](https://en.wikipedia.org/wiki/Reserpine "Reserpine") was shown to be more effective than a placebo in alleviating anxious depression, neuroleptics were being developed as [sedatives](https://en.wikipedia.org/wiki/Sedative "Sedative") and [antipsychotics](https://en.wikipedia.org/wiki/Antipsychotic "Antipsychotic").\[*[medical citation needed](https://en.wikipedia.org/wiki/Wikipedia:Identifying_reliable_sources_\(medicine\) "Wikipedia:Identifying reliable sources (medicine)")*\]
Attempting to improve the effectiveness of [chlorpromazine](https://en.wikipedia.org/wiki/Chlorpromazine "Chlorpromazine"), Kuhn — in conjunction with the [Geigy](https://en.wikipedia.org/wiki/Geigy "Geigy") Pharmaceutical Company — discovered the compound "G 22355", later renamed [imipramine](https://en.wikipedia.org/wiki/Imipramine "Imipramine"). Imipramine had a beneficial effect on patients with depression who showed mental and [motor retardation](https://en.wikipedia.org/wiki/Motor_retardation "Motor retardation"). Kuhn described his new compound as a "thymoleptic" "taking hold of the emotions," in contrast with neuroleptics, "taking hold of the nerves" in 1955–56. These gradually became established, resulting in the patent and manufacture in the US in 1951 by Häfliger and SchinderA.[\[293\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-293)
Antidepressants became [prescription drugs](https://en.wikipedia.org/wiki/Prescription_drug "Prescription drug") in the 1950s. It was estimated that no more than fifty to one hundred individuals per million had the kind of depression that these new drugs would treat, and pharmaceutical companies were not enthusiastic about marketing for this small market. Sales through the 1960s remained poor compared to the sales of tranquilizers,[\[294\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-294)\[*[unreliable medical source?](https://en.wikipedia.org/wiki/Wikipedia:Identifying_reliable_sources_\(medicine\) "Wikipedia:Identifying reliable sources (medicine)")*\] which were being marketed for different uses.[\[295\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-3faces-295) Imipramine remained in common use and numerous successors were introduced. The use of monoamine oxidase inhibitors (MAOI) increased after the development and introduction of "reversible" forms affecting only the MAO-A subtype of inhibitors, making this drug safer to use.[\[295\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-3faces-295)[\[296\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-296)
By the 1960s, it was thought that the mode of action of tricyclics was to inhibit norepinephrine reuptake. However, norepinephrine reuptake became associated with stimulating effects. Later tricyclics were thought to affect [serotonin](https://en.wikipedia.org/wiki/Serotonin "Serotonin") as proposed in 1969 by Carlsson and Lindqvist as well as Lapin and Oxenkrug.\[*[medical citation needed](https://en.wikipedia.org/wiki/Wikipedia:Identifying_reliable_sources_\(medicine\) "Wikipedia:Identifying reliable sources (medicine)")*\]
### Second-generation antidepressants
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=46 "Edit section: Second-generation antidepressants")\]
Main article: [Second-generation antidepressants](https://en.wikipedia.org/wiki/Second-generation_antidepressants "Second-generation antidepressants")
Researchers began a process of [rational drug design](https://en.wikipedia.org/wiki/Rational_drug_design "Rational drug design") to isolate antihistamine-derived compounds that would selectively target these systems. The first such compound to be patented was [zimelidine](https://en.wikipedia.org/wiki/Zimelidine "Zimelidine") in 1971, while the first released clinically was [indalpine](https://en.wikipedia.org/wiki/Indalpine "Indalpine"). [Fluoxetine](https://en.wikipedia.org/wiki/Fluoxetine "Fluoxetine") was approved for commercial use by the US [Food and Drug Administration](https://en.wikipedia.org/wiki/Food_and_Drug_Administration "Food and Drug Administration") (FDA) in 1988, becoming the first [blockbuster](https://en.wikipedia.org/wiki/Blockbuster_drug "Blockbuster drug") SSRI. Fluoxetine was developed at [Eli Lilly and Company](https://en.wikipedia.org/wiki/Eli_Lilly_and_Company "Eli Lilly and Company") in the early 1970s by [Bryan Molloy](https://en.wikipedia.org/wiki/Bryan_Molloy "Bryan Molloy"), [Klaus Schmiegel](https://en.wikipedia.org/wiki/Klaus_Schmiegel "Klaus Schmiegel"), [David T. Wong](https://en.wikipedia.org/wiki/David_T._Wong "David T. Wong"), and others.[\[297\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-297)[\[298\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-298) SSRIs became known as "novel antidepressants" along with other newer drugs such as SNRIs and [NRIs](https://en.wikipedia.org/wiki/Norepinephrine_Reuptake_Inhibitor "Norepinephrine Reuptake Inhibitor") with various selective effects.[\[299\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-299)
### Rapid-acting antidepressants
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=47 "Edit section: Rapid-acting antidepressants")\]
[Esketamine](https://en.wikipedia.org/wiki/Esketamine "Esketamine") (brand name Spravato), the first rapid-acting antidepressant to be approved for clinical treatment of depression, was introduced for this indication in March 2019 in the United States.[\[266\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-SpravatoLabel-266)
#### Research
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=48 "Edit section: Research")\]
A 2016 [randomized controlled trial](https://en.wikipedia.org/wiki/Randomized_controlled_trial "Randomized controlled trial") evaluated the [rapid antidepressant](https://en.wikipedia.org/wiki/Antidepressant#Rapid-acting_antidepressants) effects of the psychedelic [Ayahuasca](https://en.wikipedia.org/wiki/Ayahuasca "Ayahuasca") in treatment-resistant depression with a positive outcome.[\[300\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-300)[\[301\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-301) In 2018, the FDA granted Breakthrough Therapy Designation for [psilocybin](https://en.wikipedia.org/wiki/Psilocybin "Psilocybin")\-assisted therapy for treatment-resistant depression and in 2019, the FDA granted Breakthrough Therapy Designation for psilocybin therapy treating major depressive disorder.[\[302\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-302)
### Publication bias and aged research
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=49 "Edit section: Publication bias and aged research")\]
A 2018 systematic review published in [The Lancet](https://en.wikipedia.org/wiki/The_Lancet "The Lancet") comparing the efficacy of 21 different first and second generation antidepressants found that antidepressant drugs tended to perform better and cause less adverse events when they were novel or experimental treatments compared to when they were evaluated again years later.[\[36\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Zhou-2020-36) Unpublished data was also associated with smaller positive effect sizes. However, the review did not find evidence of bias associated with industry funded research.
## Society and culture
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=50 "Edit section: Society and culture")\]
### Prescription trends
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=51 "Edit section: Prescription trends")\]
#### United Kingdom
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=52 "Edit section: United Kingdom")\]
In the UK, figures reported in 2010 indicated that the number of antidepressants prescribed by the [National Health Service](https://en.wikipedia.org/wiki/National_Health_Service "National Health Service") (NHS) almost doubled over a decade.[\[303\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-303) Further analysis published in 2014 showed that number of antidepressants dispensed annually in the community went up by 25 million in the 14 years between 1998 and 2012, rising from 15 million to 40 million. Nearly 50% of this rise occurred in the four years after the [Great Recession](https://en.wikipedia.org/wiki/Great_Recession "Great Recession"), during which time the annual increase in prescriptions rose from 6.7% to 8.5%.[\[304\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-304) These sources also suggest that aside from the recession, other factors that may influence changes in prescribing rates may include: improvements in diagnosis, a reduction of the [stigma](https://en.wikipedia.org/wiki/Social_stigma "Social stigma") surrounding mental health, broader prescribing trends, GP characteristics, geographical location, and housing status. Another factor that may contribute to increasing consumption of antidepressants is the fact that these medications now are used for other conditions including [social anxiety](https://en.wikipedia.org/wiki/Social_anxiety "Social anxiety") and [post-traumatic stress disorder](https://en.wikipedia.org/wiki/Post-traumatic_stress_disorder "Post-traumatic stress disorder").
Between 2005 and 2017, the number of adolescents (12 to 17 years) in England who were prescribed antidepressants has doubled. On the other hand, antidepressant prescriptions for children aged 5–11 in England decreased between 1999 and 2017.[\[305\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-305)[\[306\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-306) From April 2015, prescriptions increased for both age groups (for people aged 0 to 17) and peaked during the first COVID lockdown in March 2020.[\[307\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-307)
According to [National Institute for Health and Care Excellence](https://en.wikipedia.org/wiki/National_Institute_for_Health_and_Care_Excellence "National Institute for Health and Care Excellence") (NICE) guidelines, antidepressants for children and adolescents with depression and obsessive-compulsive disorder (OCD) should be prescribed together with therapy and after being assessed by a [child and adolescent psychiatrist](https://en.wikipedia.org/wiki/Child_and_adolescent_psychiatry "Child and adolescent psychiatry"). However, between 2006 and 2017, only 1 in 4 of 12–17 year-olds who were prescribed an SSRI by their GP had seen a specialist psychiatrist and 1 in 6 has seen a pediatrician. Half of these prescriptions were for depression and 16% for anxiety, the latter not being licensed for treatment with antidepressants.[\[42\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NIHR-2022-42)[\[308\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-308) Among the suggested possible reasons why GPs are not following the guidelines are the difficulties of accessing talking therapies, long waiting lists, and the urgency of treatment.[\[42\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NIHR-2022-42)[\[309\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-309) According to some researchers, strict adherence to treatment guidelines would limit access to effective medication for young people with mental health problems.[\[310\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-310)
#### United States
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=53 "Edit section: United States")\]
In the United States, antidepressants were the most commonly prescribed medication in 2013.[\[311\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-AJantidepressantstatsUS-311) Of the estimated 16 million "long term" (over 24 months) users, roughly 70 percent are female.[\[311\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-AJantidepressantstatsUS-311) As of 2017[\[update\]](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit), about 16.5% of white people in the United States took antidepressants compared with 5.6% of black people in the United States.[\[312\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-APP2017-312)
Structural formula of the SSRI [sertraline](https://en.wikipedia.org/wiki/Sertraline "Sertraline")
**United States:** The most commonly prescribed antidepressants in the US retail market in 2010 were:[\[313\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-313)
| **Drug name** | **Drug class** | **Total prescriptions** |
|---|---|---|
| [Sertraline](https://en.wikipedia.org/wiki/Sertraline "Sertraline") | [SSRI](https://en.wikipedia.org/wiki/SSRI "SSRI") | 33,409,838 |
| [Citalopram](https://en.wikipedia.org/wiki/Citalopram "Citalopram") | [SSRI](https://en.wikipedia.org/wiki/SSRI "SSRI") | 27,993,635 |
| [Fluoxetine](https://en.wikipedia.org/wiki/Fluoxetine "Fluoxetine") | [SSRI](https://en.wikipedia.org/wiki/SSRI "SSRI") | 24,473,994 |
| [Escitalopram](https://en.wikipedia.org/wiki/Escitalopram "Escitalopram") | [SSRI](https://en.wikipedia.org/wiki/SSRI "SSRI") | 23,000,456 |
| [Trazodone](https://en.wikipedia.org/wiki/Trazodone "Trazodone") | [SARI](https://en.wikipedia.org/wiki/Serotonin_antagonist_and_reuptake_inhibitor "Serotonin antagonist and reuptake inhibitor") | 18,786,495 |
| [Venlafaxine](https://en.wikipedia.org/wiki/Venlafaxine "Venlafaxine") (all formulations) | [SNRI](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") | 16,110,606 |
| [Bupropion](https://en.wikipedia.org/wiki/Bupropion "Bupropion") (all formulations) | [NDRI](https://en.wikipedia.org/wiki/Norepinephrine%E2%80%93dopamine_reuptake_inhibitor "Norepinephrine–dopamine reuptake inhibitor") | 15,792,653 |
| [Duloxetine](https://en.wikipedia.org/wiki/Duloxetine "Duloxetine") | [SNRI](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") | 14,591,949 |
| [Paroxetine](https://en.wikipedia.org/wiki/Paroxetine "Paroxetine") | [SSRI](https://en.wikipedia.org/wiki/SSRI "SSRI") | 12,979,366 |
| [Amitriptyline](https://en.wikipedia.org/wiki/Amitriptyline "Amitriptyline") | [TCA](https://en.wikipedia.org/wiki/Tricyclic_antidepressant "Tricyclic antidepressant") | 12,611,254 |
| [Venlafaxine](https://en.wikipedia.org/wiki/Venlafaxine "Venlafaxine") XR | [SNRI](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") | 7,603,949 |
| [Bupropion](https://en.wikipedia.org/wiki/Bupropion "Bupropion") XL | [NDRI](https://en.wikipedia.org/wiki/Norepinephrine%E2%80%93dopamine_reuptake_inhibitor "Norepinephrine–dopamine reuptake inhibitor") | 7,317,814 |
| [Mirtazapine](https://en.wikipedia.org/wiki/Mirtazapine "Mirtazapine") | [TeCA](https://en.wikipedia.org/wiki/Tetracyclic_antidepressant "Tetracyclic antidepressant") | 6,308,288 |
| [Venlafaxine](https://en.wikipedia.org/wiki/Venlafaxine "Venlafaxine") ER | [SNRI](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") | 5,526,132 |
| [Bupropion](https://en.wikipedia.org/wiki/Bupropion "Bupropion") SR | [NDRI](https://en.wikipedia.org/wiki/Norepinephrine%E2%80%93dopamine_reuptake_inhibitor "Norepinephrine–dopamine reuptake inhibitor") | 4,588,996 |
| [Desvenlafaxine](https://en.wikipedia.org/wiki/Desvenlafaxine "Desvenlafaxine") | [SNRI](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") | 3,412,354 |
| [Nortriptyline](https://en.wikipedia.org/wiki/Nortriptyline "Nortriptyline") | [TCA](https://en.wikipedia.org/wiki/Tricyclic_antidepressant "Tricyclic antidepressant") | 3,210,476 |
| [Bupropion](https://en.wikipedia.org/wiki/Bupropion "Bupropion") ER | [NDRI](https://en.wikipedia.org/wiki/Norepinephrine%E2%80%93dopamine_reuptake_inhibitor "Norepinephrine–dopamine reuptake inhibitor") | 3,132,327 |
| [Venlafaxine](https://en.wikipedia.org/wiki/Venlafaxine "Venlafaxine") | [SNRI](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") | 2,980,525 |
| [Bupropion](https://en.wikipedia.org/wiki/Bupropion "Bupropion") | [NDRI](https://en.wikipedia.org/wiki/Norepinephrine%E2%80%93dopamine_reuptake_inhibitor "Norepinephrine–dopamine reuptake inhibitor") | 753,516 |
**Netherlands:** In the Netherlands, [paroxetine](https://en.wikipedia.org/wiki/Paroxetine "Paroxetine") is the most prescribed antidepressant, followed by [amitriptyline](https://en.wikipedia.org/wiki/Amitriptyline "Amitriptyline"), [citalopram](https://en.wikipedia.org/wiki/Citalopram "Citalopram") and [venlafaxine](https://en.wikipedia.org/wiki/Venlafaxine "Venlafaxine").[\[314\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-314)
### Adherence
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=54 "Edit section: Adherence")\]
Main article: [Adherence (medicine)](https://en.wikipedia.org/wiki/Adherence_\(medicine\) "Adherence (medicine)")
As of 2003[\[update\]](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit), worldwide, 30% to 60% of people did not follow their practitioner's instructions about taking their antidepressants,[\[315\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-315) and as of 2013[\[update\]](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit) in the US, it appeared that around 50% of people did not take their antidepressants as directed by their practitioner.[\[316\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Kaplan-2013-316)
When people fail to take their antidepressants, there is a greater risk that the drug will not help, that symptoms get worse, that they miss work or are less productive at work, and that the person may be hospitalized.[\[317\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Ho2016-317)
### Social science perspective
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=55 "Edit section: Social science perspective")\]
Some academics\[*[who?](https://en.wikipedia.org/wiki/Wikipedia:Manual_of_Style/Words_to_watch#Unsupported_attributions "Wikipedia:Manual of Style/Words to watch")*\] have highlighted the need to examine the use of antidepressants and other medical treatments in cross-cultural terms, because various cultures prescribe and observe different manifestations, symptoms, meanings, and associations of depression and other medical conditions within their populations.[\[318\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Ecks_2005-318)[\[319\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Lock_2010-319) These cross-cultural discrepancies, it has been argued, then have implications on the perceived efficacy and use of antidepressants and other strategies in the treatment of depression in these different cultures.[\[318\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Ecks_2005-318)[\[319\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Lock_2010-319) In India, antidepressants are largely seen as tools to combat marginality, promising the individual the ability to reintegrate into society through their use—a view and association not observed in the West.[\[318\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Ecks_2005-318)
### Environmental impacts
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=56 "Edit section: Environmental impacts")\]
Because most antidepressants function by inhibiting the reuptake of neurotransmitters serotonin, dopamine, and norepinephrine[\[320\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid17690258-320) these drugs can interfere with natural neurotransmitter levels in other organisms impacted by indirect exposure.[\[321\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-321) Antidepressants fluoxetine and sertraline have been detected in aquatic organisms residing in effluent-dominated streams.[\[322\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid15720009-322) The presence of antidepressants in surface waters and aquatic organisms has caused concern because ecotoxicological effects on aquatic organisms due to fluoxetine exposure have been demonstrated.[\[323\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid16257063-323)
Coral reef fish have been demonstrated to modulate aggressive behavior through serotonin.[\[324\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-324) Artificially increasing serotonin levels in crustaceans can temporarily reverse social status and turn subordinates into aggressive and territorial dominant males.[\[325\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid9159179-325)
Exposure to Fluoxetine has been demonstrated to increase serotonergic activity in fish, subsequently reducing aggressive behavior.[\[326\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid12954414-326) Perinatal exposure to Fluoxetine at relevant environmental concentrations has been shown to lead to significant modifications of memory processing in 1-month-old cuttlefish.[\[327\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid23474317-327) This impairment may disadvantage cuttlefish and decrease their survival. Somewhat less than 10% of orally administered Fluoxetine is excreted from humans unchanged or as [glucuronide](https://en.wikipedia.org/wiki/Glucuronide "Glucuronide").[\[328\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid10674711-328)[\[329\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid17160491-329)
## See also
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=57 "Edit section: See also")\]
[](https://en.wikipedia.org/wiki/File:Commons-logo.svg)
Wikimedia Commons has media related to [Antidepressants](https://commons.wikimedia.org/wiki/Category:Antidepressants "commons:Category:Antidepressants").
- [Antidepressants in Japan](https://en.wikipedia.org/wiki/Antidepressants_in_Japan "Antidepressants in Japan")
- [Atypical antidepressant](https://en.wikipedia.org/wiki/Atypical_antidepressant "Atypical antidepressant")
- [Depression and natural therapies](https://en.wikipedia.org/wiki/Depression_and_natural_therapies "Depression and natural therapies")
- [Depression in childhood and adolescence](https://en.wikipedia.org/wiki/Depression_in_childhood_and_adolescence "Depression in childhood and adolescence")
- [List of antidepressants](https://en.wikipedia.org/wiki/List_of_antidepressants "List of antidepressants")
- [Management of depression](https://en.wikipedia.org/wiki/Management_of_depression "Management of depression")
- [Single-dose long-acting CNS drug](https://en.wikipedia.org/wiki/Single-dose_long-acting_CNS_drug "Single-dose long-acting CNS drug")
## References
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=58 "Edit section: References")\]
1. **[^](https://en.wikipedia.org/wiki/Antidepressant#cite_ref-Ghaemi2015_1-0)**
Ghaemi SN (August 2015). "A New Nomenclature for Psychotropic Drugs". *J Clin Psychopharmacol*. **35** (4): 428–433\. [doi](https://en.wikipedia.org/wiki/Doi_\(identifier\) "Doi (identifier)"):[10\.1097/JCP.0000000000000341](https://doi.org/10.1097%2FJCP.0000000000000341). [PMID](https://en.wikipedia.org/wiki/PMID_\(identifier\) "PMID (identifier)") [26020461](https://pubmed.ncbi.nlm.nih.gov/26020461). "\[...\] Hence, the term "mood elevator" was used as well as "psychic energizer".10 Eventually, the clinical investigator, Dr Frank Ayd, propounded the term "antidepressant" in an analogy to "antibiotics".11 \[...\]"
2. ^ [***a***](https://en.wikipedia.org/wiki/Antidepressant#cite_ref-Jennings2018_2-0) [***b***](https://en.wikipedia.org/wiki/Antidepressant#cite_ref-Jennings2018_2-1)
Jennings L (2018). "Antidepressants". In Grossberg GT, Kinsella LJ (eds.). *Clinical Psychopharmacology for Neurologists*. Springer. pp. 45–71\. [doi](https://en.wikipedia.org/wiki/Doi_\(identifier\) "Doi (identifier)"):[10\.1007/978-3-319-74604-3\_4](https://doi.org/10.1007%2F978-3-319-74604-3_4). [ISBN](https://en.wikipedia.org/wiki/ISBN_\(identifier\) "ISBN (identifier)")
[978-3-319-74602-9](https://en.wikipedia.org/wiki/Special:BookSources/978-3-319-74602-9 "Special:BookSources/978-3-319-74602-9")
.
3. **[^](https://en.wikipedia.org/wiki/Antidepressant#cite_ref-3)**
Ghaemi SN (2019). *Clinical Psychopharmacology: Principles and Practice*. New York: Oxford University Press. p. 90. [ISBN](https://en.wikipedia.org/wiki/ISBN_\(identifier\) "ISBN (identifier)")
[978-0-19-999548-6](https://en.wikipedia.org/wiki/Special:BookSources/978-0-19-999548-6 "Special:BookSources/978-0-19-999548-6")
.
4. **[^](https://en.wikipedia.org/wiki/Antidepressant#cite_ref-4)**
Healy D, Le Noury J, Mangin D (May 2018). ["Enduring sexual dysfunction after treatment with antidepressants, 5α-reductase inhibitors and isotretinoin: 300 cases"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004900). *The International Journal of Risk & Safety in Medicine*. **29** (3–4\): 125–134\. [doi](https://en.wikipedia.org/wiki/Doi_\(identifier\) "Doi (identifier)"):[10\.3233/JRS-180744](https://doi.org/10.3233%2FJRS-180744). [PMC](https://en.wikipedia.org/wiki/PMC_\(identifier\) "PMC (identifier)") [6004900](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004900). [PMID](https://en.wikipedia.org/wiki/PMID_\(identifier\) "PMID (identifier)") [29733030](https://pubmed.ncbi.nlm.nih.gov/29733030).
5. **[^](https://en.wikipedia.org/wiki/Antidepressant#cite_ref-Bahrick_5-0)**
Bahrick AS (2008). ["Persistence of Sexual Dysfunction Side Effects after Discontinuation of Antidepressant Medications: Emerging Evidence"](https://doi.org/10.2174%2F1874350100801010042). *The Open Psychology Journal*. **1**: 42–50\. [doi](https://en.wikipedia.org/wiki/Doi_\(identifier\) "Doi (identifier)"):[10\.2174/1874350100801010042](https://doi.org/10.2174%2F1874350100801010042).
6. **[^](https://en.wikipedia.org/wiki/Antidepressant#cite_ref-6)**
Taylor MJ, Rudkin L, Bullemor-Day P, Lubin J, Chukwujekwu C, Hawton K (May 2013). ["Strategies for managing sexual dysfunction induced by antidepressant medication"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052305). *The Cochrane Database of Systematic Reviews*. **2013** (5) CD003382. [doi](https://en.wikipedia.org/wiki/Doi_\(identifier\) "Doi (identifier)"):[10\.1002/14651858.CD003382.pub3](https://doi.org/10.1002%2F14651858.CD003382.pub3). [PMC](https://en.wikipedia.org/wiki/PMC_\(identifier\) "PMC (identifier)") [12052305](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052305). [PMID](https://en.wikipedia.org/wiki/PMID_\(identifier\) "PMID (identifier)") [23728643](https://pubmed.ncbi.nlm.nih.gov/23728643).
7. **[^](https://en.wikipedia.org/wiki/Antidepressant#cite_ref-7)**
Kennedy SH, Rizvi S (April 2009). "Sexual dysfunction, depression, and the impact of antidepressants". *Journal of Clinical Psychopharmacology*. **29** (2): 157–164\. [doi](https://en.wikipedia.org/wiki/Doi_\(identifier\) "Doi (identifier)"):[10\.1097/jcp.0b013e31819c76e9](https://doi.org/10.1097%2Fjcp.0b013e31819c76e9). [PMID](https://en.wikipedia.org/wiki/PMID_\(identifier\) "PMID (identifier)") [19512977](https://pubmed.ncbi.nlm.nih.gov/19512977). [S2CID](https://en.wikipedia.org/wiki/S2CID_\(identifier\) "S2CID (identifier)") [739831](https://api.semanticscholar.org/CorpusID:739831).
8. **[^](https://en.wikipedia.org/wiki/Antidepressant#cite_ref-8)** [Serotonin and noradrenaline reuptake inhibitors (SNRI); selective serotonin reuptake inhibitors (SSRI) – Persistent sexual dysfunction after drug withdrawal](https://www.ema.europa.eu/en/documents/other/new-product-information-wording-extracts-prac-recommendations-signals-adopted-13-16-may-2019-prac_en.pdf) (EPITT no 19277), 11 June 20191, EMA/PRAC/265221/2019, Pharmacovigilance Risk Assessment Committee (PRAC)
9. **[^](https://en.wikipedia.org/wiki/Antidepressant#cite_ref-9)**
Sansone RA, Sansone LA (October 2010). ["SSRI-Induced Indifference"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2989833). *Psychiatry*. **7** (10): 14–18\. [PMC](https://en.wikipedia.org/wiki/PMC_\(identifier\) "PMC (identifier)") [2989833](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2989833). [PMID](https://en.wikipedia.org/wiki/PMID_\(identifier\) "PMID (identifier)") [21103140](https://pubmed.ncbi.nlm.nih.gov/21103140).
10. **[^](https://en.wikipedia.org/wiki/Antidepressant#cite_ref-10)**
["Is your antidepressant making life a little too blah?"](https://www.health.harvard.edu/depression/is-your-antidepressant-making-life-a-little-too-blah). Harvard Health Publishing. 8 November 2016. Retrieved 25 February 2021.
11. **[^](https://en.wikipedia.org/wiki/Antidepressant#cite_ref-11)**
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Rasmussen N (July 2006). "Making the first anti-depressant: amphetamine in American medicine, 1929-1950". *J Hist Med Allied Sci*. **61** (3): 288–323\. [doi](https://en.wikipedia.org/wiki/Doi_\(identifier\) "Doi (identifier)"):[10\.1093/jhmas/jrj039](https://doi.org/10.1093%2Fjhmas%2Fjrj039). [hdl](https://en.wikipedia.org/wiki/Hdl_\(identifier\) "Hdl (identifier)"):[1959\.4/43848](https://hdl.handle.net/1959.4%2F43848). [PMID](https://en.wikipedia.org/wiki/PMID_\(identifier\) "PMID (identifier)") [16492800](https://pubmed.ncbi.nlm.nih.gov/16492800).
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Ciccarone D (March 2011). ["Stimulant abuse: pharmacology, cocaine, methamphetamine, treatment, attempts at pharmacotherapy"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056348). *Prim Care*. **38** (1): 41–58\. [doi](https://en.wikipedia.org/wiki/Doi_\(identifier\) "Doi (identifier)"):[10\.1016/j.pop.2010.11.004](https://doi.org/10.1016%2Fj.pop.2010.11.004). [PMC](https://en.wikipedia.org/wiki/PMC_\(identifier\) "PMC (identifier)") [3056348](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056348). [PMID](https://en.wikipedia.org/wiki/PMID_\(identifier\) "PMID (identifier)") [21356420](https://pubmed.ncbi.nlm.nih.gov/21356420). "In 1919, Japanese chemist Akira Ogata, as part of his effort to prove the structure of ephedrine, reported the synthesis of the closely related compound we now call methamphetamine, and this result was described in the Western literature (Amatsu & Kubota, 1913; Lee, 2011; Ogata, 1920). \[...\] As a result, when competitors began to consider emulating SKF's success in the late 1930s, they turned to methamphetamine, which had nearly indistinguishable effects but—because its synthesis together with its pharmacological characteristics was published before 1920—was free from patent encumbrance. \[...\] In any event, by 1940 Benzedrine Sulfate had achieved medical acclaim and quickly growing sales as an antidepressant effective for milder forms of the condition, both in the United States and the United Kingdom. In Germany, the Temmler drug firm quickly copied SKF, marketing methamphetamine (again, unprotected by patents) tablets under the Pervitin brand, with claims that it restored "joy in work" in cases of mild depression around 1938 (Rasmussen, 2006; Steinkamp, 2006)."
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Langlitz N (6 September 2025). ["Experiments in medicalization: psychedelic therapy in Switzerland and Australia"](https://link.springer.com/10.1057/s41292-025-00369-y). *BioSocieties*. [doi](https://en.wikipedia.org/wiki/Doi_\(identifier\) "Doi (identifier)"):[10\.1057/s41292-025-00369-y](https://doi.org/10.1057%2Fs41292-025-00369-y). [ISSN](https://en.wikipedia.org/wiki/ISSN_\(identifier\) "ISSN (identifier)") [1745-8552](https://search.worldcat.org/issn/1745-8552). Retrieved 11 February 2026. "Drawing on long-term ethnographic engagement with the psychedelic research community, \[this article\] presents two case studies: Switzerland's Limited Medical Use Program and Australia's Authorized Prescriber scheme. Both allow psychedelic therapies outside clinical trials, yet neither grants market access."
