Editing Antidepressant (section)

==Medical uses==
Antidepressants are prescribed to treat [[major depressive disorder]] (MDD), [[anxiety disorder]]s, [[chronic pain]], and some addictions. Antidepressants are often used in combination with one another.<ref name="Jennings2018"/>

Despite its longstanding prominence in pharmaceutical advertising, the idea that low serotonin levels cause depression is not supported by scientific evidence.<ref>{{cite book|vauthors=Whitaker R, Cosgrove L|date=23 April 2015|title=Psychiatry Under the Influence: Institutional Corruption, Social Injury, and Prescriptions for Reform|publisher=Palgrave Macmillan US|url=https://play.google.com/store/books/details?id=QYwEogEACAAJ|isbn=9781137506924}}</ref><ref>{{cite journal|vauthors=Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA|journal=Molecular Psychiatry|title=The serotonin theory of depression: a systematic umbrella review of the evidence|pages=3243–3256|date=20 July 2022|volume=28|issue=8|issn=1359-4184|doi=10.1038/s41380-022-01661-0|pmid=35854107|pmc=10618090|s2cid=250646781|doi-access=free}}</ref><ref>{{Citation|vauthors=Ghaemi N|year=2022|title=Has the Serotonin Hypothesis Been Debunked?|url=https://www.psychologytoday.com/us/blog/mood-swings/202210/has-the-serotonin-hypothesis-been-debunked|access-date=2 May 2023}}</ref> Proponents of the [[Biology of depression|monoamine hypothesis of depression]] recommend choosing an antidepressant which impacts the most prominent symptoms. Under this practice, for example, a person with MDD who is also anxious or irritable would be treated with [[selective serotonin reuptake inhibitor]]s (SSRIs) or [[norepinephrine reuptake inhibitor]]s, while a person suffering from loss of energy and enjoyment of life would take a [[norepinephrine–dopamine reuptake inhibitor]].<ref name="pmid18494537">{{cite journal|vauthors=Nutt DJ|title=Relationship of neurotransmitters to the symptoms of major depressive disorder|journal=The Journal of Clinical Psychiatry|volume=69|issue=suppl E1|pages=4–7|date=30 April 2008|pmid=18494537|url=http://www.psychiatrist.com/jcp/article/pages/2008/v69e01/v69e0101.aspx|archive-date=3 August 2020|access-date=3 August 2020|archive-url=https://web.archive.org/web/20200803182514/http://www.psychiatrist.com/JCP/article/Pages/2008/v69e01/v69e0101.aspx|url-status=dead}}</ref>

===Major depressive disorder===
The UK [[National Institute for Health and Care Excellence]] (NICE)'s 2022 guidelines indicate that antidepressants should not be routinely used for the initial treatment of mild depression, "unless that is the person's preference".<ref name="NIHCE-2022">{{cite web|date=29 June 2022|title=Depression in adults: treatment and management|url=https://www.nice.org.uk/guidance/ng222/chapter/recommendations|website=National Institute for Health and Care Excellence}}</ref> The guidelines recommended that antidepressant treatment be considered:

* For people with a history of moderate or severe depression.
* For people with mild depression that has been present for an extended period.
* As a first-line treatment for moderate to severe depression.
* As a second-line treatment for mild depression that persists after other interventions.

The guidelines further note that in most cases, antidepressants should be used in combination with psychosocial interventions and should be continued for at least six months to reduce the risk of relapse and that SSRIs are typically better tolerated than other antidepressants.<ref name="NIHCE-2022" />

[[American Psychiatric Association]] (APA) treatment guidelines recommend that initial treatment be individually tailored based on factors including the severity of symptoms, co-existing disorders, prior treatment experience, and the person's preference. Options may include antidepressants, [[psychotherapy]], [[electroconvulsive therapy]] (ECT), [[transcranial magnetic stimulation]] (TMS), or [[light therapy]]. The APA recommends antidepressant medication as an initial treatment choice in people with mild, moderate, or severe major depression, and that should be given to all people with severe depression unless ECT is planned.<ref>{{cite web|author=Work Group on Major Depressive Disorder|url=https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf|archive-url=https://ghostarchive.org/archive/20221009/https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf|archive-date=9 October 2022|url-status=live|title=Practice Guideline for the Treatment of Patients With Major Depressive Disorder|edition=Third|publisher=American Psychiatric Association|date=October 2010}}</ref>

Reviews of antidepressants generally find that they benefit adults with depression.<ref name="CiprianiFurukawa2018"/><ref name="BarthKriston2018"/> On the other hand, some contend that most studies on antidepressant medication are confounded by several biases: the lack of an [[active placebo]], which means that many people in the placebo arm of a [[Randomized controlled trial|double-blind study]] may deduce that they are not getting any true treatment, thus destroying double-blindness; a short follow up after termination of treatment; non-systematic recording of adverse effects; very strict exclusion criteria in samples of patients; studies being paid for by the industry; selective publication of results. This means that the small beneficial effects that are found may not be statistically significant.<ref>{{cite journal|vauthors=Moncrieff J, Kirsch I|title=Empirically derived criteria cast doubt on the clinical significance of antidepressant-placebo differences|journal=Contemporary Clinical Trials|volume=43|pages=60–62|date=July 2015|pmid=25979317|doi=10.1016/j.cct.2015.05.005|doi-access=free}}</ref><ref>{{cite book|title=The Emperor's New Drugs: Exploding the Antidepressant Myth|publisher=Basic Books|date=2010|vauthors=Kirsch I|pages=[https://archive.org/details/emperorsnewdrugs0000kirs/page/80 80]|isbn=978-0-465-02016-4|title-link=The Emperor's New Drugs: Exploding the Antidepressant Myth}}</ref><ref>{{cite journal|vauthors=Antonuccio DO, Burns DD, Danton WG|date=2002|title=Antidepressants: a triumph of marketing over science?|journal=Prevention and Treatment|volume=5|doi=10.1037/1522-3736.5.1.525c}}</ref><ref>{{cite journal|vauthors=Antonuccio DO, Danton WG, DeNelsky GY, Greenberg RP, Gordon JS|title=Raising questions about antidepressants|journal=Psychotherapy and Psychosomatics|volume=68|issue=1|pages=3–14|date=1999|pmid=9873236|doi=10.1159/000012304|s2cid=13524296}}</ref><ref name=BMJ2019/>

