View source for Antidepressant

{{Short description|Class of medication used to treat depression and other conditions}}
{{for-multi|the 2025 Suede album|Antidepressants (album)|the 2006 Lloyd Cole album|Antidepressant (album)}}
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{{Use dmy dates|date=February 2023}}
{{Infobox drug class
| Pronounce = 
| Synonyms =

<!-- Class identifiers -->
| Use = [[Mood disorder#Depressive disorders|Depressive disorders]], [[anxiety disorders]], [[chronic pain]], and [[addiction]]
| ATC_prefix = N06A
| Mode_of_action = 
| Mechanism_of_action =Varies 
| Biological_target = 
| Chemical_class =Varies

<!-- Clinical data -->
| Drugs.com = {{Drugs.com|drug-class|antidepressants}}
| MedlinePlus = antidepressants
| Consumer_Reports = antidepressants
| medicinenet = antidepressants
| rxlist = 100734

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| MeshID = D000928
}}
[[File:Venlafaxine structure.svg|thumb|175px|class=skin-invert-image|The skeletal structure of the [[SNRI]] [[venlafaxine]], a typical example of an antidepressant.]]
'''Antidepressants''' are a class of [[medication]]s used to treat [[major depressive disorder]], [[anxiety disorder]]s, [[chronic pain]], and [[addiction]].<ref name="Jennings2018">{{cite book|vauthors=Jennings L|title=Clinical Psychopharmacology for Neurologists|chapter=Antidepressants|date=2018|publisher=Springer|isbn=978-3-319-74602-9|veditors=Grossberg GT, Kinsella LJ|pages=45–71|doi=10.1007/978-3-319-74604-3_4}}</ref>

Common [[side effect]]s of antidepressants include [[Xerostomia|dry mouth]], [[weight gain]], [[dizziness]], [[headache]]s, [[akathisia]],<ref>{{cite book|vauthors=Ghaemi SN|title=Clinical Psychopharmacology: Principles and Practice|date=2019|publisher=Oxford University Press|location=New York|isbn=978-0-19-999548-6|page=90}}</ref> [[sexual dysfunction]],<ref>{{cite journal|vauthors=Healy D, Le Noury J, Mangin D|title=Enduring sexual dysfunction after treatment with antidepressants, 5α-reductase inhibitors and isotretinoin: 300 cases|journal=The International Journal of Risk & Safety in Medicine|volume=29|issue=3–4|pages=125–134|date=May 2018|pmid=29733030|pmc=6004900|doi=10.3233/JRS-180744}}</ref><ref name="Bahrick">{{cite journal|doi=10.2174/1874350100801010042|title=Persistence of Sexual Dysfunction Side Effects after Discontinuation of Antidepressant Medications: Emerging Evidence|journal=The Open Psychology Journal|volume=1|pages=42–50|year=2008|vauthors=Bahrick AS|doi-access=free}}</ref><ref>{{cite journal|vauthors=Taylor MJ, Rudkin L, Bullemor-Day P, Lubin J, Chukwujekwu C, Hawton K|title=Strategies for managing sexual dysfunction induced by antidepressant medication|journal=The Cochrane Database of Systematic Reviews|volume=2013|issue=5|article-number=CD003382|date=May 2013|pmid=23728643|doi=10.1002/14651858.CD003382.pub3|doi-access=free|pmc=12052305 }}</ref><ref>{{cite journal|vauthors=Kennedy SH, Rizvi S|title=Sexual dysfunction, depression, and the impact of antidepressants|journal=Journal of Clinical Psychopharmacology|volume=29|issue=2|pages=157–164|date=April 2009|pmid=19512977|doi=10.1097/jcp.0b013e31819c76e9|s2cid=739831}}</ref><ref>[https://www.ema.europa.eu/en/documents/other/new-product-information-wording-extracts-prac-recommendations-signals-adopted-13-16-may-2019-prac_en.pdf Serotonin and noradrenaline reuptake inhibitors (SNRI); selective serotonin reuptake inhibitors (SSRI) – Persistent sexual dysfunction after drug withdrawal ](EPITT no 19277), 11 June 20191, EMA/PRAC/265221/2019, Pharmacovigilance Risk Assessment Committee (PRAC)</ref> and [[emotional blunting]].<ref>{{cite journal|vauthors=Sansone RA, Sansone LA|title=SSRI-Induced Indifference|journal=Psychiatry|volume=7|issue=10|pages=14–18|date=October 2010|pmid=21103140|pmc=2989833}}</ref><ref>{{cite web|publisher=Harvard Health Publishing|title=Is your antidepressant making life a little too blah?|url=https://www.health.harvard.edu/depression/is-your-antidepressant-making-life-a-little-too-blah|access-date=25 February 2021|date=8 November 2016}}</ref><ref>{{cite web|title=Half of Patients on Antidepressants Experience Emotional Blunting|url=https://www.hcplive.com/view/half-of-patients-on-antidepressants-experience-emotional-blunting|access-date=25 February 2021|website=HCPLive|date=19 June 2017}}</ref> There is an increased risk of [[Suicidal ideation|suicidal thinking]] and [[Suicide|behavior]] when taken by children, adolescents, and young adults.<ref>{{cite web|url=https://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM173233.pdf|archive-url=https://ghostarchive.org/archive/20221009/https://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM173233.pdf|archive-date=9 October 2022|title=Revisions to Product Labeling|publisher=FDA|access-date=10 November 2018}}</ref> [[Antidepressant discontinuation syndrome|Discontinuation syndrome]], which resembles recurrent [[Depression (mood)|depression]] in the case of the [[Selective serotonin reuptake inhibitor|SSRI]] class, may occur after stopping the intake of any antidepressant, having effects which may be permanent and irreversible. Tapering off medications gradually is shown to reduce the risk of withdrawal complications.<ref name="Wil2015">{{cite journal|vauthors=Wilson E, Lader M|title=A review of the management of antidepressant discontinuation symptoms|journal=Therapeutic Advances in Psychopharmacology|volume=5|issue=6|pages=357–368|date=December 2015|pmid=26834969|pmc=4722507|doi=10.1177/2045125315612334}}</ref><ref name="Gab2017">{{cite journal|vauthors=Gabriel M, Sharma V|title=Antidepressant discontinuation syndrome|journal=CMAJ|volume=189|issue=21|pages=E747|date=May 2017|pmid=28554948|pmc=5449237|doi=10.1503/cmaj.160991}}</ref>

