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1. Shard Calculation

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Response:

Calculated Shard: 133 (from laksa156)

2. Crawled Status Check

Query:

curl -X POST \
  'http://laksa133.int.ahrefs:8124/' \
  -H 'Content-Type: text/plain' \
  -H 'X-ClickHouse-Database: crawler3' \
  -H 'Authorization: Basic YXBpOg==' \
  -d 'SELECT getAhrefsURLFromUnparsed(src_unparsed) AS found_url, ifNull(toUnixTimestamp(download_stamp), 0) AS crawl_time, ifNull(toUnixTimestamp(props_url_first_seen), 0) AS first_indexed_time, download_http_code AS http_code, src_unparsed AS src_unparsed, src_root_hash AS src_root_hash, history_drop_reason AS history_drop_reason, meta_title AS meta_title, meta_descriptions AS meta_descriptions, attrs_boilerpipe_text AS attrs_boilerpipe_text, attrs_markdown AS attrs_markdown, attrs_readable_markdown AS attrs_readable_markdown, meta_canonical AS meta_canonical FROM crawler3.page_info_local FINAL PREWHERE (src_root_hash, src_unparsed) IN ((getAhrefsRootHashFromUnparsed(getAhrefsUnparsedNoserviceFromURL(\'https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html\')), getAhrefsUnparsedNoserviceFromURL(\'https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html\'))) FORMAT JSONEachRow'

Response:

{"found_url":"https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html","crawl_time":1776208985,"first_indexed_time":1653833197,"http_code":200,"src_unparsed":"org,aafp!www,\/pubs\/afp\/issues\/2010\/0515\/p1205.html s443","src_root_hash":"3969936278369100333","history_drop_reason":null,"meta_title":"Antidepressants for Initial Treatment of Depression | AAFP","meta_descriptions":["Which antidepressants should be used for the initial treatment of depression? This quality multiple-treatment meta-analysis gives physicians a good starting point for choosing an antidepressant. Sertraline and escitalopram should be considered first-line agents whereas bupropion, fluoxetine, paroxetine, and duloxetine were least tolerated."],"attrs_boilerpipe_text":"arrow_back\nPREV\nPREV ARTICLE\nMay 15, 2010\nNEXT\nNEXT ARTICLE\narrow_forward\nROBERT DACHS, MD, AND  FAAFP, Ellis Hospital Family Medicine Residency Program, Schenectady, New York\nMARK A. GRABER, MD, FACEP, University of Iowa Carver College of Medicine, Iowa City, Iowa\nAm Fam Physician.\n2010;81(10):1205-1212\nAuthor disclosure: Nothing to disclose.\nPurpose\nEach month, three presenters review an interesting journal article in a conversational manner. These articles involve “hot topics” that affect family physicians or “bust” commonly held medical myths. The presenters give their opinions about the clinical value of the individual study discussed. The opinions reflect the views of the presenters, not those of\nAFP\nor the AAFP.\nThis Month's Article\nCipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis.\nLancet\n. 2009;373(9665):746–758.\nAndrea\n: Family physicians regularly encounter patients with depression. With the ever-increasing number of new-generation antidepressants available and their competing claims of tolerability and effectiveness, it's hard to determine which antidepressant to use for initial treatment of major depression. The authors of this multiple-treatments meta-analysis used direct and indirect comparisons of 12 antidepressants to help determine which were effective and tolerable as first-line agents for the treatment of depression in adults.\nAndrea\n: The authors of this study reviewed 117 randomized controlled trials comparing one antidepressant with another; placebo-controlled trials were excluded. The outcomes analyzed were effectiveness (whether depression scores were reduced by at least 50 percent, or a clinical global impression of “much” or “very much improved” was achieved) and tolerability (defined by all-cause withdrawals from the trial at eight weeks).\nMultiple-treatments meta-analyses are not often seen in the literature. This type of analysis allows comparison of treatments directly (e.g., head-to-head trials) or indirectly (e.g., comparing the medications against a first-line treatment; in this case, fluoxetine [Prozac]), thus allowing physicians to determine if one treatment offers benefit over another. Standard meta-analyses only perform pairwise comparisons of treatment A versus treatment B. Often, large numbers of similar treatments are available for a given disease; therefore, conclusions have to be extrapolated from several different meta-analyses to make decisions about effectiveness.\n1\nI got a little cross-eyed interpreting these data tables. Simply stated, for effectiveness (or response rate), an odds ratio (OR) greater than 1 favored fluoxetine, and for tolerability (or drop-out rate), an OR less than 1 favored fluoxetine. Based on their comparisons, the authors conclude that sertraline (Zoloft) and escitalopram (Lexapro) are more effective (OR = 0.80; 95% confidence interval [CI], 0.69 to 0.93;\nP\n< .05 and OR = 0.76; 95% CI, 0.65 to 0.89;\nP\n< .05, respectively) and better tolerated (OR = 1.14; 95% CI, 0.96 to 1.36 and OR = 1.19; 95% CI, 0.99 to 1.44, respectively) than fluoxetine. Mirtazapine (Remeron) and venlafaxine (Effexor) perform well in effectiveness (OR = 0.73; 95% CI, 0.60 to 0.88;\nP\n< .05 and OR = 0.78; 95% CI, 0.68 to 0.90;\nP\n< .05, respectively), but are not as well tolerated as sertraline or escitalopram. Paroxetine (Paxil) and bupropion (Wellbutrin) are similar to fluoxetine in effectiveness and tolerability. Fluvoxamine and duloxetine (Cymbalta) are less effective than fluoxetine. See\nTable 1\nfor a comparison of antidepressants available in the United States.\n2\nTable 1.\nComparison of Improvement (Effectiveness) and All-Cause Withdrawal (Tolerability*) of Antidepressants for the Treatment of Major Depression\nAntidepressants\nPatient showed substantial improvement of\n≥\n50% from baseline depression symptom score (%)\n†\nAll-cause withdrawal (%)\n‡\nSertraline (Zoloft)\n62\n§\n22\nEscitalopram (Lexapro)\n59\n§\n19\nCitalopram (Celexa)\n57\n18\nMirtazapine (Remeron)\n62\n§\n25\nVenlafaxine (Effexor)\n60\n§\n25\nParoxetine (Paxil)\n56\n27\nBupropion (Wellbutrin)\n57\n28\nFluoxetine (Prozac)\n55\n28\nFluvoxamine\n52\n25\nDuloxetine (Cymbalta)\n50\n27\n*—\nNo medications used in the United States showed statistically significant improvement in tolerability compared with fluoxetine; however, those with lower drop-out rates showed a trend toward better tolerability\n.\n†—\nHigher percentage better\n.\n‡—\nLower percentage better\n.\n§—\nIndicates\nP\n< .05 for greater effectiveness compared with fluoxetine\n.\nAdapted with permission from Assessing relative efficacy of antidepressants. Oxford, UK: Bandolier; May 2009.\nhttp:\/\/www.medicine.ox.ac.uk\/bandolier\/booth\/mental\/cipriani.html\n. Accessed November 16, 2009\n.\nAndrea\n: The authors used two outcomes that we care about: effectiveness (how well the medication works) and tolerability (whether the patients actually took the medication). Adverse effects and cost of the medication can affect drop-out rates. The reality is that it doesn't matter why people stop taking their medications—we know that the medications won't work if they aren't ingested! It's notable that 18 to 28 percent of patients stopped these medications within eight weeks of prescription. The drop-out rate is likely higher in our community practices.\nBob\n: The study does have limitations that are common to nearly all meta-analyses. Pharmaceutical companies sponsored most of the studies, and many of the studies were of small size. Unfortunately, it is unlikely that we will have a similar head-to-head, non-industry–sponsored study of substantial size that will allow us to do these comparisons directly.\nMark\n: A meta-analysis can help us overcome small size by increasing the number of patients receiving any given treatment; thus, improving the strength of the conclusion. Nearly 25,000 patients participated in these trials. The mean duration of the studies was only six weeks, but that is within the window that we typically expect patients to see some effect (positive and negative) from these medications.\nAndrea\n: Meta-analyses have an insidious downside, however. They are only as good as the studies included (the “garbage in, garbage out” rule). So you shouldn't always trust the results of a meta-analysis. The validity of the results is highly influenced by the quality of the studies included, as well as by how carefully a search was done for studies to include in the meta-analysis. These authors collected studies from all available sources, including unpublished studies from pharmaceutical manufacturers, and all studies were conducted in a similar manner. Those that did not meet quality criteria were excluded from the final meta-analysis. It is reasonable to believe that the data represent the best available for prescribing decisions in the treatment of depression.\nBob\n: This study gives me a reasonable starting point for choosing antidepressants for my patients. I would likely start with sertraline over escitalopram, because it is one fourth the cost.\n3\nFluvoxamine and duloxetine will remain low on my list of first-line antidepressants.\nAndrea\n: I'm more likely to use sertraline as a first-line agent based on this information. I think it's a toss-up between citalopram (Celexa) and escitalopram based on the available data, so the cheapest medication will win in that competition. I'll certainly consider mirtazapine for my patients with depression who are also having difficulty sleeping.