Among the 21 most commonly prescribed antidepressants, the most effective and well-tolerated are [[escitalopram]], [[paroxetine]], [[sertraline]], [[agomelatine]], and [[mirtazapine]].<ref name="NIHR-2018" /><ref name="CiprianiFurukawa2018" /> For children and adolescents with moderate to severe depressive disorder, some evidence suggests [[fluoxetine]] (either with or without [[cognitive behavioral therapy]]) is the best treatment, but more research is needed to be certain.<ref name="Evidence-2020">{{cite journal|date=12 October 2020|title=Prozac may be the best treatment for young people with depression – but more research is needed|url=https://evidence.nihr.ac.uk/alert/prozac-may-be-the-best-treatment-for-young-people-with-depression-but-more-research-is-needed/|journal=NIHR Evidence|type=Plain English summary|publisher=National Institute for Health and Care Research|doi=10.3310/alert_41917|s2cid=242952585}}</ref><ref name="Zhou-2020">{{cite journal|vauthors=Zhou X, Teng T, Zhang Y, Del Giovane C, Furukawa TA, Weisz JR, Li X, Cuijpers P, Coghill D, Xiang Y, Hetrick SE, Leucht S, Qin M, Barth J, Ravindran AV, Yang L, Curry J, Fan L, Silva SG, Cipriani A, Xie P|title=Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysis|journal=The Lancet. Psychiatry|volume=7|issue=7|pages=581–601|date=July 2020|pmid=32563306|pmc=7303954|doi=10.1016/S2215-0366(20)30137-1}}</ref><ref name="Boaden-2020">{{cite journal|vauthors=Boaden K, Tomlinson A, Cortese S, Cipriani A|title=Antidepressants in Children and Adolescents: Meta-Review of Efficacy, Tolerability and Suicidality in Acute Treatment|journal=Frontiers in Psychiatry|volume=11|pages=717|date=2 September 2020|pmid=32982805|pmc=7493620|doi=10.3389/fpsyt.2020.00717|doi-access=free}}</ref><ref name="Hetrick-2021">{{cite journal|vauthors=Hetrick SE, McKenzie JE, Bailey AP, Sharma V, Moller CI, Badcock PB, Cox GR, Merry SN, Meader N|title=New generation antidepressants for depression in children and adolescents: a network meta-analysis|journal=The Cochrane Database of Systematic Reviews|volume=2021|issue=5|pages=CD013674|date=May 2021|pmid=34029378|pmc=8143444|doi=10.1002/14651858.CD013674.pub2|collaboration=Cochrane Common Mental Disorders Group}}</ref> Sertraline, escitalopram, and [[duloxetine]] may also help reduce symptoms.<ref name="Hetrick-2021" />

A 2023 [[systematic review]] and [[meta-analysis]] of [[randomized controlled trial]]s of antidepressants for major depressive disorder found that the medications provided only small or doubtful benefits in terms of [[quality of life]].<ref name="pmid36905396">{{cite journal|vauthors=Wiesinger T, Kremer S, Bschor T, Baethge C|title=Antidepressants and Quality of Life in Patients with Major Depressive Disorder – Systematic Review and Meta-analysis of Double-blind, Placebo-controlled RCTs|journal=Acta Psychiatr Scand|volume=147|issue=6|pages=545–560|date=March 2023|pmid=36905396|doi=10.1111/acps.13541|s2cid=257438412|doi-access=free}}</ref> Likewise, a 2022 systematic review and meta-analysis of randomized controlled trials of antidepressants for major depressive disorder in children and adolescents found small improvements in quality of life.<ref name="pmid35508443">{{cite journal|vauthors=Teng T, Zhang Z, Yin B, Guo T, Wang X, Hu J, Ran X, Dai Q, Zhou X|title=Effect of antidepressants on functioning and quality of life outcomes in children and adolescents with major depressive disorder: a systematic review and meta-analysis|journal=Transl Psychiatry|volume=12|issue=1|pages=183|date=May 2022|pmid=35508443|pmc=9068747|doi=10.1038/s41398-022-01951-9}}</ref> Quality of life as an outcome measure is often selectively reported in trials of antidepressants.<ref name="Paludan-Müller 2021">{{cite journal|vauthors=Paludan-Müller AS, Sharma T, Rasmussen K, Gøtzsche PC|title=Extensive selective reporting of quality of life in clinical study reports and publications of placebo-controlled trials of antidepressants|journal=Int J Risk Saf Med|volume=32|issue=2|pages=87–99|date=May 2021|pmid=33044196|doi=10.3233/JRS-200051|s2cid=222299860}}</ref>