The effectiveness of antidepressants for treating depression in adults has strong support, though studies also highlight potential risks and limitations.<ref name="BarthKriston2018">{{cite journal|vauthors=Barth M, Kriston L, Klostermann S, Barbui C, Cipriani A, Linde K|title=Efficacy of selective serotonin reuptake inhibitors and adverse events: meta-regression and mediation analysis of placebo-controlled trials|journal=The British Journal of Psychiatry|volume=208|issue=2|pages=114–119|date=February 2016|pmid=26834168|doi=10.1192/bjp.bp.114.150136|doi-access=free}}</ref><ref name="BMJ2019">{{cite journal|vauthors=Jakobsen JC, Gluud C, Kirsch I|title=Should antidepressants be used for major depressive disorder?|journal=BMJ Evidence-Based Medicine|volume=25|issue=4|page=130|date=August 2020|pmid=31554608|pmc=7418603|doi=10.1136/bmjebm-2019-111238|doi-access=free}}</ref> In children and adolescents, evidence of efficacy is more limited, despite a marked increase in antidepressant prescriptions for these age groups since the 2000s.<ref name="CiprianiZhou2016">{{cite journal|vauthors=Cipriani A, Zhou X, Del Giovane C, Hetrick SE, Qin B, Whittington C, Coghill D, Zhang Y, Hazell P, Leucht S, Cuijpers P, Pu J, Cohen D, Ravindran AV, Liu Y, Michael KD, Yang L, Liu L, Xie P|date=August 2016|title=Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis|journal=Lancet|volume=388|issue=10047|pages=881–890|doi=10.1016/S0140-6736(16)30385-3|pmid=27289172|quote=When considering the risk-benefit profile of antidepressants in the acute treatment of major depressive disorder, these drugs do not seem to offer a clear advantage for children and adolescents. All antidepressants were more efficacious than a placebo in adults with major depressive disorder|s2cid=19728203|hdl=11380/1279478|url=https://ora.ox.ac.uk/objects/uuid:e0b5ae23-d562-4348-94b8-84f70b7812c5|hdl-access=free}}</ref><ref>{{cite journal|vauthors=Safer DJ, Zito JM|title=Short- and Long-Term Antidepressant Clinical Trials for Major Depressive Disorder in Youth: Findings and Concerns|journal=Frontiers in Psychiatry|volume=10|article-number=705|date=2019|pmid=31681028|pmc=6797591|doi=10.3389/fpsyt.2019.00705|doi-access=free}}</ref><ref>{{cite journal|vauthors=Hengartner MP|title=Editorial: Antidepressant Prescriptions in Children and Adolescents|journal=Frontiers in Psychiatry|volume=11|article-number=600283|date=2020|pmid=33192742|pmc=7661954|doi=10.3389/fpsyt.2020.600283|doi-access=free}}</ref>  A 2018 meta-analysis reported that the 21 most commonly prescribed antidepressants were found in all studies to be more effective than [[placebo]]s for the short-term treatment of [[major depressive disorder]] in adults. However, other research suggests that some benefits may be attributable to the placebo effect. Response to antidepressants is highly variable, and medications that are effective for certain patients may have no effect or a negative effect for others. Research into the factors that influence individual responses to antidepressants is ongoing.<ref name="NIHR-2018">{{cite journal|date=3 April 2018|title=The most effective antidepressants for adults revealed in major review|url=https://evidence.nihr.ac.uk/alert/the-most-effective-antidepressants-for-adults-revealed-in-major-review|journal=NIHR Evidence|type=Plain English summary|publisher=National Institute for Health and Care Research|doi=10.3310/signal-00580|url-access=subscription}}</ref><ref name="CiprianiFurukawa2018">{{cite journal|vauthors=Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner EH, Higgins JP, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JP, Geddes JR|date=April 2018|title=Comparative efficacy and acceptability of twenty-one antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis|journal=Lancet|volume=391|issue=10128|pages=1357–1366|doi=10.1016/S0140-6736(17)32802-7|pmc=5889788|pmid=29477251}}</ref><ref>{{cite journal|vauthors=Kirsch I|title=Antidepressants and the Placebo Effect|journal=Zeitschrift für Psychologie|volume=222|issue=3|pages=128–134|date=January 2014|pmid=25279271|pmc=4172306|doi=10.1027/2151-2604/a000176}}</ref><ref name="TurnerRosenthal2008">{{cite journal|vauthors=Turner EH, Rosenthal R|title=Efficacy of antidepressants|journal=The BMJ|volume=336|issue=7643|pages=516–517|date=March 2008|pmid=18319297|pmc=2265347|doi=10.1136/bmj.39510.531597.80}}</ref><ref>Penn, Elizabeth, and Derek K. Tracy. “The Drugs Don’t Work? Antidepressants and the Current and Future Pharmacological Management of Depression.” Therapeutic Advances in Psychopharmacology, vol. 2, no. 5, 30 Apr. 2012, pp. 179–188, pmc.ncbi.nlm.nih.gov/articles/PMC3736946/, https://doi.org/10.1177/2045125312445469.</ref>
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==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=978-1-137-50692-4}}</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}}</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|url-access=subscription}}</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|article-number=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|article-number=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|article-number=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|url-access=subscription}}</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|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. [[Vortioxetine]] may be of benefit. [[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|article-number=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|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|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|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.<ref>{{Citation |last1=Wilson |first1=Marcia |title=Clomipramine |date=2025 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK541006/ |access-date=2025-05-24 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=31082050 |last2=Tripp |first2=Jayson}}</ref> 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|article-number=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|article-number=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.medlineplus.gov/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|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]], [[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|article-number=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|article-number=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|article-number=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/health-information/disorders/narcolepsy|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|article-number=CD008920|date=November 2011|pmid=22071859|doi=10.1002/14651858.CD008920.pub2|pmc=12214451 }}</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|article-number=CD007503|date=March 2010|pmid=20238354|doi=10.1002/14651858.CD007503.pub2|pmc=12279289}}</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://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|archive-url=https://web.archive.org/web/20250511111827/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|archive-date=2025-05-11}}</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|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|doi=10.1139/jpn.0242 |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|article-number=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|article-number=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|article-number=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|article-number=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|article-number=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|article-number=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|article-number=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|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>

==Adverse effects==
Antidepressants can cause various [[adverse effects]], depending on the individual and the drug in question.<ref>{{cite web|url=https://www.webmd.com/depression/features/coping-with-side-effects-of-depression-treatment|title=Coping With Side Effects of Depression Treatment|vauthors=Allen A|website=WebMD|access-date=4 February 2019}}</ref>

Almost any medication involved with serotonin regulation has the potential to cause [[serotonin syndrome|serotonin toxicity]] (also known as ''serotonin syndrome'') – an excess of serotonin that can induce mania, restlessness, agitation, [[emotional lability]], insomnia, and confusion as its primary symptoms.<ref name="pmid12771076">{{cite journal|vauthors=Birmes P, Coppin D, Schmitt L, Lauque D|title=Serotonin syndrome: a brief review|journal=CMAJ|volume=168|issue=11|pages=1439–1442|date=May 2003|pmid=12771076|pmc=155963}}</ref><ref name="pmid15784664">{{cite journal|vauthors=Boyer EW, Shannon M|title=The serotonin syndrome|journal=The New England Journal of Medicine|volume=352|issue=11|pages=1112–1120|date=March 2005|pmid=15784664|doi=10.1056/NEJMra041867|url=http://toxicology.ucsd.edu/art%203%20serotonin%20syndrome.pdf|archive-url=https://web.archive.org/web/20130618053344/http://toxicology.ucsd.edu/art%203%20serotonin%20syndrome.pdf|archive-date=18 June 2013}}</ref> Although the condition is serious, it is not particularly common, generally only appearing at high doses or while on other medications. Assuming proper medical intervention has been taken (within about 24&nbsp;hours) it is rarely fatal.<ref name="pmid10941349">{{cite journal|vauthors=Mason PJ, Morris VA, Balcezak TJ|title=Serotonin syndrome. Presentation of 2 cases and review of the literature|journal=Medicine|volume=79|issue=4|pages=201–209|date=July 2000|pmid=10941349|doi=10.1097/00005792-200007000-00001|s2cid=41036864|doi-access=free}}</ref><ref name="pmid10818648">{{cite journal|vauthors=Sampson E, Warner JP|title=Serotonin syndrome: potentially fatal but difficult to recognize|journal=The British Journal of General Practice|volume=49|issue=448|pages=867–868|date=November 1999|pmid=10818648|pmc=1313553}}</ref> Antidepressants appear to increase the risk of [[diabetes]] by about 1.3-fold.<ref name="Salvi 2017">{{cite journal|vauthors=Salvi V, Grua I, Cerveri G, Mencacci C, Barone-Adesi F|title=The risk of new-onset diabetes in antidepressant users – A systematic review and meta-analysis|journal=PLOS ONE|volume=12|issue=7|article-number=e0182088|date=31 July 2017|pmid=28759599|pmc=5536271|doi=10.1371/journal.pone.0182088|quote=In our meta-analysis we found an association between exposure to ADs and new-onset diabetes, with a relative risk of 1.27. When we restricted the analysis to the studies to high NOS score the association between ADs and diabetes was even stronger. The results are in line with those from two previous meta-analyses that reported a 1.5-fold increase of diabetes among AD users.|doi-access=free|bibcode=2017PLoSO..1282088S}}</ref>

[[MAOIs]] tend to have pronounced (sometimes fatal) interactions with a wide variety of medications and [[over-the-counter drug]]s. If taken with foods that contain very high levels of [[tyramine]] (e.g., mature cheese, cured meats, or yeast extracts), they may cause a potentially lethal [[hypertensive crisis]]. At lower doses, the person may only experience a headache due to an increase in blood pressure.<ref name="pmid19742203">{{cite journal|vauthors=Sathyanarayana Rao TS, Yeragani VK|title=Hypertensive crisis and cheese|journal=Indian J Psychiatry|volume=51|issue=1|pages=65–6|year=2009|pmid=19742203|pmc=2738414|doi=10.4103/0019-5545.44910|doi-access=free}}</ref>

In response to these adverse effects, a different type of MAOI, the class of [[reversible inhibitor of monoamine oxidase A]] (RIMA), has been developed. The primary advantage of RIMAs is that they do not require the person to follow a special diet while being purportedly effective as SSRIs and tricyclics in treating depressive disorders.<ref name="pmid7717091">{{cite journal|vauthors=Paykel ES|title=Clinical efficacy of reversible and selective inhibitors of monoamine oxidase A in major depression|journal=Acta Psychiatrica Scandinavica. Supplementum|volume=386|pages=22–27|year=1995|pmid=7717091|doi=10.1111/j.1600-0447.1995.tb05920.x|s2cid=20488192}}</ref>

Tricyclics and SSRI can cause the so-called [[drug-induced QT prolongation]], especially in older adults;<ref>{{cite journal|vauthors=Rochester MP, Kane AM, Linnebur SA, Fixen DR|title=Evaluating the risk of QTc prolongation associated with antidepressant use in older adults: a review of the evidence|journal=Therapeutic Advances in Drug Safety|volume=9|issue=6|pages=297–308|date=June 2018|pmid=29854391|pmc=5971403|doi=10.1177/2042098618772979}}</ref> this condition can degenerate into a specific type of [[Heart arrhythmia|abnormal heart rhythm]] called [[Torsades de pointes|Torsades de points]], which can potentially lead to [[Cardiac arrest|sudden cardiac arrest]].<ref>{{cite journal|vauthors=Ayad RF, Assar MD, Simpson L, Garner JB, Schussler JM|title=Causes and management of drug-induced long QT syndrome|journal=Proceedings|volume=23|issue=3|pages=250–255|date=July 2010|pmid=20671821|pmc=2900977|doi=10.1080/08998280.2010.11928628}}</ref>

Some antidepressants are also believed to increase thoughts of [[suicidal ideation]].