\nMark\n: Based on this study and the 2006 STAR⋆D trial, it appears that bupropion may be better as an augmenting agent than as a primary treatment for depression. In the STAR⋆D trial, some patients who did not respond to initial treatment with citalopram showed improvement in their depression scores with the addition of bupropion to their regimen.\n4\nInterestingly, citalopram and bupropion had similar effectiveness in this multiple-treatments meta-analysis; citalopram was better tolerated than bupropion.\nAndrea\n: I'd like to see more multiple-treatments meta-analyses for other medications that we use often, including statins, beta blockers, diuretics, and benign prostatic hyperplasia medications. Physicians and their patients are often tasked with choosing among multiple treatment options for any given condition. A multiple-treatments meta-analysis will allow us to be better informed about the options that are available and will allow development of treatment guidelines that reflect the best available evidence.\nConsider sertraline and escitalopram as first-line agents for initial treatment of major depression in adults.\nThe least tolerated antidepressants in this study were bupropion, fluoxetine, paroxetine, and duloxetine.\nA multiple-treatments meta-analysis allows you to compare treatments directly (e.g., head-to-head trials) and indirectly (e.g., against a first-line treatment). This increases the number of comparisons available and may allow the development of decision tools for effective treatment prioritization.\nSimilar to other meta-analyses, a multiple-treatments meta-analysis can be limited by low numbers of patients and poorly designed or heterogeneous studies (the “garbage in, garbage out” rule).\nAddress correspondence to Andrea Darby-Stewart, MD, at\nadstewart@shc.org\nReprints are not available from the authors\n.\nAuthor disclosure: Nothing to disclose.\nCaldwell DM, Ades AE, Higgins JP. Simultaneous comparison of multiple treatments: combining direct and indirect evidence.\nBMJ.\n2005;331(7521):897-900.\nAssessing relative efficacy of antidepressants. Oxford, UK: Bandolier; May 2009.\nhttp:\/\/www.medicine.ox.ac.uk\/bandolier\/booth\/mental\/cipriani.html\n. Accessed November 16, 2009.\nDrugstore.com.\nhttp:\/\/www.drugstore.com\n. Accessed December 17, 2009.\nRush AJ, Trivedi MH, Wisnlewski SR, et al.; STAR⋆D Study Team. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression.\nN Engl J Med.\n2006;354(12):1231-1242.\nContinue Reading\nMay 15, 2010","attrs_markdown":"![Leave a Message](https:\/\/lpcdn.lpsnmedia.net\/gallery\/libraries\/chat\/images\/assets\/live-chat.png)\n\n[Advertisement]()\n\n- [AAFP](https:\/\/www.aafp.org\/home.html)[AAFP](https:\/\/www.aafp.org\/home.html)\n- [AAFP Foundation](https:\/\/www.aafpfoundation.org\/home.html)[Foundation](https:\/\/www.aafpfoundation.org\/home.html)\n- [AFP Journal](https:\/\/www.aafp.org\/pubs\/afp.html)[AFP](https:\/\/www.aafp.org\/pubs\/afp.html)\n- [FPM Journal](https:\/\/www.aafp.org\/pubs\/fpm.html)[FPM](https:\/\/www.aafp.org\/pubs\/fpm.html)\n- [FUTURE](https:\/\/www.aafp.org\/events\/future-conference.html)[FUTURE](https:\/\/www.aafp.org\/events\/future-conference.html)\n- [FMX](https:\/\/www.aafp.org\/events\/fmx.html)[FMX](https:\/\/www.aafp.org\/events\/fmx.html)\n- [familydoctor.org](https:\/\/familydoctor.org\/)[familydoctor.org](https:\/\/familydoctor.org\/)\n\n[*shopping\\_cart*](https:\/\/www.aafp.org\/ams\/ecommerce\/store\/cart \"0\")\n\n[*account\\_circle*Log In](https:\/\/www.aafp.org\/cgi-bin\/lg.pl?redirect=https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html)\n\n[![brand logo](https:\/\/www.aafp.org\/content\/dam\/AAFP\/images\/logos_internal\/afp-masthead-2025.png)](https:\/\/www.aafp.org\/pubs\/afp.html)\n\nMenu*menu*\n\nSearch *search*\n\n- [*chevron\\_left*Issues*chevron\\_right*]()\n- [*chevron\\_left*AFP By Topic*chevron\\_right*]()\n- [*chevron\\_left*Collections*chevron\\_right*]()\n- [*chevron\\_left*CME Quiz*chevron\\_right*]()\n- [*chevron\\_left*Blog*chevron\\_right*]()\n- [*chevron\\_left*Multimedia*chevron\\_right*]()\n- [*chevron\\_left*Subscribe*chevron\\_right*]()\n\n[*arrow\\_back*PREVPREV ARTICLE](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1200.html)[May 15, 2010](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515.html)[NEXTNEXT ARTICLE*arrow\\_forward*](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1213.html)\n\n[PREV](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1200.html) [May 15, 2010](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515.html) [NEXT](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1213.html)\n\n![brand logo](https:\/\/www.aafp.org\/content\/dam\/AAFP\/images\/logos_internal\/afp-masthead-2025.png)\n\n[AFP Journal Club](https:\/\/www.aafp.org\/global-search.afp.html#&t=Publication&f:@section=[AFP%20Journal%20Club]&f:@subpublications=[AFP%20Journal])\n\nThe Story Behind the Study\n\n# Antidepressants for Initial Treatment of Depression\n\n*print*Print\n\n[*comment*Comments](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#article-comment-area)\n\nANDREA DARBY-STEWART, MD, Scottsdale Healthcare Family Medicine Residency, Scottsdale, Arizona\n\nROBERT DACHS, MD, AND FAAFP, Ellis Hospital Family Medicine Residency Program, Schenectady, New York\n\nMARK A. GRABER, MD, FACEP, University of Iowa Carver College of Medicine, Iowa City, Iowa\n\ninfo\n\n*Am Fam Physician.* 2010;81(10):1205-1212\n\nassignment\n\nAuthor disclosure: Nothing to disclose.\n\n**Purpose**\n\nEach month, three presenters review an interesting journal article in a conversational manner. These articles involve “hot topics” that affect family physicians or “bust” commonly held medical myths. The presenters give their opinions about the clinical value of the individual study discussed. The opinions reflect the views of the presenters, not those of *AFP* or the AAFP.\n\n**This Month's Article**\n\nCipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. *Lancet*. 2009;373(9665):746–758.\n## Which antidepressants should be used for the initial treatment of depression?\n*Andrea*: Family physicians regularly encounter patients with depression. With the ever-increasing number of new-generation antidepressants available and their competing claims of tolerability and effectiveness, it's hard to determine which antidepressant to use for initial treatment of major depression. The authors of this multiple-treatments meta-analysis used direct and indirect comparisons of 12 antidepressants to help determine which were effective and tolerable as first-line agents for the treatment of depression in adults.\n\n## What does this article say?\n*Andrea*: The authors of this study reviewed 117 randomized controlled trials comparing one antidepressant with another; placebo-controlled trials were excluded. The outcomes analyzed were effectiveness (whether depression scores were reduced by at least 50 percent, or a clinical global impression of “much” or “very much improved” was achieved) and tolerability (defined by all-cause withdrawals from the trial at eight weeks).\n\nMultiple-treatments meta-analyses are not often seen in the literature. This type of analysis allows comparison of treatments directly (e.g., head-to-head trials) or indirectly (e.g., comparing the medications against a first-line treatment; in this case, fluoxetine \\[Prozac\\]), thus allowing physicians to determine if one treatment offers benefit over another. Standard meta-analyses only perform pairwise comparisons of treatment A versus treatment B. Often, large numbers of similar treatments are available for a given disease; therefore, conclusions have to be extrapolated from several different meta-analyses to make decisions about effectiveness.[1](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-b1)\n\nI got a little cross-eyed interpreting these data tables. Simply stated, for effectiveness (or response rate), an odds ratio (OR) greater than 1 favored fluoxetine, and for tolerability (or drop-out rate), an OR less than 1 favored fluoxetine. Based on their comparisons, the authors conclude that sertraline (Zoloft) and escitalopram (Lexapro) are more effective (OR = 0.80; 95% confidence interval \\[CI\\], 0.69 to 0.93; *P* \\< .05 and OR = 0.76; 95% CI, 0.65 to 0.89; *P* \\< .05, respectively) and better tolerated (OR = 1.14; 95% CI, 0.96 to 1.36 and OR = 1.19; 95% CI, 0.99 to 1.44, respectively) than fluoxetine. Mirtazapine (Remeron) and venlafaxine (Effexor) perform well in effectiveness (OR = 0.73; 95% CI, 0.60 to 0.88; *P* \\< .05 and OR = 0.78; 95% CI, 0.68 to 0.90; *P* \\< .05, respectively), but are not as well tolerated as sertraline or escitalopram. Paroxetine (Paxil) and bupropion (Wellbutrin) are similar to fluoxetine in effectiveness and tolerability. Fluvoxamine and duloxetine (Cymbalta) are less effective than fluoxetine. See *[Table 1](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-t1)* for a comparison of antidepressants available in the United States.[2](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-b2)\n\n*Table 1.