===Anxiety disorders===
For children and adolescents, [[fluvoxamine]] and [[escitalopram]] are effective in treating a range of anxiety disorders.<ref name="NIHR-2022">{{cite journal|date=3 November 2022|title=Antidepressants for children and teenagers: what works for anxiety and depression?|url=https://evidence.nihr.ac.uk/collection/antidepressants-for-children-and-teenagers-what-works-anxiety-depression/|journal=NIHR Evidence|type=Plain English summary|publisher=National Institute for Health and Care Research|doi=10.3310/nihrevidence_53342|s2cid=253347210}}</ref><ref name="Boaden-2020" /><ref name="Correll-2021">{{cite journal|vauthors=Correll CU, Cortese S, Croatto G, Monaco F, Krinitski D, Arrondo G, Ostinelli EG, Zangani C, Fornaro M, Estradé A, Fusar-Poli P, Carvalho AF, Solmi M|date=June 2021|title=Efficacy and acceptability of pharmacological, psychosocial, and brain stimulation interventions in children and adolescents with mental disorders: an umbrella review|journal=World Psychiatry|volume=20|issue=2|pages=244–275|doi=10.1002/wps.20881|pmc=8129843|pmid=34002501}}</ref> Fluoxetine, sertraline, and paroxetine can also help with managing various forms of anxiety in children and adolescents.<ref name="NIHR-2022" /><ref name="Boaden-2020" /><ref name="Correll-2021" />

Meta-analyses of published and unpublished trials have found that antidepressants have a [[placebo group|placebo]]-subtracted [[effect size]] ([[standardized mean difference]] or SMD) in the treatment of anxiety disorders of around 0.3, which equates to a small improvement and is roughly the same magnitude of benefit as their effectiveness in the treatment of depression.<ref name="pmid31249537" /> The effect size (SMD) for improvement with placebo in trials of antidepressants for anxiety disorders is approximately 1.0, which is a large improvement in terms of effect size definitions.<ref name="pmid31573058">{{cite journal|vauthors=Li F, Nasir M, Olten B, Bloch MH|title=Meta-Analysis of Placebo Response in Adult Antidepressant Trials|journal=CNS Drugs|volume=33|issue=10|pages=971–980|date=October 2019|pmid=31573058|doi=10.1007/s40263-019-00662-y|s2cid=203609845}}</ref> In relation to this, most of the benefit of antidepressants for anxiety disorders is attributable to placebo responses rather than to the effects of the antidepressants themselves.<ref name="pmid31249537" /><ref name="pmid31573058" />

====Generalized anxiety disorder====
Antidepressants are recommended by the National Institute for Health and Care Excellence (NICE) for the treatment of [[generalized anxiety disorder]] (GAD) that has failed to respond to conservative measures such as education and self-help activities. GAD is a common disorder in which the central feature is excessively worrying about numerous events. Key symptoms include excessive anxiety about events and issues going on around them and difficulty controlling worrisome thoughts that persists for at least 6 months.

Antidepressants provide a modest to moderate reduction in anxiety in GAD.<ref name="urlwww.nice.org.uk">{{cite web|url=http://www.nice.org.uk/nicemedia/live/13314/52599/52599.pdf|author=National Collaborating Centre for Mental Health and the National Collaborating Centre for Primary Care|title=Generalised anxiety disorder and panic disorder (with or without agoraphobia) in adults|work=NICE clinical guideline 113|date=January 2011|access-date=20 February 2013|url-status=dead|archive-url=https://web.archive.org/web/20121021044157/http://www.nice.org.uk/nicemedia/live/13314/52599/52599.pdf|archive-date=21 October 2012}}</ref> The efficacy of different antidepressants is similar.<ref name="urlwww.nice.org.uk" />

====Social anxiety disorder====
Some antidepressants are used as a treatment for [[social anxiety disorder]], but their efficacy is not entirely convincing, as only a small proportion of antidepressants showed some effectiveness for this condition. Paroxetine was the first drug to be FDA-approved for this disorder. Its efficacy is considered beneficial, although not everyone responds favorably to the drug. Sertraline and fluvoxamine extended-release were later approved for it as well, while escitalopram is used [[Off-label use|off-label]] with acceptable efficiency. However, there is not enough evidence to support [[Citalopram]] for treating social anxiety disorder, and fluoxetine was no better than a placebo in clinical trials. [[Selective serotonin reuptake inhibitor|SSRIs]] are used as a first-line treatment for social anxiety, but they do not work for everyone. One alternative would be [[venlafaxine]], an [[Serotonin–norepinephrine reuptake inhibitor|SNRI]], which has shown benefits for social phobia in five clinical trials against a placebo, while the other SNRIs are not considered particularly useful for this disorder as many of them did not undergo testing for it. {{As of|2008}}, it is unclear if duloxetine and [[desvenlafaxine]] can provide benefits for people with social anxiety. However, another class of antidepressants called [[Monoamine oxidase inhibitor|MAOIs]] are considered effective for social anxiety, but they come with many unwanted side effects and are rarely used. [[Phenelzine]] was shown to be a good treatment option, but its use is limited by dietary restrictions. [[Moclobemide]] is a [[Reversible inhibitor of MAO-A|RIMA]] and showed mixed results, but still received approval in some European countries for social anxiety disorder. [[Tricyclic antidepressant|TCA antidepressants]], such as [[clomipramine]] and [[imipramine]], are not considered effective for this anxiety disorder in particular. This leaves out SSRIs such as paroxetine, sertraline, and fluvoxamine CR as acceptable and tolerated treatment options for this disorder.<ref>{{cite journal|vauthors=Canton J, Scott KM, Glue P|title=Optimal treatment of social phobia: systematic review and meta-analysis|journal=Neuropsychiatric Disease and Treatment|volume=8|pages=203–215|date=May 2012|pmid=22665997|pmc=3363138|doi=10.2147/NDT.S23317|doi-access=free}}</ref><ref>{{cite journal|vauthors=Hansen RA, Gaynes BN, Gartlehner G, Moore CG, Tiwari R, Lohr KN|title=Efficacy and tolerability of second-generation antidepressants in social anxiety disorder|journal=International Clinical Psychopharmacology|volume=23|issue=3|pages=170–179|date=May 2008|pmid=18408531|pmc=2657552|doi=10.1097/YIC.0b013e3282f4224a}}</ref>