Antidepressants have been associated with an increased risk of [[dementia]] in older adults.<ref name="pmid37834986">{{cite journal|vauthors=Wang GH, Li P, Wang Y, Guo J, Wilson DL, Lo-Ciganic WH|title=Association between Antidepressants and Dementia Risk in Older Adults with Depression: A Systematic Review and Meta-Analysis|journal=J Clin Med|volume=12|issue=19|date=October 2023|page=6342|pmid=37834986|doi=10.3390/jcm12196342|pmc=10573169|doi-access=free}}</ref>

Researchers have developed a tool that allows people to rate their concern about common side effects of antidepressants. The tool ranks potential treatment options in a visual display that highlights the drugs with side effects of least concern to an individual.<ref>{{cite journal|vauthors=Pillinger T, Howes OD, Correll CU, Leucht S, Huhn M, Schneider-Thoma J, Gaughran F, Jauhar S, McGuire PK, Taylor DM, Young AH, McCutcheon RA|title=Antidepressant and antipsychotic side-effects and personalised prescribing: a systematic review and digital tool development|journal=The Lancet. Psychiatry|volume=10|issue=11|pages=860–876|date=November 2023|pmid=37774723|pmc=10878984|doi=10.1016/s2215-0366(23)00262-6}}</ref><ref>{{Cite journal|date=5 September 2024|title=How to choose the right antidepressant or antipsychotic|url=https://evidence.nihr.ac.uk/alert/how-to-choose-the-right-antidepressant-or-antipsychotic/|journal=NIHR Evidence}}</ref>

===Pregnancy===
SSRI use in pregnancy has been associated with a variety of risks with varying degrees of proof of causation. As depression is independently associated with negative pregnancy outcomes, determining the extent to which observed associations between antidepressant use and specific adverse outcomes reflect a causative relationship has been difficult in some cases.<ref>{{cite journal|author=Malm H|s2cid=22875385|title=Prenatal exposure to selective serotonin reuptake inhibitors and infant outcome|journal=Ther Drug Monit|volume=34|issue=6|pages=607–14|date=December 2012|pmid=23042258|doi=10.1097/FTD.0b013e31826d07ea}}</ref> In other cases, the attribution of adverse outcomes to antidepressant exposure seems fairly clear.

SSRI use in pregnancy is associated with an increased risk of spontaneous abortion of about 1.7-fold,<ref>{{cite journal|vauthors=Rahimi R, Nikfar S, Abdollahi M|title=Pregnancy outcomes following exposure to serotonin reuptake inhibitors: a meta-analysis of clinical trials|journal=Reproductive Toxicology|volume=22|issue=4|pages=571–575|year=2006|pmid=16720091|doi=10.1016/j.reprotox.2006.03.019|bibcode=2006RepTx..22..571R }}</ref><ref name="pmid23351929">{{cite journal|vauthors=Nikfar S, Rahimi R, Hendoiee N, Abdollahi M|title=Increasing the risk of spontaneous abortion and major malformations in newborns following use of serotonin reuptake inhibitors during pregnancy: A systematic review and updated meta-analysis|journal=DARU Journal of Pharmaceutical Sciences|volume=20|issue=1|article-number=75|year=2012|pmid=23351929|pmc=3556001|doi=10.1186/2008-2231-20-75|doi-access=free}}</ref> and is associated with preterm birth and low birth weight.<ref>{{cite journal|vauthors=Huang H, Coleman S, Bridge JA, Yonkers K, Katon W|title=A meta-analysis of the relationship between antidepressant use in pregnancy and the risk of preterm birth and low birth weight|journal=General Hospital Psychiatry|volume=36|issue=1|pages=13–8|year=2014|pmid=24094568|pmc=3877723|doi=10.1016/j.genhosppsych.2013.08.002}}</ref>

A systematic review of the risk of major birth defects in antidepressant-exposed pregnancies found a small increase (3% to 24%) in the risk of major malformations and a risk of cardiovascular birth defects that did not differ from non-exposed pregnancies.<ref>{{cite journal|vauthors=Einarson TR, Kennedy D, Einarson A|title=Do findings differ across research design? The case of antidepressant use in pregnancy and malformations|journal=J Popul Ther Clin Pharmacol|volume=19|issue=2|pages=e334–48|year=2012|pmid=22946124|url=https://jptcp.com/index.php/jptcp/article/view/428}}</ref> A study of fluoxetine-exposed pregnancies found a 12% increase in the risk of major malformations that did not reach statistical significance.<ref>{{cite journal|vauthors=Riggin L, Frankel Z, Moretti M, Pupco A, Koren G|title=The fetal safety of fluoxetine: a systematic review and meta-analysis|journal=J Obstet Gynaecol Can|volume=35|issue=4|pages=362–9|date=April 2013|pmid=23660045|doi=10.1016/S1701-2163(15)30965-8|doi-access=free}}</ref> Other studies have found an increased risk of cardiovascular birth defects among depressed mothers not undergoing SSRI treatment, suggesting the possibility of ascertainment bias, e.g. that worried mothers may pursue more aggressive testing of their infants.<ref>{{cite journal|vauthors=Koren G, Nordeng HM|title=Selective serotonin reuptake inhibitors and malformations: case closed?|journal=Semin Fetal Neonatal Med|volume=18|issue=1|pages=19–22|date=February 2013|pmid=23228547|doi=10.1016/j.siny.2012.10.004}}</ref> Another study found no increase in cardiovascular birth defects and a 27% increased risk of major malformations in SSRI exposed pregnancies.<ref name=pmid23351929/> The FDA advises for the risk of birth defects with the use of paroxetine<ref>{{cite press release|publisher=U.S. Food and Drug Administration|title=FDA Advising of Risk of Birth Defects with Paxil|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2005/ucm108527.htm|access-date=29 November 2012|archive-url=https://web.archive.org/web/20131203022919/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2005/ucm108527.htm|archive-date=3 December 2013}}</ref> and the MAOI should be avoided.

A 2013 systematic review and meta-analysis found that antidepressant use during pregnancy was statistically significantly associated with some pregnancy outcomes, such as gestational age and preterm birth, but not with other outcomes. The same review cautioned that because differences between the exposed and unexposed groups were small, it was doubtful whether they were clinically significant.<ref>{{cite journal|vauthors=Ross LE, Grigoriadis S, Mamisashvili L, Vonderporten EH, Roerecke M, Rehm J, Dennis CL, Koren G, Steiner M, Mousmanis P, Cheung A|title=Selected pregnancy and delivery outcomes after exposure to antidepressant medication: a systematic review and meta-analysis|journal=JAMA Psychiatry|volume=70|issue=4|pages=436–443|date=April 2013|pmid=23446732|doi=10.1001/jamapsychiatry.2013.684|s2cid=2065578}}</ref>

A [[neonate]] (infant less than 28&nbsp;days old) may experience a [[withdrawal syndrome]] from abrupt discontinuation of the antidepressant at birth. Antidepressants can be present in varying amounts in breast milk, but their effects on infants are currently unknown.<ref>{{cite journal|vauthors=Lanza di Scalea T, Wisner KL|title=Antidepressant Medication Use During Breastfeeding|journal=Clinical Obstetrics and Gynecology|volume=52|issue=3|pages=483–97|year=2009|pmid=19661763|pmc=2902256|doi=10.1097/GRF.0b013e3181b52bd6}}</ref>

Moreover, SSRIs inhibit nitric oxide synthesis, which plays an important role in setting the vascular tone. Several studies have pointed to an increased risk of prematurity associated with SSRI use, and this association may be due to an increased risk of [[pre-eclampsia]] during pregnancy.<ref>{{cite journal|vauthors=Sivagnanam G|title=Antidepressants|journal=Journal of Pharmacology and Pharmacotherapeutics|year=2012|volume=3|issue=3|pages=287–288|doi=10.1177/0976500X20120302|s2cid=248110770|id={{ProQuest|1033762996}}|url=http://www.jpharmacol.com/text.asp?2012%2F3%2F3%2F287%2F99452|access-date=21 March 2013|archive-date=1 July 2018|archive-url=https://web.archive.org/web/20180701165032/http://www.jpharmacol.com/text.asp?2012%2F3%2F3%2F287%2F99452}}</ref>

===Antidepressant-induced mania===
Another possible problem with antidepressants is the chance of antidepressant-induced [[mania]] or [[hypomania]] in people with or without a diagnosis of [[bipolar disorder]]. Many cases of bipolar depression are very similar to those of unipolar depression. Therefore, the person can be misdiagnosed with unipolar depression and be given antidepressants. Studies have shown that antidepressant-induced mania can occur in 20–40% of people with bipolar disorder.<ref>{{cite journal|vauthors=Goldberg JF, Truman CJ|title=Antidepressant-induced mania: An overview of current controversies|journal=Bipolar Disorders|volume=5|issue=6|pages=407–20|year=2003|pmid=14636364|doi=10.1046/j.1399-5618.2003.00067.x}}</ref> For bipolar depression, antidepressants (most frequently SSRIs) can exacerbate or trigger symptoms of hypomania and mania.<ref name="pmid9387089">{{cite journal|author=Benazzi F|title=Antidepressant-associated hypomania in outpatient depression: a 203-case study in private practice|journal=J Affect Disord|volume=46|issue=1|pages=73–7|year=1997|pmid=9387089|doi=10.1016/S0165-0327(97)00082-7}}</ref> [[Bupropion]] has been associated with a lower risk of mood switch than other antidepressants.<ref name="pmid37119556">{{cite journal|vauthors=Barbuti M, Menculini G, Verdolini N, Pacchiarotti I, Kotzalidis GD, Tortorella A, Vieta E, Perugi G|title=A systematic review of manic/hypomanic and depressive switches in patients with bipolar disorder in naturalistic settings: The role of antidepressant and antipsychotic drugs|journal=Eur Neuropsychopharmacol|volume=73|pages=1–15|date=April 2023|pmid=37119556|doi=10.1016/j.euroneuro.2023.04.013|s2cid=258334982|hdl=2445/210406|hdl-access=free}}</ref>