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Nutt DJ, Hunt P, Schlag AK, Fitzgerald P (December 2024). ["The Australia story: Current status and future challenges for the clinical applications of psychedelics"](https://doi.org/10.1111%2Fbph.17398). *Br J Pharmacol*. [doi](https://en.wikipedia.org/wiki/Doi_\(identifier\) "Doi (identifier)"):[10\.1111/bph.17398](https://doi.org/10.1111%2Fbph.17398). [PMID](https://en.wikipedia.org/wiki/PMID_\(identifier\) "PMID (identifier)") [39701143](https://pubmed.ncbi.nlm.nih.gov/39701143). "\[...\] in 2023, the Australian Therapeutic Goods Administration (TGA) approved the use of psilocybin for treatment-resistant depression and MDMA for PTSD to take effect from 1 July 2023. \[...\] compassionate use \[of psychedelics\] has been allowed in Switzerland for decades and more recently in Canada (TheraPsil, 2024) and Israel."
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Liechti ME, Gasser P, Aicher HD, Mueller F, Hawrot T, Schmid Y (2025). ["Implementing psychedelic-assisted therapy: History and characteristics of the Swiss limited medical use program"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12341733). *Neurosci Appl*. **4** 105525. [doi](https://en.wikipedia.org/wiki/Doi_\(identifier\) "Doi (identifier)"):[10\.1016/j.nsa.2025.105525](https://doi.org/10.1016%2Fj.nsa.2025.105525). [PMC](https://en.wikipedia.org/wiki/PMC_\(identifier\) "PMC (identifier)") [12341733](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12341733). [PMID](https://en.wikipedia.org/wiki/PMID_\(identifier\) "PMID (identifier)") [40800003](https://pubmed.ncbi.nlm.nih.gov/40800003). "This article describes the Swiss limited access program for psychedelic/3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy. The Swiss Federal Office of Public Health can issue authorizations for the limited medical use of otherwise prohibited substances. To be eligible, patients suffer from a mostly incurable disease, the prohibited substance can alleviate the suffering, and there are no alternative treatments, or such treatments have already extensively been used with insufficient outcome. The current program started in 2014 with two physicians. In 2024, there were approximately 100 physicians who held authorizations to treat 723 patients with MDMA (245 patients), lysergic acid diethylamide (130 patients), or psilocybin (348 patients). \[...\]"
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## Further reading
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=59 "Edit section: Further reading")\]
- Stahl SM (1997). *Psychopharmacology of Antidepressants*. Informa Healthcare. [ISBN](https://en.wikipedia.org/wiki/ISBN_\(identifier\) "ISBN (identifier)")
[978-1-85317-513-8](https://en.wikipedia.org/wiki/Special:BookSources/978-1-85317-513-8 "Special:BookSources/978-1-85317-513-8")
.
## External links
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=60 "Edit section: External links")\]
[](https://en.wikipedia.org/wiki/File:Wiktionary-logo-en-v2.svg)
Look up ***[antidepressant](https://en.wiktionary.org/wiki/antidepressant "wiktionary:antidepressant")*** in Wiktionary, the free dictionary.
- [](https://en.wikipedia.org/wiki/File:Commons-logo.svg) Media related to [Antidepressants](https://commons.wikimedia.org/wiki/Category:Antidepressants "commons:Category:Antidepressants") at Wikimedia Commons
[Antidepressants](https://en.wikipedia.org/wiki/Category:Antidepressants "Category:Antidepressants")
Category *Drug classes defined by psychological effects* not found
[Drugs by psychological effects](https://en.wikipedia.org/wiki/Category:Drugs_by_psychological_effects "Category:Drugs by psychological effects")
[Psychoactive drugs](https://en.wikipedia.org/wiki/Category:Psychoactive_drugs "Category:Psychoactive drugs")
| [v](https://en.wikipedia.org/wiki/Template:Antidepressants "Template:Antidepressants") [t](https://en.wikipedia.org/wiki/Template_talk:Antidepressants "Template talk:Antidepressants") [e](https://en.wikipedia.org/wiki/Special:EditPage/Template:Antidepressants "Special:EditPage/Template:Antidepressants")[Antidepressants]() ([N06A](https://en.wikipedia.org/wiki/ATC_code_N06#N06A "ATC code N06")) | |
|---|---|
| Specific [reuptake inhibitors](https://en.wikipedia.org/wiki/Reuptake_inhibitor "Reuptake inhibitor") or [receptor modulators](https://en.wikipedia.org/wiki/Receptor_modulator "Receptor modulator") | |
| | |
| [SSRIs](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitors "Selective serotonin reuptake inhibitors")Tooltip Selective serotonin reuptake inhibitors | [Citalopram](https://en.wikipedia.org/wiki/Citalopram "Citalopram")\# [Escitalopram](https://en.wikipedia.org/wiki/Escitalopram "Escitalopram")\# [Fluoxetine](https://en.wikipedia.org/wiki/Fluoxetine "Fluoxetine")\# [Fluvoxamine](https://en.wikipedia.org/wiki/Fluvoxamine "Fluvoxamine")\# [Indalpine](https://en.wikipedia.org/wiki/Indalpine "Indalpine")‡ [Paroxetine](https://en.wikipedia.org/wiki/Paroxetine "Paroxetine")\# [Sertraline](https://en.wikipedia.org/wiki/Sertraline "Sertraline")\# [Zimelidine](https://en.wikipedia.org/wiki/Zimelidine "Zimelidine")‡ |
| [SNRIs](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitors "Serotonin–norepinephrine reuptake inhibitors")Tooltip Serotonin–norepinephrine reuptake inhibitors | [Desvenlafaxine](https://en.wikipedia.org/wiki/Desvenlafaxine "Desvenlafaxine") [Duloxetine](https://en.wikipedia.org/wiki/Duloxetine "Duloxetine") [Levomilnacipran](https://en.wikipedia.org/wiki/Levomilnacipran "Levomilnacipran") [Milnacipran](https://en.wikipedia.org/wiki/Milnacipran "Milnacipran") [Tofenacin](https://en.wikipedia.org/wiki/Tofenacin "Tofenacin") [Venlafaxine](https://en.wikipedia.org/wiki/Venlafaxine "Venlafaxine") |
| [NRIs](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitors "Norepinephrine reuptake inhibitors")Tooltip Norepinephrine reuptake inhibitors | [Atomoxetine](https://en.wikipedia.org/wiki/Atomoxetine "Atomoxetine") [Reboxetine](https://en.wikipedia.org/wiki/Reboxetine "Reboxetine") [Viloxazine](https://en.wikipedia.org/wiki/Viloxazine "Viloxazine") |
| [NDRIs](https://en.wikipedia.org/wiki/Norepinephrine%E2%80%93dopamine_reuptake_inhibitors "Norepinephrine–dopamine reuptake inhibitors")Tooltip Norepinephrine–dopamine reuptake inhibitors | [Amineptine](https://en.wikipedia.org/wiki/Amineptine "Amineptine")‡ [Bupropion](https://en.wikipedia.org/wiki/Bupropion "Bupropion") [Nomifensine](https://en.wikipedia.org/wiki/Nomifensine "Nomifensine")‡ |
| [NaSSAs](https://en.wikipedia.org/wiki/Noradrenergic_and_specific_serotonergic_antidepressants "Noradrenergic and specific serotonergic antidepressants")Tooltip Noradrenergic and specific serotonergic antidepressants | [Mianserin](https://en.wikipedia.org/wiki/Mianserin "Mianserin") [Mirtazapine](https://en.wikipedia.org/wiki/Mirtazapine "Mirtazapine") [Setiptiline](https://en.wikipedia.org/wiki/Setiptiline "Setiptiline") |
| [SARIs](https://en.wikipedia.org/wiki/Serotonin_antagonist_and_reuptake_inhibitors "Serotonin antagonist and reuptake inhibitors")Tooltip Serotonin antagonist and reuptake inhibitors | [Etoperidone](https://en.wikipedia.org/wiki/Etoperidone "Etoperidone") [Nefazodone](https://en.wikipedia.org/wiki/Nefazodone "Nefazodone") [Trazodone](https://en.wikipedia.org/wiki/Trazodone "Trazodone") |
| [SMS](https://en.wikipedia.org/wiki/Serotonin_modulator_and_stimulators "Serotonin modulator and stimulators")Tooltip Serotonin modulator and stimulators | [Vilazodone](https://en.wikipedia.org/wiki/Vilazodone "Vilazodone") [Vortioxetine](https://en.wikipedia.org/wiki/Vortioxetine "Vortioxetine") |
| Others | [Agomelatine](https://en.wikipedia.org/wiki/Agomelatine "Agomelatine") [Amisulpride](https://en.wikipedia.org/wiki/Amisulpride "Amisulpride") [Dextromethorphan/bupropion](https://en.wikipedia.org/wiki/Dextromethorphan/bupropion "Dextromethorphan/bupropion") [Esketamine](https://en.wikipedia.org/wiki/Esketamine "Esketamine") [Etryptamine](https://en.wikipedia.org/wiki/Alpha-Ethyltryptamine "Alpha-Ethyltryptamine")‡ [Gepirone](https://en.wikipedia.org/wiki/Gepirone "Gepirone") [Indeloxazine](https://en.wikipedia.org/wiki/Indeloxazine "Indeloxazine") [Flupentixol](https://en.wikipedia.org/wiki/Flupentixol "Flupentixol") [Ketamine](https://en.wikipedia.org/wiki/Ketamine "Ketamine")§ [Medifoxamine](https://en.wikipedia.org/wiki/Medifoxamine "Medifoxamine")‡ [Metryptamine](https://en.wikipedia.org/wiki/Alpha-Methyltryptamine "Alpha-Methyltryptamine")‡ [Oxaflozane](https://en.wikipedia.org/wiki/Oxaflozane "Oxaflozane")‡ [Pivagabine](https://en.wikipedia.org/wiki/Pivagabine "Pivagabine")‡ [Tandospirone](https://en.wikipedia.org/wiki/Tandospirone "Tandospirone") [Teniloxazine](https://en.wikipedia.org/wiki/Teniloxazine "Teniloxazine") [Tianeptine](https://en.wikipedia.org/wiki/Tianeptine "Tianeptine") |
| [Tricyclic](https://en.wikipedia.org/wiki/Tricyclic "Tricyclic") and [tetracyclic antidepressants](https://en.wikipedia.org/wiki/Tetracyclic_antidepressant "Tetracyclic antidepressant") | |
| | |
| [TCAs](https://en.wikipedia.org/wiki/Tricyclic_antidepressants "Tricyclic antidepressants")Tooltip Tricyclic antidepressants | [Amineptine](https://en.wikipedia.org/wiki/Amineptine "Amineptine")‡ [Amitriptyline](https://en.wikipedia.org/wiki/Amitriptyline "Amitriptyline")\# [Amitriptylinoxide](https://en.wikipedia.org/wiki/Amitriptylinoxide "Amitriptylinoxide") [Amoxapine](https://en.wikipedia.org/wiki/Amoxapine "Amoxapine") [Butriptyline](https://en.wikipedia.org/wiki/Butriptyline "Butriptyline")‡ [Clomipramine](https://en.wikipedia.org/wiki/Clomipramine "Clomipramine")\# [Demexiptiline](https://en.wikipedia.org/wiki/Demexiptiline "Demexiptiline")‡ [Desipramine](https://en.wikipedia.org/wiki/Desipramine "Desipramine") [Dibenzepin](https://en.wikipedia.org/wiki/Dibenzepin "Dibenzepin") [Dimetacrine](https://en.wikipedia.org/wiki/Dimetacrine "Dimetacrine")‡ [Dosulepin](https://en.wikipedia.org/wiki/Dosulepin "Dosulepin") [Doxepin](https://en.wikipedia.org/wiki/Doxepin "Doxepin") [Imipramine](https://en.wikipedia.org/wiki/Imipramine "Imipramine") [Imipraminoxide](https://en.wikipedia.org/wiki/Imipraminoxide "Imipraminoxide")‡ [Iprindole](https://en.wikipedia.org/wiki/Iprindole "Iprindole")‡ [Lofepramine](https://en.wikipedia.org/wiki/Lofepramine "Lofepramine") [Melitracen](https://en.wikipedia.org/wiki/Melitracen "Melitracen") [Metapramine](https://en.wikipedia.org/wiki/Metapramine "Metapramine")‡ [Nitroxazepine](https://en.wikipedia.org/wiki/Nitroxazepine "Nitroxazepine") [Nortriptyline](https://en.wikipedia.org/wiki/Nortriptyline "Nortriptyline") [Noxiptiline](https://en.wikipedia.org/wiki/Noxiptiline "Noxiptiline") [Opipramol](https://en.wikipedia.org/wiki/Opipramol "Opipramol") [Pipofezine](https://en.wikipedia.org/wiki/Pipofezine "Pipofezine") [Propizepine](https://en.wikipedia.org/wiki/Propizepine "Propizepine")‡ [Protriptyline](https://en.wikipedia.org/wiki/Protriptyline "Protriptyline") [Quinupramine](https://en.wikipedia.org/wiki/Quinupramine "Quinupramine")‡ [Tianeptine](https://en.wikipedia.org/wiki/Tianeptine "Tianeptine") [Trimipramine](https://en.wikipedia.org/wiki/Trimipramine "Trimipramine") |
| [TeCAs](https://en.wikipedia.org/wiki/Tetracyclic_antidepressants "Tetracyclic antidepressants")Tooltip Tetracyclic antidepressants | [Maprotiline](https://en.wikipedia.org/wiki/Maprotiline "Maprotiline") [Mianserin](https://en.wikipedia.org/wiki/Mianserin "Mianserin") [Mirtazapine](https://en.wikipedia.org/wiki/Mirtazapine "Mirtazapine") [Setiptiline](https://en.wikipedia.org/wiki/Setiptiline "Setiptiline") |
| Others | [Tiazesim](https://en.wikipedia.org/wiki/Tiazesim "Tiazesim") |
| [Monoamine oxidase inhibitors](https://en.wikipedia.org/wiki/Monoamine_oxidase_inhibitor "Monoamine oxidase inhibitor") | |
| | |
| Non-selective | *Irreversible:* [Benmoxin](https://en.wikipedia.org/wiki/Benmoxin "Benmoxin")‡ [Iproclozide](https://en.wikipedia.org/wiki/Iproclozide "Iproclozide")‡ [Iproniazid](https://en.wikipedia.org/wiki/Iproniazid "Iproniazid")‡ [Isocarboxazid](https://en.wikipedia.org/wiki/Isocarboxazid "Isocarboxazid") [Isoniazid](https://en.wikipedia.org/wiki/Isoniazid "Isoniazid")\# [Linezolid](https://en.wikipedia.org/wiki/Linezolid "Linezolid")\# [Mebanazine](https://en.wikipedia.org/wiki/Mebanazine "Mebanazine")‡ [Nialamide](https://en.wikipedia.org/wiki/Nialamide "Nialamide")‡ [Octamoxin](https://en.wikipedia.org/wiki/Octamoxin "Octamoxin")‡ [Phenelzine](https://en.wikipedia.org/wiki/Phenelzine "Phenelzine") [Pheniprazine](https://en.wikipedia.org/wiki/Pheniprazine "Pheniprazine")‡ [Phenoxypropazine](https://en.wikipedia.org/wiki/Phenoxypropazine "Phenoxypropazine")‡ [Pivhydrazine](https://en.wikipedia.org/wiki/Pivhydrazine "Pivhydrazine")‡ [Safrazine](https://en.wikipedia.org/wiki/Safrazine "Safrazine")‡ [Tedizolid](https://en.wikipedia.org/wiki/Tedizolid "Tedizolid") [Tranylcypromine](https://en.wikipedia.org/wiki/Tranylcypromine "Tranylcypromine") *Reversible:* [Caroxazone](https://en.wikipedia.org/wiki/Caroxazone "Caroxazone")‡ *Mixed:* [Bifemelane](https://en.wikipedia.org/wiki/Bifemelane "Bifemelane") |
| [MAOA](https://en.wikipedia.org/wiki/Monoamine_oxidase_A "Monoamine oxidase A")Tooltip Monoamine oxidase A\-selective | *Reversible:* [Eprobemide](https://en.wikipedia.org/wiki/Eprobemide "Eprobemide") [Metralindole](https://en.wikipedia.org/wiki/Metralindole "Metralindole") [Minaprine](https://en.wikipedia.org/wiki/Minaprine "Minaprine")‡ [Moclobemide](https://en.wikipedia.org/wiki/Moclobemide "Moclobemide") [Pirlindole](https://en.wikipedia.org/wiki/Pirlindole "Pirlindole") [Tetrindole](https://en.wikipedia.org/wiki/Tetrindole "Tetrindole") [Toloxatone](https://en.wikipedia.org/wiki/Toloxatone "Toloxatone") |
| [MAOB](https://en.wikipedia.org/wiki/Monoamine_oxidase_B "Monoamine oxidase B")Tooltip Monoamine oxidase B\-selective | *Irreversible:* [Selegiline](https://en.wikipedia.org/wiki/Selegiline "Selegiline") |
| [Adjunctive therapies](https://en.wikipedia.org/wiki/Adjuvant_therapy "Adjuvant therapy") | |
| [Atypical antipsychotics](https://en.wikipedia.org/wiki/Atypical_antipsychotic "Atypical antipsychotic") ([aripiprazole](https://en.wikipedia.org/wiki/Aripiprazole "Aripiprazole"), [brexpiprazole](https://en.wikipedia.org/wiki/Brexpiprazole "Brexpiprazole"), [lurasidone](https://en.wikipedia.org/wiki/Lurasidone "Lurasidone"), [olanzapine](https://en.wikipedia.org/wiki/Olanzapine "Olanzapine"), [quetiapine](https://en.wikipedia.org/wiki/Quetiapine "Quetiapine"), [risperidone](https://en.wikipedia.org/wiki/Risperidone "Risperidone")) [Buspirone](https://en.wikipedia.org/wiki/Buspirone "Buspirone") [Lithium](https://en.wikipedia.org/wiki/Lithium_\(medication\) "Lithium (medication)") ([lithium carbonate](https://en.wikipedia.org/wiki/Lithium_carbonate "Lithium carbonate"), [lithium citrate](https://en.wikipedia.org/wiki/Lithium_citrate "Lithium citrate")) [Thyroid hormones](https://en.wikipedia.org/wiki/Thyroid_hormone "Thyroid hormone") ([triiodothyronine](https://en.wikipedia.org/wiki/Triiodothyronine "Triiodothyronine") (T3), [levothyroxine](https://en.wikipedia.org/wiki/Levothyroxine "Levothyroxine") (T4)) | |
| Miscellaneous | |
| [Ademetionine (SAMe)](https://en.wikipedia.org/wiki/Ademetionine "Ademetionine") [GABAkine](https://en.wikipedia.org/wiki/GABAA_receptor_positive_allosteric_modulator "GABAA receptor positive allosteric modulator") [neurosteroids](https://en.wikipedia.org/wiki/Neurosteroid "Neurosteroid") ([brexanolone](https://en.wikipedia.org/wiki/Allopregnanolone "Allopregnanolone"), [zuranolone](https://en.wikipedia.org/wiki/Zuranolone "Zuranolone")) [*Hypericum perforatum* (St. John's Wort)](https://en.wikipedia.org/wiki/Hypericum_perforatum "Hypericum perforatum") [Oxitriptan (5-HTP)](https://en.wikipedia.org/wiki/Oxitriptan "Oxitriptan") [Rubidium chloride (RbCl)](https://en.wikipedia.org/wiki/Rubidium_chloride "Rubidium chloride") [Tryptophan](https://en.wikipedia.org/wiki/Tryptophan "Tryptophan") | |
| \#[WHO-EM](https://en.wikipedia.org/wiki/WHO_Model_List_of_Essential_Medicines "WHO Model List of Essential Medicines") ‡[Withdrawn](https://en.wikipedia.org/wiki/List_of_withdrawn_drugs "List of withdrawn drugs") from market [Clinical trials](https://en.wikipedia.org/wiki/Clinical_trial "Clinical trial"): †[Phase III](https://en.wikipedia.org/wiki/Phases_of_clinical_research#Phase_III "Phases of clinical research") §Never to phase III | |
| [v](https://en.wikipedia.org/wiki/Template:Major_drug_groups "Template:Major drug groups") [t](https://en.wikipedia.org/wiki/Template_talk:Major_drug_groups "Template talk:Major drug groups") [e](https://en.wikipedia.org/wiki/Special:EditPage/Template:Major_drug_groups "Special:EditPage/Template:Major drug groups")Major chemical drug groups – based upon the [Anatomical Therapeutic Chemical Classification System](https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System "Anatomical Therapeutic Chemical Classification System") | |
|---|---|
| [gastrointestinal tract](https://en.wikipedia.org/wiki/Human_gastrointestinal_tract "Human gastrointestinal tract") / [metabolism](https://en.wikipedia.org/wiki/Metabolism "Metabolism") ([A](https://en.wikipedia.org/wiki/ATC_code_A "ATC code A")) | *stomach acid* [Antacids](https://en.wikipedia.org/wiki/Antacid "Antacid") [H2 antagonists](https://en.wikipedia.org/wiki/H2_antagonist "H2 antagonist") [Proton-pump inhibitors](https://en.wikipedia.org/wiki/Proton-pump_inhibitor "Proton-pump inhibitor") [Antiemetics](https://en.wikipedia.org/wiki/Antiemetic "Antiemetic") [Laxatives](https://en.wikipedia.org/wiki/Laxative "Laxative") [Antidiarrhoeals](https://en.wikipedia.org/wiki/Antidiarrhoeal "Antidiarrhoeal") / [Antipropulsives](https://en.wikipedia.org/wiki/Antipropulsive "Antipropulsive") [Anti-obesity drugs](https://en.wikipedia.org/wiki/Anti-obesity_medication "Anti-obesity medication") [Diabetes medication](https://en.wikipedia.org/wiki/Diabetes_medication "Diabetes medication") [Vitamins](https://en.wikipedia.org/wiki/Vitamin "Vitamin") [Dietary minerals](https://en.wikipedia.org/wiki/Dietary_mineral "Dietary mineral") |
| [blood](https://en.wikipedia.org/wiki/Blood "Blood") and blood forming organs ([B](https://en.wikipedia.org/wiki/ATC_code_B "ATC code B")) | [Antithrombotics](https://en.wikipedia.org/wiki/Antithrombotic "Antithrombotic") [Antiplatelets](https://en.wikipedia.org/wiki/Antiplatelet_drug "Antiplatelet drug") [Anticoagulants](https://en.wikipedia.org/wiki/Anticoagulant "Anticoagulant") [Thrombolytics / fibrinolytics](https://en.wikipedia.org/wiki/Thrombolytic_drug "Thrombolytic drug") [Antihemorrhagics](https://en.wikipedia.org/wiki/Antihemorrhagic "Antihemorrhagic") [Platelets](https://en.wikipedia.org/wiki/Platelet "Platelet") [Coagulants](https://en.wikipedia.org/wiki/Coagulation "Coagulation") [Antifibrinolytics](https://en.wikipedia.org/wiki/Antifibrinolytic "Antifibrinolytic") |
| [cardiovascular system](https://en.wikipedia.org/wiki/Circulatory_system "Circulatory system") ([C](https://en.wikipedia.org/wiki/ATC_code_C "ATC code C")) | *cardiac therapy / [antianginals](https://en.wikipedia.org/wiki/Antianginal "Antianginal")* [Cardiac glycosides](https://en.wikipedia.org/wiki/Cardiac_glycoside "Cardiac glycoside") [Antiarrhythmics](https://en.wikipedia.org/wiki/Antiarrhythmic_agent "Antiarrhythmic agent") [Cardiac stimulants](https://en.wikipedia.org/wiki/Cardiac_stimulant "Cardiac stimulant") [Antihypertensives](https://en.wikipedia.org/wiki/Antihypertensive_drug "Antihypertensive drug") [Diuretics](https://en.wikipedia.org/wiki/Diuretic "Diuretic") [Vasodilators](https://en.wikipedia.org/wiki/Vasodilation "Vasodilation") [Beta blockers](https://en.wikipedia.org/wiki/Beta_blocker "Beta blocker") [Calcium channel blockers](https://en.wikipedia.org/wiki/Calcium_channel_blocker "Calcium channel blocker") *[renin–angiotensin system](https://en.wikipedia.org/wiki/Renin%E2%80%93angiotensin_system "Renin–angiotensin system")* [ACE inhibitors](https://en.wikipedia.org/wiki/ACE_inhibitor "ACE inhibitor") [Angiotensin II receptor antagonists](https://en.wikipedia.org/wiki/Angiotensin_II_receptor_antagonist "Angiotensin II receptor antagonist") [Renin inhibitors](https://en.wikipedia.org/wiki/Renin_inhibitor "Renin inhibitor") [Antihyperlipidemics](https://en.wikipedia.org/wiki/Hypolipidemic_agent "Hypolipidemic agent") [Statins](https://en.wikipedia.org/wiki/Statin "Statin") [Fibrates](https://en.wikipedia.org/wiki/Fibrate "Fibrate") [Bile acid sequestrants](https://en.wikipedia.org/wiki/Bile_acid_sequestrant "Bile acid sequestrant") |
| [skin](https://en.wikipedia.org/wiki/Human_skin "Human skin") ([D](https://en.wikipedia.org/wiki/ATC_code_D "ATC code D")) | [Emollients](https://en.wikipedia.org/wiki/Emollient "Emollient") [Cicatrizants](https://en.wikipedia.org/wiki/Cicatrizant "Cicatrizant") [Antipruritics](https://en.wikipedia.org/wiki/Antipruritic "Antipruritic") [Antipsoriatics](https://en.wikipedia.org/wiki/Antipsoriatic "Antipsoriatic") [Medicated dressings](https://en.wikipedia.org/wiki/ATC_code_D09 "ATC code D09") |
| [genitourinary system](https://en.wikipedia.org/wiki/Genitourinary_system "Genitourinary system") ([G](https://en.wikipedia.org/wiki/ATC_code_G "ATC code G")) | [Hormonal contraception](https://en.wikipedia.org/wiki/Hormonal_contraception "Hormonal contraception") [Fertility agents](https://en.wikipedia.org/wiki/Fertility_medication "Fertility medication") [Selective estrogen receptor modulators](https://en.wikipedia.org/wiki/Selective_estrogen_receptor_modulator "Selective estrogen receptor modulator") [Sex hormones](https://en.wikipedia.org/wiki/Sex_steroid "Sex steroid") |
| [endocrine system](https://en.wikipedia.org/wiki/Endocrine_system "Endocrine system") ([H](https://en.wikipedia.org/wiki/ATC_code_H "ATC code H")) | [Hypothalamic–pituitary hormones](https://en.wikipedia.org/wiki/Hypothalamic%E2%80%93pituitary_hormone "Hypothalamic–pituitary hormone") [Corticosteroids](https://en.wikipedia.org/wiki/Corticosteroid "Corticosteroid") [Glucocorticoids](https://en.wikipedia.org/wiki/Glucocorticoid "Glucocorticoid") [Mineralocorticoids](https://en.wikipedia.org/wiki/Mineralocorticoid "Mineralocorticoid") [Sex hormones](https://en.wikipedia.org/wiki/Sex_steroid "Sex steroid") [Thyroid hormones](https://en.wikipedia.org/wiki/Thyroid_hormone "Thyroid hormone") / [Antithyroid agents](https://en.wikipedia.org/wiki/Antithyroid_agent "Antithyroid agent") |
| [infections](https://en.wikipedia.org/wiki/Infection "Infection") and [infestations](https://en.wiktionary.org/wiki/infestation "wikt:infestation") ([J](https://en.wikipedia.org/wiki/ATC_code_J "ATC code J"), [P](https://en.wikipedia.org/wiki/ATC_code_P "ATC code P"), [QI](https://en.wikipedia.org/wiki/ATCvet_code_QI "ATCvet code QI")) | [Antimicrobials](https://en.wikipedia.org/wiki/Antimicrobial "Antimicrobial"): [Antibacterials](https://en.wikipedia.org/wiki/Antibacterial "Antibacterial") ([Antimycobacterials](https://en.wikipedia.org/wiki/Antimycobacterial "Antimycobacterial")) [Antifungals](https://en.wikipedia.org/wiki/Antifungal_drug "Antifungal drug") [Antivirals](https://en.wikipedia.org/wiki/Antiviral_drug "Antiviral drug") [Antiparasitics](https://en.wikipedia.org/wiki/Antiparasitic "Antiparasitic") [Antiprotozoals](https://en.wikipedia.org/wiki/Antiprotozoal_agent "Antiprotozoal agent") [Anthelmintics](https://en.wikipedia.org/wiki/Anthelmintic "Anthelmintic") [Ectoparasiticides](https://en.wikipedia.org/wiki/Ectoparasiticide "Ectoparasiticide") [Intravenous immunoglobulin](https://en.wikipedia.org/wiki/Intravenous_immunoglobulin "Intravenous immunoglobulin") [Vaccines](https://en.wikipedia.org/wiki/Vaccine "Vaccine") |
| [malignant](https://en.wikipedia.org/wiki/Malignancy "Malignancy") disease ([L01–L02](https://en.wikipedia.org/wiki/ATC_code_L "ATC code L")) | [Anticancer agents](https://en.wikipedia.org/wiki/Chemotherapy "Chemotherapy") [Antimetabolites](https://en.wikipedia.org/wiki/Antimetabolite "Antimetabolite") [Alkylating](https://en.wikipedia.org/wiki/Alkylating_antineoplastic_agent "Alkylating antineoplastic agent") [Spindle poisons](https://en.wikipedia.org/wiki/Spindle_poison "Spindle poison") [Antineoplastic](https://en.wikipedia.org/wiki/Antineoplastic "Antineoplastic") [Topoisomerase inhibitors](https://en.wikipedia.org/wiki/Topoisomerase_inhibitor "Topoisomerase inhibitor") |
| [immune](https://en.wikipedia.org/wiki/Immune_system "Immune system") disease ([L03–L04](https://en.wikipedia.org/wiki/ATC_code_L "ATC code L")) | [Immunomodulators](https://en.wikipedia.org/wiki/Immunomodulator "Immunomodulator") [Immunostimulants](https://en.wikipedia.org/wiki/Immunostimulant "Immunostimulant") [Immunosuppressants](https://en.wikipedia.org/wiki/Immunosuppressive_drug "Immunosuppressive drug") |
| [muscles](https://en.wikipedia.org/wiki/Muscle "Muscle"), [bones](https://en.wikipedia.org/wiki/Bone "Bone"), and [joints](https://en.wikipedia.org/wiki/Joint "Joint") ([M](https://en.wikipedia.org/wiki/ATC_code_M "ATC code M")) | [Anabolic steroids](https://en.wikipedia.org/wiki/Anabolic_steroid "Anabolic steroid") [Anti-inflammatories](https://en.wikipedia.org/wiki/Anti-inflammatory "Anti-inflammatory") [Non-steroidal anti-inflammatory drugs](https://en.wikipedia.org/wiki/Non-steroidal_anti-inflammatory_drug "Non-steroidal anti-inflammatory drug") [Antirheumatics](https://en.wikipedia.org/wiki/Disease-modifying_antirheumatic_drug "Disease-modifying antirheumatic drug") [Corticosteroids](https://en.wikipedia.org/wiki/Corticosteroid "Corticosteroid") [Muscle relaxants](https://en.wikipedia.org/wiki/Muscle_relaxant "Muscle relaxant") [Bisphosphonates](https://en.wikipedia.org/wiki/Bisphosphonate "Bisphosphonate") |
| [brain](https://en.wikipedia.org/wiki/Human_brain "Human brain") and [nervous system](https://en.wikipedia.org/wiki/Nervous_system "Nervous system") ([N](https://en.wikipedia.org/wiki/ATC_code_N "ATC code N")) | [Analgesics](https://en.wikipedia.org/wiki/Analgesic "Analgesic") [Anesthetics](https://en.wikipedia.org/wiki/Anesthetic "Anesthetic") [General](https://en.wikipedia.org/wiki/General_anaesthetic "General anaesthetic") [Local](https://en.wikipedia.org/wiki/Local_anesthetic "Local anesthetic") [Anorectics](https://en.wikipedia.org/wiki/Anorectic "Anorectic") [Anti-ADHD agents](https://en.wikipedia.org/wiki/Antihyperkinetic "Antihyperkinetic") [Antiaddictives](https://en.wikipedia.org/wiki/Addiction_medicine "Addiction medicine") [Anticonvulsants](https://en.wikipedia.org/wiki/Anticonvulsant "Anticonvulsant") [Antidementia agents](https://en.wikipedia.org/wiki/Antidementia_drug "Antidementia drug") [Antidepressants]() [Antimigraine agents](https://en.wikipedia.org/wiki/Antimigraine_drug "Antimigraine drug") [Antiparkinson agents](https://en.wikipedia.org/wiki/Management_of_Parkinson%27s_disease#Medication "Management of Parkinson's disease") [Antipsychotics](https://en.wikipedia.org/wiki/Antipsychotic "Antipsychotic") [Anxiolytics](https://en.wikipedia.org/wiki/Anxiolytic "Anxiolytic") [Aphrodisiacs](https://en.wikipedia.org/wiki/Aphrodisiac "Aphrodisiac") [Depressants](https://en.wikipedia.org/wiki/Depressant "Depressant") [Entactogens](https://en.wikipedia.org/wiki/Entactogen "Entactogen") [Entheogens](https://en.wikipedia.org/wiki/Entheogen "Entheogen") [Euphoriants](https://en.wikipedia.org/wiki/Euphoriant "Euphoriant") [Hallucinogens](https://en.wikipedia.org/wiki/Hallucinogen "Hallucinogen") [Psychedelics](https://en.wikipedia.org/wiki/Psychedelic_drug "Psychedelic drug") [Dissociatives](https://en.wikipedia.org/wiki/Dissociative "Dissociative") [Deliriants](https://en.wikipedia.org/wiki/Deliriant "Deliriant") [Hypnotics](https://en.wikipedia.org/wiki/Hypnotic "Hypnotic") / [Sedatives](https://en.wikipedia.org/wiki/Sedative "Sedative") [Mood stabilizers](https://en.wikipedia.org/wiki/Mood_stabilizer "Mood stabilizer") [Motivation-enhancing drug](https://en.wikipedia.org/wiki/Motivation-enhancing_drug "Motivation-enhancing drug") [Neuroprotectives](https://en.wikipedia.org/wiki/Neuroprotective "Neuroprotective") [Nootropics](https://en.wikipedia.org/wiki/Nootropic "Nootropic") [Neurotoxins](https://en.wikipedia.org/wiki/Neurotoxin "Neurotoxin") [Orexigenics](https://en.wikipedia.org/wiki/Orexigenic "Orexigenic") [Serenics](https://en.wikipedia.org/wiki/Serenic "Serenic") [Stimulants](https://en.wikipedia.org/wiki/Stimulant "Stimulant") [Wakefulness-promoting agents](https://en.wikipedia.org/wiki/Wakefulness-promoting_agent "Wakefulness-promoting agent") |