====Obsessive–compulsive disorder====
SSRIs are a [[Second-line medication|second-line]] treatment for adult [[obsessive–compulsive disorder]] (OCD) with mild functional impairment, and a first-line treatment for those with moderate or severe impairment.<ref>{{cite journal|vauthors=Soomro GM, Altman D, Rajagopal S, Oakley-Browne M|date=January 2008|title=Selective serotonin re-uptake inhibitors (SSRIs) versus placebo for obsessive compulsive disorder (OCD)|journal=The Cochrane Database of Systematic Reviews|volume=2008|issue=1|pages=CD001765|doi=10.1002/14651858.CD001765.pub3|pmc=7025764|pmid=18253995}}</ref><ref>{{cite journal|vauthors=Fineberg NA, Brown A, Reghunandanan S, Pampaloni I|date=September 2012|title=Evidence-based pharmacotherapy of obsessive-compulsive disorder|journal=The International Journal of Neuropsychopharmacology|volume=15|issue=8|pages=1173–1191|doi=10.1017/S1461145711001829|pmid=22226028|doi-access=free|hdl=2299/216|hdl-access=free}}</ref><ref>{{cite web|title=Paroxetine prescribing information|url=https://www.apotex.com/us/en/products/downloads/pil/paxil_irtb_ins.pdf|url-status=dead|archive-url=https://web.archive.org/web/20150219055046/https://www.apotex.com/us/en/products/downloads/pil/paxil_irtb_ins.pdf|archive-date=19 February 2015|access-date=30 January 2015}}</ref><ref>{{cite web|title=Sertraline prescribing information|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019839s070,020990s032lbl.pdf|url-status=live|archive-url=https://web.archive.org/web/20150616011817/http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019839s070,020990s032lbl.pdf|archive-date=16 June 2015|access-date=30 January 2015}}</ref>

In children, SSRIs are considered as a second-line therapy in those with moderate-to-severe impairment, with close monitoring for psychiatric adverse effects.<ref>{{cite web|url=http://www.nice.org.uk/nicemedia/pdf/cg031niceguideline.pdf|title=Obsessive-compulsive disorder|work=Clinical Guideline 31|publisher=The National Institute for Health and Care Excellence|date=November 2005|url-status=dead|archive-url=https://web.archive.org/web/20081206033654/https://www.nice.org.uk/nicemedia/pdf/cg031niceguideline.pdf|archive-date=6 December 2008}}</ref> Sertraline and fluoxetine are effective in treating OCD for children and adolescents.<ref name="NIHR-2022" /><ref name="Boaden-2020" /><ref name="Correll-2021" />

[[Clomipramine]], a TCA drug, is considered effective and useful for OCD. However, it is used as a second-line treatment because it is less well-tolerated than SSRIs. Despite this, it has not shown superiority to fluvoxamine in trials. All SSRIs can be used effectively for OCD. SNRI use may also be attempted, though no SNRIs have been approved for the treatment of OCD. Despite these treatment options, many patients remain symptomatic after initiating the medication, and less than half achieve [[Remission (medicine)|remission]].<ref>{{cite journal|vauthors=Kellner M|title=Drug treatment of obsessive-compulsive disorder|journal=Dialogues in Clinical Neuroscience|volume=12|issue=2|pages=187–197|date=June 2010|pmid=20623923|pmc=3181958|doi=10.31887/DCNS.2010.12.2/mkellner}}</ref>

Placebo responses are a large component of the benefit of antidepressants in the treatment of depression and anxiety.<ref name="pmid31249537" /><ref name="pmid31573058" /> However, placebo responses with antidepressants are lower in magnitude in the treatment of OCD compared to depression and anxiety.<ref name="pmid31573058" /><ref name="pmid28477500">{{cite journal|vauthors=Sugarman MA, Kirsch I, Huppert JD|title=Obsessive-compulsive disorder has a reduced placebo (and antidepressant) response compared to other anxiety disorders: A meta-analysis|journal=J Affect Disord|volume=218|pages=217–226|date=August 2017|pmid=28477500|doi=10.1016/j.jad.2017.04.068}}</ref> A 2019 meta-analysis found placebo improvement effect sizes (SMD) of about 1.2 for depression, 1.0 for anxiety disorders, and 0.6 for OCD with antidepressants.<ref name="pmid31573058" />

==== Post–traumatic stress disorder ====
Antidepressants are one of the treatment options for [[Post-traumatic stress disorder|PTSD]]. However, their efficacy is not well established. Paroxetine and sertraline have been FDA approved for the treatment of PTSD. Paroxetine has slightly higher response and remission rates than sertraline for this condition. However, neither drug is considered very helpful for a broad patient demographic. Fluoxetine and venlafaxine are used off-label. Fluoxetine has produced unsatisfactory mixed results. Venlafaxine showed response rates of 78%, which is significantly higher than what paroxetine and sertraline achieved. However, it did not address as many symptoms of PTSD as paroxetine and sertraline, in part due to the fact that venlafaxine is an [[Serotonin–norepinephrine reuptake inhibitor|SNRI]]. This class of drugs inhibits the reuptake of norepinephrine, which may cause anxiety in some patients. Fluvoxamine, escitalopram, and citalopram were not well-tested for this disorder. [[Monoamine oxidase inhibitor|MAOIs]], while some of them may be helpful, are not used much because of their unwanted side effects. This leaves paroxetine and sertraline as acceptable treatment options for some people, although more effective antidepressants are needed.<ref>{{cite journal|vauthors=Alexander W|title=Pharmacotherapy for Post-traumatic Stress Disorder in Combat Veterans: Focus on Antidepressants and Atypical Antipsychotic Agents|journal=P & T|volume=37|issue=1|pages=32–38|date=January 2012|pmid=22346334|pmc=3278188}}</ref>