===Suicide===
{{Main|Antidepressants and suicide risk}}

Studies have shown that the use of antidepressants is correlated with an increased risk of suicidal behavior and thinking (suicidality) in those aged under 25 years old.<ref name="StoneETAL" /> This problem has been serious enough to warrant government intervention by the US Food and Drug Administration (FDA) to warn of the increased risk of suicidality during antidepressant treatment.<ref name="pmid17485726">{{cite journal|vauthors=Friedman RA, Leon AC|title=Expanding the black box – depression, antidepressants, and the risk of suicide|journal=N. Engl. J. Med.|volume=356|issue=23|pages=2343–6|year=2007|pmid=17485726|doi=10.1056/NEJMp078015|doi-access=free}}</ref> According to the FDA, the heightened risk of suicidality occurs within the first one to two months of treatment.<ref>{{cite web|url=https://www.fda.gov/drugs/drugsafety/informationbydrugclass/ucm096273|title=Antidepressant Use in Children, Adolescents, and Adults|website=[[Food and Drug Administration]]|archive-url=https://web.archive.org/web/20161219143824/https://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/UCM096273|archive-date=19 December 2016}}</ref><ref>{{cite web|url=https://www.fda.gov/downloads/Drugs/DrugSafety/ucm088660.pdf%E2%80%8E|title=FDA Medication Guide for Antidepressants|website=[[Food and Drug Administration]]|access-date=5 June 2014|archive-url=https://web.archive.org/web/20140818020916/https://www.fda.gov/downloads/Drugs/DrugSafety/ucm088660.pdf%E2%80%8E|archive-date=18 August 2014}}</ref> The National Institute for Health and Care Excellence (NICE) places the excess risk in the "early stages of treatment".<ref>{{cite web|url=http://www.nice.org.uk/nicemedia/pdf/CG90NICEguideline.pdf|title=Depression in adults: recognition and management|work=Clinical guideline [CG90]|publisher=The National Institute for Health and Care Excellence (NICE)|date=28 October 2009|url-status=live|archive-url=https://web.archive.org/web/20121018055710/http://www.nice.org.uk/nicemedia/pdf/CG90NICEguideline.pdf|archive-date=18 October 2012}}</ref> A [[meta-analysis]] suggests that the relationship between antidepressant use and suicidal behavior or thoughts is age-dependent.<ref name="StoneETAL" /> Compared with placebo, the use of antidepressants is associated with an increase in suicidal behavior or thoughts among those 25 years old or younger ([[odds ratio|OR]]=1.62). A review of RCTs and epidemiological studies by Healy and Whitaker found an increase in suicidal acts by a factor of 2.4.<ref>{{cite journal|title=Antidepressants and suicide: risk-benefit conundrums|journal=Journal of Psychiatry and Neuroscience|year=2003|vauthors=Healy D, Whitaker C|volume=28|issue=5|pages=331–337|doi=10.1139/jpn.0340 |pmid=14517576|pmc=193979}}</ref> There is no effect or possibly a mild protective effect among those aged 25 to 64 (OR=0.79). Antidepressant treatment has a protective effect against suicidality among those aged 65 and over (OR=0.37).<ref name="StoneETAL">{{cite journal|vauthors=Stone M, Laughren T, Jones ML, Levenson M, Holland PC, Hughes A, Hammad TA, Temple R, Rochester G|title=Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration|journal=The BMJ|volume=339|article-number=b2880|year=2009|pmid=19671933|pmc=2725270|doi=10.1136/bmj.b2880}}</ref><ref name="dhintrev">{{cite journal|vauthors=Healy D, Aldred G|s2cid=6599566|year=2005|title=Antidepressant drug use and the risk of suicide|url=http://www.davidhealy.org.php53-23.dfw1-1.websitetestlink.com/wp-content/uploads/2012/05/2005-Healy-Aldred-Antidepressants-and-Suicide1.pdf|journal=[[International Review of Psychiatry]]|volume=17|issue=3|pages=163–172|doi=10.1080/09540260500071624|pmid=16194787|archive-url=https://web.archive.org/web/20131021043728/http://www.davidhealy.org.php53-23.dfw1-1.websitetestlink.com/wp-content/uploads/2012/05/2005-Healy-Aldred-Antidepressants-and-Suicide1.pdf|archive-date=21 October 2013}}</ref>

===Sexual dysfunction===
Sexual side effects are also common with SSRIs, such as loss of [[sexual drive]], [[anorgasmia|failure to reach orgasm]], and [[erectile dysfunction]].<ref>{{cite book|veditors=Grant JE, Potenza MN|title=The Oxford handbook of impulse control disorders|year=2012|publisher=Oxford University Press|location=Oxford|isbn=978-0-19-538971-5}}</ref> Although usually reversible, these sexual side-effects can, in rare cases, continue after the drug has been completely withdrawn.<ref name="pmid18173768">{{cite journal|vauthors=Csoka AB, Csoka A, Bahrick A, Mehtonen OP|title=Persistent sexual dysfunction after discontinuation of selective serotonin reuptake inhibitors|journal=The Journal of Sexual Medicine|volume=5|issue=1|pages=227–233|date=January 2008|pmid=18173768|doi=10.1111/j.1743-6109.2007.00630.x|s2cid=15471717}}</ref><ref>{{cite journal|vauthors=Healy D, Le Noury J, Mangin D|title=Enduring sexual dysfunction after treatment with antidepressants, 5α-reductase inhibitors and isotretinoin: 300 cases|journal=The International Journal of Risk & Safety in Medicine|volume=29|issue=3–4|pages=125–134|date=4 June 2018|pmid=29733030|pmc=6004900|doi=10.3233/JRS-180744}}</ref>

In a study of 1,022 outpatients, overall sexual dysfunction with all antidepressants averaged 59.1%<ref name="pmid11229449">{{cite journal|vauthors=Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F|title=Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction|journal=The Journal of Clinical Psychiatry|volume=62|issue=Suppl 3|pages=10–21|year=2001|pmid=11229449}}</ref> with SSRI values between 57% and 73%, mirtazapine 24%, nefazodone 8%, amineptine 7%, and [[moclobemide]] 4%. Moclobemide, a selective reversible MAO-A inhibitor, does not cause sexual dysfunction<ref name="pmid19440080">{{cite journal|vauthors=Serretti A, Chiesa A|title=Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis|journal=Journal of Clinical Psychopharmacology|volume=29|issue=3|pages=259–266|date=June 2009|pmid=19440080|doi=10.1097/JCP.0b013e3181a5233f|s2cid=1663570}}</ref> and can lead to an improvement in all aspects of sexual function.<ref name="pmid9696909">{{cite journal|vauthors=Chebili S, Abaoub A, Mezouane B, Le Goff JF|title=[Antidepressants and sexual stimulation: the correlation]|language=fr|journal=L'Encephale|volume=24|issue=3|pages=180–184|year=1998|pmid=9696909}}</ref>

Biochemical mechanisms suggested as causative include increased serotonin, particularly affecting [[5-HT2 receptor|5-HT<sub>2</sub>]] and [[5HT3 receptor|5-HT<sub>3</sub> receptors]]; decreased [[dopamine]]; decreased [[norepinephrine]]; blockade of [[cholinergic receptor|cholinergic]] and [[alpha-1 adrenergic receptor|α<sub>1</sub>adrenergic receptors]]; inhibition of [[nitric oxide synthase|nitric oxide synthetase]]; and elevation of [[prolactin]] levels.<ref>{{cite journal|vauthors=Keltner NL, McAfee KM, Taylor CL|title=Biological Perspectives|journal=Perspectives in Psychiatric Care|volume=38|issue=3|pages=111–6|year=2009|pmid=12385082|doi=10.1111/j.1744-6163.2002.tb00665.x|doi-access=free}}</ref> [[Mirtazapine]] is reported to have fewer sexual side effects, most likely because it antagonizes 5-HT<sub>2</sub> and 5-HT<sub>3</sub> receptors and may, in some cases, reverse sexual dysfunction induced by SSRIs by the same mechanism.<ref name="pmid18278806">{{cite journal|vauthors=Ozmenler NK, Karlidere T, Bozkurt A, Yetkin S, Doruk A, Sutcigil L, Cansever A, Uzun O, Ozgen F, Ozsahin A|s2cid=39616771|title=Mirtazapine augmentation in depressed patients with sexual dysfunction due to selective serotonin reuptake inhibitors|journal=Hum Psychopharmacol|volume=23|issue=4|pages=321–6|year=2008|pmid=18278806|doi=10.1002/hup.929}}</ref>

[[Bupropion]], a weak NDRI and nicotinic antagonist, may be useful in treating reduced libido as a result of [[SSRI]] treatment.<ref name="Schwasinger-Schmidt2018">{{cite book|vauthors=Schwasinger-Schmidt TE, Macaluso M|title=Antidepressants|chapter=Other Antidepressants|series=Handbook of Experimental Pharmacology|volume=250|pages=325–355|date=8 September 2018|pmid=30194544|doi=10.1007/164_2018_167|isbn=978-3-030-10948-6}}</ref>