| [respiratory system](https://en.wikipedia.org/wiki/Respiratory_system "Respiratory system") ([R](https://en.wikipedia.org/wiki/ATC_code_R "ATC code R")) | [Decongestants](https://en.wikipedia.org/wiki/Decongestant "Decongestant") [Bronchodilators](https://en.wikipedia.org/wiki/Bronchodilator "Bronchodilator") [Cough medicines](https://en.wikipedia.org/wiki/Cough_medicine "Cough medicine") [H1 antagonists](https://en.wikipedia.org/wiki/H1_antagonist "H1 antagonist") |
| [sensory organs](https://en.wikipedia.org/wiki/Sense "Sense") ([S](https://en.wikipedia.org/wiki/ATC_code_S "ATC code S")) | [Ophthalmologicals](https://en.wikipedia.org/wiki/Ophthalmology "Ophthalmology") [Otologicals](https://en.wikipedia.org/wiki/Otology "Otology") |
| other [ATC](https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System "Anatomical Therapeutic Chemical Classification System") ([V](https://en.wikipedia.org/wiki/ATC_code_V "ATC code V")) | [Antidotes](https://en.wikipedia.org/wiki/Antidote "Antidote") [Contrast media](https://en.wikipedia.org/wiki/Contrast_medium "Contrast medium") [Radiopharmaceuticals](https://en.wikipedia.org/wiki/Radiopharmacology "Radiopharmacology") [Dressings](https://en.wikipedia.org/wiki/Dressing_\(medicine\) "Dressing (medicine)") [Senotherapeutics](https://en.wikipedia.org/wiki/Senotherapeutics "Senotherapeutics") |
|  [Drugs](https://en.wikipedia.org/wiki/Category:Drugs "Category:Drugs") [Pharmacological classification systems](https://en.wikipedia.org/wiki/Category:Pharmacological_classification_systems "Category:Pharmacological classification systems") [ATC codes](https://en.wikipedia.org/wiki/Category:ATC_codes "Category:ATC codes") [](https://en.wikipedia.org/wiki/File:Symbol_portal_class.svg "Portal") [Medicine portal](https://en.wikipedia.org/wiki/Portal:Medicine "Portal:Medicine") | |
| [v](https://en.wikipedia.org/wiki/Template:Chemical_classes_of_psychoactive_drugs "Template:Chemical classes of psychoactive drugs") [t](https://en.wikipedia.org/wiki/Template_talk:Chemical_classes_of_psychoactive_drugs "Template talk:Chemical classes of psychoactive drugs") [e](https://en.wikipedia.org/wiki/Special:EditPage/Template:Chemical_classes_of_psychoactive_drugs "Special:EditPage/Template:Chemical classes of psychoactive drugs")[Chemical classes](https://en.wikipedia.org/wiki/Chemical_class "Chemical class") of [psychoactive drugs](https://en.wikipedia.org/wiki/Psychoactive_drug "Psychoactive drug") | |
|---|---|
| [Stimulants](https://en.wikipedia.org/wiki/Stimulant "Stimulant") | *Amphetamine-type/dopamine releasing agents:* [Alkylamines](https://en.wikipedia.org/wiki/Psychotropic_alkylamine "Psychotropic alkylamine") [Cycloalkylaminopropanes](https://en.wikipedia.org/wiki/Cycloalkylaminopropane "Cycloalkylaminopropane") [Arylpiperazines](https://en.wikipedia.org/wiki/Substituted_piperazine "Substituted piperazine") [Benzylpiperazines](https://en.wikipedia.org/wiki/Substituted_benzylpiperazine "Substituted benzylpiperazine") [Phenylpiperazines](https://en.wikipedia.org/wiki/Substituted_phenylpiperazine "Substituted phenylpiperazine") [Phenethylamines](https://en.wikipedia.org/wiki/Substituted_phenethylamine "Substituted phenethylamine") [Aminorexes/phenyloxazolamines](https://en.wikipedia.org/wiki/List_of_aminorex_analogues "List of aminorex analogues") [Amphetamines/α-methylphenethylamines](https://en.wikipedia.org/wiki/Substituted_amphetamine "Substituted amphetamine") [Cathinones/β-ketoamphetamines](https://en.wikipedia.org/wiki/Substituted_cathinone "Substituted cathinone") [β-Hydroxyamphetamines/cathinols](https://en.wikipedia.org/wiki/Substituted_%CE%B2-hydroxyamphetamine "Substituted β-hydroxyamphetamine") [Naphthylaminopropanes](https://en.wikipedia.org/wiki/Substituted_naphthylethylamine "Substituted naphthylethylamine") [Phentermines](https://en.wikipedia.org/wiki/Substituted_phentermine "Substituted phentermine") [Phenylisobutylamines/α-ethylphenethylamines](https://en.wikipedia.org/wiki/Phenylisobutylamine "Phenylisobutylamine") [α-Propylphenethylamines](https://en.wikipedia.org/wiki/%CE%91-Propylphenethylamine "Α-Propylphenethylamine") [Phenylmorpholines/phenmetrazines](https://en.wikipedia.org/wiki/Substituted_phenylmorpholine "Substituted phenylmorpholine") [Thiopropamines/thienylaminopropanes](https://en.wikipedia.org/wiki/Thiopropamine "Thiopropamine") *Cocaine-type/typical dopamine reuptake inhibitors:* [Phenethylamines](https://en.wikipedia.org/wiki/Substituted_phenethylamine "Substituted phenethylamine") [Phenidates](https://en.wikipedia.org/wiki/List_of_methylphenidate_analogues "List of methylphenidate analogues")/[benzylpiperidines](https://en.wikipedia.org/wiki/2-benzylpiperidine "2-benzylpiperidine") [Phenylethylpyrrolidines](https://en.wikipedia.org/wiki/Phenylethylpyrrolidine "Phenylethylpyrrolidine") [Pyrrolidinophenones](https://en.wikipedia.org/wiki/Pyrrolidinophenone "Pyrrolidinophenone") [Phenyltropanes](https://en.wikipedia.org/wiki/List_of_phenyltropanes "List of phenyltropanes")/[cocaine analogues](https://en.wikipedia.org/wiki/List_of_cocaine_analogues "List of cocaine analogues") *Modafinil-type/atypical dopamine reuptake inhibitors:* [Modafinil analogues](https://en.wikipedia.org/wiki/List_of_modafinil_analogues_and_derivatives "List of modafinil analogues and derivatives") [Phenylpiracetams](https://en.wikipedia.org/wiki/Phenylpiracetam "Phenylpiracetam") *Caffeine-type/adenosine receptor antagonists:* [Xanthines](https://en.wikipedia.org/wiki/Xanthine "Xanthine")/[methylxanthines](https://en.wikipedia.org/wiki/Methylxanthine "Methylxanthine") *Nicotine-type/nicotinic acetylcholine receptor agonists:* [Nicotine analogues](https://en.wikipedia.org/wiki/Nicotine_analogue "Nicotine analogue") |
| [Depressants](https://en.wikipedia.org/wiki/Central_depressant "Central depressant") | *GABAA receptor positive allosteric modulators:* [Alcohols](https://en.wikipedia.org/wiki/Alcohol_\(chemistry\) "Alcohol (chemistry)")/[ethanol analogues](https://en.wikipedia.org/wiki/Alcohol_\(drug\)#Analogues "Alcohol (drug)") [Barbiturates](https://en.wikipedia.org/wiki/Barbiturate "Barbiturate") [Benzodiazepines](https://en.wikipedia.org/wiki/Benzodiazepine "Benzodiazepine") [Pyrrolobenzodiazepines](https://en.wikipedia.org/wiki/Pyrrolobenzodiazepine "Pyrrolobenzodiazepine") [Thienobenzodiazepines](https://en.wikipedia.org/wiki/Thienobenzodiazepine "Thienobenzodiazepine") [Thienodiazepines](https://en.wikipedia.org/wiki/Thienodiazepine "Thienodiazepine") [Thienotriazolodiazepines](https://en.wikipedia.org/wiki/Thienotriazolodiazepine "Thienotriazolodiazepine") [Triazolobenzodiazepines](https://en.wikipedia.org/wiki/Triazolobenzodiazepine "Triazolobenzodiazepine") [Carbamates](https://en.wikipedia.org/wiki/Carbamate "Carbamate") [Ethers](https://en.wikipedia.org/wiki/Ether "Ether") [Neuroactive steroids](https://en.wikipedia.org/wiki/Neuroactive_steroid "Neuroactive steroid") [Nonbenzodiazepines](https://en.wikipedia.org/wiki/Nonbenzodiazepine "Nonbenzodiazepine") [β-Carbolines](https://en.wikipedia.org/wiki/Substituted_%CE%B2-carboline "Substituted β-carboline") [Cyclopyrrolones](https://en.wikipedia.org/wiki/Cyclopyrrolones "Cyclopyrrolones") [Imidazopyridines](https://en.wikipedia.org/wiki/Imidazopyridine "Imidazopyridine") [Pyrazolopyrimidines](https://en.wikipedia.org/wiki/Pyrazolopyrimidine "Pyrazolopyrimidine") [Phenols](https://en.wikipedia.org/wiki/Phenol "Phenol") [Piperidinediones](https://en.wikipedia.org/wiki/Piperidinedione "Piperidinedione") [Quinazolinones](https://en.wikipedia.org/wiki/Quinazolinone "Quinazolinone") *GABAA receptor agonists:* [Isoxazoles](https://en.wikipedia.org/wiki/Isoxazole "Isoxazole") *GHB receptor agonists:* [1,4-Butanediols](https://en.wikipedia.org/wiki/Substituted_1,4-butanediol "Substituted 1,4-butanediol") *α2δ subunit-containing voltage-gated calcium channel blockers:* [Gabapentinoids](https://en.wikipedia.org/wiki/Gabapentinoid "Gabapentinoid") *Opioids/μ-opioid receptor agonists:* [Benzimidazoles](https://en.wikipedia.org/wiki/List_of_benzimidazole_opioids "List of benzimidazole opioids") [Nitazenes](https://en.wikipedia.org/wiki/Nitazenes "Nitazenes") [Fentanyl analogues](https://en.wikipedia.org/wiki/List_of_fentanyl_analogues "List of fentanyl analogues")/[phenylpiperidines](https://en.wikipedia.org/wiki/Phenylpiperidines "Phenylpiperidines") [*Mitragyna* alkaloids](https://en.wikipedia.org/wiki/Mitragyna_alkaloid "Mitragyna alkaloid") [Morphinans](https://en.wikipedia.org/wiki/Morphinan "Morphinan")/[phenanthrenes](https://en.wikipedia.org/wiki/Phenanthrene "Phenanthrene") [Opiates](https://en.wikipedia.org/wiki/Opiate "Opiate")/[opium alkaloids](https://en.wikipedia.org/wiki/Opium_alkaloid "Opium alkaloid") [Utopioids](https://en.wikipedia.org/wiki/Utopioid_\(drug_class\) "Utopioid (drug class)") *Antihistamines/H1 receptor antagonists:* [Benzimidazoles](https://en.wikipedia.org/wiki/Benzimidazole "Benzimidazole") [Diarylmethanes](https://en.wikipedia.org/wiki/Substituted_diarylmethane "Substituted diarylmethane") [Ethylenediamines](https://en.wikipedia.org/wiki/Ethylenediamine "Ethylenediamine") [Tricyclics](https://en.wikipedia.org/wiki/Tricyclic_compound "Tricyclic compound") [Dibenzocycloheptenes](https://en.wikipedia.org/wiki/Dibenzocycloheptene "Dibenzocycloheptene") |
| [Hallucinogens](https://en.wikipedia.org/wiki/Hallucinogen "Hallucinogen") | *Serotonergic psychedelics/serotonin 5-HT2A receptor agonists:* [Arylpiperazines](https://en.wikipedia.org/wiki/Substituted_arylpiperazine "Substituted arylpiperazine") [Phenylpiperazines](https://en.wikipedia.org/wiki/Substituted_phenylpiperazine "Substituted phenylpiperazine") [Quinolinylpiperazines](https://en.wikipedia.org/wiki/Substituted_quinolinylpiperazine "Substituted quinolinylpiperazine") [Cyclized phenethylamines](https://en.wikipedia.org/wiki/Cyclized_phenethylamine "Cyclized phenethylamine") [3-Benzazepines](https://en.wikipedia.org/wiki/Substituted_3-benzazepine "Substituted 3-benzazepine") [Cyclized tryptamines](https://en.wikipedia.org/wiki/Cyclized_tryptamine "Cyclized tryptamine") [Azepinoindoles](https://en.wikipedia.org/wiki/Azepinoindole "Azepinoindole") [Ibogalogs](https://en.wikipedia.org/wiki/Ibogalog "Ibogalog") [*Iboga* alkaloids](https://en.wikipedia.org/wiki/Iboga-type_alkaloid "Iboga-type alkaloid") [β-Carbolines](https://en.wikipedia.org/wiki/Substituted_%CE%B2-carboline "Substituted β-carboline") [Harmala alkaloids](https://en.wikipedia.org/wiki/Harmala_alkaloid "Harmala alkaloid") [Ergolines](https://en.wikipedia.org/wiki/Substituted_ergoline "Substituted ergoline") [Lysergamides](https://en.wikipedia.org/wiki/Substituted_lysergamide "Substituted lysergamide") [Simplified/partial lysergamides](https://en.wikipedia.org/wiki/Simplified/partial_lysergamide "Simplified/partial lysergamide") [Phenethylamines](https://en.wikipedia.org/wiki/Substituted_phenethylamine "Substituted phenethylamine") ([methoxyphenethylamines](https://en.wikipedia.org/wiki/Substituted_methoxyphenethylamine "Substituted methoxyphenethylamine")) [2Cs](https://en.wikipedia.org/wiki/2C_\(psychedelics\) "2C (psychedelics)") [25-NB/NBOMes](https://en.wikipedia.org/wiki/25-NB "25-NB") [2C-Os](https://en.wikipedia.org/wiki/2C-O "2C-O") [2C-Ts](https://en.wikipedia.org/wiki/2C-T "2C-T") [HOT-x](https://en.wikipedia.org/wiki/HOT-x "HOT-x") [TWEETIOs](https://en.wikipedia.org/wiki/TWEETIO "TWEETIO") [Amphetamines/α-methylphenethylamines](https://en.wikipedia.org/wiki/Substituted_amphetamine "Substituted amphetamine") [3Cs](https://en.wikipedia.org/wiki/3C_\(psychedelics\) "3C (psychedelics)") [Dimethoxyamphetamines/DMAs](https://en.wikipedia.org/wiki/Dimethoxyamphetamine "Dimethoxyamphetamine") [DOx](https://en.wikipedia.org/wiki/DOx "DOx") [Alephs](https://en.wikipedia.org/wiki/Aleph_\(psychedelic\) "Aleph (psychedelic)") [Ethylenedioxyamphetamines/EDxx](https://en.wikipedia.org/wiki/Substituted_ethylenedioxyphenethylamine "Substituted ethylenedioxyphenethylamine") [Methylenedioxyamphetamines/MDxx](https://en.wikipedia.org/wiki/Substituted_methylenedioxyphenethylamine "Substituted methylenedioxyphenethylamine") [Trimethoxyamphetamines/TMAs](https://en.wikipedia.org/wiki/Trimethoxyamphetamine "Trimethoxyamphetamine") [BOx](https://en.wikipedia.org/wiki/BOx_\(psychedelics\) "BOx (psychedelics)") [FLYs](https://en.wikipedia.org/wiki/FLY_\(psychedelics\) "FLY (psychedelics)")/[benzofurans](https://en.wikipedia.org/wiki/Substituted_benzofuran "Substituted benzofuran") [Phenylisobutylamines/α-ethylphenethylamines](https://en.wikipedia.org/wiki/Phenylisobutylamine "Phenylisobutylamine") [4Cs](https://en.wikipedia.org/wiki/4C_\(psychedelics\) "4C (psychedelics)") [Scalines](https://en.wikipedia.org/wiki/Scaline "Scaline") [Ψ-PEAs](https://en.wikipedia.org/wiki/%CE%A8-PEA "Ψ-PEA") [Tryptamines](https://en.wikipedia.org/wiki/Substituted_tryptamine "Substituted tryptamine") [α-Alkyltryptamines](https://en.wikipedia.org/wiki/Substituted_%CE%B1-alkyltryptamine "Substituted α-alkyltryptamine") [α-Alkyl-β-ketotryptamines](https://en.wikipedia.org/wiki/Substituted_%CE%B2-ketotryptamine "Substituted β-ketotryptamine") [4-Hydroxytryptamines](https://en.wikipedia.org/wiki/Substituted_4-hydroxytryptamine "Substituted 4-hydroxytryptamine") [5-Hydroxytryptamines](https://en.wikipedia.org/wiki/Substituted_5-hydroxytryptamine "Substituted 5-hydroxytryptamine") [5-Methoxytryptamines](https://en.wikipedia.org/wiki/Substituted_5-methoxytryptamine "Substituted 5-methoxytryptamine") [Miscellaneous](https://en.wikipedia.org/wiki/List_of_miscellaneous_5-HT2A_receptor_agonists "List of miscellaneous 5-HT2A receptor agonists") *Dissociatives/NMDA receptor antagonists:* [Adamantanes](https://en.wikipedia.org/wiki/Adamantane "Adamantane") [Arylcyclohexylamines](https://en.wikipedia.org/wiki/Arylcyclohexylamine "Arylcyclohexylamine") [Diarylethylamines](https://en.wikipedia.org/wiki/Diarylethylamine "Diarylethylamine") [Morphinans](https://en.wikipedia.org/wiki/Morphinan "Morphinan") *κ-Opioid receptor agonists:* [Benzomorphans](https://en.wikipedia.org/wiki/Benzomorphan "Benzomorphan") [Salvinorins](https://en.wikipedia.org/wiki/Salvinorin "Salvinorin") *GABAA receptor agonists:* [Isoxazoles](https://en.wikipedia.org/wiki/Isoxazole "Isoxazole") *Deliriants/anticholinergics/muscarinic acetylcholine receptor antagonists:* [Diarylmethanes](https://en.wikipedia.org/wiki/Substituted_diarylmethane "Substituted diarylmethane") [Tropanes](https://en.wikipedia.org/wiki/Tropanes "Tropanes") *Others:* [Cyclized tryptamines](https://en.wikipedia.org/wiki/Cyclized_tryptamine "Cyclized tryptamine") [Azepinoindoles](https://en.wikipedia.org/wiki/Azepinoindole "Azepinoindole") [*Iboga* alkaloids](https://en.wikipedia.org/wiki/Iboga-type_alkaloid "Iboga-type alkaloid") [(Phyto)cannabinoids](https://en.wikipedia.org/wiki/Cannabinoid "Cannabinoid") |
| [Entactogens](https://en.wikipedia.org/wiki/Entactogen "Entactogen") | *Serotonin releasing agents:* [Phenethylamines](https://en.wikipedia.org/wiki/Substituted_phenethylamine "Substituted phenethylamine") [2-Aminoindanes](https://en.wikipedia.org/wiki/Substituted_2-aminoindane "Substituted 2-aminoindane") [2-Aminotetralins](https://en.wikipedia.org/wiki/Substituted_2-aminotetralin "Substituted 2-aminotetralin") [Amphetamines](https://en.wikipedia.org/wiki/Substituted_amphetamine "Substituted amphetamine") [Benzofuranylaminopropanes](https://en.wikipedia.org/wiki/Substituted_benzofuran "Substituted benzofuran") [Benzothiophenylaminopropanes](https://en.wikipedia.org/wiki/Substituted_benzothiophene "Substituted benzothiophene") [Ethylenedioxyamphetamines/EDxx](https://en.wikipedia.org/wiki/Substituted_methylenedioxyphenethylamine "Substituted methylenedioxyphenethylamine") [Indanylaminopropanes](https://en.wikipedia.org/wiki/Indanylaminopropane "Indanylaminopropane") [Indolylaminopropanes](https://en.wikipedia.org/wiki/Indolylaminopropane "Indolylaminopropane") [Methylenedioxyamphetamines/MDxx](https://en.wikipedia.org/wiki/Substituted_methylenedioxyphenethylamine "Substituted methylenedioxyphenethylamine") [Tetralinylaminopropanes](https://en.wikipedia.org/wiki/Tetralinylaminopropane "Tetralinylaminopropane") [Tryptamines](https://en.wikipedia.org/wiki/Substituted_tryptamine "Substituted tryptamine") [α-Alkyltryptamines](https://en.wikipedia.org/wiki/Substituted_%CE%B1-alkyltryptamine "Substituted α-alkyltryptamine") [Miscellaneous](https://en.wikipedia.org/wiki/Substituted_methylenedioxyphenethylamine#Related_compounds "Substituted methylenedioxyphenethylamine") |
| [Psychiatric drugs](https://en.wikipedia.org/wiki/Psychiatric_drug "Psychiatric drug") | *Anxiolytics:* [Azapirones](https://en.wikipedia.org/wiki/Azapirone "Azapirone") [Benzodiazepines](https://en.wikipedia.org/wiki/Benzodiazepine "Benzodiazepine") [Pyrrolobenzodiazepines](https://en.wikipedia.org/wiki/Pyrrolobenzodiazepine "Pyrrolobenzodiazepine") [Thienobenzodiazepines](https://en.wikipedia.org/wiki/Thienobenzodiazepine "Thienobenzodiazepine") [Thienodiazepines](https://en.wikipedia.org/wiki/Thienodiazepine "Thienodiazepine") [Thienotriazolodiazepines](https://en.wikipedia.org/wiki/Thienotriazolodiazepine "Thienotriazolodiazepine") [Triazolobenzodiazepines](https://en.wikipedia.org/wiki/Triazolobenzodiazepine "Triazolobenzodiazepine") *Antidepressants:* [Tricyclic antidepressants](https://en.wikipedia.org/wiki/Tricyclic_antidepressant "Tricyclic antidepressant") [Dibenzazepines](https://en.wikipedia.org/wiki/Dibenzazepine "Dibenzazepine") [Dibenzocycloheptenes](https://en.wikipedia.org/wiki/Dibenzocycloheptene "Dibenzocycloheptene") [Dibenzothiepins](https://en.wikipedia.org/wiki/Dibenzothiepin "Dibenzothiepin") [Dibenzoxazepines](https://en.wikipedia.org/wiki/Dibenzoxazepine "Dibenzoxazepine") [Dibenzoxepins](https://en.wikipedia.org/wiki/Dibenzoxepin "Dibenzoxepin") [Tetracyclic antidepressants](https://en.wikipedia.org/wiki/Tetracyclic_antidepressant "Tetracyclic antidepressant") *Antipsychotics/dopamine D2 receptor antagonists or partial agonists:* [Benzamides](https://en.wikipedia.org/wiki/Benzamide "Benzamide") [Benzimidazoles](https://en.wikipedia.org/wiki/Benzimidazole "Benzimidazole") [Benzisothiazoles](https://en.wikipedia.org/wiki/Benzothiazole "Benzothiazole") [Benzisoxazoles](https://en.wikipedia.org/wiki/Benzisoxazole "Benzisoxazole") [Butyrophenones](https://en.wikipedia.org/wiki/Butyrophenone "Butyrophenone") [Diphenylbutylpiperidines](https://en.wikipedia.org/wiki/Diphenylbutylpiperidine "Diphenylbutylpiperidine") [Phenylpiperazines](https://en.wikipedia.org/wiki/Phenylpiperazine "Phenylpiperazine") [Tricyclics](https://en.wikipedia.org/wiki/Tricyclic_compound "Tricyclic compound") [Dibenzazepines](https://en.wikipedia.org/wiki/Dibenzazepine "Dibenzazepine") [Dibenzodiazepines](https://en.wikipedia.org/wiki/Dibenzodiazepine "Dibenzodiazepine") [Dibenzothiazepines](https://en.wikipedia.org/wiki/Dibenzothiazepine "Dibenzothiazepine") [Dibenzothiepins](https://en.wikipedia.org/wiki/Dibenzothiepin "Dibenzothiepin") [Dibenzoxazepines](https://en.wikipedia.org/wiki/Dibenzoxazepine "Dibenzoxazepine") [Phenothiazines](https://en.wikipedia.org/wiki/Phenothiazine "Phenothiazine") [Thienobenzodiazepines](https://en.wikipedia.org/wiki/Thienobenzodiazepine "Thienobenzodiazepine") *Mood stabilizers/anticonvulsants:* [Gabapentinoids](https://en.wikipedia.org/wiki/Gabapentinoid "Gabapentinoid") [Tricyclics](https://en.wikipedia.org/wiki/Tricyclic_compound "Tricyclic compound") [Dibenzazepines](https://en.wikipedia.org/wiki/Dibenzazepine "Dibenzazepine") [Valproates](https://en.wikipedia.org/wiki/Valproate "Valproate") |
| Others | *Nootropics:* [Racetams](https://en.wikipedia.org/wiki/Racetam "Racetam") [Phenylpiracetams](https://en.wikipedia.org/wiki/Phenylpiracetam "Phenylpiracetam") *Miscellaneous:* [3-Benzazepines](https://en.wikipedia.org/wiki/Substituted_3-benzazepine "Substituted 3-benzazepine") [Adamantanes](https://en.wikipedia.org/wiki/Adamantane "Adamantane") [Catecholamines](https://en.wikipedia.org/wiki/Catecholamine "Catecholamine") [Tetrahydroisoquinolines](https://en.wikipedia.org/wiki/Substituted_tetrahydroisoquinoline "Substituted tetrahydroisoquinoline") [Yohimbans](https://en.wikipedia.org/wiki/Yohimban "Yohimban") |
| [Authority control databases](https://en.wikipedia.org/wiki/Help:Authority_control "Help:Authority control") [](https://www.wikidata.org/wiki/Q76560#identifiers "Edit this at Wikidata") | |
|---|---|
| International | [GND](https://d-nb.info/gnd/4002263-8) [FAST](https://id.worldcat.org/fast/810483) |
| National | [United States](https://id.loc.gov/authorities/sh85005661) [France](https://catalogue.bnf.fr/ark:/12148/cb11944046z) [BnF data](https://data.bnf.fr/ark:/12148/cb11944046z) [Japan](https://id.ndl.go.jp/auth/ndlna/01140705) [Czech Republic](https://aleph.nkp.cz/F/?func=find-c&local_base=aut&ccl_term=ica=ph137961&CON_LNG=ENG) [Spain](https://datos.bne.es/resource/XX528348) [Israel](https://www.nli.org.il/en/authorities/987007295550405171) |
| Other | [Yale LUX](https://lux.collections.yale.edu/view/concept/b8cbd1c5-e082-4351-b418-dd947316aa3a) |
Retrieved from "<https://en.wikipedia.org/w/index.php?title=Antidepressant&oldid=1347339395>"
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Antidepressant
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[Add topic](https://en.wikipedia.org/wiki/Antidepressant) |
| Readable Markdown | | Antidepressant | |
|---|---|
| *[Drug class](https://en.wikipedia.org/wiki/Drug_class "Drug class")* | |
| [](https://en.wikipedia.org/wiki/File:Venlafaxine_structure.svg)[Venlafaxine](https://en.wikipedia.org/wiki/Venlafaxine "Venlafaxine") (brand name Effexor), an antidepressant acting as a [serotonin–norepinephrine reuptake inhibitor](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") (SNRI). | |
| Class identifiers | |
| [Synonyms](https://en.wikipedia.org/wiki/Synonym "Synonym") | Psychic energizer; Mood elevator; Thymoleptic; Depression pill |
| Use | [Depressive disorders](https://en.wikipedia.org/wiki/Mood_disorder#Depressive_disorders "Mood disorder"), [anxiety disorders](https://en.wikipedia.org/wiki/Anxiety_disorders "Anxiety disorders"), [chronic pain](https://en.wikipedia.org/wiki/Chronic_pain "Chronic pain"), and [addiction](https://en.wikipedia.org/wiki/Addiction "Addiction") |
| [ATC code](https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System "Anatomical Therapeutic Chemical Classification System") | [N06A](https://en.wikipedia.org/wiki/ATC_code_N06A "ATC code N06A") |
| [Mechanism of action](https://en.wikipedia.org/wiki/Mechanism_of_action "Mechanism of action") | Varies |
| [Chemical class](https://en.wikipedia.org/wiki/Chemical_classification "Chemical classification") | Varies |
| Clinical data | |
| [Drugs.com](https://en.wikipedia.org/wiki/Drugs.com "Drugs.com") | [Drug Classes](https://www.drugs.com/drug-class/antidepressants.html) |
| [Consumer Reports](https://en.wikipedia.org/wiki/Consumer_Reports "Consumer Reports") | [Best Buy Drugs](http://www.consumerreports.org/health/best-buy-drugs/antidepressants.htm) |
| [WebMD](https://en.wikipedia.org/wiki/WebMD "WebMD") | [MedicineNet](http://www.medicinenet.com/antidepressants/article.htm) [RxList](http://www.rxlist.com/script/main/art.asp?articlekey=100734) |
| External links | |
| [MeSH](https://en.wikipedia.org/wiki/Medical_Subject_Headings "Medical Subject Headings") | [D000928](https://meshb.nlm.nih.gov/record/ui?ui=D000928) |
| Legal status | |
| [In Wikidata](https://www.wikidata.org/wiki/Q76560 "d:Q76560") | |
**Antidepressants**, also known in the past as **psychic energizers**,[\[1\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Ghaemi2015-1) are a class of [medications](https://en.wikipedia.org/wiki/Medication "Medication") used to treat [major depressive disorder](https://en.wikipedia.org/wiki/Major_depressive_disorder "Major depressive disorder"), [anxiety disorders](https://en.wikipedia.org/wiki/Anxiety_disorder "Anxiety disorder"), [chronic pain](https://en.wikipedia.org/wiki/Chronic_pain "Chronic pain"), and [addiction](https://en.wikipedia.org/wiki/Addiction "Addiction").[\[2\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Jennings2018-2)
Common [side effects](https://en.wikipedia.org/wiki/Side_effect "Side effect") of antidepressants include [dry mouth](https://en.wikipedia.org/wiki/Xerostomia "Xerostomia"), [weight gain](https://en.wikipedia.org/wiki/Weight_gain "Weight gain"), [dizziness](https://en.wikipedia.org/wiki/Dizziness "Dizziness"), [headaches](https://en.wikipedia.org/wiki/Headache "Headache"), [akathisia](https://en.wikipedia.org/wiki/Akathisia "Akathisia"),[\[3\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-3) [sexual dysfunction](https://en.wikipedia.org/wiki/Sexual_dysfunction "Sexual dysfunction"),[\[4\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-4)[\[5\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Bahrick-5)[\[6\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-6)[\[7\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-7)[\[8\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-8) and [emotional blunting](https://en.wikipedia.org/wiki/Emotional_blunting "Emotional blunting").[\[9\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-9)[\[10\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-10)[\[11\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-11) There is an increased risk of [suicidal thinking](https://en.wikipedia.org/wiki/Suicidal_ideation "Suicidal ideation") and [behavior](https://en.wikipedia.org/wiki/Suicide "Suicide") when taken by children, adolescents, and young adults.[\[12\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-12) [Discontinuation syndrome](https://en.wikipedia.org/wiki/Antidepressant_discontinuation_syndrome "Antidepressant discontinuation syndrome"), which resembles recurrent [depression](https://en.wikipedia.org/wiki/Depression_\(mood\) "Depression (mood)") in the case of the [SSRI](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor "Selective serotonin reuptake inhibitor") class, may occur after stopping the intake of any antidepressant, having effects which may be permanent and irreversible. [Tapering](https://en.wikipedia.org/wiki/Tapering_\(medicine\) "Tapering (medicine)") off medications gradually is shown to reduce the risk of [withdrawal](https://en.wikipedia.org/wiki/Antidepressant_discontinuation_syndrome "Antidepressant discontinuation syndrome") complications.[\[13\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Wil2015-13)[\[14\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Gab2017-14)
The effectiveness of antidepressants for treating depression in adults has strong support, though studies also highlight potential risks and limitations.[\[15\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-BarthKriston2018-15)[\[16\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-BMJ2019-16) In children and adolescents, evidence of efficacy is more limited, despite a marked increase in antidepressant prescriptions for these age groups since the 2000s.[\[17\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-CiprianiZhou2016-17)[\[18\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-18)[\[19\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-19) A 2018 meta-analysis reported that the 21 most commonly prescribed antidepressants were found in all studies to be more effective than [placebos](https://en.wikipedia.org/wiki/Placebo "Placebo") for the short-term treatment of [major depressive disorder](https://en.wikipedia.org/wiki/Major_depressive_disorder "Major depressive disorder") in adults. However, other research suggests that some benefits may be attributable to the placebo effect. Response to antidepressants is highly variable, and medications that are effective for certain patients may have no effect or a negative effect for others. Research into the factors that influence individual responses to antidepressants is ongoing.[\[20\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NIHR-2018-20)[\[21\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-CiprianiFurukawa2018-21)[\[22\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-22)[\[23\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-TurnerRosenthal2008-23)[\[24\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-24)
Antidepressants are prescribed to treat [major depressive disorder](https://en.wikipedia.org/wiki/Major_depressive_disorder "Major depressive disorder") (MDD), [anxiety disorders](https://en.wikipedia.org/wiki/Anxiety_disorder "Anxiety disorder"), [chronic pain](https://en.wikipedia.org/wiki/Chronic_pain "Chronic pain"), and some addictions. Antidepressants are often used in combination with one another.[\[2\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Jennings2018-2)