====Panic disorder====
[[Panic disorder]] is treated relatively well with medications compared to other disorders. Several classes of antidepressants have shown efficacy for this disorder, with SSRIs and SNRIs used first-line. Paroxetine, sertraline, and fluoxetine are FDA-approved for panic disorder, while fluvoxamine, escitalopram, and citalopram are also considered effective for them. SNRI venlafaxine is also approved for this condition. Unlike [[social anxiety]] and [[Post-traumatic stress disorder|PTSD]], some [[Tricyclic antidepressant|TCAs antidepressants]], like clomipramine and imipramine, have shown efficacy for panic disorder. Moreover, the [[Monoamine oxidase inhibitor|MAOI]] [[phenelzine]] is also considered useful. Panic disorder has many drugs for its treatment. However, the starting dose must be lower than the one used for major depressive disorder because people have reported an increase in anxiety as a result of starting the medication. In conclusion, while panic disorder's treatment options seem acceptable and useful for this condition, many people are still symptomatic after treatment with residual symptoms.<ref>{{cite journal|vauthors=Bighelli I, Castellazzi M, Cipriani A, Girlanda F, Guaiana G, Koesters M, Turrini G, Furukawa TA, Barbui C|title=Antidepressants versus placebo for panic disorder in adults|journal=The Cochrane Database of Systematic Reviews|volume=2018|issue=4|pages=CD010676|date=April 2018|pmid=29620793|pmc=6494573|doi=10.1002/14651858.CD010676.pub2}}</ref><ref>{{cite journal|vauthors=Bighelli I, Trespidi C, Castellazzi M, Cipriani A, Furukawa TA, Girlanda F, Guaiana G, Koesters M, Barbui C|title=Antidepressants and benzodiazepines for panic disorder in adults|journal=The Cochrane Database of Systematic Reviews|volume=2016|issue=9|pages=CD011567|date=September 2016|pmid=27618521|pmc=6457579|doi=10.1002/14651858.CD011567.pub2}}</ref><ref>{{cite journal|vauthors=Andrisano C, Chiesa A, Serretti A|title=Newer antidepressants and panic disorder: a meta-analysis|journal=International Clinical Psychopharmacology|volume=28|issue=1|pages=33–45|date=January 2013|pmid=23111544|doi=10.1097/YIC.0b013e32835a5d2e|s2cid=24967691|doi-access=free}}</ref>

===Eating disorders===
Antidepressants are recommended as an alternative or additional first step to self-help programs in the treatment of [[bulimia nervosa]].<ref name="urlwww.nice.org.uk2">{{cite web|url=http://www.nice.org.uk/nicemedia/pdf/CG9FullGuideline.pdf|title=Eating disorders in over 8s: management|date=28 January 2004|work=Clinical guideline [CG9]|publisher=National Institute for Health Care Excellence (NICE)|location=United Kingdom|url-status=live|archive-url=https://web.archive.org/web/20140327055429/http://www.nice.org.uk/nicemedia/pdf/CG9FullGuideline.pdf|archive-date=27 March 2014}}</ref> SSRIs (fluoxetine in particular) are preferred over other antidepressants due to their acceptability, tolerability, and superior reduction of symptoms in short-term trials. Long-term efficacy remains poorly characterized. [[Bupropion]] is not recommended for the treatment of eating disorders, due to an increased risk of seizure.<ref>{{cite web|url=https://www.nlm.nih.gov/medlineplus/druginfo/meds/a695033.html|title=Bupropion: MedlinePlus Drug Information|access-date=24 May 2016|url-status=live|archive-url=https://web.archive.org/web/20160508110157/https://www.nlm.nih.gov/medlineplus/druginfo/meds/a695033.html|archive-date=8 May 2016}}</ref>

Similar recommendations apply to [[binge eating disorder]].<ref name="urlwww.nice.org.uk2" /> SSRIs provide short-term reductions in binge eating behavior, but have not been associated with significant weight loss.<ref name="urlNational Guideline Clearinghouse | Practice guideline for the treatment of patients with eating disorders.">{{cite web|url=http://www.guidelines.gov/content.aspx?id=9318+|work=National Guideline Clearinghouse|publisher=Agency for Healthcare Research and Quality|title=Practice guideline for the treatment of patients with eating disorders|url-status=dead|archive-url=https://web.archive.org/web/20130525135033/http://www.guidelines.gov/content.aspx?id=9318+|archive-date=25 May 2013|date=5 July 2018}}</ref>

Clinical trials have generated mostly negative results for the use of SSRIs in the treatment of [[anorexia nervosa]].<ref name="pmid21414249">{{cite journal|vauthors=Flament MF, Bissada H, Spettigue W|title=Evidence-based pharmacotherapy of eating disorders|journal=Int. J. Neuropsychopharmacol.|volume=15|issue=2|pages=189–207|date=March 2012|pmid=21414249|doi=10.1017/S1461145711000381|doi-access=free}}</ref> Treatment guidelines from the National Institute of Health and Care Excellence (NICE)<ref name="urlwww.nice.org.uk2" /> recommend against the use of SSRIs in this disorder. Those from the American Psychiatric Association (APA) note that SSRIs confer no advantage regarding weight gain, but may be used for the treatment of co-existing depressive, anxiety, or obsessive–compulsive disorders.<ref name="urlNational Guideline Clearinghouse | Practice guideline for the treatment of patients with eating disorders." />