*\n\n### Comparison of Improvement (Effectiveness) and All-Cause Withdrawal (Tolerability\\*) of Antidepressants for the Treatment of Major Depression\n[*zoom\\_out\\_map*Enlarge](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205\/jcr:content\/root\/aafp-article-primary-content-container\/aafp_article_main_par\/aafp_tables_content.enlarge.html)[*print*Print](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205\/jcr:content\/root\/aafp-article-primary-content-container\/aafp_article_main_par\/aafp_tables_content.print.html)\n\n| *Antidepressants* | *Patient showed substantial improvement of* ≥ *50% from baseline depression symptom score (%)*[†](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-tfn2) | *All-cause withdrawal (%)*[‡](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-tfn3) |\n|---|---|---|\n| Sertraline (Zoloft) | 62[§](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-tfn4) | 22 |\n| Escitalopram (Lexapro) | 59[§](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-tfn4) | 19 |\n| Citalopram (Celexa) | 57 | 18 |\n| Mirtazapine (Remeron) | 62[§](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-tfn4) | 25 |\n| Venlafaxine (Effexor) | 60[§](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-tfn4) | 25 |\n| Paroxetine (Paxil) | 56 | 27 |\n| Bupropion (Wellbutrin) | 57 | 28 |\n| Fluoxetine (Prozac) | 55 | 28 |\n| Fluvoxamine | 52 | 25 |\n| Duloxetine (Cymbalta) | 50 | 27 |\n\n\\*— *No medications used in the United States showed statistically significant improvement in tolerability compared with fluoxetine; however, those with lower drop-out rates showed a trend toward better tolerability*.\n\n†— *Higher percentage better*.\n\n‡— *Lower percentage better*.\n\n§— *Indicates* P *\\< .05 for greater effectiveness compared with fluoxetine*.\n\n*Adapted with permission from Assessing relative efficacy of antidepressants. Oxford, UK: Bandolier; May 2009. <http:\/\/www.medicine.ox.ac.uk\/bandolier\/booth\/mental\/cipriani.html>. Accessed November 16, 2009*.\n## Should we believe this study?\n*Andrea*: The authors used two outcomes that we care about: effectiveness (how well the medication works) and tolerability (whether the patients actually took the medication). Adverse effects and cost of the medication can affect drop-out rates. The reality is that it doesn't matter why people stop taking their medications—we know that the medications won't work if they aren't ingested! It's notable that 18 to 28 percent of patients stopped these medications within eight weeks of prescription. The drop-out rate is likely higher in our community practices.\n\n*Bob*: The study does have limitations that are common to nearly all meta-analyses. Pharmaceutical companies sponsored most of the studies, and many of the studies were of small size. Unfortunately, it is unlikely that we will have a similar head-to-head, non-industry–sponsored study of substantial size that will allow us to do these comparisons directly.\n\n*Mark*: A meta-analysis can help us overcome small size by increasing the number of patients receiving any given treatment; thus, improving the strength of the conclusion. Nearly 25,000 patients participated in these trials. The mean duration of the studies was only six weeks, but that is within the window that we typically expect patients to see some effect (positive and negative) from these medications.\n\n*Andrea*: Meta-analyses have an insidious downside, however. They are only as good as the studies included (the “garbage in, garbage out” rule). So you shouldn't always trust the results of a meta-analysis. The validity of the results is highly influenced by the quality of the studies included, as well as by how carefully a search was done for studies to include in the meta-analysis. These authors collected studies from all available sources, including unpublished studies from pharmaceutical manufacturers, and all studies were conducted in a similar manner. Those that did not meet quality criteria were excluded from the final meta-analysis. It is reasonable to believe that the data represent the best available for prescribing decisions in the treatment of depression.\n\n## What should the family physician do?\n*Bob*: This study gives me a reasonable starting point for choosing antidepressants for my patients. I would likely start with sertraline over escitalopram, because it is one fourth the cost.[3](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-b3) Fluvoxamine and duloxetine will remain low on my list of first-line antidepressants.\n\n*Andrea*: I'm more likely to use sertraline as a first-line agent based on this information. I think it's a toss-up between citalopram (Celexa) and escitalopram based on the available data, so the cheapest medication will win in that competition. I'll certainly consider mirtazapine for my patients with depression who are also having difficulty sleeping.\n\n*Mark*: Based on this study and the 2006 STAR⋆D trial, it appears that bupropion may be better as an augmenting agent than as a primary treatment for depression. In the STAR⋆D trial, some patients who did not respond to initial treatment with citalopram showed improvement in their depression scores with the addition of bupropion to their regimen.[4](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-b4) Interestingly, citalopram and bupropion had similar effectiveness in this multiple-treatments meta-analysis; citalopram was better tolerated than bupropion.\n\n*Andrea*: I'd like to see more multiple-treatments meta-analyses for other medications that we use often, including statins, beta blockers, diuretics, and benign prostatic hyperplasia medications. Physicians and their patients are often tasked with choosing among multiple treatment options for any given condition. A multiple-treatments meta-analysis will allow us to be better informed about the options that are available and will allow development of treatment guidelines that reflect the best available evidence.\n\n## Main Points\n- Consider sertraline and escitalopram as first-line agents for initial treatment of major depression in adults.\n- The least tolerated antidepressants in this study were bupropion, fluoxetine, paroxetine, and duloxetine.\n## EBM Points\n- A multiple-treatments meta-analysis allows you to compare treatments directly (e.g., head-to-head trials) and indirectly (e.g., against a first-line treatment). This increases the number of comparisons available and may allow the development of decision tools for effective treatment prioritization.\n- Similar to other meta-analyses, a multiple-treatments meta-analysis can be limited by low numbers of patients and poorly designed or heterogeneous studies (the “garbage in, garbage out” rule).\n\n## expand\\_moreAuthor Information\n*Address correspondence to Andrea Darby-Stewart, MD, at [adstewart@shc.org](mailto:adstewart@shc.org) Reprints are not available from the authors*.\n\nAuthor disclosure: Nothing to disclose.\n\n## expand\\_moreReference(s)\n1. Caldwell DM, Ades AE, Higgins JP. Simultaneous comparison of multiple treatments: combining direct and indirect evidence. *BMJ.*  2005;331(7521):897-900.\n2. Assessing relative efficacy of antidepressants. Oxford, UK: Bandolier; May 2009. <http:\/\/www.medicine.ox.ac.uk\/bandolier\/booth\/mental\/cipriani.html>. Accessed November 16, 2009.\n3. Drugstore.com. <http:\/\/www.drugstore.com>. Accessed December 17, 2009.\n4. Rush AJ, Trivedi MH, Wisnlewski SR, et al.; STAR⋆D Study Team. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. *N Engl J Med.*  2006;354(12):1231-1242.\n\n1. Caldwell DM, Ades AE, Higgins JP. Simultaneous comparison of multiple treatments: combining direct and indirect evidence. *BMJ.*  2005;331(7521):897-900.\n2. Assessing relative efficacy of antidepressants. Oxford, UK: Bandolier; May 2009. <http:\/\/www.medicine.ox.ac.uk\/bandolier\/booth\/mental\/cipriani.html>. Accessed November 16, 2009.\n3. Drugstore.com. <http:\/\/www.drugstore.com>. Accessed December 17, 2009.\n4. Rush AJ, Trivedi MH, Wisnlewski SR, et al.; STAR⋆D Study Team. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. *N Engl J Med.*  2006;354(12):1231-1242.\n\nAdd\/View Comments\n\n0 comments\n\n*lock* [Log In]() to comment\n\n## Continue Reading\n[![](https:\/\/www.aafp.org\/content\/dam\/brand\/aafp\/pubs\/afp\/issues\/2010\/0515\/cover.jpg.169.resized\/cover.jpg)](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515.html)\n\nMay 15, 2010\n\n[![](https:\/\/www.aafp.org\/content\/dam\/brand\/aafp\/pubs\/afp\/issues\/2010\/0515\/cover.jpg.169.resized\/cover.jpg)](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515.html)\n\n## May 15, 2010\nPrevious: [Family Physicians and Nursing Home Medicine: Forging a Partnership for Quality Care](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1200.html)\n\nNext: [Greater Family Medicine Presence at NIH Could Improve Research Relevance and Reach](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1213.html)\n\n[View the full table of contents*chevron\\_right*](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515.html)\n\n[Advertisement]()\n\n## More in *AFP*\n#### Editor's Collections\n[AFP Journal Club](https:\/\/www.aafp.org\/global-search.afp.html#&t=Publication&f:@section=[AFP%20Journal%20Club]&f:@subpublications=[AFP%20Journal])\n\n#### Related Content\n[Depression and Bipolar Disorder](https:\/\/www.aafp.org\/pubs\/afp\/collections\/taxonomy.depression-and-bipolar-disorder.html)\n\n## More in PubMed\n[Citation](http:\/\/www.ncbi.nlm.nih.gov\/entrez\/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=20507044)\n\n[Related Articles](http:\/\/www.ncbi.nlm.nih.gov\/entrez\/query.fcgi?db=pubmed&cmd=Display&dopt=pubmed_pubmed&from_uid=20507044)\n\n![Mar 2026](https:\/\/www.aafp.org\/content\/dam\/brand\/aafp\/pubs\/afp\/issues\/2026\/0300\/cover.jpg)\n\n[Most Recent IssueMar 2026](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2026\/0300.html)\n\n### AFP Email Alerts\nFree e-newsletter and email table of contents.\n\n[SIGN UP NOW](https:\/\/www.aafp.org\/pubs\/afp\/subscribe\/by-email.html)\n\nCopyright © 2010 by the American Academy of Family Physicians.\n\nThis content is owned by the AAFP. 