Despite its longstanding prominence in pharmaceutical advertising, the idea that low serotonin levels cause depression is not supported by scientific evidence.[\[25\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-25)[\[26\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-26)[\[27\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-27) Proponents of the [monoamine hypothesis of depression](https://en.wikipedia.org/wiki/Biology_of_depression "Biology of depression") recommend choosing an antidepressant which impacts the most prominent symptoms. Under this practice, for example, a person with MDD who is also anxious or irritable would be treated with [selective serotonin reuptake inhibitors](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor "Selective serotonin reuptake inhibitor") (SSRIs) or [norepinephrine reuptake inhibitors](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitor "Norepinephrine reuptake inhibitor"), while a person suffering from loss of energy and enjoyment of life would take a [norepinephrine–dopamine reuptake inhibitor](https://en.wikipedia.org/wiki/Norepinephrine%E2%80%93dopamine_reuptake_inhibitor "Norepinephrine–dopamine reuptake inhibitor").[\[28\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid18494537-28)
### Major depressive disorder
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=2 "Edit section: Major depressive disorder")\]
The UK [National Institute for Health and Care Excellence](https://en.wikipedia.org/wiki/National_Institute_for_Health_and_Care_Excellence "National Institute for Health and Care Excellence") (NICE)'s 2022 guidelines indicate that antidepressants should not be routinely used for the initial treatment of mild depression, "unless that is the person's preference".[\[29\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NIHCE-2022-29) The guidelines recommended that antidepressant treatment be considered:
- For people with a history of moderate or severe depression.
- For people with mild depression that has been present for an extended period.
- As a first-line treatment for moderate to severe depression.
- As a second-line treatment for mild depression that persists after other interventions.
The guidelines further note that in most cases, antidepressants should be used in combination with psychosocial interventions and should be continued for at least six months to reduce the risk of relapse and that SSRIs are typically better tolerated than other antidepressants.[\[29\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NIHCE-2022-29)
[American Psychiatric Association](https://en.wikipedia.org/wiki/American_Psychiatric_Association "American Psychiatric Association") (APA) treatment guidelines recommend that initial treatment be individually tailored based on factors including the severity of symptoms, co-existing disorders, prior treatment experience, and the person's preference. Options may include antidepressants, [psychotherapy](https://en.wikipedia.org/wiki/Psychotherapy "Psychotherapy"), [electroconvulsive therapy](https://en.wikipedia.org/wiki/Electroconvulsive_therapy "Electroconvulsive therapy") (ECT), [transcranial magnetic stimulation](https://en.wikipedia.org/wiki/Transcranial_magnetic_stimulation "Transcranial magnetic stimulation") (TMS), or [light therapy](https://en.wikipedia.org/wiki/Light_therapy "Light therapy"). The APA recommends antidepressant medication as an initial treatment choice in people with mild, moderate, or severe major depression, and that should be given to all people with severe depression unless ECT is planned.[\[30\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-30)
Reviews of antidepressants generally find that they benefit adults with depression.[\[21\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-CiprianiFurukawa2018-21)[\[15\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-BarthKriston2018-15) On the other hand, some contend that most studies on antidepressant medication are confounded by several biases: the lack of an [active placebo](https://en.wikipedia.org/wiki/Active_placebo "Active placebo"), which means that many people in the placebo arm of a [double-blind study](https://en.wikipedia.org/wiki/Randomized_controlled_trial "Randomized controlled trial") may deduce that they are not getting any true treatment, thus destroying double-blindness; a short follow up after termination of treatment; non-systematic recording of adverse effects; very strict exclusion criteria in samples of patients; studies being paid for by the industry; selective publication of results. This means that the small beneficial effects that are found may not be statistically significant.[\[31\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-31)[\[32\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-32)[\[33\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-33)[\[34\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-34)[\[16\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-BMJ2019-16)
Among the 21 most commonly prescribed antidepressants, the most effective and well-tolerated are [escitalopram](https://en.wikipedia.org/wiki/Escitalopram "Escitalopram"), [paroxetine](https://en.wikipedia.org/wiki/Paroxetine "Paroxetine"), [sertraline](https://en.wikipedia.org/wiki/Sertraline "Sertraline"), [agomelatine](https://en.wikipedia.org/wiki/Agomelatine "Agomelatine"), and [mirtazapine](https://en.wikipedia.org/wiki/Mirtazapine "Mirtazapine").[\[20\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NIHR-2018-20)[\[21\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-CiprianiFurukawa2018-21) For children and adolescents with moderate to severe depressive disorder, some evidence suggests [fluoxetine](https://en.wikipedia.org/wiki/Fluoxetine "Fluoxetine") (either with or without [cognitive behavioral therapy](https://en.wikipedia.org/wiki/Cognitive_behavioral_therapy "Cognitive behavioral therapy")) is the best treatment, but more research is needed to be certain.[\[35\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Evidence-2020-35)[\[36\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Zhou-2020-36)[\[37\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Boaden-2020-37)[\[38\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Hetrick-2021-38) Sertraline, escitalopram, and [duloxetine](https://en.wikipedia.org/wiki/Duloxetine "Duloxetine") may also help reduce symptoms.[\[38\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Hetrick-2021-38)
A 2023 [systematic review](https://en.wikipedia.org/wiki/Systematic_review "Systematic review") and [meta-analysis](https://en.wikipedia.org/wiki/Meta-analysis "Meta-analysis") of [randomized controlled trials](https://en.wikipedia.org/wiki/Randomized_controlled_trial "Randomized controlled trial") of antidepressants for major depressive disorder found that the medications provided only small or doubtful benefits in terms of [quality of life](https://en.wikipedia.org/wiki/Quality_of_life "Quality of life").[\[39\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid36905396-39) Likewise, a 2022 systematic review and meta-analysis of randomized controlled trials of antidepressants for major depressive disorder in children and adolescents found small improvements in quality of life.[\[40\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35508443-40) Quality of life as an outcome measure is often selectively reported in trials of antidepressants.[\[41\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Paludan-M%C3%BCller_2021-41)
For children and adolescents, [fluvoxamine](https://en.wikipedia.org/wiki/Fluvoxamine "Fluvoxamine") and [escitalopram](https://en.wikipedia.org/wiki/Escitalopram "Escitalopram") are effective in treating a range of anxiety disorders.[\[42\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NIHR-2022-42)[\[37\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Boaden-2020-37)[\[43\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Correll-2021-43) Fluoxetine, sertraline, and paroxetine can also help with managing various forms of anxiety in children and adolescents.[\[42\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NIHR-2022-42)[\[37\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Boaden-2020-37)[\[43\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Correll-2021-43)
Meta-analyses of published and unpublished trials have found that antidepressants have a [placebo](https://en.wikipedia.org/wiki/Placebo_group "Placebo group")\-subtracted [effect size](https://en.wikipedia.org/wiki/Effect_size "Effect size") ([standardized mean difference](https://en.wikipedia.org/wiki/Standardized_mean_difference "Standardized mean difference") or SMD) in the treatment of anxiety disorders of around 0.3, which equates to a small improvement and is roughly the same magnitude of benefit as their effectiveness in the treatment of depression.[\[44\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31249537-44) The effect size (SMD) for improvement with placebo in trials of antidepressants for anxiety disorders is approximately 1.0, which is a large improvement in terms of effect size definitions.[\[45\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31573058-45) In relation to this, most of the benefit of antidepressants for anxiety disorders is attributable to placebo responses rather than to the effects of the antidepressants themselves.[\[44\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31249537-44)[\[45\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31573058-45)
#### Generalized anxiety disorder
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=4 "Edit section: Generalized anxiety disorder")\]
Antidepressants are recommended by the National Institute for Health and Care Excellence (NICE) for the treatment of [generalized anxiety disorder](https://en.wikipedia.org/wiki/Generalized_anxiety_disorder "Generalized anxiety disorder") (GAD) that has failed to respond to conservative measures such as education and self-help activities. GAD is a common disorder in which the central feature is excessively worrying about numerous events. Key symptoms include excessive anxiety about events and issues going on around them and difficulty controlling worrisome thoughts that persists for at least 6 months.
Antidepressants provide a modest to moderate reduction in anxiety in GAD.[\[46\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-urlwww.nice.org.uk-46) The efficacy of different antidepressants is similar.[\[46\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-urlwww.nice.org.uk-46)
Some antidepressants are used as a treatment for [social anxiety disorder](https://en.wikipedia.org/wiki/Social_anxiety_disorder "Social anxiety disorder"), but their efficacy is not entirely convincing, as only a small proportion of antidepressants showed some effectiveness for this condition. Paroxetine was the first drug to be FDA-approved for this disorder. Its efficacy is considered beneficial, although not everyone responds favorably to the drug. Sertraline and fluvoxamine extended-release were later approved for it as well, while escitalopram is used [off-label](https://en.wikipedia.org/wiki/Off-label_use "Off-label use") with acceptable efficiency. However, there is not enough evidence to support [citalopram](https://en.wikipedia.org/wiki/Citalopram "Citalopram") for treating social anxiety disorder, and fluoxetine was no better than a placebo in clinical trials. [Vortioxetine](https://en.wikipedia.org/wiki/Vortioxetine "Vortioxetine") may be of benefit. [SSRIs](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor "Selective serotonin reuptake inhibitor") are used as a first-line treatment for social anxiety, but they do not work for everyone. One alternative would be [venlafaxine](https://en.wikipedia.org/wiki/Venlafaxine "Venlafaxine"), an [SNRI](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor"), which has shown benefits for social phobia in five clinical trials against a placebo, while the other SNRIs are not considered particularly useful for this disorder as many of them did not undergo testing for it. As of 2008, it is unclear if duloxetine and [desvenlafaxine](https://en.wikipedia.org/wiki/Desvenlafaxine "Desvenlafaxine") can provide benefits for people with social anxiety. However, another class of antidepressants called [MAOIs](https://en.wikipedia.org/wiki/Monoamine_oxidase_inhibitor "Monoamine oxidase inhibitor") are considered effective for social anxiety, but they come with many unwanted side effects and are rarely used. [Phenelzine](https://en.wikipedia.org/wiki/Phenelzine "Phenelzine") was shown to be a good treatment option, but its use is limited by dietary restrictions. [Moclobemide](https://en.wikipedia.org/wiki/Moclobemide "Moclobemide") is a [RIMA](https://en.wikipedia.org/wiki/Reversible_inhibitor_of_MAO-A "Reversible inhibitor of MAO-A") and showed mixed results, but still received approval in some European countries for social anxiety disorder. [TCA antidepressants](https://en.wikipedia.org/wiki/Tricyclic_antidepressant "Tricyclic antidepressant"), such as [clomipramine](https://en.wikipedia.org/wiki/Clomipramine "Clomipramine") and [imipramine](https://en.wikipedia.org/wiki/Imipramine "Imipramine"), are not considered effective for this anxiety disorder in particular. This leaves out SSRIs such as paroxetine, sertraline, and fluvoxamine CR as acceptable and tolerated treatment options for this disorder.[\[47\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-47)[\[48\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-48)
#### Obsessive–compulsive disorder
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=6 "Edit section: Obsessive–compulsive disorder")\]
SSRIs are a [second-line](https://en.wikipedia.org/wiki/Second-line_medication "Second-line medication") treatment for adult [obsessive–compulsive disorder](https://en.wikipedia.org/wiki/Obsessive%E2%80%93compulsive_disorder "Obsessive–compulsive disorder") (OCD) with mild functional impairment, and a first-line treatment for those with moderate or severe impairment.[\[49\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-49)[\[50\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-50)[\[51\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-51)[\[52\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-52)
In children, SSRIs are considered as a second-line therapy in those with moderate-to-severe impairment, with close monitoring for psychiatric adverse effects.[\[53\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-53) Sertraline and fluoxetine are effective in treating OCD for children and adolescents.[\[42\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NIHR-2022-42)[\[37\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Boaden-2020-37)[\[43\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Correll-2021-43)
[Clomipramine](https://en.wikipedia.org/wiki/Clomipramine "Clomipramine"), a TCA drug, is considered effective and useful for OCD.[\[54\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-54) However, it is used as a second-line treatment because it is less well-tolerated than SSRIs. Despite this, it has not shown superiority to fluvoxamine in trials. All SSRIs can be used effectively for OCD. SNRI use may also be attempted, though no SNRIs have been approved for the treatment of OCD. Despite these treatment options, many patients remain symptomatic after initiating the medication, and less than half achieve [remission](https://en.wikipedia.org/wiki/Remission_\(medicine\) "Remission (medicine)").[\[55\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-55)
Placebo responses are a large component of the benefit of antidepressants in the treatment of depression and anxiety.[\[44\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31249537-44)[\[45\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31573058-45) However, placebo responses with antidepressants are lower in magnitude in the treatment of OCD compared to depression and anxiety.[\[45\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31573058-45)[\[56\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid28477500-56) A 2019 meta-analysis found placebo improvement effect sizes (SMD) of about 1.2 for depression, 1.0 for anxiety disorders, and 0.6 for OCD with antidepressants.[\[45\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31573058-45)
#### Post–traumatic stress disorder
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=7 "Edit section: Post–traumatic stress disorder")\]
Antidepressants are one of the treatment options for [PTSD](https://en.wikipedia.org/wiki/Post-traumatic_stress_disorder "Post-traumatic stress disorder"). However, their efficacy is not well established. Paroxetine and sertraline have been FDA approved for the treatment of PTSD. Paroxetine has slightly higher response and remission rates than sertraline for this condition. However, neither drug is considered very helpful for a broad patient demographic. Fluoxetine and venlafaxine are used off-label. Fluoxetine has produced unsatisfactory mixed results. Venlafaxine showed response rates of 78%, which is significantly higher than what paroxetine and sertraline achieved. However, it did not address as many symptoms of PTSD as paroxetine and sertraline, in part due to the fact that venlafaxine is an [SNRI](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor"). This class of drugs inhibits the reuptake of norepinephrine, which may cause anxiety in some patients. Fluvoxamine, escitalopram, and citalopram were not well-tested for this disorder. [MAOIs](https://en.wikipedia.org/wiki/Monoamine_oxidase_inhibitor "Monoamine oxidase inhibitor"), while some of them may be helpful, are not used much because of their unwanted side effects. This leaves paroxetine and sertraline as acceptable treatment options for some people, although more effective antidepressants are needed.[\[57\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-57)
[Panic disorder](https://en.wikipedia.org/wiki/Panic_disorder "Panic disorder") is treated relatively well with medications compared to other disorders. Several classes of antidepressants have shown efficacy for this disorder, with SSRIs and SNRIs used first-line. Paroxetine, sertraline, and fluoxetine are FDA-approved for panic disorder, while fluvoxamine, escitalopram, and citalopram are also considered effective for them. SNRI venlafaxine is also approved for this condition. Unlike [social anxiety](https://en.wikipedia.org/wiki/Social_anxiety "Social anxiety") and [PTSD](https://en.wikipedia.org/wiki/Post-traumatic_stress_disorder "Post-traumatic stress disorder"), some [TCAs antidepressants](https://en.wikipedia.org/wiki/Tricyclic_antidepressant "Tricyclic antidepressant"), like clomipramine and imipramine, have shown efficacy for panic disorder. Moreover, the [MAOI](https://en.wikipedia.org/wiki/Monoamine_oxidase_inhibitor "Monoamine oxidase inhibitor") [phenelzine](https://en.wikipedia.org/wiki/Phenelzine "Phenelzine") is also considered useful. Panic disorder has many drugs for its treatment. However, the starting dose must be lower than the one used for major depressive disorder because people have reported an increase in anxiety as a result of starting the medication. In conclusion, while panic disorder's treatment options seem acceptable and useful for this condition, many people are still symptomatic after treatment with residual symptoms.[\[58\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-58)[\[59\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-59)[\[60\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-60)
Antidepressants are recommended as an alternative or additional first step to self-help programs in the treatment of [bulimia nervosa](https://en.wikipedia.org/wiki/Bulimia_nervosa "Bulimia nervosa").[\[61\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-urlwww.nice.org.uk2-61) SSRIs (fluoxetine in particular) are preferred over other antidepressants due to their acceptability, tolerability, and superior reduction of symptoms in short-term trials. Long-term efficacy remains poorly characterized. [Bupropion](https://en.wikipedia.org/wiki/Bupropion "Bupropion") is not recommended for the treatment of eating disorders, due to an increased risk of seizure.[\[62\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-62)
Similar recommendations apply to [binge eating disorder](https://en.wikipedia.org/wiki/Binge_eating_disorder "Binge eating disorder").[\[61\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-urlwww.nice.org.uk2-61) SSRIs provide short-term reductions in binge eating behavior, but have not been associated with significant weight loss.[\[63\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-urlNational_Guideline_Clearinghouse_|_Practice_guideline_for_the_treatment_of_patients_with_eating_disorders.-63)
Clinical trials have generated mostly negative results for the use of SSRIs in the treatment of [anorexia nervosa](https://en.wikipedia.org/wiki/Anorexia_nervosa "Anorexia nervosa").[\[64\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid21414249-64) Treatment guidelines from the National Institute of Health and Care Excellence (NICE)[\[61\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-urlwww.nice.org.uk2-61) recommend against the use of SSRIs in this disorder. Those from the American Psychiatric Association (APA) note that SSRIs confer no advantage regarding weight gain, but may be used for the treatment of co-existing depressive, anxiety, or obsessive–compulsive disorders.[\[63\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-urlNational_Guideline_Clearinghouse_|_Practice_guideline_for_the_treatment_of_patients_with_eating_disorders.-63)
A 2012 [meta-analysis](https://en.wikipedia.org/wiki/Meta-analysis "Meta-analysis") concluded that antidepressant treatment favorably affects pain, health-related quality of life, depression, and sleep in [fibromyalgia](https://en.wikipedia.org/wiki/Fibromyalgia "Fibromyalgia") syndrome. [Tricyclics](https://en.wikipedia.org/wiki/Tricyclic_antidepressant "Tricyclic antidepressant") appear to be the most effective class, with moderate effects on pain and sleep, and small effects on fatigue and health-related quality of life. The fraction of people experiencing a 30% pain reduction on tricyclics was 48%, versus 28% on placebo. For SSRIs and SNRIs, the fractions of people experiencing a 30% pain reduction were 36% (20% in the placebo comparator arms) and 42% (32% in the corresponding placebo comparator arms) respectively. Discontinuation of treatment due to side effects was common.[\[65\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-65) Antidepressants including [amitriptyline](https://en.wikipedia.org/wiki/Amitriptyline "Amitriptyline"), [duloxetine](https://en.wikipedia.org/wiki/Duloxetine "Duloxetine"), [milnacipran](https://en.wikipedia.org/wiki/Milnacipran "Milnacipran"), [moclobemide](https://en.wikipedia.org/wiki/Moclobemide "Moclobemide"), and [pirlindole](https://en.wikipedia.org/wiki/Pirlindole "Pirlindole") are recommended by the European League Against Rheumatism (EULAR) for the treatment of fibromyalgia based on "limited evidence".[\[66\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid17644548-66)
A 2014 meta-analysis from the [Cochrane Collaboration](https://en.wikipedia.org/wiki/Cochrane_Collaboration "Cochrane Collaboration") found the antidepressant duloxetine to be effective for the treatment of pain resulting from [diabetic neuropathy](https://en.wikipedia.org/wiki/Diabetic_neuropathy "Diabetic neuropathy").[\[67\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-67) The same group reviewed data for amitriptyline in the treatment of [neuropathic pain](https://en.wikipedia.org/wiki/Neuropathic_pain "Neuropathic pain") and found limited useful randomized clinical trial data. They concluded that the long history of successful use in the community for the treatment of fibromyalgia and neuropathic pain justified its continued use.[\[68\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Moore2015-68) The group was concerned about the potential overestimation of the amount of pain relief provided by amitriptyline, and highlighted that only a small number of people will experience significant pain relief by taking this medication.[\[68\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Moore2015-68)
Antidepressants may be modestly helpful for treating people who have both depression and [alcohol dependence](https://en.wikipedia.org/wiki/Alcohol_dependence "Alcohol dependence"), however, the evidence supporting this association is of low quality.[\[69\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-69) Bupropion is used to help people [stop smoking](https://en.wikipedia.org/wiki/Smoking_cessation "Smoking cessation"). Antidepressants are also used to control some symptoms of [narcolepsy](https://en.wikipedia.org/wiki/Narcolepsy "Narcolepsy").[\[70\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-70) Antidepressants may be used to relieve pain in people with active [rheumatoid arthritis](https://en.wikipedia.org/wiki/Rheumatoid_arthritis "Rheumatoid arthritis"). However, further research is required.[\[71\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-71) Antidepressants have been shown to be superior to placebo in treating depression in individuals with physical illness, although reporting bias may have exaggerated this finding.[\[72\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-72) Antidepressants have been shown to improve some parts of cognitive functioning for depressed users, such as memory, attention, and processing speed.[\[73\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-73)
Certain antidepressants acting as serotonin 5-HT2A receptor antagonists, such as [trazodone](https://en.wikipedia.org/wiki/Trazodone "Trazodone") and [mirtazapine](https://en.wikipedia.org/wiki/Mirtazapine "Mirtazapine"), have been used as [hallucinogen antidotes or "trip killers"](https://en.wikipedia.org/wiki/Trip_killer "Trip killer") to block the effects of [serotonergic psychedelics](https://en.wikipedia.org/wiki/Serotonergic_psychedelic "Serotonergic psychedelic") like [psilocybin](https://en.wikipedia.org/wiki/Psilocybin "Psilocybin") and [lysergic acid diethylamide](https://en.wikipedia.org/wiki/Lysergic_acid_diethylamide "Lysergic acid diethylamide") (LSD).[\[74\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-HalmanKongSarris2024-74)[\[75\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-YatesMelon2024-75)[\[76\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Suran2024-76)
### Limitations and strategies
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=14 "Edit section: Limitations and strategies")\]
Among individuals treated with a given antidepressant, between 30% and 50% do not show a response.[\[77\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-77)[\[78\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-SSRIswitch-78) Approximately one-third of people achieve a full [remission](https://en.wikipedia.org/wiki/Remission_\(medicine\) "Remission (medicine)"), one-third experience a response, and one-third are non-responders. Partial remission is characterized by the presence of poorly defined residual symptoms. These symptoms typically include depressed mood, anxiety, sleep disturbance, fatigue, and diminished interest or pleasure. It is currently unclear which factors predict partial remission. However, it is clear that residual symptoms are powerful predictors of relapse, with relapse rates three to six times higher in people with residual symptoms than in those, who experience full remission.[\[79\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-79) In addition, antidepressant drugs tend to lose efficacy throughout long-term [maintenance therapy](https://en.wikipedia.org/wiki/Maintenance_therapy "Maintenance therapy").[\[80\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-80) According to data from the [Centers for Disease Control and Prevention](https://en.wikipedia.org/wiki/Centers_for_Disease_Control_and_Prevention "Centers for Disease Control and Prevention"), less than one-third of Americans taking one antidepressant medication have seen a mental health professional in the previous year.[\[81\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-81) Several strategies are used in clinical practice to try to overcome these limits and variations.[\[82\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-82) They include switching medication, augmentation, and combination.