===Pain===

====Fibromyalgia====
A 2012 [[meta-analysis]] concluded that antidepressant treatment favorably affects pain, health-related quality of life, depression, and sleep in [[fibromyalgia]] syndrome. [[Tricyclic antidepressant|Tricyclics]] appear to be the most effective class, with moderate effects on pain and sleep, and small effects on fatigue and health-related quality of life. The fraction of people experiencing a 30% pain reduction on tricyclics was 48%, versus 28% on placebo. For SSRIs and SNRIs, the fractions of people experiencing a 30% pain reduction were 36% (20% in the placebo comparator arms) and 42% (32% in the corresponding placebo comparator arms) respectively. Discontinuation of treatment due to side effects was common.<ref>{{cite journal|vauthors=Häuser W, Wolfe F, Tölle T, Uçeyler N, Sommer C|s2cid=207301478|title=The role of antidepressants in the management of fibromyalgia syndrome: a systematic review and meta-analysis|journal=CNS Drugs|volume=26|issue=4|pages=297–307|date=April 2012|pmid=22452526|doi=10.2165/11598970-000000000-00000}}</ref> Antidepressants including [[amitriptyline]], fluoxetine, duloxetine, [[milnacipran]], [[moclobemide]], and [[pirlindole]] are recommended by the European League Against Rheumatism (EULAR) for the treatment of fibromyalgia based on "limited evidence".<ref name="pmid17644548">{{cite journal|vauthors=Carville SF, Arendt-Nielsen L, Arendt-Nielsen S, Bliddal H, Blotman F, Branco JC, Buskila D, Da Silva JA, Danneskiold-Samsøe B, Dincer F, Henriksson C, Henriksson KG, Kosek E, Longley K, McCarthy GM, Perrot S, Puszczewicz M, Sarzi-Puttini P, Silman A, Späth M, Choy EH|title=EULAR evidence-based recommendations for the management of fibromyalgia syndrome|journal=Annals of the Rheumatic Diseases|volume=67|issue=4|pages=536–541|date=April 2008|pmid=17644548|doi=10.1136/ard.2007.071522|s2cid=12121672|doi-access=free|hdl=2434/664614|hdl-access=free}}</ref>

====Neuropathic pain====
A 2014 meta-analysis from the [[Cochrane Collaboration]] found the antidepressant duloxetine to be effective for the treatment of pain resulting from [[diabetic neuropathy]].<ref>{{cite journal|vauthors=Lunn MP, Hughes RA, Wiffen PJ|title=Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia|journal=The Cochrane Database of Systematic Reviews|volume=1|issue=1|pages=CD007115|date=January 2014|pmid=24385423|doi=10.1002/14651858.CD007115.pub3|pmc=10711341}}</ref> The same group reviewed data for amitriptyline in the treatment of [[neuropathic pain]] and found limited useful randomized clinical trial data. They concluded that the long history of successful use in the community for the treatment of fibromyalgia and neuropathic pain justified its continued use.<ref name="Moore2015">{{cite journal|vauthors=Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ|title=Amitriptyline for neuropathic pain in adults|journal=The Cochrane Database of Systematic Reviews|issue=7|pages=CD008242|date=July 2015|volume=2015|pmid=26146793|pmc=6447238|doi=10.1002/14651858.CD008242.pub3}}</ref> The group was concerned about the potential overestimation of the amount of pain relief provided by amitriptyline, and highlighted that only a small number of people will experience significant pain relief by taking this medication.<ref name=Moore2015 />

===Other uses===
Antidepressants may be modestly helpful for treating people who have both depression and [[alcohol dependence]], however, the evidence supporting this association is of low quality.<ref>{{cite journal|vauthors=Agabio R, Trogu E, Pani PP|title=Antidepressants for the treatment of people with co-occurring depression and alcohol dependence|journal=The Cochrane Database of Systematic Reviews|volume=2018|issue=4|pages=CD008581|date=April 2018|pmid=29688573|pmc=6494437|doi=10.1002/14651858.CD008581.pub2}}</ref> Bupropion is used to help people [[Smoking cessation|stop smoking]]. Antidepressants are also used to control some symptoms of [[narcolepsy]].<ref>{{cite web|url=https://www.ninds.nih.gov/Disorders/All-Disorders/Narcolepsy-Information-Page|title=Narcolepsy Information Page|date=27 March 2019|website=National Institute of Neurological Disorders and Stroke|access-date=11 April 2020}}</ref> Antidepressants may be used to relieve pain in people with active [[rheumatoid arthritis]]. However, further research is required.<ref>{{cite journal|vauthors=Richards BL, Whittle SL, Buchbinder R|title=Antidepressants for pain management in rheumatoid arthritis|journal=The Cochrane Database of Systematic Reviews|issue=11|pages=CD008920|date=November 2011|pmid=22071859|doi=10.1002/14651858.CD008920.pub2}}</ref> Antidepressants have been shown to be superior to placebo in treating depression in individuals with physical illness, although reporting bias may have exaggerated this finding.<ref>{{cite journal|vauthors=Rayner L, Price A, Evans A, Valsraj K, Higginson IJ, Hotopf M|title=Antidepressants for depression in physically ill people|journal=The Cochrane Database of Systematic Reviews|issue=3|pages=CD007503|date=March 2010|pmid=20238354|doi=10.1002/14651858.CD007503.pub2}}</ref> Antidepressants have been shown to improve some parts of cognitive functioning for depressed users, such as memory, attention, and processing speed.<ref>{{cite journal|vauthors=Prado CE, Watt S, Crowe SF|title=A meta-analysis of the effects of antidepressants on cognitive functioning in depressed and non-depressed samples|journal=Neuropsychology Review|volume=28|issue=1|pages=32–72|date=March 2018|pmid=29446012|doi=10.1007/s11065-018-9369-5}}</ref>

