Editing Antidepressant (section)

===Limitations and strategies===
Among individuals treated with a given antidepressant, between 30% and 50% do not show a response.<ref>{{cite journal|vauthors=Baghai TC, Möller HJ, Rupprecht R|title=Recent progress in pharmacological and non-pharmacological treatment options of major depression|journal=Current Pharmaceutical Design|volume=12|issue=4|pages=503–515|year=2006|pmid=16472142|doi=10.2174/138161206775474422}}</ref><ref name="SSRIswitch">{{cite journal|vauthors=Ruhé HG, Huyser J, Swinkels JA, Schene AH|title=Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review|journal=The Journal of Clinical Psychiatry|volume=67|issue=12|pages=1836–1855|date=December 2006|pmid=17194261|doi=10.4088/JCP.v67n1203|url=http://pdfs.semanticscholar.org/02f0/a7fcfd218854147e6c3e52c3f213ab2d95e4.pdf|url-status=dead|s2cid=9758110|archive-url=https://web.archive.org/web/20190216221042/http://pdfs.semanticscholar.org/02f0/a7fcfd218854147e6c3e52c3f213ab2d95e4.pdf|archive-date=16 February 2019}}</ref> Approximately one-third of people achieve a full [[remission (medicine)|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&nbsp;times higher in people with residual symptoms than in those, who experience full remission.<ref>{{cite journal|vauthors=Tranter R, O'Donovan C, Chandarana P, Kennedy S|title=Prevalence and outcome of partial remission in depression|journal=Journal of Psychiatry & Neuroscience|volume=27|issue=4|pages=241–247|date=July 2002|pmid=12174733|pmc=161658}}</ref> In addition, antidepressant drugs tend to lose efficacy throughout long-term [[maintenance therapy]].<ref>{{cite journal|vauthors=Byrne SE, Rothschild AJ|title=Loss of antidepressant efficacy during maintenance therapy: possible mechanisms and treatments|journal=The Journal of Clinical Psychiatry|volume=59|issue=6|pages=279–288|date=June 1998|pmid=9671339|doi=10.4088/JCP.v59n0602}}</ref> 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.<ref>{{cite web|title=Antidepressant Use in Persons Aged 12 and Over: United States, 2005–2008|url=https://www.cdc.gov/nchs/data/databriefs/db76.htm|website=cdc.gov|access-date=4 February 2016|publisher=Centers for Disease Control and Prevention|series=Products – Data Briefs – Number 76 – October 2011|url-status=live|archive-url=https://web.archive.org/web/20160204212849/http://www.cdc.gov/nchs/data/databriefs/db76.htm|archive-date=4 February 2016}}</ref> Several strategies are used in clinical practice to try to overcome these limits and variations.<ref>{{cite journal|vauthors=Mischoulon D, Nierenberg AA, Kizilbash L, Rosenbaum JF, Fava M|title=Strategies for managing depression refractory to selective serotonin reuptake inhibitor treatment: a survey of clinicians|journal=Canadian Journal of Psychiatry|volume=45|issue=5|pages=476–481|date=June 2000|pmid=10900529|doi=10.1177/070674370004500509|s2cid=12904378}}</ref> They include switching medication, augmentation, and combination.