There is controversy amongst researchers regarding the efficacy and risk-benefit ratio of antidepressants.[\[83\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Wilson2018-83)[\[84\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Warren2020-84) Although antidepressants consistently out-perform a placebo in meta-analyses, the difference is modest and it is not clear that their statistical superiority results in clinical efficacy.[\[21\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-CiprianiFurukawa2018-21)[\[85\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35918097-85)[\[86\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid30386270-86)[\[87\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-McCormack2018-87) The aggregate effect of antidepressants typically results in changes below the threshold of clinical significance on depression rating scales.[\[88\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31554608-88)[\[89\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid25979317-89) Proponents of antidepressants counter that the most common scale, the [HDRS](https://en.wikipedia.org/wiki/HDRS "HDRS"), is not suitable for assessing drug action, that the threshold for clinical significance is arbitrary, and that antidepressants consistently result in significantly raised scores on the mood item of the scale.[\[90\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Pariante2022-90) Assessments of antidepressants using alternative, more sensitive scales, such as the [MADRS](https://en.wikipedia.org/wiki/Montgomery%E2%80%93%C3%85sberg_Depression_Rating_Scale "Montgomery–Åsberg Depression Rating Scale"), do not result in marked difference from the HDRS and likewise only find a marginal clinical benefit.[\[91\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid32101579-91) Another hypothesis proposed to explain the poor performance of antidepressants in clinical trials is a high treatment response heterogeneity. Some patients, that differ strongly in their response to antidepressants, could influence the average response, while the heterogeneity could itself be obscured by the averaging. Studies have not supported this hypothesis, but it is very difficult to measure treatment effect heterogeneity.[\[92\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Luedtke2021-92) Poor and complex clinical trial design might also account for the small effects seen for antidepressants.[\[93\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Khan2015-93)[\[94\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Nutt2008-94) The randomized controlled trials used to approve drugs are short, and may not capture the full effect of antidepressants.[\[94\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Nutt2008-94) Additionally, the placebo effect might be inflated in these trials by frequent clinical consultation, lowering the comparative performance of antidepressants.[\[94\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Nutt2008-94) Critics agree that current clinical trials are poorly-designed, which limits the knowledge on antidepressants.[\[95\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Boesen2021-95) More naturalistic studies, such as [STAR\*D](https://en.wikipedia.org/wiki/STAR*D "STAR*D"), have produced results, which suggest that antidepressants may be less effective in clinical practice than in randomized controlled trials.[\[96\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Read2022-96)[\[97\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-97)
Critics of antidepressants maintain that the superiority of antidepressants over placebo is the result of systemic flaws in clinical trials and the research literature.[\[96\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Read2022-96)[\[88\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31554608-88) Trials conducted with industry involvement tend to produce more favorable results, and accordingly many of the trials included in meta-analyses are at high risk of bias.[\[98\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31248914-98)[\[88\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31554608-88) Additionally, meta-analyses co-authored by industry employees find more favorable results for antidepressants.[\[88\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31554608-88) The results of antidepressant trials are significantly more likely to be published if they are favorable, and unfavorable results are very often left unpublished or misreported, a phenomenon called [publication bias](https://en.wikipedia.org/wiki/Publication_bias "Publication bias") or selective publication.[\[99\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Turner2008-99) Although this issue has diminished with time, it remains an obstacle to accurately assessing the efficacy of antidepressants.[\[100\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Turner2022-100) Misreporting of clinical trial outcomes and of serious adverse events, such as suicide, is common.[\[101\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Hughes2014-101)[\[98\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31248914-98)[\[102\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Hengartner2022-102) [Ghostwriting](https://en.wikipedia.org/wiki/Ghostwriting "Ghostwriting") of antidepressant trials is widespread, a practice in which prominent researchers, or so-called key opinion leaders, attach their names to studies actually written by pharmaceutical company employees or consultants.[\[102\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Hengartner2022-102) A particular concern is that the psychoactive effects of antidepressants may lead to the unblinding of participants or researchers, enhancing the placebo effect and biasing results.[\[44\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31249537-44)[\[103\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Kirsch2014-103)[\[98\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31248914-98) Some have therefore maintained that antidepressants may only be active placebos.[\[96\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Read2022-96)[\[88\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31554608-88) When these and other flaws in the research literature are not taken into account, meta-analyses may find inflated results on the basis of poor evidence.[\[98\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31248914-98)
Critics contend that antidepressants have not been proven sufficiently effective by RCTs or in clinical practice and that the widespread use of antidepressants is not evidence-based.[\[96\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Read2022-96)[\[88\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31554608-88) They also note that adverse effects, including withdrawal difficulties, are likely underreported, skewing clinicians' ability to make risk-benefit judgements.[\[84\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Warren2020-84)[\[104\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Sharma2016-104)[\[105\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Bielefeldt2016-105)[\[96\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Read2022-96) Accordingly, they believe antidepressants are overused, particularly for non-severe depression and conditions in which they are not indicated.[\[84\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Warren2020-84)[\[106\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Fava2014-106) Critics charge that the widespread use and public acceptance of antidepressants is the result of pharmaceutical advertising, research manipulation, and misinformation.[\[107\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid16268734-107)[\[108\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-LacasseLeo2015-108)[\[109\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Lacasse2005-109)[\[110\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-AngHorowitzMoncrieff2022-110)
Current mainstream psychiatric opinion recognizes the limitations of antidepressants but recommends their use in adults with more severe depression as a first-line treatment.[\[111\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-nrdp2016-111)[\[112\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NICE2022-112)
### Switching antidepressants
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=15 "Edit section: Switching antidepressants")\]
The [American Psychiatric Association](https://en.wikipedia.org/wiki/American_Psychiatric_Association "American Psychiatric Association") 2000 Practice Guideline advises that where no response is achieved within the following six to eight weeks of treatment with an antidepressant, switch to an antidepressant in the same class, and then to a different class. A 2006 meta-analysis review found wide variation in the findings of prior studies: for people who had failed to respond to an SSRI antidepressant, between 12% and 86% showed a response to a new drug. However, the more antidepressants an individual had previously tried, the less likely they were to benefit from a new antidepressant trial.[\[78\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-SSRIswitch-78) However, a later meta-analysis found no difference between switching to a new drug and staying on the old medication: although 34% of [treatment-resistant](https://en.wikipedia.org/wiki/Treatment-resistant_depression "Treatment-resistant depression") people responded when switched to the new drug, 40% responded without being switched.[\[113\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-113)
### Augmentation and combination
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=16 "Edit section: Augmentation and combination")\]
For a partial response, the American Psychiatric Association (APA) guidelines suggest [augmentation](https://en.wikipedia.org/wiki/Augmentation_\(pharmacology\) "Augmentation (pharmacology)") or adding a drug from a different class. These include [lithium](https://en.wikipedia.org/wiki/Lithium_\(medication\) "Lithium (medication)") and [thyroid](https://en.wikipedia.org/wiki/Thyroid "Thyroid") augmentation, [dopamine agonists](https://en.wikipedia.org/wiki/Dopamine_agonist "Dopamine agonist"), [sex steroids](https://en.wikipedia.org/wiki/Sex_steroid "Sex steroid"), [NRIs](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitor "Norepinephrine reuptake inhibitor"), [glucocorticoid](https://en.wikipedia.org/wiki/Glucocorticoid "Glucocorticoid")\-specific agents, or the newer [anticonvulsants](https://en.wikipedia.org/wiki/Anticonvulsant "Anticonvulsant").[\[114\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-augment-114)
A combination strategy involves adding another antidepressant, usually from a different class to affect other mechanisms. Although this may be used in clinical practice, there is little evidence for the relative efficacy or adverse effects of this strategy.[\[115\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-115) Other tests conducted include the use of [psychostimulants](https://en.wikipedia.org/wiki/Psychostimulant "Psychostimulant") as an augmentation therapy. Several studies have shown the efficacy of combining [modafinil](https://en.wikipedia.org/wiki/Modafinil "Modafinil") for treatment-resistant people. It has been used to help combat SSRI-associated fatigue.[\[116\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-116)
### Long-term use and stopping
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=17 "Edit section: Long-term use and stopping")\]
The effects of antidepressants typically do not continue once the course of medication ends. This results in a high rate of [relapse](https://en.wikipedia.org/wiki/Relapse "Relapse"). In 2003, a [meta-analysis](https://en.wikipedia.org/wiki/Meta-analysis "Meta-analysis") found that 18% of people who had responded to an antidepressant relapsed while still taking it, compared to 41% whose antidepressant was switched for a [placebo](https://en.wikipedia.org/wiki/Placebo "Placebo").[\[117\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-117)
A gradual loss of therapeutic benefit occurs in a minority of people during the course of treatment.[\[118\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-118)[\[119\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-fava-119) A strategy involving the use of [pharmacotherapy](https://en.wikipedia.org/wiki/Pharmacotherapy "Pharmacotherapy") in the treatment of the acute episode, followed by psychotherapy in its residual phase, has been suggested by some studies.[\[120\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-120)[\[121\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-121) For patients who wish to stop their antidepressants, engaging in brief psychological interventions such as Preventive Cognitive Therapy[\[122\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-122) or [mindfulness-based cognitive therapy](https://en.wikipedia.org/wiki/Mindfulness-based_cognitive_therapy "Mindfulness-based cognitive therapy") while [tapering](https://en.wikipedia.org/wiki/Tapering_\(medicine\) "Tapering (medicine)") down has been found to diminish the risk for [relapse](https://en.wikipedia.org/wiki/Relapse_prevention "Relapse prevention").[\[123\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-123)
Antidepressants can cause various [adverse effects](https://en.wikipedia.org/wiki/Adverse_effects "Adverse effects"), depending on the individual and the drug in question.[\[124\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-124)
Almost any medication involved with serotonin regulation has the potential to cause [serotonin toxicity](https://en.wikipedia.org/wiki/Serotonin_syndrome "Serotonin syndrome") (also known as *serotonin syndrome*) – an excess of serotonin that can induce mania, restlessness, agitation, [emotional lability](https://en.wikipedia.org/wiki/Emotional_lability "Emotional lability"), insomnia, and confusion as its primary symptoms.[\[125\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid12771076-125)[\[126\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid15784664-126) Although the condition is serious, it is not particularly common, generally only appearing at high doses or while on other medications. Assuming proper medical intervention has been taken (within about 24 hours) it is rarely fatal.[\[127\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid10941349-127)[\[128\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid10818648-128) Antidepressants appear to increase the risk of [diabetes](https://en.wikipedia.org/wiki/Diabetes "Diabetes") by about 1.3-fold.[\[129\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Salvi_2017-129)
[MAOIs](https://en.wikipedia.org/wiki/MAOIs "MAOIs") tend to have pronounced (sometimes fatal) interactions with a wide variety of medications and [over-the-counter drugs](https://en.wikipedia.org/wiki/Over-the-counter_drug "Over-the-counter drug"). If taken with foods that contain very high levels of [tyramine](https://en.wikipedia.org/wiki/Tyramine "Tyramine") (e.g., mature cheese, cured meats, or yeast extracts), they may cause a potentially lethal [hypertensive crisis](https://en.wikipedia.org/wiki/Hypertensive_crisis "Hypertensive crisis"). At lower doses, the person may only experience a headache due to an increase in blood pressure.[\[130\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid19742203-130)
In response to these adverse effects, a different type of MAOI, the class of [reversible inhibitor of monoamine oxidase A](https://en.wikipedia.org/wiki/Reversible_inhibitor_of_monoamine_oxidase_A "Reversible inhibitor of monoamine oxidase A") (RIMA), has been developed. The primary advantage of RIMAs is that they do not require the person to follow a special diet while being purportedly effective as SSRIs and tricyclics in treating depressive disorders.[\[131\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid7717091-131)
Tricyclics and SSRI can cause the so-called [drug-induced QT prolongation](https://en.wikipedia.org/wiki/Drug-induced_QT_prolongation "Drug-induced QT prolongation"), especially in older adults;[\[132\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-132) this condition can degenerate into a specific type of [abnormal heart rhythm](https://en.wikipedia.org/wiki/Heart_arrhythmia "Heart arrhythmia") called [torsades de pointes](https://en.wikipedia.org/wiki/Torsades_de_pointes "Torsades de pointes"), which can potentially lead to [sudden cardiac arrest](https://en.wikipedia.org/wiki/Cardiac_arrest "Cardiac arrest").[\[133\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-133)
Some antidepressants are also believed to increase thoughts of [suicidal ideation](https://en.wikipedia.org/wiki/Suicidal_ideation "Suicidal ideation").
Antidepressants have been associated with an increased risk of [dementia](https://en.wikipedia.org/wiki/Dementia "Dementia") in older adults.[\[134\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid37834986-134)
Researchers have developed a tool that allows people to rate their concern about common side effects of antidepressants. The tool ranks potential treatment options in a visual display that highlights the drugs with side effects of least concern to an individual.[\[135\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-135)[\[136\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-136)
SSRI use in pregnancy has been associated with a variety of risks with varying degrees of proof of causation. As depression is independently associated with negative pregnancy outcomes, determining the extent to which observed associations between antidepressant use and specific adverse outcomes reflect a causative relationship has been difficult in some cases.[\[137\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-137) In other cases, the attribution of adverse outcomes to antidepressant exposure seems fairly clear.
SSRI use in pregnancy is associated with an increased risk of spontaneous abortion of about 1.7-fold,[\[138\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-138)[\[139\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid23351929-139) and is associated with preterm birth and low birth weight.[\[140\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-140)
A systematic review of the risk of major birth defects in antidepressant-exposed pregnancies found a small increase (3% to 24%) in the risk of major malformations and a risk of cardiovascular birth defects that did not differ from non-exposed pregnancies.[\[141\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-141) A study of fluoxetine-exposed pregnancies found a 12% increase in the risk of major malformations that did not reach statistical significance.[\[142\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-142) Other studies have found an increased risk of cardiovascular birth defects among depressed mothers not undergoing SSRI treatment, suggesting the possibility of ascertainment bias, e.g. that worried mothers may pursue more aggressive testing of their infants.[\[143\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-143) Another study found no increase in cardiovascular birth defects and a 27% increased risk of major malformations in SSRI exposed pregnancies.[\[139\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid23351929-139) The FDA advises for the risk of birth defects with the use of paroxetine[\[144\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-144) and the MAOI should be avoided.
A 2013 systematic review and meta-analysis found that antidepressant use during pregnancy was statistically significantly associated with some pregnancy outcomes, such as gestational age and preterm birth, but not with other outcomes. The same review cautioned that because differences between the exposed and unexposed groups were small, it was doubtful whether they were clinically significant.[\[145\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-145)
A [neonate](https://en.wikipedia.org/wiki/Neonate "Neonate") (infant less than 28 days old) may experience a [withdrawal syndrome](https://en.wikipedia.org/wiki/Withdrawal_syndrome "Withdrawal syndrome") from abrupt discontinuation of the antidepressant at birth. Antidepressants can be present in varying amounts in breast milk, but their effects on infants are currently unknown.[\[146\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-146)
Moreover, SSRIs inhibit nitric oxide synthesis, which plays an important role in setting the vascular tone. Several studies have pointed to an increased risk of prematurity associated with SSRI use, and this association may be due to an increased risk of [pre-eclampsia](https://en.wikipedia.org/wiki/Pre-eclampsia "Pre-eclampsia") during pregnancy.[\[147\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-147)
### Antidepressant-induced mania
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=20 "Edit section: Antidepressant-induced mania")\]
Another possible problem with antidepressants is the chance of antidepressant-induced [mania](https://en.wikipedia.org/wiki/Mania "Mania") or [hypomania](https://en.wikipedia.org/wiki/Hypomania "Hypomania") in people with or without a diagnosis of [bipolar disorder](https://en.wikipedia.org/wiki/Bipolar_disorder "Bipolar disorder"). Many cases of bipolar depression are very similar to those of unipolar depression. Therefore, the person can be misdiagnosed with unipolar depression and be given antidepressants. Studies have shown that antidepressant-induced mania can occur in 20–40% of people with bipolar disorder.[\[148\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-148) For bipolar depression, antidepressants (most frequently SSRIs) can exacerbate or trigger symptoms of hypomania and mania.[\[149\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid9387089-149) [Bupropion](https://en.wikipedia.org/wiki/Bupropion "Bupropion") has been associated with a lower risk of mood switch than other antidepressants.[\[150\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid37119556-150)
Studies have shown that the use of antidepressants is correlated with an increased risk of suicidal behavior and thinking (suicidality) in those aged under 25 years old.[\[151\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-StoneETAL-151) This problem has been serious enough to warrant government intervention by the US Food and Drug Administration (FDA) to warn of the increased risk of suicidality during antidepressant treatment.[\[152\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid17485726-152) According to the FDA, the heightened risk of suicidality occurs within the first one to two months of treatment.[\[153\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-153)[\[154\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-154) The National Institute for Health and Care Excellence (NICE) places the excess risk in the "early stages of treatment".[\[155\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-155) A [meta-analysis](https://en.wikipedia.org/wiki/Meta-analysis "Meta-analysis") suggests that the relationship between antidepressant use and suicidal behavior or thoughts is age-dependent.[\[151\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-StoneETAL-151) Compared with placebo, the use of antidepressants is associated with an increase in suicidal behavior or thoughts among those 25 years old or younger ([OR](https://en.wikipedia.org/wiki/Odds_ratio "Odds ratio")\=1.62). A review of RCTs and epidemiological studies by Healy and Whitaker found an increase in suicidal acts by a factor of 2.4.[\[156\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-156) There is no effect or possibly a mild protective effect among those aged 25 to 64 (OR=0.79). Antidepressant treatment has a protective effect against suicidality among those aged 65 and over (OR=0.37).[\[151\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-StoneETAL-151)[\[157\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-dhintrev-157)
Sexual side effects are common with SSRIs, such as loss of [sexual drive](https://en.wikipedia.org/wiki/Sexual_drive "Sexual drive"), [failure to reach orgasm](https://en.wikipedia.org/wiki/Anorgasmia "Anorgasmia"), and [erectile dysfunction](https://en.wikipedia.org/wiki/Erectile_dysfunction "Erectile dysfunction").[\[158\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-158) Although usually reversible, these sexual side-effects can, in rare cases, continue after the drug has been completely withdrawn.[\[159\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid18173768-159)[\[160\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-160)
In a study of 1,022 outpatients, overall sexual dysfunction with all antidepressants averaged 59.1%[\[161\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid11229449-161) with SSRI values between 57% and 73%, mirtazapine 24%, nefazodone 8%, amineptine 7%, and [moclobemide](https://en.wikipedia.org/wiki/Moclobemide "Moclobemide") 4%. Moclobemide, a selective reversible MAO-A inhibitor, does not cause sexual dysfunction[\[162\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid19440080-162) and can lead to an improvement in all aspects of sexual function.[\[163\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid9696909-163)
Biochemical mechanisms suggested as causative include increased serotonin, particularly affecting [5-HT2](https://en.wikipedia.org/wiki/5-HT2_receptor "5-HT2 receptor") and [5-HT3 receptors](https://en.wikipedia.org/wiki/5HT3_receptor "5HT3 receptor"); decreased [dopamine](https://en.wikipedia.org/wiki/Dopamine "Dopamine"); decreased [norepinephrine](https://en.wikipedia.org/wiki/Norepinephrine "Norepinephrine"); blockade of [cholinergic](https://en.wikipedia.org/wiki/Cholinergic_receptor "Cholinergic receptor") and [α1adrenergic receptors](https://en.wikipedia.org/wiki/Alpha-1_adrenergic_receptor "Alpha-1 adrenergic receptor"); inhibition of [nitric oxide synthetase](https://en.wikipedia.org/wiki/Nitric_oxide_synthase "Nitric oxide synthase"); and elevation of [prolactin](https://en.wikipedia.org/wiki/Prolactin "Prolactin") levels.[\[164\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-164) [Mirtazapine](https://en.wikipedia.org/wiki/Mirtazapine "Mirtazapine") is reported to have fewer sexual side effects, most likely because it antagonizes 5-HT2 and 5-HT3 receptors and may, in some cases, reverse sexual dysfunction induced by SSRIs by the same mechanism.[\[165\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid18278806-165)
[Bupropion](https://en.wikipedia.org/wiki/Bupropion "Bupropion"), a weak NDRI and nicotinic antagonist, may be useful in treating reduced libido as a result of [SSRI](https://en.wikipedia.org/wiki/SSRI "SSRI") treatment.[\[166\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Schwasinger-Schmidt2018-166)
Certain antidepressants may cause [emotional blunting](https://en.wikipedia.org/wiki/Emotional_blunting "Emotional blunting"), characterized by a reduced intensity of both positive and negative emotions as well as symptoms of [apathy](https://en.wikipedia.org/wiki/Apathy "Apathy"), [indifference](https://en.wikipedia.org/wiki/Psychological_indifference "Psychological indifference"), and [amotivation](https://en.wikipedia.org/wiki/Amotivational_syndrome "Amotivational syndrome").[\[167\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid34908941-167)[\[168\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid34970173-168)[\[169\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid15330228-169)[\[170\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid21103140-170)[\[171\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid19721109-171)[\[172\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid28628765-172)[\[173\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid29866014-173)[\[174\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35346413-174)[\[175\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid11436958-175)\[*[excessive citations](https://en.wikipedia.org/wiki/Wikipedia:Citing_sources#Bundling_citations "Wikipedia:Citing sources")*\] It may be experienced as either beneficial or detrimental depending on the situation.[\[176\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid26407780-176) This side effect has been particularly associated with serotonergic antidepressants like SSRIs and SNRIs but may be less with atypical antidepressants like bupropion, [agomelatine](https://en.wikipedia.org/wiki/Agomelatine "Agomelatine"), and [vortioxetine](https://en.wikipedia.org/wiki/Vortioxetine "Vortioxetine").[\[168\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid34970173-168)[\[174\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35346413-174)[\[177\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid23823799-177)[\[178\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid33516560-178) In addition, it is not associated with the [serotonergic psychedelic](https://en.wikipedia.org/wiki/Serotonergic_psychedelic "Serotonergic psychedelic") [psilocybin](https://en.wikipedia.org/wiki/Psilocybin "Psilocybin").[\[179\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-SiegelListonNicol2026-179) Higher doses of antidepressants seem to be more likely to produce emotional blunting than lower doses.[\[168\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid34970173-168) Emotional blunting can be decreased by reducing dosage, discontinuing the medication, or switching to a different antidepressant that may have less propensity for causing this side effect.[\[168\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid34970173-168)
Changes in appetite or weight are common among antidepressants but are largely drug-dependent and related to which neurotransmitters they affect. Mirtazapine and [paroxetine](https://en.wikipedia.org/wiki/Paroxetine "Paroxetine"), for example, may be associated with weight gain and/or increased appetite,[\[180\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Stimmel-180)[\[181\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-181)[\[182\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-autogenerated1032-182) while others (such as bupropion and [venlafaxine](https://en.wikipedia.org/wiki/Venlafaxine "Venlafaxine")) achieve the opposite effect.[\[183\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Bupropion_weight-183)[\[184\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-184)
The [antihistaminic](https://en.wikipedia.org/wiki/Antihistamine "Antihistamine") properties of certain TCA- and TeCA-class antidepressants have been shown to contribute to the common side effects of increased appetite and weight gain associated with these classes of medication.