Certain antidepressants acting as serotonin 5-HT<sub>2A</sub> receptor antagonists, such as [[trazodone]] and [[mirtazapine]], have been used as [[trip killer|hallucinogen antidotes or "trip killers"]] to block the effects of [[serotonergic psychedelic]]s like [[psilocybin]] and [[lysergic acid diethylamide]] (LSD).<ref name="HalmanKongSarris2024">{{cite journal|vauthors=Halman A, Kong G, Sarris J, Perkins D|title=Drug-drug interactions involving classic psychedelics: A systematic review|journal=J Psychopharmacol|volume=38|issue=1|pages=3–18|date=January 2024|pmid=37982394|pmc=10851641|doi=10.1177/02698811231211219}}</ref><ref name="YatesMelon2024">{{cite journal|vauthors=Yates G, Melon E|title=Trip-killers: a concerning practice associated with psychedelic drug use|journal=Emerg Med J|volume=41|issue=2|pages=112–113|date=January 2024|pmid=38123961|doi=10.1136/emermed-2023-213377 | url=https://web.archive.org/web/20250511111827oe_/https://s3.amazonaws.com/crawl.prod.proquest.com/fpcache/71f445805bfb61341cbc438c8ae23bd3.pdf?X-Amz-Security-Token=IQoJb3JpZ2luX2VjEBMaCXVzLWVhc3QtMSJIMEYCIQDETX7YpaG5THA%2FNbKR0d92wr6h%2Bgg9preNcKjAsEqo%2BQIhAIlPGGWOeUc23LqhBzRYbxvSXB9aqSe2vVonl4nacAhhKp0CCLz%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEQABoMNTE4MzQ2ODQ4MzQxIgy9ji58Qtbi%2BavuKeYq8QEDL1U5KZDQ0bXFyVapeqJgE%2FX6x8DcJfFU8DAXYZPSQEwrIdfPbZWcYsH340deru%2FUHnNaGGpuHFoVzui%2FMbqBz7MANcowj%2FL1%2BQZzQ5hXh5KM3BW8E6NRzrQyuPRmBy7kQUkx8%2BjTN%2BXSMgF%2FCAs6Dn9fScgBGz3ddkwRZXDkjasqMP65RCPKhagK68cyMbf3oX%2BKS8a4Kltc2rk3CnWEhOKrZU4mIxq07DikLAXQbl8YRZJIkeOhN5TgBaLWJqyn1td2VWCMymAaFsqtPWHwXnEfsolRlfDooe6QXfE2YwX5PxBVJU7GPXRgrAqPjwtJMOCHgsEGOpwBYif%2BaDMBdz3IEghuvCvorAS0mkHzdcOz%2Fi7AzuN9nch%2FIm8llhMsN41aAWHuSG25pnhhftauFsg7rbGsrW2nl2kq2upi9zP7y%2Fnqk93jcP0kr0jM8zU12bYoSTsToQJsshH4N%2BTQUMwlzRQfeVv8MXdq%2BgSTTzJrWNwT1yNzye3rSHjvOumbNl6sgBISw7QqRzhB6hZTuf8AcI%2B7&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20250511T111826Z&X-Amz-SignedHeaders=host&X-Amz-Credential=ASIAXRL7BHBKRAKCQVVB%2F20250511%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Expires=3600&X-Amz-Signature=20bb1b90e4c8dbaa4115c954387617ebe2f55269bdd517692f1380193ed3f769}}</ref><ref name="Suran2024">{{cite journal|vauthors=Suran M|title=Study Finds Hundreds of Reddit Posts on "Trip-Killers" for Psychedelic Drugs|journal=JAMA|volume=331|issue=8|pages=632–634|date=February 2024|pmid=38294772|doi=10.1001/jama.2023.28257}}</ref>

===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>

===Switching antidepressants===
{{See also|Treatment-resistant depression#Switching antidepressants}}

The [[American Psychiatric Association]] 2000 Practice Guideline advises that where no response is achieved within the following six to eight weeks of treatment with an antidepressant, switch to an antidepressant in the same class, and then to a different class. A 2006 meta-analysis review found wide variation in the findings of prior studies: for people who had failed to respond to an SSRI antidepressant, between 12% and 86% showed a response to a new drug. However, the more antidepressants an individual had previously tried, the less likely they were to benefit from a new antidepressant trial.<ref name="SSRIswitch" /> However, a later meta-analysis found no difference between switching to a new drug and staying on the old medication: although 34% of [[Treatment-resistant depression|treatment-resistant]] people responded when switched to the new drug, 40% responded without being switched.<ref>{{cite journal|vauthors=Bschor T, Baethge C|title=No evidence for switching the antidepressant: Systematic review and meta-analysis of RCTs of a common therapeutic strategy|journal=[[Acta Psychiatrica Scandinavica]]|volume=121|issue=3|pages=174–9|year=2010|pmid=19703121|doi=10.1111/j.1600-0447.2009.01458.x|s2cid=8341512}}</ref>