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All Rights Reserved.\n\n[About This Site](https:\/\/www.aafp.org\/about\/this-site.html)\\|[Privacy Policy](https:\/\/www.aafp.org\/about\/this-site\/privacy.html)\\|[Terms of Use](https:\/\/www.aafp.org\/about\/this-site\/terms.html)\n\n[Connect on Facebook](https:\/\/www.facebook.com\/AFPJournal)\n\n[Connect on X (Twitter)](https:\/\/twitter.com\/AFPJournal)\n\n[Connect on Instagram](https:\/\/www.instagram.com\/afpjournal\/)\n\n![](https:\/\/px.ads.linkedin.com\/collect\/?pid=1094194&fmt=gif)\n\n![](https:\/\/www.facebook.com\/tr?id=965457068161902&ev=PageView&noscript=1)","attrs_readable_markdown":"[*arrow\\_back*PREVPREV ARTICLE](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1200.html)[May 15, 2010](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515.html)[NEXTNEXT ARTICLE*arrow\\_forward*](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1213.html)\n\n![brand logo](https:\/\/www.aafp.org\/content\/dam\/AAFP\/images\/logos_internal\/afp-masthead-2025.png)\n\nROBERT DACHS, MD, AND FAAFP, Ellis Hospital Family Medicine Residency Program, Schenectady, New York\n\nMARK A. GRABER, MD, FACEP, University of Iowa Carver College of Medicine, Iowa City, Iowa\n\n*Am Fam Physician.* 2010;81(10):1205-1212\n\nAuthor disclosure: Nothing to disclose.\n\n**Purpose**\n\nEach month, three presenters review an interesting journal article in a conversational manner. These articles involve “hot topics” that affect family physicians or “bust” commonly held medical myths. The presenters give their opinions about the clinical value of the individual study discussed. The opinions reflect the views of the presenters, not those of *AFP* or the AAFP.\n\n**This Month's Article**\n\nCipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. *Lancet*. 2009;373(9665):746–758.\n\n*Andrea*: Family physicians regularly encounter patients with depression. With the ever-increasing number of new-generation antidepressants available and their competing claims of tolerability and effectiveness, it's hard to determine which antidepressant to use for initial treatment of major depression. The authors of this multiple-treatments meta-analysis used direct and indirect comparisons of 12 antidepressants to help determine which were effective and tolerable as first-line agents for the treatment of depression in adults.\n\n*Andrea*: The authors of this study reviewed 117 randomized controlled trials comparing one antidepressant with another; placebo-controlled trials were excluded. The outcomes analyzed were effectiveness (whether depression scores were reduced by at least 50 percent, or a clinical global impression of “much” or “very much improved” was achieved) and tolerability (defined by all-cause withdrawals from the trial at eight weeks).\n\nMultiple-treatments meta-analyses are not often seen in the literature. This type of analysis allows comparison of treatments directly (e.g., head-to-head trials) or indirectly (e.g., comparing the medications against a first-line treatment; in this case, fluoxetine \\[Prozac\\]), thus allowing physicians to determine if one treatment offers benefit over another. Standard meta-analyses only perform pairwise comparisons of treatment A versus treatment B. Often, large numbers of similar treatments are available for a given disease; therefore, conclusions have to be extrapolated from several different meta-analyses to make decisions about effectiveness.[1](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-b1)\n\nI got a little cross-eyed interpreting these data tables. Simply stated, for effectiveness (or response rate), an odds ratio (OR) greater than 1 favored fluoxetine, and for tolerability (or drop-out rate), an OR less than 1 favored fluoxetine. Based on their comparisons, the authors conclude that sertraline (Zoloft) and escitalopram (Lexapro) are more effective (OR = 0.80; 95% confidence interval \\[CI\\], 0.69 to 0.93; *P* \\< .05 and OR = 0.76; 95% CI, 0.65 to 0.89; *P* \\< .05, respectively) and better tolerated (OR = 1.14; 95% CI, 0.96 to 1.36 and OR = 1.19; 95% CI, 0.99 to 1.44, respectively) than fluoxetine. Mirtazapine (Remeron) and venlafaxine (Effexor) perform well in effectiveness (OR = 0.73; 95% CI, 0.60 to 0.88; *P* \\< .05 and OR = 0.78; 95% CI, 0.68 to 0.90; *P* \\< .05, respectively), but are not as well tolerated as sertraline or escitalopram. Paroxetine (Paxil) and bupropion (Wellbutrin) are similar to fluoxetine in effectiveness and tolerability. Fluvoxamine and duloxetine (Cymbalta) are less effective than fluoxetine. See *[Table 1](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-t1)* for a comparison of antidepressants available in the United States.[2](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-b2)\n\n*Table 1.*\n\nComparison of Improvement (Effectiveness) and All-Cause Withdrawal (Tolerability\\*) of Antidepressants for the Treatment of Major Depression\n\n| *Antidepressants* | *Patient showed substantial improvement of* ≥ *50% from baseline depression symptom score (%)*[†](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-tfn2) | *All-cause withdrawal (%)*[‡](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-tfn3) |\n|---|---|---|\n| Sertraline (Zoloft) | 62[§](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-tfn4) | 22 |\n| Escitalopram (Lexapro) | 59[§](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-tfn4) | 19 |\n| Citalopram (Celexa) | 57 | 18 |\n| Mirtazapine (Remeron) | 62[§](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-tfn4) | 25 |\n| Venlafaxine (Effexor) | 60[§](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-tfn4) | 25 |\n| Paroxetine (Paxil) | 56 | 27 |\n| Bupropion (Wellbutrin) | 57 | 28 |\n| Fluoxetine (Prozac) | 55 | 28 |\n| Fluvoxamine | 52 | 25 |\n| Duloxetine (Cymbalta) | 50 | 27 |\n\n\\*— *No medications used in the United States showed statistically significant improvement in tolerability compared with fluoxetine; however, those with lower drop-out rates showed a trend toward better tolerability*.\n\n†— *Higher percentage better*.\n\n‡— *Lower percentage better*.\n\n§— *Indicates* P *\\< .05 for greater effectiveness compared with fluoxetine*.\n\n*Adapted with permission from Assessing relative efficacy of antidepressants. Oxford, UK: Bandolier; May 2009. <http:\/\/www.medicine.ox.ac.uk\/bandolier\/booth\/mental\/cipriani.html>. Accessed November 16, 2009*.\n\n*Andrea*: The authors used two outcomes that we care about: effectiveness (how well the medication works) and tolerability (whether the patients actually took the medication). Adverse effects and cost of the medication can affect drop-out rates. The reality is that it doesn't matter why people stop taking their medications—we know that the medications won't work if they aren't ingested! It's notable that 18 to 28 percent of patients stopped these medications within eight weeks of prescription. The drop-out rate is likely higher in our community practices.\n\n*Bob*: The study does have limitations that are common to nearly all meta-analyses. Pharmaceutical companies sponsored most of the studies, and many of the studies were of small size. Unfortunately, it is unlikely that we will have a similar head-to-head, non-industry–sponsored study of substantial size that will allow us to do these comparisons directly.\n\n*Mark*: A meta-analysis can help us overcome small size by increasing the number of patients receiving any given treatment; thus, improving the strength of the conclusion. Nearly 25,000 patients participated in these trials. The mean duration of the studies was only six weeks, but that is within the window that we typically expect patients to see some effect (positive and negative) from these medications.\n\n*Andrea*: Meta-analyses have an insidious downside, however. They are only as good as the studies included (the “garbage in, garbage out” rule). So you shouldn't always trust the results of a meta-analysis. The validity of the results is highly influenced by the quality of the studies included, as well as by how carefully a search was done for studies to include in the meta-analysis. These authors collected studies from all available sources, including unpublished studies from pharmaceutical manufacturers, and all studies were conducted in a similar manner. Those that did not meet quality criteria were excluded from the final meta-analysis. It is reasonable to believe that the data represent the best available for prescribing decisions in the treatment of depression.\n\n*Bob*: This study gives me a reasonable starting point for choosing antidepressants for my patients. I would likely start with sertraline over escitalopram, because it is one fourth the cost.[3](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-b3) Fluvoxamine and duloxetine will remain low on my list of first-line antidepressants.\n\n*Andrea*: I'm more likely to use sertraline as a first-line agent based on this information. I think it's a toss-up between citalopram (Celexa) and escitalopram based on the available data, so the cheapest medication will win in that competition. I'll certainly consider mirtazapine for my patients with depression who are also having difficulty sleeping.\n\n*Mark*: Based on this study and the 2006 STAR⋆D trial, it appears that bupropion may be better as an augmenting agent than as a primary treatment for depression. In the STAR⋆D trial, some patients who did not respond to initial treatment with citalopram showed improvement in their depression scores with the addition of bupropion to their regimen.