A 2021 nationwide [cohort study](https://en.wikipedia.org/wiki/Cohort_study "Cohort study") in South Korea observed a link between SSRI use and bone loss, particularly in recent users. The study also stressed the need of further research to better understand these effects.[\[185\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-185) A 2012 review found that SSRIs along with tricyclic antidepressants were associated with a significant increase in the risk of osteoporotic fractures, peaking in the months after initiation, and moving back towards baseline during the year after treatment was stopped. These effects exhibited a [dose–response relationship](https://en.wikipedia.org/wiki/Dose%E2%80%93response_relationship "Dose–response relationship") within SSRIs which varied between different drugs of that class.[\[186\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-186) A 2018 meta-analysis of 11 small studies found a reduction in bone density of the lumbar spine in SSRI users which affected older people the most.[\[187\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-187)
A 2017 [meta-analysis](https://en.wikipedia.org/wiki/Meta-analysis "Meta-analysis") found that antidepressants were associated with a significantly increased [risk of death](https://en.wikipedia.org/wiki/Mortality_rate "Mortality rate") (+33%) and new [cardiovascular complications](https://en.wikipedia.org/wiki/Cardiovascular_complication "Cardiovascular complication") (+14%) in the general population.[\[188\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid28903117-188) Conversely, risks were not greater in people with existing [cardiovascular disease](https://en.wikipedia.org/wiki/Cardiovascular_disease "Cardiovascular disease").[\[188\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid28903117-188)
### Discontinuation syndrome
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=27 "Edit section: Discontinuation syndrome")\]
Antidepressant discontinuation syndrome, also called antidepressant withdrawal syndrome, is a condition that can occur following the interruption, reduction, or [discontinuation](https://en.wikipedia.org/wiki/Medication_discontinuation "Medication discontinuation") of antidepressant medication.[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189) The symptoms may include [flu-like symptoms](https://en.wikipedia.org/wiki/Flu-like_symptoms "Flu-like symptoms"), trouble sleeping, nausea, poor balance, sensory changes, and [anxiety](https://en.wikipedia.org/wiki/Anxiety "Anxiety").[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189)[\[14\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Gab2017-14)[\[190\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Dav2018-190) The problem usually begins within three days and may last for several months.[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189)[\[190\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Dav2018-190) Rarely [psychosis](https://en.wikipedia.org/wiki/Psychosis "Psychosis") may occur.[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189)
A discontinuation syndrome can occur after stopping any antidepressant including [selective serotonin reuptake inhibitors](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor "Selective serotonin reuptake inhibitor") (SSRIs), [serotonin–norepinephrine reuptake inhibitors](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") (SNRIs), and [tricyclic antidepressants](https://en.wikipedia.org/wiki/Tricyclic_antidepressants "Tricyclic antidepressants") (TCAs).[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189)[\[14\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Gab2017-14) The risk is greater among those who have taken the medication for longer and when the medication in question has a short [half-life](https://en.wikipedia.org/wiki/Half-life "Half-life").[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189) The underlying reason for its occurrence is unclear.[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189) The diagnosis is based on the symptoms.[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189)
Methods of prevention include gradually decreasing the dose ([tapering](https://en.wikipedia.org/wiki/Tapering_\(medicine\) "Tapering (medicine)")) among those who wish to stop, though it is possible for symptoms to occur with tapering.[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189)[\[13\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Wil2015-13)[\[190\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Dav2018-190) Treatment may include restarting the medication and slowly decreasing the dose.[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189) People may also be switched to the long-acting antidepressant [fluoxetine](https://en.wikipedia.org/wiki/Fluoxetine "Fluoxetine"), which can then be gradually decreased.[\[13\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Wil2015-13)
Approximately 20–50% of people who suddenly stop an antidepressant develop an antidepressant discontinuation syndrome.[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189)[\[14\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Gab2017-14)[\[190\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Dav2018-190) The condition is generally not serious,[\[189\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-War2006-189) though about half of people with symptoms describe them as severe.[\[190\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Dav2018-190) Some restart antidepressants due to the severity of the symptoms.[\[190\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Dav2018-190)
Antidepressants act via a large number of different [mechanisms of action](https://en.wikipedia.org/wiki/Mechanism_of_action "Mechanism of action").[\[191\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Fasipe2018-191)[\[192\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35714379-192)[\[193\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Stahl2020-193) This includes [serotonin reuptake inhibition](https://en.wikipedia.org/wiki/Serotonin_reuptake_inhibition "Serotonin reuptake inhibition") (SSRIs, SNRIs, TCAs, vilazodone, vortioxetine), [norepinephrine reuptake inhibition](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibition "Norepinephrine reuptake inhibition") (NRIs, SNRIs, TCAs), [dopamine reuptake inhibition](https://en.wikipedia.org/wiki/Dopamine_reuptake_inhibition "Dopamine reuptake inhibition") (bupropion, amineptine, nomifensine), direct [modulation](https://en.wikipedia.org/wiki/Receptor_modulation "Receptor modulation") of [monoamine receptors](https://en.wikipedia.org/wiki/Monoamine_receptor "Monoamine receptor") (vilazodone, vortioxetine, SARIs, agomelatine, TCAs, TeCAs, antipsychotics), [monoamine oxidase inhibition](https://en.wikipedia.org/wiki/Monoamine_oxidase_inhibition "Monoamine oxidase inhibition") (MAOIs), and [NMDA receptor antagonism](https://en.wikipedia.org/wiki/NMDA_receptor_antagonism "NMDA receptor antagonism") (ketamine, esketamine, dextromethorphan), among others (e.g., brexanolone, tianeptine).[\[191\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Fasipe2018-191)[\[192\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35714379-192)[\[193\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Stahl2020-193) Some antidepressants also have additional actions, like [sigma receptor](https://en.wikipedia.org/wiki/Sigma_receptor "Sigma receptor") modulation (certain SSRIs, TCAs, dextromethorphan) and [antagonism](https://en.wikipedia.org/wiki/Receptor_antagonism "Receptor antagonism") of [histamine](https://en.wikipedia.org/wiki/Histamine "Histamine") [H1](https://en.wikipedia.org/wiki/H1_receptor "H1 receptor") and [muscarinic acetylcholine receptors](https://en.wikipedia.org/wiki/Muscarinic_acetylcholine_receptor "Muscarinic acetylcholine receptor") (TCAs, TeCAs).[\[194\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-BolandKeller2008-194)[\[193\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Stahl2020-193)
| Class | Action(s) | Examples | Introduced |
|---|---|---|---|
| [Opioids](https://en.wikipedia.org/wiki/Opioid "Opioid") (mostly no longer used)[\[196\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-SaxenaBodkin2019-196)[\[197\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NishioLindsleyBender2024-197) | [μ-Opioid receptor](https://en.wikipedia.org/wiki/%CE%9C-Opioid_receptor "Μ-Opioid receptor") [agonism](https://en.wikipedia.org/wiki/Agonist "Agonist") | [Codeine](https://en.wikipedia.org/wiki/Codeine "Codeine") • [Heroin](https://en.wikipedia.org/wiki/Heroin "Heroin") • [Morphine](https://en.wikipedia.org/wiki/Morphine "Morphine") • [Opium](https://en.wikipedia.org/wiki/Opium "Opium") • [Tianeptine](https://en.wikipedia.org/wiki/Tianeptine "Tianeptine") (1983) | 1800s |
| [Amphetamine psychostimulants](https://en.wikipedia.org/wiki/Amphetamine-type_stimulant "Amphetamine-type stimulant") (mostly no longer used)[\[198\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Rasmussen2006-198)[\[199\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Ciccarone2011-199)[\[200\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Rasmussen2015-200)[\[201\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-HealSmithGosden2013-201) | [Norepinephrine release induction](https://en.wikipedia.org/wiki/Norepinephrine_releasing_agent "Norepinephrine releasing agent") • [Dopamine release induction](https://en.wikipedia.org/wiki/Dopamine_releasing_agent "Dopamine releasing agent") | [Amphetamine](https://en.wikipedia.org/wiki/Amphetamine "Amphetamine") • [Dextroamphetamine](https://en.wikipedia.org/wiki/Dextroamphetamine "Dextroamphetamine") • [Methamphetamine](https://en.wikipedia.org/wiki/Methamphetamine "Methamphetamine") | 1930s |
| [Monoamine oxidase inhibitors](https://en.wikipedia.org/wiki/Monoamine_oxidase_inhibitor "Monoamine oxidase inhibitor") (MAOIs) | [Monoamine oxidase](https://en.wikipedia.org/wiki/Monoamine_oxidase "Monoamine oxidase") [inhibition](https://en.wikipedia.org/wiki/Enzyme_inhibitor "Enzyme inhibitor") • Other actions in some cases | [Iproniazid](https://en.wikipedia.org/wiki/Iproniazid "Iproniazid") • [Isocarboxazid](https://en.wikipedia.org/wiki/Isocarboxazid "Isocarboxazid") • [Isoniazid](https://en.wikipedia.org/wiki/Isoniazid "Isoniazid") • [Moclobemide](https://en.wikipedia.org/wiki/Moclobemide "Moclobemide") (1989) • [Nialamide](https://en.wikipedia.org/wiki/Nialamide "Nialamide") • [Phenelzine](https://en.wikipedia.org/wiki/Phenelzine "Phenelzine") • [Selegiline](https://en.wikipedia.org/wiki/Selegiline "Selegiline") (1977/2006) • [Tranylcypromine](https://en.wikipedia.org/wiki/Tranylcypromine "Tranylcypromine") | 1950s |
| [Tricyclic antidepressants](https://en.wikipedia.org/wiki/Tricyclic_antidepressant "Tricyclic antidepressant") (TCAs) | [Serotonin reuptake inhibition](https://en.wikipedia.org/wiki/Serotonin_reuptake_inhibitor "Serotonin reuptake inhibitor") • [Norepinephrine reuptake inhibition](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitor "Norepinephrine reuptake inhibitor") • [Serotonin receptor antagonism](https://en.wikipedia.org/wiki/Serotonin_receptor_antagonist "Serotonin receptor antagonist") • [Adrenergic receptor antagonism](https://en.wikipedia.org/wiki/Adrenergic_receptor_antagonist "Adrenergic receptor antagonist") • [Histamine H1 receptor antagonism](https://en.wikipedia.org/wiki/H1_antagonist "H1 antagonist") • [Muscarinic acetylcholine receptor antagonism](https://en.wikipedia.org/wiki/Muscarinic_antagonist "Muscarinic antagonist") • Other actions | [Amitriptyline](https://en.wikipedia.org/wiki/Amitriptyline "Amitriptyline") • [Butriptyline](https://en.wikipedia.org/wiki/Butriptyline "Butriptyline") • [Clomipramine](https://en.wikipedia.org/wiki/Clomipramine "Clomipramine") • [Desipramine](https://en.wikipedia.org/wiki/Desipramine "Desipramine") • [Dosulepin (dothiepin)](https://en.wikipedia.org/wiki/Dosulepin "Dosulepin") • [Doxepin](https://en.wikipedia.org/wiki/Doxepin "Doxepin") • [Imipramine](https://en.wikipedia.org/wiki/Imipramine "Imipramine") • [Iprindole](https://en.wikipedia.org/wiki/Iprindole "Iprindole") • [Lofepramine](https://en.wikipedia.org/wiki/Lofepramine "Lofepramine") • [Nortriptyline](https://en.wikipedia.org/wiki/Nortriptyline "Nortriptyline") • [Protriptyline](https://en.wikipedia.org/wiki/Protriptyline "Protriptyline") • [Trimipramine](https://en.wikipedia.org/wiki/Trimipramine "Trimipramine") | 1950s |
| [Tetracyclic antidepressants](https://en.wikipedia.org/wiki/Tetracyclic_antidepressant "Tetracyclic antidepressant") (TeCAs) | [Serotonin reuptake inhibition](https://en.wikipedia.org/wiki/Serotonin_reuptake_inhibitor "Serotonin reuptake inhibitor") • [Norepinephrine reuptake inhibition](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitor "Norepinephrine reuptake inhibitor") • [Serotonin receptor antagonism](https://en.wikipedia.org/wiki/Serotonin_receptor_antagonist "Serotonin receptor antagonist") • [Adrenergic receptor antagonism](https://en.wikipedia.org/wiki/Adrenergic_receptor_antagonist "Adrenergic receptor antagonist") • [Histamine H1 receptor antagonism](https://en.wikipedia.org/wiki/H1_antagonist "H1 antagonist") • [Muscarinic acetylcholine receptor antagonism](https://en.wikipedia.org/wiki/Muscarinic_antagonist "Muscarinic antagonist") • Other actions | [Amoxapine](https://en.wikipedia.org/wiki/Amoxapine "Amoxapine") • [Maprotiline](https://en.wikipedia.org/wiki/Maprotiline "Maprotiline") • [Mianserin](https://en.wikipedia.org/wiki/Mianserin "Mianserin") • [Mirtazapine](https://en.wikipedia.org/wiki/Mirtazapine "Mirtazapine") • [Setiptiline](https://en.wikipedia.org/wiki/Setiptiline "Setiptiline") | 1970s |
| [Norepinephrine reuptake inhibitors](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitor "Norepinephrine reuptake inhibitor") (NRIs) | [Norepinephrine reuptake inhibition](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitor "Norepinephrine reuptake inhibitor") | [Atomoxetine](https://en.wikipedia.org/wiki/Atomoxetine "Atomoxetine") (off-label) • [Teniloxazine](https://en.wikipedia.org/wiki/Teniloxazine "Teniloxazine") • [Reboxetine](https://en.wikipedia.org/wiki/Reboxetine "Reboxetine") • [Viloxazine](https://en.wikipedia.org/wiki/Viloxazine "Viloxazine") | 1970s |
| [Norepinephrine–dopamine reuptake inhibitors](https://en.wikipedia.org/wiki/Norepinephrine%E2%80%93dopamine_reuptake_inhibitor "Norepinephrine–dopamine reuptake inhibitor") (NDRIs) | [Norepinephrine reuptake inhibition](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitor "Norepinephrine reuptake inhibitor") • [Dopamine reuptake inhibition](https://en.wikipedia.org/wiki/Dopamine_reuptake_inhibitor "Dopamine reuptake inhibitor") | [Amineptine](https://en.wikipedia.org/wiki/Amineptine "Amineptine") • [Bupropion](https://en.wikipedia.org/wiki/Bupropion "Bupropion") • [Methylphenidate](https://en.wikipedia.org/wiki/Methylphenidate "Methylphenidate") (off-label) • [Nomifensine](https://en.wikipedia.org/wiki/Nomifensine "Nomifensine") | 1970s |
| [Serotonin antagonists and reuptake inhibitors](https://en.wikipedia.org/wiki/Serotonin_antagonists_and_reuptake_inhibitors "Serotonin antagonists and reuptake inhibitors") (SARIs) | [Serotonin receptor antagonism](https://en.wikipedia.org/wiki/Serotonin_receptor_antagonist "Serotonin receptor antagonist") • [Adrenergic receptor antagonism](https://en.wikipedia.org/wiki/Adrenergic_receptor_antagonist "Adrenergic receptor antagonist") • Weak [monoamine reuptake inhibition](https://en.wikipedia.org/wiki/Monoamine_reuptake_inhibitor "Monoamine reuptake inhibitor") • Other actions | [Etoperidone](https://en.wikipedia.org/wiki/Etoperidone "Etoperidone") • [Nefazodone](https://en.wikipedia.org/wiki/Nefazodone "Nefazodone") • [Trazodone](https://en.wikipedia.org/wiki/Trazodone "Trazodone") | 1980s |
| [Selective serotonin reuptake inhibitors](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor "Selective serotonin reuptake inhibitor") (SSRIs) | [Serotonin reuptake inhibition](https://en.wikipedia.org/wiki/Serotonin_reuptake_inhibitor "Serotonin reuptake inhibitor") | [Citalopram](https://en.wikipedia.org/wiki/Citalopram "Citalopram") • [Escitalopram](https://en.wikipedia.org/wiki/Escitalopram "Escitalopram") • [Fluoxetine](https://en.wikipedia.org/wiki/Fluoxetine "Fluoxetine") • [Fluvoxamine](https://en.wikipedia.org/wiki/Fluvoxamine "Fluvoxamine") • [Indalpine](https://en.wikipedia.org/wiki/Indalpine "Indalpine") • [Paroxetine](https://en.wikipedia.org/wiki/Paroxetine "Paroxetine") • [Sertraline](https://en.wikipedia.org/wiki/Sertraline "Sertraline") • [Zimelidine](https://en.wikipedia.org/wiki/Zimelidine "Zimelidine") | 1980s |
| [Serotonin](https://en.wikipedia.org/wiki/Serotonin "Serotonin") [5-HT1A receptor](https://en.wikipedia.org/wiki/5-HT1A_receptor "5-HT1A receptor") [agonists](https://en.wikipedia.org/wiki/Agonist "Agonist") ([azapirones](https://en.wikipedia.org/wiki/Azapirone "Azapirone")) | [Serotonin](https://en.wikipedia.org/wiki/Serotonin "Serotonin") [5-HT1A receptor](https://en.wikipedia.org/wiki/5-HT1A_receptor "5-HT1A receptor") [partial agonism](https://en.wikipedia.org/wiki/Partial_agonist "Partial agonist") • Other actions | [Buspirone](https://en.wikipedia.org/wiki/Buspirone "Buspirone") (off-label) • [Gepirone](https://en.wikipedia.org/wiki/Gepirone "Gepirone") • [Tandospirone](https://en.wikipedia.org/wiki/Tandospirone "Tandospirone") | 1980s |
| [Serotonin–norepinephrine reuptake inhibitors](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") (SNRIs) | [Serotonin reuptake inhibition](https://en.wikipedia.org/wiki/Serotonin_reuptake_inhibitor "Serotonin reuptake inhibitor") • [Norepinephrine reuptake inhibition](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitor "Norepinephrine reuptake inhibitor") | [Desvenlafaxine](https://en.wikipedia.org/wiki/Desvenlafaxine "Desvenlafaxine") • [Duloxetine](https://en.wikipedia.org/wiki/Duloxetine "Duloxetine") • [Levomilnacipran](https://en.wikipedia.org/wiki/Levomilnacipran "Levomilnacipran") • [Milnacipran](https://en.wikipedia.org/wiki/Milnacipran "Milnacipran") (off-label) • [Venlafaxine](https://en.wikipedia.org/wiki/Venlafaxine "Venlafaxine") | 1990s |
| [Serotonin modulators and stimulators](https://en.wikipedia.org/wiki/Serotonin_modulators_and_stimulators "Serotonin modulators and stimulators") (SMSs) | [Serotonin reuptake inhibition](https://en.wikipedia.org/wiki/Serotonin_reuptake_inhibitor "Serotonin reuptake inhibitor") • [Serotonin receptor](https://en.wikipedia.org/wiki/Serotonin_receptor "Serotonin receptor") [modulation](https://en.wikipedia.org/wiki/Receptor_modulator "Receptor modulator") | [Vilazodone](https://en.wikipedia.org/wiki/Vilazodone "Vilazodone") • [Vortioxetine](https://en.wikipedia.org/wiki/Vortioxetine "Vortioxetine") | 2000s |
| [Atypical antipsychotics](https://en.wikipedia.org/wiki/Atypical_antipsychotic "Atypical antipsychotic") | [Serotonin receptor](https://en.wikipedia.org/wiki/Serotonin_receptor "Serotonin receptor") [modulation](https://en.wikipedia.org/wiki/Receptor_modulation "Receptor modulation") • [Dopamine receptor](https://en.wikipedia.org/wiki/Dopamine_receptor "Dopamine receptor") [modulation](https://en.wikipedia.org/wiki/Receptor_modulator "Receptor modulator") • Other actions | [Amisulpride](https://en.wikipedia.org/wiki/Amisulpride "Amisulpride") • [Aripiprazole](https://en.wikipedia.org/wiki/Aripiprazole "Aripiprazole") • [Brexpiprazole](https://en.wikipedia.org/wiki/Brexpiprazole "Brexpiprazole") • [Lumateperone](https://en.wikipedia.org/wiki/Lumateperone "Lumateperone") • [Lurasidone](https://en.wikipedia.org/wiki/Lurasidone "Lurasidone") • [Olanzapine](https://en.wikipedia.org/wiki/Olanzapine "Olanzapine") • [Quetiapine](https://en.wikipedia.org/wiki/Quetiapine "Quetiapine") • [Risperidone](https://en.wikipedia.org/wiki/Risperidone "Risperidone") (off-label) • [Sulpiride](https://en.wikipedia.org/wiki/Sulpiride "Sulpiride") | 2000s |
| [NMDA receptor antagonists](https://en.wikipedia.org/wiki/NMDA_receptor_antagonist "NMDA receptor antagonist") | [NMDA receptor antagonism](https://en.wikipedia.org/wiki/NMDA_receptor_antagonism "NMDA receptor antagonism") • Possibly other actions | [Dextromethorphan/bupropion](https://en.wikipedia.org/wiki/Dextromethorphan/bupropion "Dextromethorphan/bupropion") • [Esketamine](https://en.wikipedia.org/wiki/Esketamine "Esketamine") • [Ketamine](https://en.wikipedia.org/wiki/Ketamine "Ketamine") (off-label) | 2010s |
| [Serotonergic psychedelics](https://en.wikipedia.org/wiki/Serotonergic_psychedelic "Serotonergic psychedelic")[\[202\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Langlitz2025-202)[\[203\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NuttHuntSchlag2024-203)[\[204\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-AicherM%C3%BCllerGasser2025-204)[\[205\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-LiechtiGasserAicher2025-205) | [Serotonin 5-HT2A receptor agonism](https://en.wikipedia.org/wiki/Serotonin_5-HT2A_receptor_agonist "Serotonin 5-HT2A receptor agonist") | [Psilocybin](https://en.wikipedia.org/wiki/Psilocybin "Psilocybin") • [LSD](https://en.wikipedia.org/wiki/LSD "LSD") • Others | 2010s |
| [Neurosteroid](https://en.wikipedia.org/wiki/Neurosteroid "Neurosteroid")\-type [GABAA receptor positive allosteric modulators](https://en.wikipedia.org/wiki/GABAA_receptor_positive_allosteric_modulator "GABAA receptor positive allosteric modulator") | [GABAA receptor positive allosteric modulation](https://en.wikipedia.org/wiki/GABAA_receptor_positive_allosteric_modulator "GABAA receptor positive allosteric modulator") | [Brexanolone](https://en.wikipedia.org/wiki/Brexanolone "Brexanolone") • [Zuranolone](https://en.wikipedia.org/wiki/Zuranolone "Zuranolone") | 2010s |
| [Serotonin–norepinephrine–dopamine reuptake inhibitors](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine%E2%80%93dopamine_reuptake_inhibitor "Serotonin–norepinephrine–dopamine reuptake inhibitor") | [Serotonin reuptake inhibition](https://en.wikipedia.org/wiki/Serotonin_reuptake_inhibitor "Serotonin reuptake inhibitor") • [Norepinephrine reuptake inhibition](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitor "Norepinephrine reuptake inhibitor") • [Dopamine reuptake inhibition](https://en.wikipedia.org/wiki/Dopamine_reuptake_inhibitor "Dopamine reuptake inhibitor") | [Toludesvenlafaxine](https://en.wikipedia.org/wiki/Toludesvenlafaxine "Toludesvenlafaxine") | 2020s |
| [Other agents](https://en.wikipedia.org/wiki/Atypical_antidepressant "Atypical antidepressant") | Various/mixed actions | [α-Methyltryptamine](https://en.wikipedia.org/wiki/%CE%91-Methyltryptamine "Α-Methyltryptamine") • [Ademetionine (SAMe)](https://en.wikipedia.org/wiki/Ademetionine "Ademetionine") • [Agomelatine](https://en.wikipedia.org/wiki/Agomelatine "Agomelatine") • [D-Phenylalanine](https://en.wikipedia.org/wiki/D-Phenylalanine "D-Phenylalanine") • [Etryptamine](https://en.wikipedia.org/wiki/Etryptamine "Etryptamine") • [*Hypericum perforatum* (St John's wort)](https://en.wikipedia.org/wiki/Hypericum_perforatum "Hypericum perforatum") [Indeloxazine](https://en.wikipedia.org/wiki/Indeloxazine "Indeloxazine") • [Lithium](https://en.wikipedia.org/wiki/Lithium_\(medication\) "Lithium (medication)") (off-label) • [Medifoxamine](https://en.wikipedia.org/wiki/Medifoxamine "Medifoxamine") • [Opipramol](https://en.wikipedia.org/wiki/Opipramol "Opipramol") • [Oxaflozane](https://en.wikipedia.org/wiki/Oxaflozane "Oxaflozane") • [Oxitriptan (5-HTP)](https://en.wikipedia.org/wiki/Oxitriptan "Oxitriptan") • [Pivagabine](https://en.wikipedia.org/wiki/Pivagabine "Pivagabine") • [Thyroid hormone](https://en.wikipedia.org/wiki/Thyroid_hormone "Thyroid hormone") (off-label) • [Tiazesim](https://en.wikipedia.org/wiki/Tiazesim "Tiazesim") • [Tofenacin](https://en.wikipedia.org/wiki/Tofenacin "Tofenacin") • [Tryptophan](https://en.wikipedia.org/wiki/Tryptophan "Tryptophan") | Various |
| **Notes:** (1) Opioids and amphetamines largely ceased being used by the 1950s with the introduction of modern antidepressants. (2) Some antidepressants can also have alternative classifications, such as [mirtazapine](https://en.wikipedia.org/wiki/Mirtazapine "Mirtazapine") being a "[noradrenergic and specific serotonergic antidepressant](https://en.wikipedia.org/wiki/Noradrenergic_and_specific_serotonergic_antidepressant "Noradrenergic and specific serotonergic antidepressant")" (NaSSA) or [moclobemide](https://en.wikipedia.org/wiki/Moclobemide "Moclobemide") being a "[reversible inhibitor of monoamine oxidase A](https://en.wikipedia.org/wiki/Reversible_inhibitor_of_monoamine_oxidase_A "Reversible inhibitor of monoamine oxidase A")" (RIMA). (3) See [list of antidepressants](https://en.wikipedia.org/wiki/List_of_antidepressants "List of antidepressants") for a complete list of approved/marketed antidepressants. (4) See [list of investigational antidepressants](https://en.wikipedia.org/wiki/List_of_investigational_antidepressants "List of investigational antidepressants") for an extensive list of modern investigational antidepressants (including discontinued agents). | | | |
### Monoamine hypothesis
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=29 "Edit section: Monoamine hypothesis")\]
The earliest and most widely known [scientific theory](https://en.wikipedia.org/wiki/Scientific_theory "Scientific theory") of antidepressant action is the [monoamine hypothesis](https://en.wikipedia.org/wiki/Monoamine_hypothesis "Monoamine hypothesis"), which can be traced back to the 1950s and 1960s.[\[206\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-GG-206)[\[207\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid12953623-207) This theory states that depression is due to an imbalance, most often a deficiency, of the [monoamine neurotransmitters](https://en.wikipedia.org/wiki/Monoamine_neurotransmitter "Monoamine neurotransmitter"), namely [serotonin](https://en.wikipedia.org/wiki/Serotonin "Serotonin"), [norepinephrine](https://en.wikipedia.org/wiki/Norepinephrine "Norepinephrine"), and/or [dopamine](https://en.wikipedia.org/wiki/Dopamine "Dopamine").[\[206\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-GG-206)[\[207\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid12953623-207) However, serotonin in particular has been implicated, as in the serotonin hypothesis of depression.[\[208\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35854107-208) The monoamine hypothesis was originally proposed based on observations that [reserpine](https://en.wikipedia.org/wiki/Reserpine "Reserpine"), a drug which depletes the monoamine neurotransmitters, produced depressive effects in people,[\[207\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid12953623-207) and that certain [hydrazine](https://en.wikipedia.org/wiki/Hydrazine "Hydrazine") [antituberculosis agents](https://en.wikipedia.org/wiki/Antituberculosis_agent "Antituberculosis agent") like [iproniazid](https://en.wikipedia.org/wiki/Iproniazid "Iproniazid"), which [prevent the breakdown of monoamine neurotransmitters](https://en.wikipedia.org/wiki/Monoamine_oxidase_inhibitor "Monoamine oxidase inhibitor"), produced apparent antidepressant effects.[\[206\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-GG-206) Most currently marketed antidepressants, which are [monoaminergic](https://en.wikipedia.org/wiki/Monoaminergic "Monoaminergic") in their actions, are theoretically consistent with the monoamine hypothesis.[\[206\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-GG-206) Despite the widespread nature of the monoamine hypothesis, it has a number of limitations: for one, all monoaminergic antidepressants have a delayed onset of action of at least a week; and secondly, many people with depression do not respond to monoaminergic antidepressants.[\[209\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Infl-209)[\[210\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-glut-210)
In 2022, a major systematic [umbrella review](https://en.wikipedia.org/wiki/Umbrella_review "Umbrella review") by [Joanna Moncrieff](https://en.wikipedia.org/wiki/Joanna_Moncrieff "Joanna Moncrieff") and colleagues showed that the serotonin theory of depression was not supported by evidence from a wide variety of areas.[\[208\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35854107-208) The authors concluded that there is no association between serotonin and depression, and that there is no evidence that strongly supports the theory that depression is caused by low serotonin activity or concentrations.[\[208\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35854107-208) Other literature had described the lack of support for the theory previously.[\[107\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid16268734-107)[\[108\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-LacasseLeo2015-108)[\[110\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-AngHorowitzMoncrieff2022-110) In many of the expert responses to the review, it was stated that the monoamine hypothesis had already long been abandoned by psychiatry.[\[211\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-ScienceMediaCentre2022-211)[\[212\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-MadInAmerica2022-212) This is in spite of about 90% of the general public in Western countries believing the theory to be true and many in the field of psychiatry continuing to promote the theory up to recent times.[\[212\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-MadInAmerica2022-212)[\[110\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-AngHorowitzMoncrieff2022-110) In addition to the serotonin umbrella review, reviews have found that [reserpine](https://en.wikipedia.org/wiki/Reserpine "Reserpine"), a drug that depletes the monoamine neurotransmitters—including serotonin, norepinephrine, and dopamine—shows no consistent evidence of producing depressive effects.[\[207\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid12953623-207)[\[213\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid36000248-213) Instead, findings of reserpine and mood are highly mixed, with similar proportions of studies finding that it has no influence on mood, produces depressive effects, or actually has antidepressant effects.[\[213\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid36000248-213) In relation to this, the general monoamine hypothesis, as opposed to only the serotonin theory of depression, likewise does not appear to be well-supported by evidence.[\[207\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid12953623-207)[\[213\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid36000248-213)[\[110\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-AngHorowitzMoncrieff2022-110)
The serotonin and monoamine hypotheses of depression have been heavily promoted by the [pharmaceutical industry](https://en.wikipedia.org/wiki/Pharmaceutical_industry "Pharmaceutical industry") (e.g., in [advertisements](https://en.wikipedia.org/wiki/Advertisement "Advertisement")) and by the psychiatric profession at large despite the lack of evidence in support of them.[\[107\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid16268734-107)[\[108\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-LacasseLeo2015-108)[\[207\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid12953623-207)[\[214\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-LeoLacasse2007-214)[\[110\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-AngHorowitzMoncrieff2022-110)[\[109\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Lacasse2005-109) In the case of the pharmaceutical industry, this can be attributed to obvious financial incentives, with the theory creating a bias against [non-pharmacological treatments](https://en.wikipedia.org/wiki/Non-pharmacological_treatment "Non-pharmacological treatment") for depression.[\[109\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Lacasse2005-109)[\[107\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid16268734-107)[\[108\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-LacasseLeo2015-108)[\[207\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid12953623-207)
### Other biological theories
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=30 "Edit section: Other biological theories")\]
Besides the monoamine hypothesis, a number of alternative biological hypotheses of depression and antidepressant action have been proposed, including hypotheses involving [glutamate](https://en.wikipedia.org/wiki/Glutamate "Glutamate"), [neurogenesis](https://en.wikipedia.org/wiki/Neurogenesis "Neurogenesis"), [neuroplasticity](https://en.wikipedia.org/wiki/Neuroplasticity "Neuroplasticity"), [epigenetics](https://en.wikipedia.org/wiki/Epigenetics "Epigenetics"), [cortisol](https://en.wikipedia.org/wiki/Cortisol "Cortisol") [hypersecretion](https://en.wikipedia.org/wiki/Hypersecretion "Hypersecretion"), and [inflammation](https://en.wikipedia.org/wiki/Inflammation "Inflammation"), among others.[\[209\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Infl-209)[\[210\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-glut-210)[\[215\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Epig-215)[\[216\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Epig2-216)[\[179\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-SiegelListonNicol2026-179)
An alternative theory for antidepressant action proposed by certain academics such as [Irving Kirsch](https://en.wikipedia.org/wiki/Irving_Kirsch "Irving Kirsch") and [Joanna Moncrieff](https://en.wikipedia.org/wiki/Joanna_Moncrieff "Joanna Moncrieff") is that they work largely or entirely via [placebo](https://en.wikipedia.org/wiki/Placebo "Placebo") mechanisms.[\[44\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31249537-44)[\[103\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Kirsch2014-103)[\[217\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Kirsch2010-217)[\[218\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35100527-218) This is supported by meta-analyses of [randomized controlled trials](https://en.wikipedia.org/wiki/Randomized_controlled_trial "Randomized controlled trial") of antidepressants for depression, which consistently show that placebo groups in trials improve about 80 to 90% as much as antidepressant groups on average[\[44\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31249537-44)[\[219\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-HengartnerPl%C3%B6derl2018-219) and that antidepressants are only marginally more effective for depression than placebos.[\[98\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31248914-98)[\[91\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid32101579-91)[\[220\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid29477251-220)[\[85\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35918097-85)[\[86\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid30386270-86) The difference between antidepressants and placebo corresponds to an [effect size](https://en.wikipedia.org/wiki/Effect_size "Effect size") ([SMD](https://en.wikipedia.org/wiki/Standardized_mean_difference "Standardized mean difference")) of about 0.3, which in turn equates to about a 2- to 3-point additional improvement on the 0–52-point ([HRSD](https://en.wikipedia.org/wiki/Hamilton_Depression_Rating_Scale "Hamilton Depression Rating Scale")) and 0–60-point ([MADRS](https://en.wikipedia.org/wiki/Montgomery%E2%80%93%C3%85sberg_Depression_Rating_Scale "Montgomery–Åsberg Depression Rating Scale")) [depression rating scales](https://en.wikipedia.org/wiki/Depression_rating_scale "Depression rating scale") used in trials.[\[98\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31248914-98)[\[91\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid32101579-91)[\[220\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid29477251-220)[\[85\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35918097-85)[\[86\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid30386270-86) Differences in effectiveness between different antidepressants are small and not clinically meaningful.[\[221\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid36638223-221)[\[220\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid29477251-220) The small advantage of antidepressants over placebo is often [statistically significant](https://en.wikipedia.org/wiki/Statistically_significant "Statistically significant") and is the basis for their regulatory approval, but is sufficiently modest that its [clinical significance](https://en.wikipedia.org/wiki/Clinical_significance "Clinical significance") is doubtful.[\[89\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid25979317-89)[\[222\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid33593736-222)[\[91\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid32101579-91)[\[86\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid30386270-86) Moreover, the small advantage of antidepressants over placebo may simply be a [methodological artifact](https://en.wikipedia.org/wiki/Methodological_artifact "Methodological artifact") caused by [unblinding](https://en.wikipedia.org/wiki/Unblinding "Unblinding") due to the [psychoactive](https://en.wikipedia.org/wiki/Psychoactive "Psychoactive") effects and [side effects](https://en.wikipedia.org/wiki/Side_effect "Side effect") of antidepressants, in turn resulting in [amplified placebo effects](https://en.wikipedia.org/wiki/Amplified_placebo_effect "Amplified placebo effect") and apparent antidepressant efficacy.[\[44\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31249537-44)[\[86\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid30386270-86)[\[103\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Kirsch2014-103) Placebos have been found to modify the activity of several brain regions and to increase levels of dopamine and [endogenous](https://en.wikipedia.org/wiki/Endogenous "Endogenous") [opioids](https://en.wikipedia.org/wiki/Opioid "Opioid") in the [reward pathways](https://en.wikipedia.org/wiki/Reward_pathway "Reward pathway").[\[223\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid35078210-223)[\[224\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid36006479-224)[\[225\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid15874901-225) It has been argued by Kirsch that although antidepressants may be used efficaciously for depression as [active placebos](https://en.wikipedia.org/wiki/Active_placebo "Active placebo"), they are limited by significant pharmacological [side effects](https://en.wikipedia.org/wiki/Side_effect "Side effect") and risks, and therefore [non-pharmacological therapies](https://en.wikipedia.org/wiki/Non-pharmaceutical_intervention "Non-pharmaceutical intervention"), such as [psychotherapy](https://en.wikipedia.org/wiki/Psychotherapy "Psychotherapy") and lifestyle changes, which can have similar efficacy to antidepressants but do not have their adverse effects, ought to be preferred as treatments in people with depression.[\[88\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31554608-88)
The [placebo response](https://en.wikipedia.org/wiki/Placebo_response "Placebo response"), or the improvement in scores in the placebo group in clinical trials, is not only due to the [placebo effect](https://en.wikipedia.org/wiki/Placebo_effect "Placebo effect"), but is also due to other phenomena such as [spontaneous remission](https://en.wikipedia.org/wiki/Spontaneous_remission "Spontaneous remission") and [regression to the mean](https://en.wikipedia.org/wiki/Regression_to_the_mean "Regression to the mean").[\[44\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31249537-44)[\[226\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid30975717-226) Depression tends to have an episodic course, with people eventually recovering even with no medical intervention, and people tend to seek treatment, as well as enroll in clinical trials, when they are feeling their worst.[\[102\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Hengartner2022-102)[\[226\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid30975717-226) In meta-analyses of trials of depression therapies, Kirsch estimated based on improvement in untreated waiting-list controls that spontaneous remission and regression to the mean only account for about 25% of the improvement in depression scores with antidepressant therapy.[\[44\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid31249537-44)[\[227\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid22860015-227)[\[228\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-KirschSapirstein1998-228)[\[229\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid20170046-229)[\[102\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Hengartner2022-102) However, another academic, [Michael P. Hengartner](https://en.wikipedia.org/wiki/Michael_P._Hengartner "Michael P. Hengartner"), has argued and presented evidence that spontaneous remission and regression to the mean might actually account for most of the improvement in depression scores with antidepressants, and that the substantial placebo effect observed in clinical trials might largely be a methodological artifact.[\[226\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid30975717-226) This suggests that antidepressants may be associated with much less genuine treatment benefit, whether due to the placebo effect or to the antidepressant itself, than has been traditionally assumed.[\[226\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid30975717-226)
It has been proposed that [psychedelics](https://en.wikipedia.org/wiki/Psychedelic_drug "Psychedelic drug") used for therapeutic purposes may act as [active](https://en.wikipedia.org/wiki/Active_placebo "Active placebo") "super placebos".[\[230\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-DupuisVeissi%C3%A8re2022-230)[\[231\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-vanElkYaden2022-231) However, due to issues like the [inverse placebo effect](https://en.wikipedia.org/wiki/Inverse_placebo_effect "Inverse placebo effect") caused by unblinding, psychedelics may actually be no more effective than traditional antidepressants.[\[232\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-WilliamsBarnettSzigeti2026-232)[\[233\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-AnsariElliottHolmes2026-233)[\[234\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Hamzelou2026-234)[\[235\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Busby2026-235)
### Selective serotonin reuptake inhibitors
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=33 "Edit section: Selective serotonin reuptake inhibitors")\]
[](https://en.wikipedia.org/wiki/File:Paroxetine-2D-skeletal.svg)
2D chemical structure of Paxil ([Paroxetine](https://en.wikipedia.org/wiki/Paroxetine "Paroxetine")), a [selective serotonin reuptake inhibitor](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor "Selective serotonin reuptake inhibitor")
[Selective serotonin reuptake inhibitors](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor "Selective serotonin reuptake inhibitor") (SSRIs) are believed to increase the [extracellular](https://en.wikipedia.org/wiki/Extracellular "Extracellular") level of the [neurotransmitter](https://en.wikipedia.org/wiki/Neurotransmitter "Neurotransmitter") serotonin by [limiting](https://en.wikipedia.org/wiki/Reuptake_inhibitor "Reuptake inhibitor") its [reabsorption](https://en.wikipedia.org/wiki/Reuptake "Reuptake") into the [presynaptic cell](https://en.wikipedia.org/wiki/Presynaptic_cell "Presynaptic cell"), increasing the level of [serotonin](https://en.wikipedia.org/wiki/Serotonin "Serotonin") in the [synaptic cleft](https://en.wikipedia.org/wiki/Synaptic_cleft "Synaptic cleft") available to bind to the [postsynaptic receptor](https://en.wikipedia.org/wiki/Postsynaptic_receptor "Postsynaptic receptor"). They have varying degrees of selectivity for the other [monoamine transporters](https://en.wikipedia.org/wiki/Monoamine_transporter "Monoamine transporter"), with pure SSRIs having only weak affinity for the [norepinephrine](https://en.wikipedia.org/wiki/Norepinephrine_transporter "Norepinephrine transporter") and [dopamine transporters](https://en.wikipedia.org/wiki/Dopamine_transporter "Dopamine transporter").