===Augmentation and combination===
For a partial response, the American Psychiatric Association (APA) guidelines suggest [[Augmentation (pharmacology)|augmentation]] or adding a drug from a different class. These include [[Lithium (medication)|lithium]] and [[thyroid]] augmentation, [[dopamine agonist]]s, [[sex steroid]]s, [[Norepinephrine reuptake inhibitor|NRIs]], [[glucocorticoid]]-specific agents, or the newer [[anticonvulsant]]s.<ref name="augment">{{cite journal|vauthors=DeBattista C, Lembke A|s2cid=25499899|title=Update on augmentation of antidepressant response in resistant depression|journal=Current Psychiatry Reports|volume=7|issue=6|pages=435–40|year=2005|pmid=16318821|doi=10.1007/s11920-005-0064-x}}</ref>

A combination strategy involves adding another antidepressant, usually from a different class to affect other mechanisms. Although this may be used in clinical practice, there is little evidence for the relative efficacy or adverse effects of this strategy.<ref>{{cite journal|vauthors=Lam RW, Wan DD, Cohen NL, Kennedy SH|title=Combining Antidepressants for Treatment-Resistant Depression|journal=The Journal of Clinical Psychiatry|volume=63|issue=8|pages=685–93|year=2002|pmid=12197448|doi=10.4088/JCP.v63n0805}}</ref> Other tests conducted include the use of [[psychostimulant]]s as an augmentation therapy. Several studies have shown the efficacy of combining [[modafinil]] for treatment-resistant people. It has been used to help combat SSRI-associated fatigue.<ref>{{cite journal|vauthors=Goss AJ, Kaser M, Costafreda SG, Sahakian BJ, Fu CH|s2cid=13911763|title=Modafinil augmentation therapy in unipolar and bipolar depression: a systematic review and meta-analysis of randomized controlled trials|journal=The Journal of Clinical Psychiatry|volume=74|issue=11|pages=1101–7|year=2013|pmid=24330897|doi=10.4088/JCP.13r08560|url=https://pdfs.semanticscholar.org/754c/e4bb94f6be37d53b562ffe90fcec9a17073b.pdf|archive-url=https://web.archive.org/web/20200215045012/https://pdfs.semanticscholar.org/754c/e4bb94f6be37d53b562ffe90fcec9a17073b.pdf|url-status=dead|archive-date=15 February 2020}}</ref>

===Long-term use and stopping===
The effects of antidepressants typically do not continue once the course of medication ends. This results in a high rate of [[relapse]]. In 2003, a [[meta-analysis]] found that 18% of people who had responded to an antidepressant relapsed while still taking it, compared to 41% whose antidepressant was switched for a [[placebo]].<ref>{{cite journal|vauthors=Geddes JR, Carney SM, Davies C, Furukawa TA, Kupfer DJ, Frank E, Goodwin GM|s2cid=20198748|title=Relapse prevention with antidepressant drug treatment in depressive disorders: A systematic review|journal=The Lancet|volume=361|issue=9358|pages=653–61|year=2003|pmid=12606176|doi=10.1016/S0140-6736(03)12599-8}}</ref>

A gradual loss of therapeutic benefit occurs in a minority of people during the course of treatment.<ref>{{cite journal|vauthors=Targum SD|title=Identification and treatment of antidepressant tachyphylaxis|journal=Innovations in Clinical Neuroscience|volume=11|issue=3–4|pages=24–28|date=March 2014|pmid=24800130|pmc=4008298}}</ref><ref name="fava">{{cite journal|vauthors=Fava GA, Offidani E|title=The mechanisms of tolerance in antidepressant action|journal=Progress in Neuro-Psychopharmacology & Biological Psychiatry|volume=35|issue=7|pages=1593–1602|date=August 2011|pmid=20728491|doi=10.1016/j.pnpbp.2010.07.026|s2cid=207409469}}</ref> A strategy involving the use of [[pharmacotherapy]] in the treatment of the acute episode, followed by psychotherapy in its residual phase, has been suggested by some studies.<ref>{{cite journal|vauthors=Fava GA, Park SK, Sonino N|title=Treatment of recurrent depression|journal=Expert Review of Neurotherapeutics|volume=6|issue=11|pages=1735–1740|date=November 2006|pmid=17144786|doi=10.1586/14737175.6.11.1735|s2cid=22808803}}</ref><ref>{{cite journal|vauthors=Petersen TJ|title=Enhancing the efficacy of antidepressants with psychotherapy|journal=Journal of Psychopharmacology|volume=20|issue=3 Suppl|pages=19–28|date=May 2006|pmid=16644768|doi=10.1177/1359786806064314|s2cid=23649861}}</ref> For patients who wish to stop their antidepressants, engaging in brief psychological interventions such as Preventive Cognitive Therapy<ref>{{cite web|title=Voorkom Depressie – Preventieve Cognitieve Therapie|url=https://www.voorkomdepressie.nl/|website=voorkomdepressie.nl}}</ref> or [[mindfulness-based cognitive therapy]] while tapering down has been found to diminish the risk for [[Relapse prevention|relapse]].<ref>{{cite journal|vauthors=Breedvelt JJ, Warren FC, Segal Z, Kuyken W, Bockting CL|title=Continuation of Antidepressants vs Sequential Psychological Interventions to Prevent Relapse in Depression: An Individual Participant Data Meta-analysis|journal=JAMA Psychiatry|volume=78|issue=8|pages=868–875|date=August 2021|pmid=34009273|pmc=8135055|doi=10.1001/jamapsychiatry.2021.0823}}</ref>