[4](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515\/p1205.html#afp20100515p1205-b4) Interestingly, citalopram and bupropion had similar effectiveness in this multiple-treatments meta-analysis; citalopram was better tolerated than bupropion.\n\n*Andrea*: I'd like to see more multiple-treatments meta-analyses for other medications that we use often, including statins, beta blockers, diuretics, and benign prostatic hyperplasia medications. Physicians and their patients are often tasked with choosing among multiple treatment options for any given condition. A multiple-treatments meta-analysis will allow us to be better informed about the options that are available and will allow development of treatment guidelines that reflect the best available evidence.\n\n- Consider sertraline and escitalopram as first-line agents for initial treatment of major depression in adults.\n- The least tolerated antidepressants in this study were bupropion, fluoxetine, paroxetine, and duloxetine.\n\n- A multiple-treatments meta-analysis allows you to compare treatments directly (e.g., head-to-head trials) and indirectly (e.g., against a first-line treatment). This increases the number of comparisons available and may allow the development of decision tools for effective treatment prioritization.\n- Similar to other meta-analyses, a multiple-treatments meta-analysis can be limited by low numbers of patients and poorly designed or heterogeneous studies (the “garbage in, garbage out” rule).\n\n##\n*Address correspondence to Andrea Darby-Stewart, MD, at [adstewart@shc.org](mailto:adstewart@shc.org) Reprints are not available from the authors*.\n\nAuthor disclosure: Nothing to disclose.\n\n##\n1. Caldwell DM, Ades AE, Higgins JP. Simultaneous comparison of multiple treatments: combining direct and indirect evidence. *BMJ.*  2005;331(7521):897-900.\n2. Assessing relative efficacy of antidepressants. Oxford, UK: Bandolier; May 2009. <http:\/\/www.medicine.ox.ac.uk\/bandolier\/booth\/mental\/cipriani.html>. Accessed November 16, 2009.\n3. Drugstore.com. [http:\/\/www.drugstore.com](http:\/\/www.drugstore.com\/). Accessed December 17, 2009.\n4. Rush AJ, Trivedi MH, Wisnlewski SR, et al.; STAR⋆D Study Team. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. *N Engl J Med.*  2006;354(12):1231-1242.\n\n## Continue Reading\n[![](https:\/\/www.aafp.org\/content\/dam\/brand\/aafp\/pubs\/afp\/issues\/2010\/0515\/cover.jpg.169.resized\/cover.jpg)](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515.html)\n\nMay 15, 2010\n\n[![](https:\/\/www.aafp.org\/content\/dam\/brand\/aafp\/pubs\/afp\/issues\/2010\/0515\/cover.jpg.169.resized\/cover.jpg)](https:\/\/www.aafp.org\/pubs\/afp\/issues\/2010\/0515.html)","meta_canonical":null}

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Meta Title	Antidepressants for Initial Treatment of Depression \| AAFP
Meta Description	Which antidepressants should be used for the initial treatment of depression? This quality multiple-treatment meta-analysis gives physicians a good starting point for choosing an antidepressant. Sertraline and escitalopram should be considered first-line agents whereas bupropion, fluoxetine, paroxetine, and duloxetine were least tolerated.
Meta Canonical	null
Boilerpipe Text	arrow_back PREV PREV ARTICLE May 15, 2010 NEXT NEXT ARTICLE arrow_forward ROBERT DACHS, MD, AND FAAFP, Ellis Hospital Family Medicine Residency Program, Schenectady, New York MARK A. GRABER, MD, FACEP, University of Iowa Carver College of Medicine, Iowa City, Iowa Am Fam Physician. 2010;81(10):1205-1212 Author disclosure: Nothing to disclose. Purpose Each month, three presenters review an interesting journal article in a conversational manner. These articles involve “hot topics” that affect family physicians or “bust” commonly held medical myths. The presenters give their opinions about the clinical value of the individual study discussed. The opinions reflect the views of the presenters, not those of AFP or the AAFP. This Month's Article Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet . 2009;373(9665):746–758. Andrea : Family physicians regularly encounter patients with depression. With the ever-increasing number of new-generation antidepressants available and their competing claims of tolerability and effectiveness, it's hard to determine which antidepressant to use for initial treatment of major depression. The authors of this multiple-treatments meta-analysis used direct and indirect comparisons of 12 antidepressants to help determine which were effective and tolerable as first-line agents for the treatment of depression in adults. Andrea : The authors of this study reviewed 117 randomized controlled trials comparing one antidepressant with another; placebo-controlled trials were excluded. The outcomes analyzed were effectiveness (whether depression scores were reduced by at least 50 percent, or a clinical global impression of “much” or “very much improved” was achieved) and tolerability (defined by all-cause withdrawals from the trial at eight weeks). Multiple-treatments meta-analyses are not often seen in the literature. This type of analysis allows comparison of treatments directly (e.g., head-to-head trials) or indirectly (e.g., comparing the medications against a first-line treatment; in this case, fluoxetine [Prozac]), thus allowing physicians to determine if one treatment offers benefit over another. Standard meta-analyses only perform pairwise comparisons of treatment A versus treatment B. Often, large numbers of similar treatments are available for a given disease; therefore, conclusions have to be extrapolated from several different meta-analyses to make decisions about effectiveness. 1 I got a little cross-eyed interpreting these data tables. Simply stated, for effectiveness (or response rate), an odds ratio (OR) greater than 1 favored fluoxetine, and for tolerability (or drop-out rate), an OR less than 1 favored fluoxetine. Based on their comparisons, the authors conclude that sertraline (Zoloft) and escitalopram (Lexapro) are more effective (OR = 0.80; 95% confidence interval [CI], 0.69 to 0.93; P < .05 and OR = 0.76; 95% CI, 0.65 to 0.89; P < .05, respectively) and better tolerated (OR = 1.14; 95% CI, 0.96 to 1.36 and OR = 1.19; 95% CI, 0.99 to 1.44, respectively) than fluoxetine. Mirtazapine (Remeron) and venlafaxine (Effexor) perform well in effectiveness (OR = 0.73; 95% CI, 0.60 to 0.88; P < .05 and OR = 0.78; 95% CI, 0.68 to 0.90; P < .05, respectively), but are not as well tolerated as sertraline or escitalopram. Paroxetine (Paxil) and bupropion (Wellbutrin) are similar to fluoxetine in effectiveness and tolerability. Fluvoxamine and duloxetine (Cymbalta) are less effective than fluoxetine. See Table 1 for a comparison of antidepressants available in the United States. 2 Table 1. Comparison of Improvement (Effectiveness) and All-Cause Withdrawal (Tolerability) of Antidepressants for the Treatment of Major Depression Antidepressants Patient showed substantial improvement of ≥ 50% from baseline depression symptom score (%) † All-cause withdrawal (%) ‡ Sertraline (Zoloft) 62 § 22 Escitalopram (Lexapro) 59 § 19 Citalopram (Celexa) 57 18 Mirtazapine (Remeron) 62 § 25 Venlafaxine (Effexor) 60 § 25 Paroxetine (Paxil) 56 27 Bupropion (Wellbutrin) 57 28 Fluoxetine (Prozac) 55 28 Fluvoxamine 52 25 Duloxetine (Cymbalta) 50 27 — No medications used in the United States showed statistically significant improvement in tolerability compared with fluoxetine; however, those with lower drop-out rates showed a trend toward better tolerability . †— Higher percentage better . ‡— Lower percentage better . §— Indicates P < .05 for greater effectiveness compared with fluoxetine . Adapted with permission from Assessing relative efficacy of antidepressants. Oxford, UK: Bandolier; May 2009. http://www.medicine.ox.ac.uk/bandolier/booth/mental/cipriani.html . Accessed November 16, 2009 . Andrea : The authors used two outcomes that we care about: effectiveness (how well the medication works) and tolerability (whether the patients actually took the medication). Adverse effects and cost of the medication can affect drop-out rates. The reality is that it doesn't matter why people stop taking their medications—we know that the medications won't work if they aren't ingested! It's notable that 18 to 28 percent of patients stopped these medications within eight weeks of prescription. The drop-out rate is likely higher in our community practices. Bob : The study does have limitations that are common to nearly all meta-analyses. Pharmaceutical companies sponsored most of the studies, and many of the studies were of small size. Unfortunately, it is unlikely that we will have a similar head-to-head, non-industry–sponsored study of substantial size that will allow us to do these comparisons directly. Mark : A meta-analysis can help us overcome small size by increasing the number of patients receiving any given treatment; thus, improving the strength of the conclusion. Nearly 25,000 patients participated in these trials. The mean duration of the studies was only six weeks, but that is within the window that we typically expect patients to see some effect (positive and negative) from these medications. Andrea : Meta-analyses have an insidious downside, however. They are only as good as the studies included (the “garbage in, garbage out” rule). So you shouldn't always trust the results of a meta-analysis. The validity of the results is highly influenced by the quality of the studies included, as well as by how carefully a search was done for studies to include in the meta-analysis. These authors collected studies from all available sources, including unpublished studies from pharmaceutical manufacturers, and all studies were conducted in a similar manner. Those that did not meet quality criteria were excluded from the final meta-analysis. It is reasonable to believe that the data represent the best available for prescribing decisions in the treatment of depression. Bob : This study gives me a reasonable starting point for choosing antidepressants for my patients. I would likely start with sertraline over escitalopram, because it is one fourth the cost. 3 Fluvoxamine and duloxetine will remain low on my list of first-line antidepressants. Andrea : I'm more likely to use sertraline as a first-line agent based on this information. I think it's a toss-up between citalopram (Celexa) and escitalopram based on the available data, so the cheapest medication will win in that competition. I'll certainly consider mirtazapine for my patients with depression who are also having difficulty sleeping. Mark : Based on this study and the 2006 STAR⋆D trial, it appears that bupropion may be better as an augmenting agent than as a primary treatment for depression. In the STAR⋆D trial, some patients who did not respond to initial treatment with citalopram showed improvement in their depression scores with the addition of bupropion to their regimen. 