===Emotional blunting===
Certain antidepressants may cause [[emotional blunting]], characterized by a reduced intensity of both positive and negative emotions as well as symptoms of [[apathy]], [[psychological indifference|indifference]], and [[amotivational syndrome|amotivation]].<ref name="pmid34908941">{{cite journal|vauthors=Marazziti D, Mucci F, Tripodi B, Carbone MG, Muscarella A, Falaschi V, Baroni S|title=Emotional Blunting, Cognitive Impairment, Bone Fractures, and Bleeding as Possible Side Effects of Long-Term Use of SSRIs|journal=Clin Neuropsychiatry|volume=16|issue=2|pages=75–85|date=April 2019|pmid=34908941|pmc=8650205}}</ref><ref name="pmid34970173">{{cite journal|vauthors=Ma H, Cai M, Wang H|title=Emotional Blunting in Patients With Major Depressive Disorder: A Brief Non-systematic Review of Current Research|journal=Front Psychiatry|volume=12|article-number=792960|date=2021|pmid=34970173|pmc=8712545|doi=10.3389/fpsyt.2021.792960|doi-access=free}}</ref><ref name="pmid15330228">{{cite journal|vauthors=Barnhart WJ, Makela EH, Latocha MJ|title=SSRI-induced apathy syndrome: a clinical review|journal=J Psychiatr Pract|volume=10|issue=3|pages=196–9|date=May 2004|pmid=15330228|doi=10.1097/00131746-200405000-00010|s2cid=26935586}}</ref><ref name="pmid21103140">{{cite journal|vauthors=Sansone RA, Sansone LA|title=SSRI-Induced Indifference|journal=Psychiatry (Edgmont)|volume=7|issue=10|pages=14–8|date=October 2010|pmid=21103140|pmc=2989833}}</ref><ref name="pmid19721109">{{cite journal|vauthors=Price J, Cole V, Goodwin GM|title=Emotional side-effects of selective serotonin reuptake inhibitors: qualitative study|journal=Br J Psychiatry|volume=195|issue=3|pages=211–7|date=September 2009|pmid=19721109|doi=10.1192/bjp.bp.108.051110|doi-access=free}}</ref><ref name="pmid28628765">{{cite journal|vauthors=Goodwin GM, Price J, De Bodinat C, Laredo J|title=Emotional blunting with antidepressant treatments: A survey among depressed patients|journal=J Affect Disord|volume=221|pages=31–35|date=October 2017|pmid=28628765|doi=10.1016/j.jad.2017.05.048|s2cid=3755520|url=https://ora.ox.ac.uk/objects/uuid:8a7067a3-7b21-481f-ac80-32f1929d3ff7}}</ref><ref name="pmid29866014">{{cite journal|vauthors=Read J, Williams J|title=Adverse Effects of Antidepressants Reported by a Large International Cohort: Emotional Blunting, Suicidality, and Withdrawal Effects|journal=Curr Drug Saf|volume=13|issue=3|pages=176–186|date=2018|pmid=29866014|doi=10.2174/1574886313666180605095130|s2cid=46934452|url=http://roar.uel.ac.uk/7564/1/7564.pdf}}</ref><ref name="pmid35346413">{{cite journal|vauthors=Camino S, Strejilevich SA, Godoy A, Smith J, Szmulewicz A|title=Are all antidepressants the same? The consumer has a point|journal=Psychol Med|volume=53|issue=9|pages=4004–4011|date=March 2022|pmid=35346413|doi=10.1017/S0033291722000678|s2cid=247777403}}</ref><ref name="pmid11436958">{{cite journal|vauthors=Garland EJ, Baerg EA|title=Amotivational syndrome associated with selective serotonin reuptake inhibitors in children and adolescents|journal=J Child Adolesc Psychopharmacol|volume=11|issue=2|pages=181–6|date=2001|pmid=11436958|doi=10.1089/104454601750284090}}</ref> It may be experienced as either beneficial or detrimental depending on the situation.<ref name="pmid26407780">{{cite journal|vauthors=Moncrieff J|title=Antidepressants: misnamed and misrepresented|journal=World Psychiatry|volume=14|issue=3|pages=302–3|date=October 2015|pmid=26407780|pmc=4592647|doi=10.1002/wps.20243}}</ref> This side effect has been particularly associated with serotonergic antidepressants like SSRIs and SNRIs but may be less with atypical antidepressants like bupropion, [[agomelatine]], and [[vortioxetine]].<ref name="pmid34970173" /><ref name="pmid35346413" /><ref name="pmid23823799">{{cite journal|vauthors=Corruble E, de Bodinat C, Belaïdi C, Goodwin GM|title=Efficacy of Aomelatine and Escitalopram on depression, subjective sleep and emotional experiences in patients with major depressive disorder: a 24-wk randomized, controlled, double-blind trial|journal=Int J Neuropsychopharmacol|volume=16|issue=10|pages=2219–34|date=November 2013|pmid=23823799|doi=10.1017/S1461145713000679|doi-access=free}}</ref><ref name="pmid33516560">{{cite journal|vauthors=Fagiolini A, Florea I, Loft H, Christensen MC|title=Effectiveness of Vortioxetine on Emotional Blunting in Patients with Major Depressive Disorder with inadequate response to SSRI/SNRI treatment|journal=J Affect Disord|volume=283|pages=472–479|date=March 2021|pmid=33516560|doi=10.1016/j.jad.2020.11.106|s2cid=228877905|doi-access=free|hdl=11365/1137950|hdl-access=free}}</ref> Higher doses of antidepressants seem to be more likely to produce emotional blunting than lower doses.<ref name="pmid34970173" /> Emotional blunting can be decreased by reducing dosage, discontinuing the medication, or switching to a different antidepressant that may have less propensity for causing this side effect.<ref name="pmid34970173" />

===Changes in weight===
Changes in appetite or weight are common among antidepressants but are largely drug-dependent and related to which neurotransmitters they affect. Mirtazapine and [[paroxetine]], for example, may be associated with weight gain and/or increased appetite,<ref name="Stimmel">{{cite journal|vauthors=Stimmel GL, Dopheide JA, Stahl SM|title=Mirtazapine: An antidepressant with noradrenergic and specific serotonergic effects|journal=Pharmacotherapy|volume=17|issue=1|pages=10–21|year=1997|pmid=9017762|doi=10.1002/j.1875-9114.1997.tb03674.x|s2cid=2454536|url=https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1002/j.1875-9114.1997.tb03674.x|access-date=17 January 2020|archive-date=25 May 2021|archive-url=https://web.archive.org/web/20210525180455/https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1002/j.1875-9114.1997.tb03674.x|url-access=subscription}}</ref><ref>{{cite web|title=mirtazapine (Rx) – Remeron, Remeron SolTab|website=Medscape|publisher=WebMD|access-date=19 November 2013|url=http://reference.medscape.com/drug/remeron-soltab-mirtazapine-342966|archive-url=https://web.archive.org/web/20131029200106/http://reference.medscape.com/drug/remeron-soltab-mirtazapine-342966|archive-date=29 October 2013}}</ref><ref name="autogenerated1032">{{cite journal|author=Papakostas GI|title=Tolerability of modern antidepressants|journal=J Clin Psychiatry|volume=69|issue=Suppl E1|pages=8–13|year=2008|pmid=18494538}}</ref> while others (such as bupropion and [[venlafaxine]]) achieve the opposite effect.<ref name="Bupropion weight">{{cite journal|vauthors=Li Z, Maglione M, Tu W, Mojica W, Arterburn D, Shugarman LR, Hilton L, Suttorp M, Solomon V, Shekelle PG, Morton SC|s2cid=6964051|title=Meta-analysis: pharmacologic treatment of obesity|journal=Ann. Intern. Med.|volume=142|issue=7|pages=532–46|date=April 2005|pmid=15809465|doi=10.7326/0003-4819-142-7-200504050-00012|doi-access=free}}</ref><ref>{{cite web|year=2006|title=Effexor Medicines Data Sheet|publisher=Wyeth Pharmaceuticals Inc|url=http://www.wyeth.com/content/showlabeling.asp?id=99|access-date=17 September 2006|archive-url=https://web.archive.org/web/20060917025654/http://www.wyeth.com/content/ShowLabeling.asp?id=99|archive-date=17 September 2006}}</ref>

The [[antihistamine|antihistaminic]] properties of certain TCA- and TeCA-class antidepressants have been shown to contribute to the common side effects of increased appetite and weight gain associated with these classes of medication.