There is controversy amongst researchers regarding the efficacy and risk-benefit ratio of antidepressants.<ref name="Wilson2018">{{cite news|vauthors=Wilson C|title=Nobody can agree about antidepressants. Here's what you need to know|url=https://www.newscientist.com/article/mg23931980-100-nobody-can-agree-about-antidepressants-heres-what-you-need-to-know/|access-date=23 January 2023|work=New Scientist|publisher=New Scientist Ltd|date=2 October 2018}}</ref><ref name="Warren2020">{{cite journal|vauthors=Warren JB|title=The trouble with antidepressants: why the evidence overplays evidence and underplays risks—an essay by John B Warren|journal=The BMJ|date=2020|volume=370|page=m3200|doi=10.1136/bmj.m3200|pmid=32883743|s2cid=221468976}}</ref> 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.<ref name="CiprianiFurukawa2018" /><ref name="pmid35918097" /><ref name="pmid30386270" /><ref name="McCormack2018">{{cite journal|vauthors=McCormack J, Korownyk C|title=Effectiveness of antidepressants|journal=The BMJ|date=2018|volume=360|page=k1073|doi=10.1136/bmj.k1073|pmid=29523598|s2cid=3925654}}</ref> The aggregate effect of antidepressants typically results in changes below the threshold of clinical significance on depression rating scales.<ref name="pmid31554608" /><ref name="pmid25979317" /> 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.<ref name="Pariante2022">{{cite journal|vauthors=Pariante CM|title=Depression is both psychosocial and biological; antidepressants are both effective and in need of improvement; psychiatrists are both caring human beings and doctors who prescribe medications. Can we all agree on this? a commentary on 'Read & Moncrieff – depression: why drugs and electricity are not the answer'|journal=Psychological Medicine|date=2022|volume=52|issue=8|pages=1411–1413|doi=10.1017/S0033291722000770|pmid=35362404|doi-access=free}}</ref> Assessments of antidepressants using alternative, more sensitive scales, such as the [[Montgomery–Åsberg Depression Rating Scale|MADRS]], do not result in marked difference from the HDRS and likewise only find a marginal clinical benefit.<ref name="pmid32101579" /> 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.<ref name="Luedtke2021">{{cite journal|vauthors=Luedtke A, Kessler RC|title=New Directions in Research on Heterogeneity of Treatment Effects for Major Depression|journal=JAMA Psychiatry|date=2021|volume=78|issue=5|pages=478–480|doi=10.1001/jamapsychiatry.2020.4489|pmid=33595616|s2cid=231944660}}</ref> Poor and complex clinical trial design might also account for the small effects seen for antidepressants.<ref name="Khan2015">{{cite journal|vauthors=Khan A, Brown WA|title=Antidepressants versus placebo in major depression: an overview|journal=World Psychiatry|date=2015|volume=14|issue=3|pages=294–300|doi=10.1002/wps.20241|pmid=26407778|pmc=4592645}}</ref><ref name="Nutt2008">{{cite journal|vauthors=Nutt DJ, Malizia AL|title=Why does the world have such a 'down' on antidepressants?|journal=Journal of Psychopharmacology|date=2008|volume=22|issue=3|pages=223–226|doi=10.1177/0269881108091877|pmid=18541622|s2cid=45965987|doi-access=free}}</ref> The randomized controlled trials used to approve drugs are short, and may not capture the full effect of antidepressants.<ref name="Nutt2008" /> Additionally, the placebo effect might be inflated in these trials by frequent clinical consultation, lowering the comparative performance of antidepressants.<ref name="Nutt2008" /> Critics agree that current clinical trials are poorly-designed, which limits the knowledge on antidepressants.<ref name="Boesen2021">{{cite journal|vauthors=Boesen K, Gøtzsche PC, Ioannidis JP|title=EMA and FDA psychiatric drug trial guidelines: assessment of guideline development and trial design recommendations|journal=Epidemiology and Psychiatric Sciences|date=2021|volume=30|page=e35|doi=10.1017/S2045796021000147|pmid=33926608|pmc=8157504}}</ref> 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.<ref name="Read2022" /><ref>{{cite book|vauthors=Giraldi T|title=Unhappiness, sadness and 'depression'|date=2017|publisher=Palgrave Macmillan|location=London, UK|isbn=978-3-319-57657-2|pages=108–110}}</ref>