SSRIs are the most widely prescribed antidepressants in many countries.[\[236\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-PRESCORN2004-236) The efficacy of SSRIs in mild or moderate cases of depression has been disputed.[\[237\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-JAMA2010-237)[\[238\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Kramer-238)[\[239\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Pies-239)[\[240\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-240)
### Serotonin–norepinephrine reuptake inhibitors
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=34 "Edit section: Serotonin–norepinephrine reuptake inhibitors")\]
[](https://en.wikipedia.org/wiki/File:Venlafaxine-3D-balls.png)
The chemical structure of [venlafaxine](https://en.wikipedia.org/wiki/Venlafaxine "Venlafaxine") (Effexor), an [SNRI](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor")
[Serotonin–norepinephrine reuptake inhibitors](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") (SNRIs) are potent inhibitors of the [reuptake](https://en.wikipedia.org/wiki/Reuptake "Reuptake") of [serotonin](https://en.wikipedia.org/wiki/Serotonin "Serotonin") and [norepinephrine](https://en.wikipedia.org/wiki/Norepinephrine "Norepinephrine"). These [neurotransmitters](https://en.wikipedia.org/wiki/Neurotransmitter "Neurotransmitter") are known to play an important role in mood. SNRIs can be contrasted with the more widely used [selective serotonin reuptake inhibitors](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor "Selective serotonin reuptake inhibitor") (SSRIs), which act mostly upon serotonin alone.
The human [serotonin transporter](https://en.wikipedia.org/wiki/Serotonin_transporter "Serotonin transporter") (SERT) and [norepinephrine transporter](https://en.wikipedia.org/wiki/Norepinephrine_transporter "Norepinephrine transporter") (NET) are [membrane proteins](https://en.wikipedia.org/wiki/Membrane_protein "Membrane protein") that are responsible for the reuptake of serotonin and norepinephrine. Balanced dual inhibition of [monoamine](https://en.wikipedia.org/wiki/Monoamine "Monoamine") reuptake may offer advantages over other antidepressants drugs by treating a wider range of symptoms.[\[241\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid19740668-241)
SNRIs are sometimes also used to treat [anxiety disorders](https://en.wikipedia.org/wiki/Anxiety_disorder "Anxiety disorder"), [obsessive–compulsive disorder](https://en.wikipedia.org/wiki/Obsessive%E2%80%93compulsive_disorder "Obsessive–compulsive disorder") (OCD), [attention deficit hyperactivity disorder](https://en.wikipedia.org/wiki/Attention_deficit_hyperactivity_disorder "Attention deficit hyperactivity disorder") (ADHD), chronic [neuropathic pain](https://en.wikipedia.org/wiki/Neuropathic_pain "Neuropathic pain"), and [fibromyalgia syndrome](https://en.wikipedia.org/wiki/Fibromyalgia_syndrome "Fibromyalgia syndrome") (FMS), and for the relief of [menopausal](https://en.wikipedia.org/wiki/Menopause "Menopause") symptoms.
### Serotonin modulators and stimulators
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=35 "Edit section: Serotonin modulators and stimulators")\]
[Serotonin modulator and stimulators](https://en.wikipedia.org/wiki/Serotonin_modulator_and_stimulator "Serotonin modulator and stimulator") (SMSs), sometimes referred to more simply as "[serotonin](https://en.wikipedia.org/wiki/Serotonin "Serotonin") modulators", are a type of [drug](https://en.wikipedia.org/wiki/Drug "Drug") with a multimodal action specific to the serotonin [neurotransmitter](https://en.wikipedia.org/wiki/Neurotransmitter "Neurotransmitter") system. To be precise, SMSs simultaneously modulate one or more [serotonin receptors](https://en.wikipedia.org/wiki/Serotonin_receptor "Serotonin receptor") and inhibit the [reuptake](https://en.wikipedia.org/wiki/Reuptake "Reuptake") of serotonin. The term was coined in reference to the [mechanism of action](https://en.wikipedia.org/wiki/Mechanism_of_action "Mechanism of action") of the serotonergic antidepressant [vortioxetine](https://en.wikipedia.org/wiki/Vortioxetine "Vortioxetine"), which acts as a [serotonin reuptake inhibitor](https://en.wikipedia.org/wiki/Serotonin_reuptake_inhibitor "Serotonin reuptake inhibitor") (SRI), a [partial agonist](https://en.wikipedia.org/wiki/Partial_agonist "Partial agonist") of the [5-HT1A receptor](https://en.wikipedia.org/wiki/5-HT1A_receptor "5-HT1A receptor"), and [antagonist](https://en.wikipedia.org/wiki/Receptor_antagonist "Receptor antagonist") of the [5-HT3](https://en.wikipedia.org/wiki/5-HT3_receptor "5-HT3 receptor") and [5-HT7 receptors](https://en.wikipedia.org/wiki/5-HT7_receptor "5-HT7 receptor").[\[242\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid24391391-242)[\[243\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-AmerPharmAssoc2013-243)[\[244\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-LATimes2013-244) However, it can also technically be applied to [vilazodone](https://en.wikipedia.org/wiki/Vilazodone "Vilazodone"), which is an antidepressant as well and acts as an SRI and 5-HT1A receptor partial agonist.[\[245\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid15740724-245)
An alternative term is serotonin partial agonist/reuptake inhibitor (SPARI), which can be applied only to vilazodone.[\[246\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-246)
### Serotonin antagonists and reuptake inhibitors
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=36 "Edit section: Serotonin antagonists and reuptake inhibitors")\]
[Serotonin antagonist and reuptake inhibitors](https://en.wikipedia.org/wiki/Serotonin_antagonist_and_reuptake_inhibitors "Serotonin antagonist and reuptake inhibitors") (SARIs) while mainly used as antidepressants are also [anxiolytics](https://en.wikipedia.org/wiki/Anxiolytic "Anxiolytic") and [hypnotics](https://en.wikipedia.org/wiki/Hypnotic "Hypnotic"). They act by [antagonizing](https://en.wikipedia.org/wiki/Receptor_antagonist "Receptor antagonist") [serotonin receptors](https://en.wikipedia.org/wiki/Serotonin_receptor "Serotonin receptor") such as [5-HT2A](https://en.wikipedia.org/wiki/5-HT2A_receptor "5-HT2A receptor") and [inhibiting](https://en.wikipedia.org/wiki/Reuptake_inhibitor "Reuptake inhibitor") the [reuptake](https://en.wikipedia.org/wiki/Reuptake "Reuptake") of [serotonin](https://en.wikipedia.org/wiki/Serotonin "Serotonin"), [norepinephrine](https://en.wikipedia.org/wiki/Norepinephrine "Norepinephrine"), and/or [dopamine](https://en.wikipedia.org/wiki/Dopamine "Dopamine"). Additionally, most also act as [α1\-adrenergic receptor](https://en.wikipedia.org/wiki/Alpha-1_adrenergic_receptor "Alpha-1 adrenergic receptor") antagonists. The majority of the currently marketed SARIs belong to the [phenylpiperazine](https://en.wikipedia.org/wiki/Phenylpiperazine "Phenylpiperazine") class of compounds. They include [trazodone](https://en.wikipedia.org/wiki/Trazodone "Trazodone") and [nefazodone](https://en.wikipedia.org/wiki/Nefazodone "Nefazodone").
### Tricyclic antidepressants
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=37 "Edit section: Tricyclic antidepressants")\]
The majority of the [tricyclic antidepressants](https://en.wikipedia.org/wiki/Tricyclic_antidepressant "Tricyclic antidepressant") (TCAs) act primarily as [serotonin–norepinephrine reuptake inhibitors](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") (SNRIs) by blocking the [serotonin transporter](https://en.wikipedia.org/wiki/Serotonin_transporter "Serotonin transporter") (SERT) and the [norepinephrine transporter](https://en.wikipedia.org/wiki/Norepinephrine_transporter "Norepinephrine transporter") (NET), respectively, which results in an elevation of the [synaptic](https://en.wikipedia.org/wiki/Synapse "Synapse") concentrations of these [neurotransmitters](https://en.wikipedia.org/wiki/Neurotransmitter "Neurotransmitter"), and therefore an enhancement of [neurotransmission](https://en.wikipedia.org/wiki/Neurotransmission "Neurotransmission").[\[247\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid9537821-247)[\[248\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid17471183-248) Notably, with the sole exception of [amineptine](https://en.wikipedia.org/wiki/Amineptine "Amineptine"), the TCAs have weak [affinity](https://en.wikipedia.org/wiki/Affinity_\(pharmacology\) "Affinity (pharmacology)") for the [dopamine transporter](https://en.wikipedia.org/wiki/Dopamine_transporter "Dopamine transporter") (DAT), and therefore have low efficacy as [dopamine reuptake inhibitors](https://en.wikipedia.org/wiki/Dopamine_reuptake_inhibitor "Dopamine reuptake inhibitor") (DRIs).[\[247\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid9537821-247)
Although TCAs are sometimes [prescribed](https://en.wikipedia.org/wiki/Medical_prescription "Medical prescription") for depressive disorders, they have been largely replaced in clinical use in most parts of the world by newer antidepressants such as [selective serotonin reuptake inhibitors](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor "Selective serotonin reuptake inhibitor") (SSRIs), [serotonin–norepinephrine reuptake inhibitors](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") (SNRIs), and [norepinephrine reuptake inhibitors](https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitor "Norepinephrine reuptake inhibitor") (NRIs). Adverse effects have been found to be of a similar level between TCAs and SSRIs.[\[249\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-249)
### Tetracyclic antidepressants
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=38 "Edit section: Tetracyclic antidepressants")\]
[Tetracyclic antidepressants](https://en.wikipedia.org/wiki/Tetracyclic_antidepressants "Tetracyclic antidepressants") (TeCAs) are a class of antidepressants that were first introduced in the 1970s. They are named after their [chemical structure](https://en.wikipedia.org/wiki/Chemical_structure "Chemical structure"), which contains four [rings of atoms](https://en.wikipedia.org/wiki/Cyclic_compound "Cyclic compound"), and are closely related to [tricyclic antidepressants](https://en.wikipedia.org/wiki/Tricyclic_antidepressant "Tricyclic antidepressant") (TCAs), which contain three rings of atoms.
### Monoamine oxidase inhibitors
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=39 "Edit section: Monoamine oxidase inhibitors")\]
[Monoamine oxidase inhibitors](https://en.wikipedia.org/wiki/Monoamine_oxidase_inhibitor "Monoamine oxidase inhibitor") (MAOIs) are chemicals that inhibit the activity of the [monoamine oxidase enzyme family](https://en.wikipedia.org/wiki/Monoamine_oxidase "Monoamine oxidase"). They have a long history of use as medications prescribed for the treatment of [depression](https://en.wikipedia.org/wiki/Clinical_depression "Clinical depression"). They are particularly effective in treating [atypical depression](https://en.wikipedia.org/wiki/Atypical_depression "Atypical depression").[\[250\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-250) They are also used in the treatment of [Parkinson's disease](https://en.wikipedia.org/wiki/Parkinson%27s_disease "Parkinson's disease") and several other disorders.
Because of potentially lethal dietary and drug interactions, MAOIs have historically been reserved as a last line of treatment, used only when other classes of antidepressant drugs (for example [selective serotonin reuptake inhibitors](https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor "Selective serotonin reuptake inhibitor") and [tricyclic antidepressants](https://en.wikipedia.org/wiki/Tricyclic_antidepressant "Tricyclic antidepressant")) have failed.[\[251\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-251)
MAOIs have been found to be effective in the treatment of [panic disorder](https://en.wikipedia.org/wiki/Panic_disorder "Panic disorder") with [agoraphobia](https://en.wikipedia.org/wiki/Agoraphobia "Agoraphobia"),[\[252\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-252) [social phobia](https://en.wikipedia.org/wiki/Social_phobia "Social phobia"),[\[253\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-253)[\[254\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-254)[\[255\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-255) atypical depression[\[256\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-256)[\[257\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-257) or mixed anxiety and depression, [bulimia](https://en.wikipedia.org/wiki/Bulimia "Bulimia"),[\[258\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-258)[\[259\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-259)[\[260\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-260)[\[261\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-261) and [post-traumatic stress disorder](https://en.wikipedia.org/wiki/Post-traumatic_stress_disorder "Post-traumatic stress disorder"),[\[262\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-262) as well as [borderline personality disorder](https://en.wikipedia.org/wiki/Borderline_personality_disorder "Borderline personality disorder").[\[263\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-263) MAOIs appear to be particularly effective in the management of [bipolar depression](https://en.wikipedia.org/wiki/Bipolar_disorder "Bipolar disorder") according to a retrospective-analysis.[\[264\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-264) There are reports of MAOI efficacy in [obsessive–compulsive disorder](https://en.wikipedia.org/wiki/Obsessive%E2%80%93compulsive_disorder "Obsessive–compulsive disorder") (OCD), [trichotillomania](https://en.wikipedia.org/wiki/Trichotillomania "Trichotillomania"), [dysmorphophobia](https://en.wikipedia.org/wiki/Dysmorphophobia "Dysmorphophobia"), and [avoidant personality disorder](https://en.wikipedia.org/wiki/Avoidant_personality_disorder "Avoidant personality disorder"), but these reports are from uncontrolled case reports.[\[265\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid2248064-265)
MAOIs can also be used in the treatment of Parkinson's disease by targeting MAO-B in particular (therefore affecting [dopaminergic neurons](https://en.wikipedia.org/wiki/Dopaminergic_neuron "Dopaminergic neuron")), as well as providing an alternative for [migraine](https://en.wikipedia.org/wiki/Migraine "Migraine") [prophylaxis](https://en.wikipedia.org/wiki/Prophylaxis "Prophylaxis"). Inhibition of both MAO-A and MAO-B is used in the treatment of [clinical depression](https://en.wikipedia.org/wiki/Clinical_depression "Clinical depression") and [anxiety disorders](https://en.wikipedia.org/wiki/Anxiety_disorder "Anxiety disorder").
### NMDA receptor antagonists
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=40 "Edit section: NMDA receptor antagonists")\]
[NMDA receptor antagonists](https://en.wikipedia.org/wiki/NMDA_receptor_antagonist "NMDA receptor antagonist") like [ketamine](https://en.wikipedia.org/wiki/Ketamine "Ketamine") and [esketamine](https://en.wikipedia.org/wiki/Esketamine "Esketamine") are [rapid-acting antidepressants](https://en.wikipedia.org/wiki/Rapid-acting_antidepressant "Rapid-acting antidepressant") and seem to work via [blockade](https://en.wikipedia.org/wiki/Receptor_antagonist "Receptor antagonist") of the [ionotropic glutamate](https://en.wikipedia.org/wiki/Ionotropic_glutamate_receptor "Ionotropic glutamate receptor") [NMDA receptor](https://en.wikipedia.org/wiki/NMDA_receptor "NMDA receptor").[\[266\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-SpravatoLabel-266) Other NMDA antagonists may also play a role in treating depression. The combination medication [dextromethorphan/bupropion](https://en.wikipedia.org/wiki/Dextromethorphan/bupropion "Dextromethorphan/bupropion") (Auvelity), which contains the NMDA receptor antagonist [dextromethorphan](https://en.wikipedia.org/wiki/Dextromethorphan "Dextromethorphan"), was approved in the United States in 2022 for treating major depressive disorder.[\[267\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid36301443-267)[\[268\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid36943010-268)
See the [list of antidepressants](https://en.wikipedia.org/wiki/List_of_antidepressants "List of antidepressants") and [management of depression](https://en.wikipedia.org/wiki/Management_of_depression "Management of depression") for other drugs that are not specifically characterized.
Adjunct medications are an umbrella category of substances that increase the potency or "enhance" antidepressants.[\[269\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-269) They work by affecting variables very close to the antidepressant, sometimes affecting a completely different [mechanism of action](https://en.wikipedia.org/wiki/Mechanism_of_action "Mechanism of action"). This may be attempted when depression treatments have not been successful in the past.
Common types of adjunct medication techniques generally fall into the following categories:
- Two or more antidepressants taken together, from either the same or different classes (affecting the same area of the brain, often at a much higher level).
- An [antipsychotic](https://en.wikipedia.org/wiki/Antipsychotic "Antipsychotic") combined with an antidepressant, particularly [atypical antipsychotics](https://en.wikipedia.org/wiki/Atypical_antipsychotic "Atypical antipsychotic") such as [aripiprazole](https://en.wikipedia.org/wiki/Aripiprazole "Aripiprazole") (Abilify), [quetiapine](https://en.wikipedia.org/wiki/Quetiapine "Quetiapine") (Seroquel), [olanzapine](https://en.wikipedia.org/wiki/Olanzapine "Olanzapine") (Zyprexa), and [risperidone](https://en.wikipedia.org/wiki/Risperidone "Risperidone") (Risperdal).[\[270\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Maudsley-270)
It is unknown if undergoing [psychological therapy](https://en.wikipedia.org/wiki/Psychological_therapy "Psychological therapy") at the same time as taking anti-depressants enhances the anti-depressive effect of the medication.[\[271\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-271)
### Less common adjuncts
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=43 "Edit section: Less common adjuncts")\]
[Lithium](https://en.wikipedia.org/wiki/Lithium_\(medication\) "Lithium (medication)") has been used to augment antidepressant therapy in those who have failed to respond to antidepressants alone.[\[272\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid10505584-272) Furthermore, Lithium dramatically decreases the suicide risk in recurrent depression.[\[273\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid17388706-273) In addition to reducing the risk of suicide, lithium also reduces the risk of death from all causes in people with mood disorders.[\[274\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-274) There is some evidence for the addition of a thyroid hormone, [triiodothyronine](https://en.wikipedia.org/wiki/Triiodothyronine "Triiodothyronine"), in patients with normal thyroid function.[\[275\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid16946176-275)
Psychopharmacologists have also tried adding a [stimulant](https://en.wikipedia.org/wiki/Psychostimulant "Psychostimulant"), in particular, [D-amphetamine](https://en.wikipedia.org/wiki/D-amphetamine "D-amphetamine").[\[276\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-276) However, the use of stimulants in cases of treatment-resistant depression is relatively controversial.[\[277\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid1411740-277)[\[278\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid17338594-278) A review article published in 2007 found psychostimulants may be effective in treatment-resistant depression with concomitant antidepressant therapy, but a more certain conclusion could not be drawn due to substantial deficiencies in the studies available for consideration, and the somewhat contradictory nature of their results.[\[278\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid17338594-278)
[](https://en.wikipedia.org/wiki/File:Saint_John%27s_wort_flowers.jpg)
[St John's wort](https://en.wikipedia.org/wiki/Hypericum_perforatum "Hypericum perforatum")
The idea of an antidepressant, if [melancholy](https://en.wikipedia.org/wiki/Melancholia "Melancholia") is thought synonymous with depression, existed at least as early as the 1599 pamphlet *A pil to purge melancholie or, A preparative to a pvrgation: or, Topping, copping, and capping: take either or whether: or, Mash them, and squash them, and dash them, and diddle come derrie come daw them, all together..*. [Thomas d'Urfey](https://en.wikipedia.org/wiki/Thomas_d%27Urfey "Thomas d'Urfey")'s *Wit and Mirth: Or [Pills to Purge Melancholy](https://en.wikipedia.org/wiki/Pills_to_Purge_Melancholy "Pills to Purge Melancholy")*, the title of a large collection of songs, was published between 1698 and 1720.
Before the 1950s, [opioids](https://en.wikipedia.org/wiki/Opioid "Opioid") and [amphetamines](https://en.wikipedia.org/wiki/Amphetamine-type_stimulant "Amphetamine-type stimulant") were commonly used as antidepressants.[\[279\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Weber_1988_255%E2%80%9366-279)[\[280\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Amph_Uses_Dex-280)[\[198\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Rasmussen2006-198) [Amphetamine](https://en.wikipedia.org/wiki/Amphetamine "Amphetamine") has been described as the first antidepressant.[\[198\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Rasmussen2006-198) Use of opioids and amphetamines for depression was later restricted due to their addictive nature and side effects.[\[279\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Weber_1988_255%E2%80%9366-279)[\[198\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Rasmussen2006-198) Extracts from the herb [St John's wort](https://en.wikipedia.org/wiki/Hypericum_perforatum "Hypericum perforatum") have been used as a "nerve tonic" to alleviate depression.[\[281\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-281)
[St John's wort](https://en.wikipedia.org/wiki/Hypericum_perforatum "Hypericum perforatum") fell out of favor in most countries through the 19th and 20th centuries, except in [Germany](https://en.wikipedia.org/wiki/Germany "Germany"), where *[Hypericum](https://en.wikipedia.org/wiki/Hypericum "Hypericum")* extracts were eventually licensed, packaged, and prescribed. Small-scale efficacy trials were carried out in the 1970s and 1980s, and attention grew in the 1990s following a [meta-analysis](https://en.wikipedia.org/wiki/Meta-analysis "Meta-analysis").[\[282\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-282) It remains an [over-the-counter](https://en.wikipedia.org/wiki/Over-the-counter_drug "Over-the-counter drug") (OTC) supplement in most countries. Lead contamination associated with its usage has been seen as concerning, as lead levels in women in the United States taking St. John's wort are elevated by about 20% on average.[\[283\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-LeadInHerbs-283) Research continues to investigate its active component [hyperforin](https://en.wikipedia.org/wiki/Hyperforin "Hyperforin"), and to further understand its mode of action.[\[284\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-284)[\[285\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-285)
### Isoniazid, iproniazid, and imipramine
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=45 "Edit section: Isoniazid, iproniazid, and imipramine")\]
In 1951, [Irving Selikoff](https://en.wikipedia.org/wiki/Irving_Selikoff "Irving Selikoff") and Edward H. Robitzek, working out of [Sea View Hospital](https://en.wikipedia.org/wiki/Sea_View_Hospital "Sea View Hospital") on [Staten Island](https://en.wikipedia.org/wiki/Staten_Island "Staten Island"), began clinical trials on two new [anti-tuberculosis](https://en.wikipedia.org/wiki/Tuberculosis "Tuberculosis") agents developed by Hoffman-LaRoche, [isoniazid](https://en.wikipedia.org/wiki/Isoniazid "Isoniazid"), and [iproniazid](https://en.wikipedia.org/wiki/Iproniazid "Iproniazid"). Only patients with a poor [prognosis](https://en.wikipedia.org/wiki/Prognosis "Prognosis") were initially treated. Nevertheless, their condition improved dramatically. Selikoff and Robitzek noted "a subtle general stimulation ... the patients exhibited renewed vigor and indeed this occasionally served to introduce disciplinary problems."[\[286\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid14906149-286) The promise of a cure for tuberculosis in the Sea View Hospital trials was excitedly discussed in the mainstream press.