4 Interestingly, citalopram and bupropion had similar effectiveness in this multiple-treatments meta-analysis; citalopram was better tolerated than bupropion. Andrea : I'd like to see more multiple-treatments meta-analyses for other medications that we use often, including statins, beta blockers, diuretics, and benign prostatic hyperplasia medications. Physicians and their patients are often tasked with choosing among multiple treatment options for any given condition. A multiple-treatments meta-analysis will allow us to be better informed about the options that are available and will allow development of treatment guidelines that reflect the best available evidence. Consider sertraline and escitalopram as first-line agents for initial treatment of major depression in adults. The least tolerated antidepressants in this study were bupropion, fluoxetine, paroxetine, and duloxetine. A multiple-treatments meta-analysis allows you to compare treatments directly (e.g., head-to-head trials) and indirectly (e.g., against a first-line treatment). This increases the number of comparisons available and may allow the development of decision tools for effective treatment prioritization. Similar to other meta-analyses, a multiple-treatments meta-analysis can be limited by low numbers of patients and poorly designed or heterogeneous studies (the “garbage in, garbage out” rule). Address correspondence to Andrea Darby-Stewart, MD, at adstewart@shc.org Reprints are not available from the authors . Author disclosure: Nothing to disclose. Caldwell DM, Ades AE, Higgins JP. Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ. 2005;331(7521):897-900. Assessing relative efficacy of antidepressants. Oxford, UK: Bandolier; May 2009. http://www.medicine.ox.ac.uk/bandolier/booth/mental/cipriani.html . Accessed November 16, 2009. Drugstore.com. http://www.drugstore.com . Accessed December 17, 2009. Rush AJ, Trivedi MH, Wisnlewski SR, et al.; STAR⋆D Study Team. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354(12):1231-1242. Continue Reading May 15, 2010
Markdown	![Leave a Message](https://lpcdn.lpsnmedia.net/gallery/libraries/chat/images/assets/live-chat.png) [Advertisement]() - [AAFP](https://www.aafp.org/home.html)[AAFP](https://www.aafp.org/home.html) - [AAFP Foundation](https://www.aafpfoundation.org/home.html)[Foundation](https://www.aafpfoundation.org/home.html) - [AFP Journal](https://www.aafp.org/pubs/afp.html)[AFP](https://www.aafp.org/pubs/afp.html) - [FPM Journal](https://www.aafp.org/pubs/fpm.html)[FPM](https://www.aafp.org/pubs/fpm.html) - [FUTURE](https://www.aafp.org/events/future-conference.html)[FUTURE](https://www.aafp.org/events/future-conference.html) - [FMX](https://www.aafp.org/events/fmx.html)[FMX](https://www.aafp.org/events/fmx.html) - [familydoctor.org](https://familydoctor.org/)[familydoctor.org](https://familydoctor.org/) [shopping\_cart](https://www.aafp.org/ams/ecommerce/store/cart "0") [account\_circleLog In](https://www.aafp.org/cgi-bin/lg.pl?redirect=https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html) [![brand logo](https://www.aafp.org/content/dam/AAFP/images/logos_internal/afp-masthead-2025.png)](https://www.aafp.org/pubs/afp.html) Menumenu Search search - [chevron\_leftIssueschevron\_right]() - [chevron\_leftAFP By Topicchevron\_right]() - [chevron\_leftCollectionschevron\_right]() - [chevron\_leftCME Quizchevron\_right]() - [chevron\_leftBlogchevron\_right]() - [chevron\_leftMultimediachevron\_right]() - [chevron\_leftSubscribechevron\_right]() [arrow\_backPREVPREV ARTICLE](https://www.aafp.org/pubs/afp/issues/2010/0515/p1200.html)[May 15, 2010](https://www.aafp.org/pubs/afp/issues/2010/0515.html)[NEXTNEXT ARTICLEarrow\_forward](https://www.aafp.org/pubs/afp/issues/2010/0515/p1213.html) [PREV](https://www.aafp.org/pubs/afp/issues/2010/0515/p1200.html) [May 15, 2010](https://www.aafp.org/pubs/afp/issues/2010/0515.html) [NEXT](https://www.aafp.org/pubs/afp/issues/2010/0515/p1213.html) ![brand logo](https://www.aafp.org/content/dam/AAFP/images/logos_internal/afp-masthead-2025.png) [AFP Journal Club](https://www.aafp.org/global-search.afp.html#&t=Publication&f:@section=[AFP%20Journal%20Club]&f:@subpublications=[AFP%20Journal]) The Story Behind the Study # Antidepressants for Initial Treatment of Depression printPrint [commentComments](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#article-comment-area) ANDREA DARBY-STEWART, MD, Scottsdale Healthcare Family Medicine Residency, Scottsdale, Arizona ROBERT DACHS, MD, AND FAAFP, Ellis Hospital Family Medicine Residency Program, Schenectady, New York MARK A. GRABER, MD, FACEP, University of Iowa Carver College of Medicine, Iowa City, Iowa info Am Fam Physician. 2010;81(10):1205-1212 assignment Author disclosure: Nothing to disclose. Purpose Each month, three presenters review an interesting journal article in a conversational manner. These articles involve “hot topics” that affect family physicians or “bust” commonly held medical myths. The presenters give their opinions about the clinical value of the individual study discussed. The opinions reflect the views of the presenters, not those of AFP or the AAFP. This Month's Article Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373(9665):746–758. ## Which antidepressants should be used for the initial treatment of depression? Andrea: Family physicians regularly encounter patients with depression. With the ever-increasing number of new-generation antidepressants available and their competing claims of tolerability and effectiveness, it's hard to determine which antidepressant to use for initial treatment of major depression. The authors of this multiple-treatments meta-analysis used direct and indirect comparisons of 12 antidepressants to help determine which were effective and tolerable as first-line agents for the treatment of depression in adults. ## What does this article say? Andrea: The authors of this study reviewed 117 randomized controlled trials comparing one antidepressant with another; placebo-controlled trials were excluded. The outcomes analyzed were effectiveness (whether depression scores were reduced by at least 50 percent, or a clinical global impression of “much” or “very much improved” was achieved) and tolerability (defined by all-cause withdrawals from the trial at eight weeks). Multiple-treatments meta-analyses are not often seen in the literature. This type of analysis allows comparison of treatments directly (e.g., head-to-head trials) or indirectly (e.g., comparing the medications against a first-line treatment; in this case, fluoxetine \[Prozac\]), thus allowing physicians to determine if one treatment offers benefit over another. Standard meta-analyses only perform pairwise comparisons of treatment A versus treatment B. Often, large numbers of similar treatments are available for a given disease; therefore, conclusions have to be extrapolated from several different meta-analyses to make decisions about effectiveness.[1](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-b1) I got a little cross-eyed interpreting these data tables. Simply stated, for effectiveness (or response rate), an odds ratio (OR) greater than 1 favored fluoxetine, and for tolerability (or drop-out rate), an OR less than 1 favored fluoxetine. Based on their comparisons, the authors conclude that sertraline (Zoloft) and escitalopram (Lexapro) are more effective (OR = 0.80; 95% confidence interval \[CI\], 0.69 to 0.93; P \< .05 and OR = 0.76; 95% CI, 0.65 to 0.89; P \< .05, respectively) and better tolerated (OR = 1.14; 95% CI, 0.96 to 1.36 and OR = 1.19; 95% CI, 0.99 to 1.44, respectively) than fluoxetine. Mirtazapine (Remeron) and venlafaxine (Effexor) perform well in effectiveness (OR = 0.73; 95% CI, 0.60 to 0.88; P \< .05 and OR = 0.78; 95% CI, 0.68 to 0.90; P \< .05, respectively), but are not as well tolerated as sertraline or escitalopram. Paroxetine (Paxil) and bupropion (Wellbutrin) are similar to fluoxetine in effectiveness and tolerability. Fluvoxamine and duloxetine (Cymbalta) are less effective than fluoxetine. See [Table 1](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-t1) for a comparison of antidepressants available in the United States.