=== Bone loss ===
A 2021 nationwide [[cohort study]] in South Korea observed a link between SSRI use and bone loss, particularly in recent users. The study also stressed the need of further research to better understand these effects.<ref>{{cite journal|vauthors=Kang S, Han M, Park CI, Jung I, Kim EH, Boo YJ, Kang JI, Kim SJ|title=Use of serotonin reuptake inhibitors and risk of subsequent bone loss in a nationwide population-based cohort study|journal=Scientific Reports|volume=11|issue=1|article-number=13461|date=June 2021|pmid=34188108|pmc=8241982|doi=10.1038/s41598-021-92821-9|bibcode=2021NatSR..1113461K}}</ref> A 2012 review found that SSRIs along with tricyclic antidepressants were associated with a significant increase in the risk of osteoporotic fractures, peaking in the months after initiation, and moving back towards baseline during the year after treatment was stopped. These effects exhibited a [[dose–response relationship]] within SSRIs which varied between different drugs of that class.<ref>{{cite journal|vauthors=Rizzoli R, Cooper C, Reginster JY, Abrahamsen B, Adachi JD, Brandi ML, Bruyère O, Compston J, Ducy P, Ferrari S, Harvey NC, Kanis JA, Karsenty G, Laslop A, Rabenda V, Vestergaard P|title=Antidepressant medications and osteoporosis|journal=Bone|volume=51|issue=3|pages=606–613|date=September 2012|pmid=22659406|doi=10.1016/j.bone.2012.05.018}}</ref> A 2018 meta-analysis of 11 small studies found a reduction in bone density of the lumbar spine in SSRI users which affected older people the most.<ref>{{cite journal|vauthors=Zhou C, Fang L, Chen Y, Zhong J, Wang H, Xie P|title=Effect of selective serotonin reuptake inhibitors on bone mineral density: a systematic review and meta-analysis|journal=Osteoporosis International|volume=29|issue=6|pages=1243–1251|date=June 2018|pmid=29435621|doi=10.1007/s00198-018-4413-0|s2cid=23313396}}</ref>

===Risk of death===
A 2017 [[meta-analysis]] found that antidepressants were associated with a significantly increased [[mortality rate|risk of death]] (+33%) and new [[cardiovascular complication]]s (+14%) in the general population.<ref name="pmid28903117">{{cite journal|vauthors=Maslej MM, Bolker BM, Russell MJ, Eaton K, Durisko Z, Hollon SD, Swanson GM, Thomson JA, Mulsant BH, Andrews PW|title=The Mortality and Myocardial Effects of Antidepressants Are Moderated by Preexisting Cardiovascular Disease: A Meta-Analysis|journal=Psychother Psychosom|volume=86|issue=5|pages=268–282|date=2017|pmid=28903117|doi=10.1159/000477940|s2cid=4830115}}</ref> Conversely, risks were not greater in people with existing [[cardiovascular disease]].<ref name="pmid28903117" />

===Discontinuation syndrome===
{{Main|Antidepressant discontinuation syndrome}}

Antidepressant discontinuation syndrome, also called antidepressant withdrawal syndrome, is a condition that can occur following the interruption, reduction, or [[Medication discontinuation|discontinuation]] of antidepressant medication.<ref name=War2006/> The symptoms may include [[flu-like symptoms]], trouble sleeping, nausea, poor balance, sensory changes, and [[anxiety]].<ref name=War2006/><ref name=Gab2017/><ref name="Dav2018">{{cite journal|vauthors=Davies J, Read J|title=A systematic review into the incidence, severity and duration of antidepressant withdrawal effects: Are guidelines evidence-based?|journal=Addictive Behaviors|volume=97|pages=111–121|date=October 2019|pmid=30292574|doi=10.1016/j.addbeh.2018.08.027|doi-access=free}}</ref> The problem usually begins within three days and may last for several months.<ref name=War2006/><ref name=Dav2018/> Rarely [[psychosis]] may occur.<ref name=War2006/>

<!-- Risk factors and diagnosis -->
A discontinuation syndrome can occur after stopping any antidepressant including [[selective serotonin reuptake inhibitor]]s (SSRIs), [[serotonin–norepinephrine reuptake inhibitor]]s (SNRIs), and [[tricyclic antidepressants]] (TCAs).<ref name=War2006/><ref name=Gab2017/> The risk is greater among those who have taken the medication for longer and when the medication in question has a short [[half-life]].<ref name=War2006/> The underlying reason for its occurrence is unclear.<ref name=War2006/> The diagnosis is based on the symptoms.<ref name=War2006/>

<!-- Prevention and treatment -->
Methods of prevention include gradually decreasing the dose among those who wish to stop, though it is possible for symptoms to occur with tapering.<ref name=War2006/><ref name=Wil2015/><ref name=Dav2018 /> Treatment may include restarting the medication and slowly decreasing the dose.<ref name=War2006/> People may also be switched to the long-acting antidepressant [[fluoxetine]], which can then be gradually decreased.<ref name=Wil2015/>

<!-- Epidemiology and prognosis -->
Approximately 20–50% of people who suddenly stop an antidepressant develop an antidepressant discontinuation syndrome.<ref name="War2006">{{cite journal|vauthors=Warner CH, Bobo W, Warner C, Reid S, Rachal J|title=Antidepressant discontinuation syndrome|journal=American Family Physician|volume=74|issue=3|pages=449–456|date=August 2006|pmid=16913164}}</ref><ref name=Gab2017/><ref name=Dav2018 /> The condition is generally not serious,<ref name=War2006/> though about half of people with symptoms describe them as severe.<ref name=Dav2018/> Some restart antidepressants due to the severity of the symptoms.<ref name=Dav2018/>

==Pharmacology==
{{Main|Pharmacology of antidepressants}}

Antidepressants act via a large number of different [[mechanism of action|mechanisms of action]].<ref name="Fasipe2018">{{cite journal|vauthors=Fasipe O|title=Neuropharmacological classification of antidepressant agents based on their mechanisms of action|journal=Archives of Medicine and Health Sciences|date=2018|volume=6|issue=1|page=81|issn=2321-4848|doi=10.4103/amhs.amhs_7_18|s2cid=81878024|doi-access=free}}</ref><ref name="pmid35714379">{{cite journal|vauthors=Naguy A, Alamiri B|title=Antidepressants-A Misnomer? Clinical Impressionism or Scientific Empiricism?|journal=Prim Care Companion CNS Disord|volume=24|issue=3|date=June 2022|pmid=35714379|doi=10.4088/PCC.21br03084|s2cid=249652271}}</ref><ref name="Stahl2020">{{cite book|vauthors=Stahl SM|date=19 November 2020|title=Prescriber's Guide: Stahl's Essential Psychopharmacology|publisher=Cambridge University Press|isbn=978-1-108-92602-7|url=https://books.google.com/books?id=eyFGEAAAQBAJ}}</ref> This includes [[serotonin reuptake inhibition]] (SSRIs, SNRIs, TCAs, vilazodone, vortioxetine), [[norepinephrine reuptake inhibition]] (NRIs, SNRIs, TCAs), [[dopamine reuptake inhibition]] (bupropion, amineptine, nomifensine), direct [[receptor modulation|modulation]] of [[monoamine receptor]]s (vilazodone, vortioxetine, SARIs, agomelatine, TCAs, TeCAs, antipsychotics), [[monoamine oxidase inhibition]] (MAOIs), and [[NMDA receptor antagonism]] (ketamine, esketamine, dextromethorphan), among others (e.g., brexanolone, tianeptine).<ref name="Fasipe2018" /><ref name="pmid35714379" /><ref name="Stahl2020" /> Some antidepressants also have additional actions, like [[sigma receptor]] modulation (certain SSRIs, TCAs, dextromethorphan) and [[receptor antagonism|antagonism]] of [[histamine]] [[H1 receptor|H<sub>1</sub>]] and [[muscarinic acetylcholine receptor]]s (TCAs, TeCAs).<ref name="BolandKeller2008">{{cite book|title=Psychiatry|vauthors=Boland RJ, Keller MB|chapter=Antidepressants|date=8 August 2008|pages=2123–2160|publisher=John Wiley & Sons, Ltd|doi=10.1002/9780470515167.ch101|isbn=978-0-470-51516-7}}</ref><ref name="Stahl2020" />