In 1952, learning of the stimulating side effects of isoniazid, the Cincinnati psychiatrist Max Lurie tried it on his patients. In the following year, he and Harry Salzer reported that isoniazid improved depression in two-thirds of their patients, so they then coined the term *antidepressant* to refer to its action.[\[287\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-isbn0-88048-397-0-287) A similar incident took place in Paris, where [Jean Delay](https://en.wikipedia.org/wiki/Jean_Delay "Jean Delay"), head of psychiatry at Sainte-Anne Hospital, heard of this effect from his [pulmonology](https://en.wikipedia.org/wiki/Pulmonology "Pulmonology") colleagues at Cochin Hospital. In 1952 (before Lurie and Salzer), Delay, with the resident Jean-Francois Buisson, reported the positive effect of isoniazid on depressed patients.[\[288\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Healy96-288) The mode of antidepressant action of isoniazid is still unclear. It is speculated that its effect is due to the inhibition of [diamine oxidase](https://en.wikipedia.org/wiki/Diamine_oxidase "Diamine oxidase"), coupled with a weak inhibition of [monoamine oxidase A](https://en.wikipedia.org/wiki/Monoamine_oxidase_A "Monoamine oxidase A").[\[289\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-isbn1-86036-010-6-289)
Selikoff and Robitzek also experimented with another anti-tuberculosis drug, [iproniazid](https://en.wikipedia.org/wiki/Iproniazid "Iproniazid"); it showed a greater psychostimulant effect, but more pronounced toxicity.[\[290\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid12998444-290) Later, Jackson Smith, Gordon Kamman, George E. Crane, and [Frank Ayd](https://en.wikipedia.org/wiki/Frank_Ayd "Frank Ayd"), described the psychiatric applications of iproniazid. [Ernst Zeller](https://en.wikipedia.org/w/index.php?title=Ernst_Zeller&action=edit&redlink=1 "Ernst Zeller (page does not exist)") found iproniazid to be a potent [monoamine oxidase inhibitor](https://en.wikipedia.org/wiki/Monoamine_oxidase_inhibitor "Monoamine oxidase inhibitor").[\[291\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid18004120-291) Nevertheless, iproniazid remained relatively obscure until [Nathan S. Kline](https://en.wikipedia.org/wiki/Nathan_S._Kline "Nathan S. Kline"), the influential head of research at [Rockland State Hospital](https://en.wikipedia.org/wiki/Rockland_State_Hospital "Rockland State Hospital"), began to popularize it in the medical and popular press as a "psychic energizer".[\[291\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid18004120-291)[\[292\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-292) Roche put a significant marketing effort behind iproniazid.[\[291\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid18004120-291) Its sales grew until it was recalled in 1961, due to reports of lethal [hepatotoxicity](https://en.wikipedia.org/wiki/Hepatotoxicity "Hepatotoxicity").[\[291\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid18004120-291)
The antidepressant effect of a [tricyclic antidepressant](https://en.wikipedia.org/wiki/Tricyclic_antidepressant "Tricyclic antidepressant"), a three-ringed compound, was first discovered in 1957 by [Roland Kuhn](https://en.wikipedia.org/wiki/Roland_Kuhn "Roland Kuhn") in a Swiss [psychiatric hospital](https://en.wikipedia.org/wiki/Psychiatric_hospital "Psychiatric hospital"). [Antihistamine](https://en.wikipedia.org/wiki/Antihistamine "Antihistamine") derivatives were used to treat surgical shock and later as [neuroleptics](https://en.wikipedia.org/wiki/Neuroleptics "Neuroleptics"). Although in 1955, [reserpine](https://en.wikipedia.org/wiki/Reserpine "Reserpine") was shown to be more effective than a placebo in alleviating anxious depression, neuroleptics were being developed as [sedatives](https://en.wikipedia.org/wiki/Sedative "Sedative") and [antipsychotics](https://en.wikipedia.org/wiki/Antipsychotic "Antipsychotic").\[*[medical citation needed](https://en.wikipedia.org/wiki/Wikipedia:Identifying_reliable_sources_\(medicine\) "Wikipedia:Identifying reliable sources (medicine)")*\]
Attempting to improve the effectiveness of [chlorpromazine](https://en.wikipedia.org/wiki/Chlorpromazine "Chlorpromazine"), Kuhn — in conjunction with the [Geigy](https://en.wikipedia.org/wiki/Geigy "Geigy") Pharmaceutical Company — discovered the compound "G 22355", later renamed [imipramine](https://en.wikipedia.org/wiki/Imipramine "Imipramine"). Imipramine had a beneficial effect on patients with depression who showed mental and [motor retardation](https://en.wikipedia.org/wiki/Motor_retardation "Motor retardation"). Kuhn described his new compound as a "thymoleptic" "taking hold of the emotions," in contrast with neuroleptics, "taking hold of the nerves" in 1955–56. These gradually became established, resulting in the patent and manufacture in the US in 1951 by Häfliger and SchinderA.[\[293\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-293)
Antidepressants became [prescription drugs](https://en.wikipedia.org/wiki/Prescription_drug "Prescription drug") in the 1950s. It was estimated that no more than fifty to one hundred individuals per million had the kind of depression that these new drugs would treat, and pharmaceutical companies were not enthusiastic about marketing for this small market. Sales through the 1960s remained poor compared to the sales of tranquilizers,[\[294\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-294)\[*[unreliable medical source?](https://en.wikipedia.org/wiki/Wikipedia:Identifying_reliable_sources_\(medicine\) "Wikipedia:Identifying reliable sources (medicine)")*\] which were being marketed for different uses.[\[295\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-3faces-295) Imipramine remained in common use and numerous successors were introduced. The use of monoamine oxidase inhibitors (MAOI) increased after the development and introduction of "reversible" forms affecting only the MAO-A subtype of inhibitors, making this drug safer to use.[\[295\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-3faces-295)[\[296\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-296)
By the 1960s, it was thought that the mode of action of tricyclics was to inhibit norepinephrine reuptake. However, norepinephrine reuptake became associated with stimulating effects. Later tricyclics were thought to affect [serotonin](https://en.wikipedia.org/wiki/Serotonin "Serotonin") as proposed in 1969 by Carlsson and Lindqvist as well as Lapin and Oxenkrug.\[*[medical citation needed](https://en.wikipedia.org/wiki/Wikipedia:Identifying_reliable_sources_\(medicine\) "Wikipedia:Identifying reliable sources (medicine)")*\]
### Second-generation antidepressants
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=46 "Edit section: Second-generation antidepressants")\]
Researchers began a process of [rational drug design](https://en.wikipedia.org/wiki/Rational_drug_design "Rational drug design") to isolate antihistamine-derived compounds that would selectively target these systems. The first such compound to be patented was [zimelidine](https://en.wikipedia.org/wiki/Zimelidine "Zimelidine") in 1971, while the first released clinically was [indalpine](https://en.wikipedia.org/wiki/Indalpine "Indalpine"). [Fluoxetine](https://en.wikipedia.org/wiki/Fluoxetine "Fluoxetine") was approved for commercial use by the US [Food and Drug Administration](https://en.wikipedia.org/wiki/Food_and_Drug_Administration "Food and Drug Administration") (FDA) in 1988, becoming the first [blockbuster](https://en.wikipedia.org/wiki/Blockbuster_drug "Blockbuster drug") SSRI. Fluoxetine was developed at [Eli Lilly and Company](https://en.wikipedia.org/wiki/Eli_Lilly_and_Company "Eli Lilly and Company") in the early 1970s by [Bryan Molloy](https://en.wikipedia.org/wiki/Bryan_Molloy "Bryan Molloy"), [Klaus Schmiegel](https://en.wikipedia.org/wiki/Klaus_Schmiegel "Klaus Schmiegel"), [David T. Wong](https://en.wikipedia.org/wiki/David_T._Wong "David T. Wong"), and others.[\[297\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-297)[\[298\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-298) SSRIs became known as "novel antidepressants" along with other newer drugs such as SNRIs and [NRIs](https://en.wikipedia.org/wiki/Norepinephrine_Reuptake_Inhibitor "Norepinephrine Reuptake Inhibitor") with various selective effects.[\[299\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-299)
### Rapid-acting antidepressants
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=47 "Edit section: Rapid-acting antidepressants")\]
[Esketamine](https://en.wikipedia.org/wiki/Esketamine "Esketamine") (brand name Spravato), the first rapid-acting antidepressant to be approved for clinical treatment of depression, was introduced for this indication in March 2019 in the United States.[\[266\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-SpravatoLabel-266)
A 2016 [randomized controlled trial](https://en.wikipedia.org/wiki/Randomized_controlled_trial "Randomized controlled trial") evaluated the [rapid antidepressant](https://en.wikipedia.org/wiki/Antidepressant#Rapid-acting_antidepressants) effects of the psychedelic [Ayahuasca](https://en.wikipedia.org/wiki/Ayahuasca "Ayahuasca") in treatment-resistant depression with a positive outcome.[\[300\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-300)[\[301\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-301) In 2018, the FDA granted Breakthrough Therapy Designation for [psilocybin](https://en.wikipedia.org/wiki/Psilocybin "Psilocybin")\-assisted therapy for treatment-resistant depression and in 2019, the FDA granted Breakthrough Therapy Designation for psilocybin therapy treating major depressive disorder.[\[302\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-302)
### Publication bias and aged research
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=49 "Edit section: Publication bias and aged research")\]
A 2018 systematic review published in [The Lancet](https://en.wikipedia.org/wiki/The_Lancet "The Lancet") comparing the efficacy of 21 different first and second generation antidepressants found that antidepressant drugs tended to perform better and cause less adverse events when they were novel or experimental treatments compared to when they were evaluated again years later.[\[36\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Zhou-2020-36) Unpublished data was also associated with smaller positive effect sizes. However, the review did not find evidence of bias associated with industry funded research.
## Society and culture
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=50 "Edit section: Society and culture")\]
### Prescription trends
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=51 "Edit section: Prescription trends")\]
In the UK, figures reported in 2010 indicated that the number of antidepressants prescribed by the [National Health Service](https://en.wikipedia.org/wiki/National_Health_Service "National Health Service") (NHS) almost doubled over a decade.[\[303\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-303) Further analysis published in 2014 showed that number of antidepressants dispensed annually in the community went up by 25 million in the 14 years between 1998 and 2012, rising from 15 million to 40 million. Nearly 50% of this rise occurred in the four years after the [Great Recession](https://en.wikipedia.org/wiki/Great_Recession "Great Recession"), during which time the annual increase in prescriptions rose from 6.7% to 8.5%.[\[304\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-304) These sources also suggest that aside from the recession, other factors that may influence changes in prescribing rates may include: improvements in diagnosis, a reduction of the [stigma](https://en.wikipedia.org/wiki/Social_stigma "Social stigma") surrounding mental health, broader prescribing trends, GP characteristics, geographical location, and housing status. Another factor that may contribute to increasing consumption of antidepressants is the fact that these medications now are used for other conditions including [social anxiety](https://en.wikipedia.org/wiki/Social_anxiety "Social anxiety") and [post-traumatic stress disorder](https://en.wikipedia.org/wiki/Post-traumatic_stress_disorder "Post-traumatic stress disorder").
Between 2005 and 2017, the number of adolescents (12 to 17 years) in England who were prescribed antidepressants has doubled. On the other hand, antidepressant prescriptions for children aged 5–11 in England decreased between 1999 and 2017.[\[305\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-305)[\[306\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-306) From April 2015, prescriptions increased for both age groups (for people aged 0 to 17) and peaked during the first COVID lockdown in March 2020.[\[307\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-307)
According to [National Institute for Health and Care Excellence](https://en.wikipedia.org/wiki/National_Institute_for_Health_and_Care_Excellence "National Institute for Health and Care Excellence") (NICE) guidelines, antidepressants for children and adolescents with depression and obsessive-compulsive disorder (OCD) should be prescribed together with therapy and after being assessed by a [child and adolescent psychiatrist](https://en.wikipedia.org/wiki/Child_and_adolescent_psychiatry "Child and adolescent psychiatry"). However, between 2006 and 2017, only 1 in 4 of 12–17 year-olds who were prescribed an SSRI by their GP had seen a specialist psychiatrist and 1 in 6 has seen a pediatrician. Half of these prescriptions were for depression and 16% for anxiety, the latter not being licensed for treatment with antidepressants.[\[42\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NIHR-2022-42)[\[308\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-308) Among the suggested possible reasons why GPs are not following the guidelines are the difficulties of accessing talking therapies, long waiting lists, and the urgency of treatment.[\[42\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-NIHR-2022-42)[\[309\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-309) According to some researchers, strict adherence to treatment guidelines would limit access to effective medication for young people with mental health problems.[\[310\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-310)
In the United States, antidepressants were the most commonly prescribed medication in 2013.[\[311\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-AJantidepressantstatsUS-311) Of the estimated 16 million "long term" (over 24 months) users, roughly 70 percent are female.[\[311\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-AJantidepressantstatsUS-311) As of 2017, about 16.5% of white people in the United States took antidepressants compared with 5.6% of black people in the United States.[\[312\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-APP2017-312)
Structural formula of the SSRI [sertraline](https://en.wikipedia.org/wiki/Sertraline "Sertraline")
**United States:** The most commonly prescribed antidepressants in the US retail market in 2010 were:[\[313\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-313)
| **Drug name** | **Drug class** | **Total prescriptions** |
|---|---|---|
| [Sertraline](https://en.wikipedia.org/wiki/Sertraline "Sertraline") | [SSRI](https://en.wikipedia.org/wiki/SSRI "SSRI") | 33,409,838 |
| [Citalopram](https://en.wikipedia.org/wiki/Citalopram "Citalopram") | [SSRI](https://en.wikipedia.org/wiki/SSRI "SSRI") | 27,993,635 |
| [Fluoxetine](https://en.wikipedia.org/wiki/Fluoxetine "Fluoxetine") | [SSRI](https://en.wikipedia.org/wiki/SSRI "SSRI") | 24,473,994 |
| [Escitalopram](https://en.wikipedia.org/wiki/Escitalopram "Escitalopram") | [SSRI](https://en.wikipedia.org/wiki/SSRI "SSRI") | 23,000,456 |
| [Trazodone](https://en.wikipedia.org/wiki/Trazodone "Trazodone") | [SARI](https://en.wikipedia.org/wiki/Serotonin_antagonist_and_reuptake_inhibitor "Serotonin antagonist and reuptake inhibitor") | 18,786,495 |
| [Venlafaxine](https://en.wikipedia.org/wiki/Venlafaxine "Venlafaxine") (all formulations) | [SNRI](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") | 16,110,606 |
| [Bupropion](https://en.wikipedia.org/wiki/Bupropion "Bupropion") (all formulations) | [NDRI](https://en.wikipedia.org/wiki/Norepinephrine%E2%80%93dopamine_reuptake_inhibitor "Norepinephrine–dopamine reuptake inhibitor") | 15,792,653 |
| [Duloxetine](https://en.wikipedia.org/wiki/Duloxetine "Duloxetine") | [SNRI](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") | 14,591,949 |
| [Paroxetine](https://en.wikipedia.org/wiki/Paroxetine "Paroxetine") | [SSRI](https://en.wikipedia.org/wiki/SSRI "SSRI") | 12,979,366 |
| [Amitriptyline](https://en.wikipedia.org/wiki/Amitriptyline "Amitriptyline") | [TCA](https://en.wikipedia.org/wiki/Tricyclic_antidepressant "Tricyclic antidepressant") | 12,611,254 |
| [Venlafaxine](https://en.wikipedia.org/wiki/Venlafaxine "Venlafaxine") XR | [SNRI](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") | 7,603,949 |
| [Bupropion](https://en.wikipedia.org/wiki/Bupropion "Bupropion") XL | [NDRI](https://en.wikipedia.org/wiki/Norepinephrine%E2%80%93dopamine_reuptake_inhibitor "Norepinephrine–dopamine reuptake inhibitor") | 7,317,814 |
| [Mirtazapine](https://en.wikipedia.org/wiki/Mirtazapine "Mirtazapine") | [TeCA](https://en.wikipedia.org/wiki/Tetracyclic_antidepressant "Tetracyclic antidepressant") | 6,308,288 |
| [Venlafaxine](https://en.wikipedia.org/wiki/Venlafaxine "Venlafaxine") ER | [SNRI](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") | 5,526,132 |
| [Bupropion](https://en.wikipedia.org/wiki/Bupropion "Bupropion") SR | [NDRI](https://en.wikipedia.org/wiki/Norepinephrine%E2%80%93dopamine_reuptake_inhibitor "Norepinephrine–dopamine reuptake inhibitor") | 4,588,996 |
| [Desvenlafaxine](https://en.wikipedia.org/wiki/Desvenlafaxine "Desvenlafaxine") | [SNRI](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") | 3,412,354 |
| [Nortriptyline](https://en.wikipedia.org/wiki/Nortriptyline "Nortriptyline") | [TCA](https://en.wikipedia.org/wiki/Tricyclic_antidepressant "Tricyclic antidepressant") | 3,210,476 |
| [Bupropion](https://en.wikipedia.org/wiki/Bupropion "Bupropion") ER | [NDRI](https://en.wikipedia.org/wiki/Norepinephrine%E2%80%93dopamine_reuptake_inhibitor "Norepinephrine–dopamine reuptake inhibitor") | 3,132,327 |
| [Venlafaxine](https://en.wikipedia.org/wiki/Venlafaxine "Venlafaxine") | [SNRI](https://en.wikipedia.org/wiki/Serotonin%E2%80%93norepinephrine_reuptake_inhibitor "Serotonin–norepinephrine reuptake inhibitor") | 2,980,525 |
| [Bupropion](https://en.wikipedia.org/wiki/Bupropion "Bupropion") | [NDRI](https://en.wikipedia.org/wiki/Norepinephrine%E2%80%93dopamine_reuptake_inhibitor "Norepinephrine–dopamine reuptake inhibitor") | 753,516 |
**Netherlands:** In the Netherlands, [paroxetine](https://en.wikipedia.org/wiki/Paroxetine "Paroxetine") is the most prescribed antidepressant, followed by [amitriptyline](https://en.wikipedia.org/wiki/Amitriptyline "Amitriptyline"), [citalopram](https://en.wikipedia.org/wiki/Citalopram "Citalopram") and [venlafaxine](https://en.wikipedia.org/wiki/Venlafaxine "Venlafaxine").[\[314\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-314)
As of 2003, worldwide, 30% to 60% of people did not follow their practitioner's instructions about taking their antidepressants,[\[315\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-315) and as of 2013 in the US, it appeared that around 50% of people did not take their antidepressants as directed by their practitioner.[\[316\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Kaplan-2013-316)
When people fail to take their antidepressants, there is a greater risk that the drug will not help, that symptoms get worse, that they miss work or are less productive at work, and that the person may be hospitalized.[\[317\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Ho2016-317)
Some academics\[*[who?](https://en.wikipedia.org/wiki/Wikipedia:Manual_of_Style/Words_to_watch#Unsupported_attributions "Wikipedia:Manual of Style/Words to watch")*\] have highlighted the need to examine the use of antidepressants and other medical treatments in cross-cultural terms, because various cultures prescribe and observe different manifestations, symptoms, meanings, and associations of depression and other medical conditions within their populations.[\[318\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Ecks_2005-318)[\[319\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Lock_2010-319) These cross-cultural discrepancies, it has been argued, then have implications on the perceived efficacy and use of antidepressants and other strategies in the treatment of depression in these different cultures.[\[318\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Ecks_2005-318)[\[319\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Lock_2010-319) In India, antidepressants are largely seen as tools to combat marginality, promising the individual the ability to reintegrate into society through their use—a view and association not observed in the West.[\[318\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-Ecks_2005-318)
### Environmental impacts
\[[edit](https://en.wikipedia.org/w/index.php?title=Antidepressant&action=edit§ion=56 "Edit section: Environmental impacts")\]
Because most antidepressants function by inhibiting the reuptake of neurotransmitters serotonin, dopamine, and norepinephrine[\[320\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid17690258-320) these drugs can interfere with natural neurotransmitter levels in other organisms impacted by indirect exposure.[\[321\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-321) Antidepressants fluoxetine and sertraline have been detected in aquatic organisms residing in effluent-dominated streams.[\[322\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid15720009-322) The presence of antidepressants in surface waters and aquatic organisms has caused concern because ecotoxicological effects on aquatic organisms due to fluoxetine exposure have been demonstrated.[\[323\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid16257063-323)
Coral reef fish have been demonstrated to modulate aggressive behavior through serotonin.[\[324\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-324) Artificially increasing serotonin levels in crustaceans can temporarily reverse social status and turn subordinates into aggressive and territorial dominant males.[\[325\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid9159179-325)
Exposure to Fluoxetine has been demonstrated to increase serotonergic activity in fish, subsequently reducing aggressive behavior.[\[326\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid12954414-326) Perinatal exposure to Fluoxetine at relevant environmental concentrations has been shown to lead to significant modifications of memory processing in 1-month-old cuttlefish.[\[327\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid23474317-327) This impairment may disadvantage cuttlefish and decrease their survival. Somewhat less than 10% of orally administered Fluoxetine is excreted from humans unchanged or as [glucuronide](https://en.wikipedia.org/wiki/Glucuronide "Glucuronide").[\[328\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid10674711-328)[\[329\]](https://en.wikipedia.org/wiki/Antidepressant#cite_note-pmid17160491-329)
- [Antidepressants in Japan](https://en.wikipedia.org/wiki/Antidepressants_in_Japan "Antidepressants in Japan")
- [Atypical antidepressant](https://en.wikipedia.org/wiki/Atypical_antidepressant "Atypical antidepressant")
- [Depression and natural therapies](https://en.wikipedia.org/wiki/Depression_and_natural_therapies "Depression and natural therapies")
- [Depression in childhood and adolescence](https://en.wikipedia.org/wiki/Depression_in_childhood_and_adolescence "Depression in childhood and adolescence")
- [List of antidepressants](https://en.wikipedia.org/wiki/List_of_antidepressants "List of antidepressants")
- [Management of depression](https://en.wikipedia.org/wiki/Management_of_depression "Management of depression")
- [Single-dose long-acting CNS drug](https://en.wikipedia.org/wiki/Single-dose_long-acting_CNS_drug "Single-dose long-acting CNS drug")
1. **[^](https://en.wikipedia.org/wiki/Antidepressant#cite_ref-Ghaemi2015_1-0)**
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2. ^ [***a***](https://en.wikipedia.org/wiki/Antidepressant#cite_ref-Jennings2018_2-0) [***b***](https://en.wikipedia.org/wiki/Antidepressant#cite_ref-Jennings2018_2-1)
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Stahl SM (19 November 2020). [*Prescriber's Guide: Stahl's Essential Psychopharmacology*](https://books.google.com/books?id=eyFGEAAAQBAJ). Cambridge University Press. [ISBN](https://en.wikipedia.org/wiki/ISBN_\(identifier\) "ISBN (identifier)")
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Park SC, Shen WW (2023). "Medication for Depression: Monoamine Enhancers and Esketamine (Antidepressants)". *Tasman's Psychiatry*. Cham: Springer International Publishing. pp. 1–53\. [doi](https://en.wikipedia.org/wiki/Doi_\(identifier\) "Doi (identifier)"):[10\.1007/978-3-030-42825-9\_133-1](https://doi.org/10.1007%2F978-3-030-42825-9_133-1). [ISBN](https://en.wikipedia.org/wiki/ISBN_\(identifier\) "ISBN (identifier)")
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Rasmussen N (July 2006). "Making the first anti-depressant: amphetamine in American medicine, 1929-1950". *J Hist Med Allied Sci*. **61** (3): 288–323\. [doi](https://en.wikipedia.org/wiki/Doi_\(identifier\) "Doi (identifier)"):[10\.1093/jhmas/jrj039](https://doi.org/10.1093%2Fjhmas%2Fjrj039). [hdl](https://en.wikipedia.org/wiki/Hdl_\(identifier\) "Hdl (identifier)"):[1959\.4/43848](https://hdl.handle.net/1959.4%2F43848). [PMID](https://en.wikipedia.org/wiki/PMID_\(identifier\) "PMID (identifier)") [16492800](https://pubmed.ncbi.nlm.nih.gov/16492800).
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Ciccarone D (March 2011). ["Stimulant abuse: pharmacology, cocaine, methamphetamine, treatment, attempts at pharmacotherapy"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056348). *Prim Care*. **38** (1): 41–58\. [doi](https://en.wikipedia.org/wiki/Doi_\(identifier\) "Doi (identifier)"):[10\.1016/j.pop.2010.11.004](https://doi.org/10.1016%2Fj.pop.2010.11.004). [PMC](https://en.wikipedia.org/wiki/PMC_\(identifier\) "PMC (identifier)") [3056348](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056348). [PMID](https://en.wikipedia.org/wiki/PMID_\(identifier\) "PMID (identifier)") [21356420](https://pubmed.ncbi.nlm.nih.gov/21356420). "In 1919, Japanese chemist Akira Ogata, as part of his effort to prove the structure of ephedrine, reported the synthesis of the closely related compound we now call methamphetamine, and this result was described in the Western literature (Amatsu & Kubota, 1913; Lee, 2011; Ogata, 1920). \[...\] As a result, when competitors began to consider emulating SKF's success in the late 1930s, they turned to methamphetamine, which had nearly indistinguishable effects but—because its synthesis together with its pharmacological characteristics was published before 1920—was free from patent encumbrance. \[...\] In any event, by 1940 Benzedrine Sulfate had achieved medical acclaim and quickly growing sales as an antidepressant effective for milder forms of the condition, both in the United States and the United Kingdom. In Germany, the Temmler drug firm quickly copied SKF, marketing methamphetamine (again, unprotected by patents) tablets under the Pervitin brand, with claims that it restored "joy in work" in cases of mild depression around 1938 (Rasmussen, 2006; Steinkamp, 2006)."
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Langlitz N (6 September 2025). ["Experiments in medicalization: psychedelic therapy in Switzerland and Australia"](https://link.springer.com/10.1057/s41292-025-00369-y). *BioSocieties*. [doi](https://en.wikipedia.org/wiki/Doi_\(identifier\) "Doi (identifier)"):[10\.1057/s41292-025-00369-y](https://doi.org/10.1057%2Fs41292-025-00369-y). [ISSN](https://en.wikipedia.org/wiki/ISSN_\(identifier\) "ISSN (identifier)") [1745-8552](https://search.worldcat.org/issn/1745-8552). Retrieved 11 February 2026. "Drawing on long-term ethnographic engagement with the psychedelic research community, \[this article\] presents two case studies: Switzerland's Limited Medical Use Program and Australia's Authorized Prescriber scheme. Both allow psychedelic therapies outside clinical trials, yet neither grants market access."
203. **[^](https://en.wikipedia.org/wiki/Antidepressant#cite_ref-NuttHuntSchlag2024_203-0)**
Nutt DJ, Hunt P, Schlag AK, Fitzgerald P (December 2024). ["The Australia story: Current status and future challenges for the clinical applications of psychedelics"](https://doi.org/10.1111%2Fbph.17398). *Br J Pharmacol*. [doi](https://en.wikipedia.org/wiki/Doi_\(identifier\) "Doi (identifier)"):[10\.1111/bph.17398](https://doi.org/10.1111%2Fbph.17398). [PMID](https://en.wikipedia.org/wiki/PMID_\(identifier\) "PMID (identifier)") [39701143](https://pubmed.ncbi.nlm.nih.gov/39701143). "\[...\] in 2023, the Australian Therapeutic Goods Administration (TGA) approved the use of psilocybin for treatment-resistant depression and MDMA for PTSD to take effect from 1 July 2023. \[...\] compassionate use \[of psychedelics\] has been allowed in Switzerland for decades and more recently in Canada (TheraPsil, 2024) and Israel."
204. **[^](https://en.wikipedia.org/wiki/Antidepressant#cite_ref-AicherM%C3%BCllerGasser2025_204-0)**
Aicher HD, Müller F, Gasser P (March 2025). ["Further education in psychedelic-assisted therapy - experiences from Switzerland"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881254). *BMC Med Educ*. **25** (1): 341. [doi](https://en.wikipedia.org/wiki/Doi_\(identifier\) "Doi (identifier)"):[10\.1186/s12909-025-06871-y](https://doi.org/10.1186%2Fs12909-025-06871-y). [PMC](https://en.wikipedia.org/wiki/PMC_\(identifier\) "PMC (identifier)") [11881254](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881254). [PMID](https://en.wikipedia.org/wiki/PMID_\(identifier\) "PMID (identifier)") [40045361](https://pubmed.ncbi.nlm.nih.gov/40045361). "In Switzerland, MDMA, psilocybin, and LSD are applied in the framework of limited medical use as exceptional treatment options since 2014."
205. **[^](https://en.wikipedia.org/wiki/Antidepressant#cite_ref-LiechtiGasserAicher2025_205-0)**
Liechti ME, Gasser P, Aicher HD, Mueller F, Hawrot T, Schmid Y (2025). ["Implementing psychedelic-assisted therapy: History and characteristics of the Swiss limited medical use program"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12341733). *Neurosci Appl*. **4** 105525. [doi](https://en.wikipedia.org/wiki/Doi_\(identifier\) "Doi (identifier)"):[10\.1016/j.nsa.2025.105525](https://doi.org/10.1016%2Fj.nsa.2025.105525). [PMC](https://en.wikipedia.org/wiki/PMC_\(identifier\) "PMC (identifier)") [12341733](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12341733). [PMID](https://en.wikipedia.org/wiki/PMID_\(identifier\) "PMID (identifier)") [40800003](https://pubmed.ncbi.nlm.nih.gov/40800003). "This article describes the Swiss limited access program for psychedelic/3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy. The Swiss Federal Office of Public Health can issue authorizations for the limited medical use of otherwise prohibited substances. To be eligible, patients suffer from a mostly incurable disease, the prohibited substance can alleviate the suffering, and there are no alternative treatments, or such treatments have already extensively been used with insufficient outcome. The current program started in 2014 with two physicians. In 2024, there were approximately 100 physicians who held authorizations to treat 723 patients with MDMA (245 patients), lysergic acid diethylamide (130 patients), or psilocybin (348 patients). \[...\]"
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- [](https://en.wikipedia.org/wiki/File:Commons-logo.svg) Media related to [Antidepressants](https://commons.wikimedia.org/wiki/Category:Antidepressants "commons:Category:Antidepressants") at Wikimedia Commons
Category *Drug classes defined by psychological effects* not found |
| Shard | 152 (laksa) |
| Root Hash | 17790707453426894952 |
| Unparsed URL | org,wikipedia!en,/wiki/Antidepressant s443 |