[2](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-b2) Table 1. ### Comparison of Improvement (Effectiveness) and All-Cause Withdrawal (Tolerability\) of Antidepressants for the Treatment of Major Depression [zoom\_out\_mapEnlarge](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205/jcr:content/root/aafp-article-primary-content-container/aafp_article_main_par/aafp_tables_content.enlarge.html)[printPrint](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205/jcr:content/root/aafp-article-primary-content-container/aafp_article_main_par/aafp_tables_content.print.html) \| Antidepressants* \| Patient showed substantial improvement of ≥ 50% from baseline depression symptom score (%)[†](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-tfn2) \| All-cause withdrawal (%)[‡](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-tfn3) \| \|---\|---\|---\| \| Sertraline (Zoloft) \| 62[§](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-tfn4) \| 22 \| \| Escitalopram (Lexapro) \| 59[§](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-tfn4) \| 19 \| \| Citalopram (Celexa) \| 57 \| 18 \| \| Mirtazapine (Remeron) \| 62[§](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-tfn4) \| 25 \| \| Venlafaxine (Effexor) \| 60[§](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-tfn4) \| 25 \| \| Paroxetine (Paxil) \| 56 \| 27 \| \| Bupropion (Wellbutrin) \| 57 \| 28 \| \| Fluoxetine (Prozac) \| 55 \| 28 \| \| Fluvoxamine \| 52 \| 25 \| \| Duloxetine (Cymbalta) \| 50 \| 27 \| \— No medications used in the United States showed statistically significant improvement in tolerability compared with fluoxetine; however, those with lower drop-out rates showed a trend toward better tolerability. †— Higher percentage better. ‡— Lower percentage better. §— Indicates* P \< .05 for greater effectiveness compared with fluoxetine. Adapted with permission from Assessing relative efficacy of antidepressants. Oxford, UK: Bandolier; May 2009. <http://www.medicine.ox.ac.uk/bandolier/booth/mental/cipriani.html>. Accessed November 16, 2009. ## Should we believe this study? Andrea: The authors used two outcomes that we care about: effectiveness (how well the medication works) and tolerability (whether the patients actually took the medication). Adverse effects and cost of the medication can affect drop-out rates. The reality is that it doesn't matter why people stop taking their medications—we know that the medications won't work if they aren't ingested! It's notable that 18 to 28 percent of patients stopped these medications within eight weeks of prescription. The drop-out rate is likely higher in our community practices. Bob: The study does have limitations that are common to nearly all meta-analyses. Pharmaceutical companies sponsored most of the studies, and many of the studies were of small size. Unfortunately, it is unlikely that we will have a similar head-to-head, non-industry–sponsored study of substantial size that will allow us to do these comparisons directly. Mark: A meta-analysis can help us overcome small size by increasing the number of patients receiving any given treatment; thus, improving the strength of the conclusion. Nearly 25,000 patients participated in these trials. The mean duration of the studies was only six weeks, but that is within the window that we typically expect patients to see some effect (positive and negative) from these medications. Andrea: Meta-analyses have an insidious downside, however. They are only as good as the studies included (the “garbage in, garbage out” rule). So you shouldn't always trust the results of a meta-analysis. The validity of the results is highly influenced by the quality of the studies included, as well as by how carefully a search was done for studies to include in the meta-analysis. These authors collected studies from all available sources, including unpublished studies from pharmaceutical manufacturers, and all studies were conducted in a similar manner. Those that did not meet quality criteria were excluded from the final meta-analysis. It is reasonable to believe that the data represent the best available for prescribing decisions in the treatment of depression. ## What should the family physician do? Bob: This study gives me a reasonable starting point for choosing antidepressants for my patients. I would likely start with sertraline over escitalopram, because it is one fourth the cost.[3](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-b3) Fluvoxamine and duloxetine will remain low on my list of first-line antidepressants. Andrea: I'm more likely to use sertraline as a first-line agent based on this information. I think it's a toss-up between citalopram (Celexa) and escitalopram based on the available data, so the cheapest medication will win in that competition. I'll certainly consider mirtazapine for my patients with depression who are also having difficulty sleeping. Mark: Based on this study and the 2006 STAR⋆D trial, it appears that bupropion may be better as an augmenting agent than as a primary treatment for depression. In the STAR⋆D trial, some patients who did not respond to initial treatment with citalopram showed improvement in their depression scores with the addition of bupropion to their regimen.[4](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-b4) Interestingly, citalopram and bupropion had similar effectiveness in this multiple-treatments meta-analysis; citalopram was better tolerated than bupropion. Andrea: I'd like to see more multiple-treatments meta-analyses for other medications that we use often, including statins, beta blockers, diuretics, and benign prostatic hyperplasia medications. Physicians and their patients are often tasked with choosing among multiple treatment options for any given condition. A multiple-treatments meta-analysis will allow us to be better informed about the options that are available and will allow development of treatment guidelines that reflect the best available evidence. ## Main Points - Consider sertraline and escitalopram as first-line agents for initial treatment of major depression in adults. - The least tolerated antidepressants in this study were bupropion, fluoxetine, paroxetine, and duloxetine. ## EBM Points - A multiple-treatments meta-analysis allows you to compare treatments directly (e.g., head-to-head trials) and indirectly (e.g., against a first-line treatment). This increases the number of comparisons available and may allow the development of decision tools for effective treatment prioritization. - Similar to other meta-analyses, a multiple-treatments meta-analysis can be limited by low numbers of patients and poorly designed or heterogeneous studies (the “garbage in, garbage out” rule). ## expand\_moreAuthor Information Address correspondence to Andrea Darby-Stewart, MD, at [adstewart@shc.org](mailto:adstewart@shc.org) Reprints are not available from the authors. Author disclosure: Nothing to disclose. ## expand\_moreReference(s) 1. Caldwell DM, Ades AE, Higgins JP. Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ. 2005;331(7521):897-900. 2. Assessing relative efficacy of antidepressants. Oxford, UK: Bandolier; May 2009. <http://www.medicine.ox.ac.uk/bandolier/booth/mental/cipriani.html>. Accessed November 16, 2009. 3. Drugstore.com. <http://www.drugstore.com>. Accessed December 17, 2009. 4. Rush AJ, Trivedi MH, Wisnlewski SR, et al.; STAR⋆D Study Team. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354(12):1231-1242. 1. Caldwell DM, Ades AE, Higgins JP. Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ. 2005;331(7521):897-900. 2. Assessing relative efficacy of antidepressants. Oxford, UK: Bandolier; May 2009. <http://www.medicine.ox.ac.uk/bandolier/booth/mental/cipriani.html>. Accessed November 16, 2009. 3. Drugstore.com. <http://www.drugstore.com>. Accessed December 17, 2009. 4. Rush AJ, Trivedi MH, Wisnlewski SR, et al.; STAR⋆D Study Team. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354(12):1231-1242. 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Readable Markdown	[arrow\_backPREVPREV ARTICLE](https://www.aafp.org/pubs/afp/issues/2010/0515/p1200.html)[May 15, 2010](https://www.aafp.org/pubs/afp/issues/2010/0515.html)[NEXTNEXT ARTICLEarrow\_forward](https://www.aafp.org/pubs/afp/issues/2010/0515/p1213.html) ![brand logo](https://www.aafp.org/content/dam/AAFP/images/logos_internal/afp-masthead-2025.png) ROBERT DACHS, MD, AND FAAFP, Ellis Hospital Family Medicine Residency Program, Schenectady, New York MARK A. GRABER, MD, FACEP, University of Iowa Carver College of Medicine, Iowa City, Iowa Am Fam Physician. 2010;81(10):1205-1212 Author disclosure: Nothing to disclose. Purpose Each month, three presenters review an interesting journal article in a conversational manner. These articles involve “hot topics” that affect family physicians or “bust” commonly held medical myths. The presenters give their opinions about the clinical value of the individual study discussed. The opinions reflect the views of the presenters, not those of AFP or the AAFP. This Month's Article Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373(9665):746–758. Andrea: Family physicians regularly encounter patients with depression. With the ever-increasing number of new-generation antidepressants available and their competing claims of tolerability and effectiveness, it's hard to determine which antidepressant to use for initial treatment of major depression. The authors of this multiple-treatments meta-analysis used direct and indirect comparisons of 12 antidepressants to help determine which were effective and tolerable as first-line agents for the treatment of depression in adults. Andrea: The authors of this study reviewed 117 randomized controlled trials comparing one antidepressant with another; placebo-controlled trials were excluded. The outcomes analyzed were effectiveness (whether depression scores were reduced by at least 50 percent, or a clinical global impression of “much” or “very much improved” was achieved) and tolerability (defined by all-cause withdrawals from the trial at eight weeks). Multiple-treatments meta-analyses are not often seen in the literature. This type of analysis allows comparison of treatments directly (e.g., head-to-head trials) or indirectly (e.g., comparing the medications against a first-line treatment; in this case, fluoxetine \[Prozac\]), thus allowing physicians to determine if one treatment offers benefit over another. Standard meta-analyses only perform pairwise comparisons of treatment A versus treatment B. Often, large numbers of similar treatments are available for a given disease; therefore, conclusions have to be extrapolated from several different meta-analyses to make decisions about effectiveness.