{| class="wikitable" style="font-size:small;"
|+ Mechanisms of action of major antidepressant classes<ref name="Fasipe2018" /><ref name="ParkShen2023">{{cite book|last1=Park|first1=Seon-Cheol|last2=Shen|first2=Winston Wu-Dien|title=Tasman's Psychiatry|chapter=Medication for Depression: Monoamine Enhancers and Esketamine (Antidepressants)|publisher=Springer International Publishing|publication-place=Cham|year=2023|isbn=978-3-030-42825-9|doi=10.1007/978-3-030-42825-9_133-1|pages=1–53}}</ref>
|-
! Class !! Action(s) !! Examples !! Introduced
|-
| [[Opioid]]s (mostly no longer used)<ref name="SaxenaBodkin2019">{{cite journal|vauthors=Saxena PP, Bodkin JA|title=Opioidergic Agents as Antidepressants: Rationale and Promise|journal=CNS Drugs|volume=33|issue=1|pages=9–16|date=January 2019|pmid=30430396|doi=10.1007/s40263-018-0584-7}}</ref><ref name="NishioLindsleyBender2024">{{cite journal|vauthors=Nishio Y, Lindsley CW, Bender AM|title=Classics in Chemical Neuroscience: Tianeptine|journal=ACS Chem Neurosci|date=October 2024|volume=15 |issue=21 |pages=3863–3873 |pmid=39382192|doi=10.1021/acschemneuro.4c00519|doi-access=free|pmc=11587517}}</ref> || [[μ-Opioid receptor]] [[agonist|agonism]] || [[Codeine]] • [[Heroin]] • [[Morphine]] • [[Opium]] • [[Tianeptine]] (1983) || 1800s
|-
| [[Amphetamine-type stimulant|Amphetamine psychostimulant]]s (mostly no longer used)<ref name="Rasmussen2006" /><ref name="Ciccarone2011">{{cite journal|vauthors=Ciccarone D|title=Stimulant abuse: pharmacology, cocaine, methamphetamine, treatment, attempts at pharmacotherapy|journal=Prim Care|volume=38|issue=1|pages=41–58|date=March 2011|pmid=21356420|pmc=3056348|doi=10.1016/j.pop.2010.11.004|quote=In 1919, Japanese chemist Akira Ogata, as part of his effort to prove the structure of ephedrine, reported the synthesis of the closely related compound we now call methamphetamine, and this result was described in the Western literature (Amatsu & Kubota, 1913; Lee, 2011; Ogata, 1920). [...] As a result, when competitors began to consider emulating SKF's success in the late 1930s, they turned to methamphetamine, which had nearly indistinguishable effects but—because its synthesis together with its pharmacological characteristics was published before 1920—was free from patent encumbrance. [...] In any event, by 1940 Benzedrine Sulfate had achieved medical acclaim and quickly growing sales as an antidepressant effective for milder forms of the condition, both in the United States and the United Kingdom. In Germany, the Temmler drug firm quickly copied SKF, marketing methamphetamine (again, unprotected by patents) tablets under the Pervitin brand, with claims that it restored "joy in work" in cases of mild depression around 1938 (Rasmussen, 2006; Steinkamp, 2006).}}</ref><ref name="Rasmussen2015">{{cite journal|vauthors=Rasmussen N|title=Amphetamine-Type Stimulants: The Early History of Their Medical and Non-Medical Uses|journal=Int Rev Neurobiol|volume=120|pages=9–25|date=2015|pmid=26070751|doi=10.1016/bs.irn.2015.02.001|hdl=1959.4/unsworks_47518|hdl-access=free}}</ref><ref name="HealSmithGosden2013">{{cite journal|vauthors=Heal DJ, Smith SL, Gosden J, Nutt DJ|title=Amphetamine, past and present--a pharmacological and clinical perspective|journal=J Psychopharmacol|volume=27|issue=6|pages=479–496|date=June 2013|pmid=23539642|pmc=3666194|doi=10.1177/0269881113482532}}</ref> || [[Norepinephrine releasing agent|Norepinephrine release induction]] • [[Dopamine releasing agent|Dopamine release induction]] || [[Amphetamine]] • [[Dextroamphetamine]] • [[Methamphetamine]] || 1930s
|-
| [[Monoamine oxidase inhibitor]]s (MAOIs) || [[Monoamine oxidase]] [[enzyme inhibitor|inhibition]] • Other actions in some cases || [[Iproniazid]] • [[Isocarboxazid]] • [[Isoniazid]] • [[Moclobemide]] (1989) • [[Nialamide]] • [[Phenelzine]] • [[Selegiline]] (1977/2006) • [[Tranylcypromine]] || 1950s
|-
| [[Tricyclic antidepressant]]s (TCAs) || [[Serotonin reuptake inhibitor|Serotonin reuptake inhibition]] • [[Norepinephrine reuptake inhibitor|Norepinephrine reuptake inhibition]] • [[Serotonin receptor antagonist|Serotonin receptor antagonism]] • [[Adrenergic receptor antagonist|Adrenergic receptor antagonism]] • [[H1 antagonist|Histamine H<sub>1</sub> receptor antagonism]] • [[Muscarinic antagonist|Muscarinic acetylcholine receptor antagonism]] • Other actions || [[Amitriptyline]] • [[Butriptyline]] • [[Clomipramine]] • [[Desipramine]] • [[Dosulepin|Dosulepin (dothiepin)]] • [[Doxepin]] • [[Imipramine]] • [[Iprindole]] • [[Lofepramine]] • [[Nortriptyline]] • [[Protriptyline]] • [[Trimipramine]] || 1950s
|-
| [[Tetracyclic antidepressant]]s (TeCAs) || [[Serotonin reuptake inhibitor|Serotonin reuptake inhibition]] • [[Norepinephrine reuptake inhibitor|Norepinephrine reuptake inhibition]] • [[Serotonin receptor antagonist|Serotonin receptor antagonism]] • [[Adrenergic receptor antagonist|Adrenergic receptor antagonism]] • [[H1 antagonist|Histamine H<sub>1</sub> receptor antagonism]] • [[Muscarinic antagonist|Muscarinic acetylcholine receptor antagonism]] • Other actions || [[Amoxapine]] • [[Maprotiline]] • [[Mianserin]] • [[Mirtazapine]] • [[Setiptiline]] || 1970s
|-
| [[Norepinephrine reuptake inhibitor]]s (NRIs) || [[Norepinephrine reuptake inhibitor|Norepinephrine reuptake inhibition]] || [[Atomoxetine]] (off-label) • [[Teniloxazine]] • [[Reboxetine]] • [[Viloxazine]] || 1970s
|-
| [[Norepinephrine–dopamine reuptake inhibitor]]s (NDRIs) || [[Norepinephrine reuptake inhibitor|Norepinephrine reuptake inhibition]] • [[Dopamine reuptake inhibitor|Dopamine reuptake inhibition]] || [[Amineptine]] • [[Bupropion]] • [[Methylphenidate]] (off-label) • [[Nomifensine]] || 1970s
|-
| [[Serotonin antagonists and reuptake inhibitors]] (SARIs) || [[Serotonin receptor antagonist|Serotonin receptor antagonism]] • [[Adrenergic receptor antagonist|Adrenergic receptor antagonism]] • Weak [[monoamine reuptake inhibitor|monoamine reuptake inhibition]] • Other actions || [[Etoperidone]] • [[Nefazodone]] • [[Trazodone]] || 1980s
|-
| [[Selective serotonin reuptake inhibitor]]s (SSRIs) || [[Serotonin reuptake inhibitor|Serotonin reuptake inhibition]] || [[Citalopram]] • [[Escitalopram]] • [[Fluoxetine]] • [[Fluvoxamine]] • [[Indalpine]] • [[Paroxetine]] • [[Sertraline]] • [[Zimelidine]] || 1980s
|-
| [[Serotonin]] [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]] [[agonist]]s ([[azapirone]]s) || [[Serotonin]] [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]] [[partial agonist|partial agonism]] • Other actions || [[Buspirone]] (off-label) • [[Gepirone]] • [[Tandospirone]] || 1980s
|-
| [[Serotonin–norepinephrine reuptake inhibitor]]s (SNRIs) || [[Serotonin reuptake inhibitor|Serotonin reuptake inhibition]] • [[Norepinephrine reuptake inhibitor|Norepinephrine reuptake inhibition]] || [[Desvenlafaxine]] • [[Duloxetine]] • [[Levomilnacipran]] • [[Milnacipran]] (off-label) • [[Venlafaxine]] || 1990s
|-
| [[Serotonin modulators and stimulators]] (SMSs) || [[Serotonin reuptake inhibitor|Serotonin reuptake inhibition]] • [[Serotonin receptor]] [[receptor modulator|modulation]] || [[Vilazodone]] • [[Vortioxetine]] || 2000s
|-
| [[Atypical antipsychotic]]s || [[Serotonin receptor]] [[receptor modulation|modulation]] • [[Dopamine receptor]] [[receptor modulator|modulation]] • Other actions || [[Amisulpride]] • [[Aripiprazole]] • [[Brexpiprazole]] • [[Lumateperone]] • [[Lurasidone]] • [[Olanzapine]] • [[Quetiapine]] • [[Risperidone]] (off-label) • [[Sulpiride]] || 2000s
|-
| [[NMDA receptor antagonist]]s || [[NMDA receptor antagonism]] • Possibly other actions || [[Dextromethorphan/bupropion]] • [[Esketamine]] • [[Ketamine]] (off-label) || 2010s
|-
| [[Neurosteroid]]-type [[GABAA receptor positive allosteric modulator|GABA<sub>A</sub> receptor positive allosteric modulator]]s || [[GABAA receptor positive allosteric modulator|GABA<sub>A</sub> receptor positive allosteric modulation]] || [[Brexanolone]] • [[Zuranolone]] || 2010s
|-
| [[Serotonin–norepinephrine–dopamine reuptake inhibitor]]s || [[Serotonin reuptake inhibitor|Serotonin reuptake inhibition]] • [[Norepinephrine reuptake inhibitor|Norepinephrine reuptake inhibition]] • [[Dopamine reuptake inhibitor|Dopamine reuptake inhibition]] || [[Toludesvenlafaxine]] || 2020s
|-
| [[Atypical antidepressant|Other agent]]s || Various/mixed actions || [[α-Methyltryptamine]] • [[Ademetionine|Ademetionine (SAMe)]] • [[Agomelatine]] • [[D-Phenylalanine|<small>D</small>-Phenylalanine]] • [[Etryptamine]] • [[Hypericum perforatum|''Hypericum perforatum'' (St John's wort)]] [[Indeloxazine]] • [[Lithium (medication)|Lithium]] (off-label) • [[Medifoxamine]] • [[Opipramol]] • [[Oxaflozane]] • [[Oxitriptan|Oxitriptan (5-HTP)]] • [[Pivagabine]] • [[Thyroid hormone]] (off-label) • [[Tiazesim]] • [[Tofenacin]] • [[Tryptophan]] || Various
|- class="sortbottom"
| colspan="4" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' (1) Opioids and amphetamines largely ceased being used by the 1950s with the introduction of modern antidepressants. (2) Some antidepressants can also have alternative classifications, such as [[mirtazapine]] being a "[[noradrenergic and specific serotonergic antidepressant]]" (NaSSA) or [[moclobemide]] being a "[[reversible inhibitor of monoamine oxidase A]]" (RIMA). (3) See [[list of antidepressants]] for a complete list of approved/marketed antidepressants. (4) See [[list of investigational antidepressants]] for an extensive list of modern investigational antidepressants (including discontinued agents).
|}