Critics of antidepressants maintain that the superiority of antidepressants over placebo is the result of systemic flaws in clinical trials and the research literature.<ref name="Read2022">{{cite journal|vauthors=Read J, Moncrieff J|title=Depression: why drugs and electricity are not the answer|journal=Psychological Medicine|date=2022|volume=52|issue=8|pages=1401–1410|doi=10.1017/S0033291721005031|pmid=35100527|s2cid=246442707|url=https://repository.uel.ac.uk/download/0fd9663377e02e8033e12c27844d65b5e918406de4d7c7baca5031a8e8ba4c5a/408146/Read%20and%20Moncrieff%20Psych%20Med%20ROAR.pdf}}</ref><ref name="pmid31554608" /> 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.<ref name="pmid31248914" /><ref name="pmid31554608" /> Additionally, meta-analyses co-authored by industry employees find more favorable results for antidepressants.<ref name="pmid31554608" /> 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.<ref name="Turner2008">{{cite journal|vauthors=Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R|title=Selective publication of antidepressant trials and its influence on apparent efficacy|journal=The New England Journal of Medicine|date=2008|volume=358|issue=3|pages=252–260|doi=10.1056/NEJMsa065779|pmid=18199864|doi-access=free}}</ref> Although this issue has diminished with time, it remains an obstacle to accurately assessing the efficacy of antidepressants.<ref name="Turner2022">{{cite journal|vauthors=Turner EH, Cipriani A, Furukawa TA, Salanti G, de Vries YA|title=Selective publication of antidepressant trials and its influence on apparent efficacy: Updated comparisons and meta-analyses of newer versus older trials|journal=PLOS Medicine|date=2022|volume=19|issue=1|page=e1003886|doi=10.1371/journal.pmed.1003886|pmid=35045113|pmc=8769343|doi-access=free}}</ref> Misreporting of clinical trial outcomes and of serious adverse events, such as suicide, is common.<ref name="Hughes2014">{{cite journal|vauthors=Hughes S, Cohen D, Jaggi R|title=Differences in reporting serious adverse events in industry sponsored clinical trial registries and journal articles on antidepressant and antipsychotic drugs: a cross-sectional study|journal=BMJ Open|date=2014|volume=4|issue=7|page=e005535|doi=10.1136/bmjopen-2014-005535|pmid=25009136|pmc=4091397}}</ref><ref name="pmid31248914" /><ref name="Hengartner2022" /> [[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.<ref name="Hengartner2022" /> 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.<ref name="pmid31249537" /><ref name="Kirsch2014" /><ref name="pmid31248914" /> Some have therefore maintained that antidepressants may only be active placebos.<ref name="Read2022" /><ref name="pmid31554608" /> 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.<ref name="pmid31248914" />

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.<ref name="Read2022" /><ref name="pmid31554608" /> They also note that adverse effects, including withdrawal difficulties, are likely underreported, skewing clinicians' ability to make risk-benefit judgements.<ref name="Warren2020" /><ref name="Sharma2016">{{cite journal|vauthors=Sharma T, Guski LS, Freund N, Gøtzsche PC|title=Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports|journal=The BMJ|date=2016|volume=352|pages=i65|doi=10.1136/bmj.i65|pmid=26819231|pmc=4729837}}</ref><ref name="Bielefeldt2016">{{cite journal|vauthors=Bielefeldt AØ, Danborg PB, Gøtzsche PC|title=Precursors to suicidality and violence on antidepressants: systematic review of trials in adult healthy volunteers|journal=Journal of the Royal Society of Medicine|date=2016|volume=109|issue=10|pages=381–392|doi=10.1177/0141076816666805|pmid=27729596|pmc=5066537}}</ref><ref name="Read2022" /> Accordingly, they believe antidepressants are overused, particularly for non-severe depression and conditions in which they are not indicated.<ref name="Warren2020" /><ref name="Fava2014">{{cite journal|vauthors=Fava GA|title=Rational use of antidepressant drugs|journal=Psychotherapy and Psychosomatics|date=2014|volume=83|issue=4|pages=197–204|doi=10.1159/000362803|pmid=24969962|s2cid=32506580|doi-access=free}}</ref> Critics charge that the widespread use and public acceptance of antidepressants is the result of pharmaceutical advertising, research manipulation, and misinformation.<ref name="pmid16268734" /><ref name="LacasseLeo2015" /><ref name="Lacasse2005" /><ref name="AngHorowitzMoncrieff2022" />

Current mainstream psychiatric opinion recognizes the limitations of antidepressants but recommends their use in adults with more severe depression as a first-line treatment.<ref name="nrdp2016">{{cite journal|vauthors=Otte C, Gold SM, Penninx BW, Pariante CM, Etkin A, Fava M, Mohr DC, Schatzburg AF|title=Major depressive disorder|journal=Nature Reviews Disease Primers|date=2016|volume=2|page=16065|doi=10.1038/nrdp.2016.65|pmid=27629598|s2cid=4047310|url=https://kclpure.kcl.ac.uk/portal/en/publications/major-depressive-disorder(c382ec52-8506-4d39-9b77-cf86d64ad446).html}}</ref><ref name="NICE2022">{{cite journal|vauthors=Kendrick T, Pilling S, Mavranezouli I, Megnin-Viggars O, Ruane C, Eadon H, Kapur N|title=Management of depression in adults: summary of updated NICE guidance|journal=The BMJ|date=2022|volume=378|page=o1557|doi=10.1136/bmj.o1557|pmid=35858703|s2cid=250644758|url=https://discovery.ucl.ac.uk/id/eprint/10152602/}}</ref>