[1](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-b1) I got a little cross-eyed interpreting these data tables. Simply stated, for effectiveness (or response rate), an odds ratio (OR) greater than 1 favored fluoxetine, and for tolerability (or drop-out rate), an OR less than 1 favored fluoxetine. Based on their comparisons, the authors conclude that sertraline (Zoloft) and escitalopram (Lexapro) are more effective (OR = 0.80; 95% confidence interval \[CI\], 0.69 to 0.93; P \< .05 and OR = 0.76; 95% CI, 0.65 to 0.89; P \< .05, respectively) and better tolerated (OR = 1.14; 95% CI, 0.96 to 1.36 and OR = 1.19; 95% CI, 0.99 to 1.44, respectively) than fluoxetine. Mirtazapine (Remeron) and venlafaxine (Effexor) perform well in effectiveness (OR = 0.73; 95% CI, 0.60 to 0.88; P \< .05 and OR = 0.78; 95% CI, 0.68 to 0.90; P \< .05, respectively), but are not as well tolerated as sertraline or escitalopram. Paroxetine (Paxil) and bupropion (Wellbutrin) are similar to fluoxetine in effectiveness and tolerability. Fluvoxamine and duloxetine (Cymbalta) are less effective than fluoxetine. See [Table 1](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-t1) for a comparison of antidepressants available in the United States.[2](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-b2) Table 1. Comparison of Improvement (Effectiveness) and All-Cause Withdrawal (Tolerability\) of Antidepressants for the Treatment of Major Depression \| Antidepressants* \| Patient showed substantial improvement of ≥ 50% from baseline depression symptom score (%)[†](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-tfn2) \| All-cause withdrawal (%)[‡](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-tfn3) \| \|---\|---\|---\| \| Sertraline (Zoloft) \| 62[§](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-tfn4) \| 22 \| \| Escitalopram (Lexapro) \| 59[§](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-tfn4) \| 19 \| \| Citalopram (Celexa) \| 57 \| 18 \| \| Mirtazapine (Remeron) \| 62[§](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-tfn4) \| 25 \| \| Venlafaxine (Effexor) \| 60[§](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-tfn4) \| 25 \| \| Paroxetine (Paxil) \| 56 \| 27 \| \| Bupropion (Wellbutrin) \| 57 \| 28 \| \| Fluoxetine (Prozac) \| 55 \| 28 \| \| Fluvoxamine \| 52 \| 25 \| \| Duloxetine (Cymbalta) \| 50 \| 27 \| \— No medications used in the United States showed statistically significant improvement in tolerability compared with fluoxetine; however, those with lower drop-out rates showed a trend toward better tolerability. †— Higher percentage better. ‡— Lower percentage better. §— Indicates* P \< .05 for greater effectiveness compared with fluoxetine. Adapted with permission from Assessing relative efficacy of antidepressants. Oxford, UK: Bandolier; May 2009. <http://www.medicine.ox.ac.uk/bandolier/booth/mental/cipriani.html>. Accessed November 16, 2009. Andrea: The authors used two outcomes that we care about: effectiveness (how well the medication works) and tolerability (whether the patients actually took the medication). Adverse effects and cost of the medication can affect drop-out rates. The reality is that it doesn't matter why people stop taking their medications—we know that the medications won't work if they aren't ingested! It's notable that 18 to 28 percent of patients stopped these medications within eight weeks of prescription. The drop-out rate is likely higher in our community practices. Bob: The study does have limitations that are common to nearly all meta-analyses. Pharmaceutical companies sponsored most of the studies, and many of the studies were of small size. Unfortunately, it is unlikely that we will have a similar head-to-head, non-industry–sponsored study of substantial size that will allow us to do these comparisons directly. Mark: A meta-analysis can help us overcome small size by increasing the number of patients receiving any given treatment; thus, improving the strength of the conclusion. Nearly 25,000 patients participated in these trials. The mean duration of the studies was only six weeks, but that is within the window that we typically expect patients to see some effect (positive and negative) from these medications. Andrea: Meta-analyses have an insidious downside, however. They are only as good as the studies included (the “garbage in, garbage out” rule). So you shouldn't always trust the results of a meta-analysis. The validity of the results is highly influenced by the quality of the studies included, as well as by how carefully a search was done for studies to include in the meta-analysis. These authors collected studies from all available sources, including unpublished studies from pharmaceutical manufacturers, and all studies were conducted in a similar manner. Those that did not meet quality criteria were excluded from the final meta-analysis. It is reasonable to believe that the data represent the best available for prescribing decisions in the treatment of depression. Bob: This study gives me a reasonable starting point for choosing antidepressants for my patients. I would likely start with sertraline over escitalopram, because it is one fourth the cost.[3](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-b3) Fluvoxamine and duloxetine will remain low on my list of first-line antidepressants. Andrea: I'm more likely to use sertraline as a first-line agent based on this information. I think it's a toss-up between citalopram (Celexa) and escitalopram based on the available data, so the cheapest medication will win in that competition. I'll certainly consider mirtazapine for my patients with depression who are also having difficulty sleeping. Mark: Based on this study and the 2006 STAR⋆D trial, it appears that bupropion may be better as an augmenting agent than as a primary treatment for depression. In the STAR⋆D trial, some patients who did not respond to initial treatment with citalopram showed improvement in their depression scores with the addition of bupropion to their regimen.[4](https://www.aafp.org/pubs/afp/issues/2010/0515/p1205.html#afp20100515p1205-b4) Interestingly, citalopram and bupropion had similar effectiveness in this multiple-treatments meta-analysis; citalopram was better tolerated than bupropion. Andrea: I'd like to see more multiple-treatments meta-analyses for other medications that we use often, including statins, beta blockers, diuretics, and benign prostatic hyperplasia medications. Physicians and their patients are often tasked with choosing among multiple treatment options for any given condition. A multiple-treatments meta-analysis will allow us to be better informed about the options that are available and will allow development of treatment guidelines that reflect the best available evidence. - Consider sertraline and escitalopram as first-line agents for initial treatment of major depression in adults. - The least tolerated antidepressants in this study were bupropion, fluoxetine, paroxetine, and duloxetine. - A multiple-treatments meta-analysis allows you to compare treatments directly (e.g., head-to-head trials) and indirectly (e.g., against a first-line treatment). This increases the number of comparisons available and may allow the development of decision tools for effective treatment prioritization. - Similar to other meta-analyses, a multiple-treatments meta-analysis can be limited by low numbers of patients and poorly designed or heterogeneous studies (the “garbage in, garbage out” rule). ## Address correspondence to Andrea Darby-Stewart, MD, at [adstewart@shc.org](mailto:adstewart@shc.org) Reprints are not available from the authors. Author disclosure: Nothing to disclose. ## 1. Caldwell DM, Ades AE, Higgins JP. Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ. 2005;331(7521):897-900. 2. Assessing relative efficacy of antidepressants. Oxford, UK: Bandolier; May 2009. <http://www.medicine.ox.ac.uk/bandolier/booth/mental/cipriani.html>. Accessed November 16, 2009. 3. Drugstore.com. [http://www.drugstore.com](http://www.drugstore.com/). Accessed December 17, 2009. 4. Rush AJ, Trivedi MH, Wisnlewski SR, et al.; STAR⋆D Study Team. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354(12):1231-1242. ## Continue Reading [![](https://www.aafp.org/content/dam/brand/aafp/pubs/afp/issues/2010/0515/cover.jpg.169.resized/cover.jpg)](https://www.aafp.org/pubs/afp/issues/2010/0515.html) May 15, 2010 [![](https://www.aafp.org/content/dam/brand/aafp/pubs/afp/issues/2010/0515/cover.jpg.169.resized/cover.jpg)](https://www.aafp.org/pubs/afp/issues/2010/0515.html)
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