The earliest and most widely known [[scientific theory]] of antidepressant action is the [[monoamine hypothesis]], which can be traced back to the 1950s and 1960s.<ref name="GG">{{cite book|veditors=Brunton LL, Chabner B, Knollmann BC|title=Goodman and Gilman's The Pharmacological Basis of Therapeutics|year=2011|publisher=McGraw-Hill Professional|isbn=978-0-07-162442-8|edition=12th|location=New York|title-link=Goodman and Gilman's The Pharmacological Basis of Therapeutics}}{{update inline|date=January 2018}}</ref><ref name="pmid12953623">{{cite journal|vauthors=Baumeister AA, Hawkins MF, Uzelac SM|title=The myth of reserpine-induced depression: role in the historical development of the monoamine hypothesis|journal=J Hist Neurosci|volume=12|issue=2|pages=207–20|date=June 2003|pmid=12953623|doi=10.1076/jhin.12.2.207.15535|s2cid=42407412}}</ref> This theory states that depression is due to an imbalance, most often a deficiency, of the [[monoamine neurotransmitter]]s, namely [[serotonin]], [[norepinephrine]], and/or [[dopamine]].<ref name="GG" /><ref name="pmid12953623" /> However, serotonin in particular has been implicated, as in the serotonin hypothesis of depression.<ref name="pmid35854107" /> The monoamine hypothesis was originally proposed based on observations that [[reserpine]], a drug which depletes the monoamine neurotransmitters, produced depressive effects in people,<ref name="pmid12953623" /> and that certain [[hydrazine]] [[antituberculosis agent]]s like [[iproniazid]], which [[monoamine oxidase inhibitor|prevent the breakdown of monoamine neurotransmitters]], produced apparent antidepressant effects.<ref name=GG /> Most currently marketed antidepressants, which are [[monoaminergic]] in their actions, are theoretically consistent with the monoamine hypothesis.<ref name=GG /> Despite the widespread nature of the monoamine hypothesis, it has a number of limitations: for one, all monoaminergic antidepressants have a delayed onset of action of at least a week; and secondly, many people with depression do not respond to monoaminergic antidepressants.<ref name="Infl">{{cite journal|vauthors=Maes M, Yirmyia R, Noraberg J, Brene S, Hibbeln J, Perini G, Kubera M, Bob P, Lerer B, Maj M|s2cid=4564675|title=The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression|journal=Metabolic Brain Disease|volume=24|issue=1|pages=27–53|date=March 2009|pmid=19085093|doi=10.1007/s11011-008-9118-1|hdl=11577/2380064|hdl-access=free}}</ref><ref name="glut">{{cite journal|author-link1=Gerard Sanacora|vauthors=Sanacora G, Treccani G, Popoli M|title=Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders|journal=Neuropharmacology|volume=62|issue=1|pages=63–77|date=January 2012|pmid=21827775|doi=10.1016/j.neuropharm.2011.07.036|pmc=3205453}}</ref> A number of alternative hypotheses have been proposed, including hypotheses involving [[glutamate]], [[neurogenesis]], [[epigenetics]], [[cortisol]] [[hypersecretion]], and [[inflammation]], among others.<ref name=Infl /><ref name=glut /><ref name="Epig">{{cite journal|vauthors=Menke A, Klengel T, Binder EB|title=Epigenetics, depression and antidepressant treatment|journal=Current Pharmaceutical Design|volume=18|issue=36|pages=5879–5889|year=2012|pmid=22681167|doi=10.2174/138161212803523590}}</ref><ref name="Epig2">{{cite journal|vauthors=Vialou V, Feng J, Robison AJ, Nestler EJ|title=Epigenetic mechanisms of depression and antidepressant action|journal=Annual Review of Pharmacology and Toxicology|volume=53|issue=1|pages=59–87|date=January 2013|pmid=23020296|doi=10.1146/annurev-pharmtox-010611-134540|pmc=3711377}}</ref>

In 2022, a major systematic [[umbrella review]] by [[Joanna Moncrieff]] and colleagues showed that the serotonin theory of depression was not supported by evidence from a wide variety of areas.<ref name="pmid35854107">{{cite journal|vauthors=Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA|title=The serotonin theory of depression: a systematic umbrella review of the evidence|journal=Mol Psychiatry|volume=28|issue=8|pages=3243–3256|date=July 2022|pmid=35854107|doi=10.1038/s41380-022-01661-0|pmc=10618090|s2cid=250646781|doi-access=free}}</ref> The authors concluded that there is no association between serotonin and depression, and that there is no evidence that strongly supports the theory that depression is caused by low serotonin activity or concentrations.<ref name="pmid35854107" /> Other literature had described the lack of support for the theory previously.<ref name="pmid16268734">{{cite journal|vauthors=Lacasse JR, Leo J|title=Serotonin and depression: a disconnect between the advertisements and the scientific literature|journal=PLOS Med|volume=2|issue=12|article-number=e392|date=December 2005|pmid=16268734|pmc=1277931|doi=10.1371/journal.pmed.0020392|doi-access=free}}</ref><ref name="LacasseLeo2015">{{cite journal|vauthors=Lacasse JR, Leo J|title=Antidepressants and the Chemical Imbalance Theory of Depression: A Reflection and Update on the Discourse|journal=The Behavior Therapist|volume=38|issue=7|pages=206–213|date=October 2015|url=http://purl.flvc.org/fsu/fd/FSU_migr_csw_faculty_publications-0084}}</ref><ref name="AngHorowitzMoncrieff2022" /> In many of the expert responses to the review, it was stated that the monoamine hypothesis had already long been abandoned by psychiatry.<ref name="ScienceMediaCentre2022">{{cite web|vauthors=Knudsen GM, Bloomfield M, Nutt D, Cowen P, de Picker L, Young A, Curtis D, ((Royal College of Psychiatrists))|title=Expert reaction to a review paper on the 'Serotonin Theory of Depression'|publisher=Science Media Centre|url=https://www.sciencemediacentre.org/expert-reaction-to-a-review-paper-on-the-serotonin-theory-of-depression/|access-date=28 August 2022}}</ref><ref name="MadInAmerica2022">{{cite web|vauthors=Moncrieff J, Horowitz M|date=28 July 2022|title=Response to Criticism of Our Serotonin Paper|website=Mad in America|url=https://www.madinamerica.com/2022/07/response-criticism-serotonin-paper/|access-date=28 August 2022}}</ref> This is in spite of about 90% of the general public in Western countries believing the theory to be true and many in the field of psychiatry continuing to promote the theory up to recent times.<ref name="MadInAmerica2022" /><ref name="AngHorowitzMoncrieff2022" /> In addition to the serotonin umbrella review, reviews have found that [[reserpine]], a drug that depletes the monoamine neurotransmitters—including serotonin, norepinephrine, and dopamine—shows no consistent evidence of producing depressive effects.<ref name="pmid12953623" /><ref name="pmid36000248">{{cite journal|vauthors=Strawbridge R, Javed RR, Cave J, Jauhar S, Young AH|title=The effects of reserpine on depression: A systematic review|journal=J Psychopharmacol|volume=37|issue=3|pages=248–260|date=August 2022|pmid=36000248|doi=10.1177/02698811221115762|pmc=10076328|s2cid=251765916}}</ref> Instead, findings of reserpine and mood are highly mixed, with similar proportions of studies finding that it has no influence on mood, produces depressive effects, or actually has antidepressant effects.<ref name="pmid36000248" /> In relation to this, the general monoamine hypothesis, as opposed to only the serotonin theory of depression, likewise does not appear to be well-supported by evidence.<ref name="pmid12953623" /><ref name="pmid36000248" /><ref name="AngHorowitzMoncrieff2022" />

The serotonin and monoamine hypotheses of depression have been heavily promoted by the [[pharmaceutical industry]] (e.g., in [[advertisement]]s) and by the psychiatric profession at large despite the lack of evidence in support of them.<ref name="pmid16268734" /><ref name="LacasseLeo2015" /><ref name="pmid12953623" /><ref name="LeoLacasse2007">{{cite journal|vauthors=Leo J, Lacasse JR|title=The Media and the Chemical Imbalance Theory of Depression|journal=Society|date=28 November 2007|volume=45|issue=1|pages=35–45|issn=0147-2011|eissn=1936-4725|doi=10.1007/s12115-007-9047-3|s2cid=2176245|doi-access=free}}</ref><ref name="AngHorowitzMoncrieff2022">{{cite journal|vauthors=Ang B, Horowitz M, Moncrieff J|title=Is the chemical imbalance an 'urban legend'? An exploration of the status of the serotonin theory of depression in the scientific literature|journal=SSM – Mental Health|date=December 2022|volume=2|article-number=100098|issn=2666-5603|doi=10.1016/j.ssmmh.2022.100098|s2cid=248246338|doi-access=free}}</ref><ref name="Lacasse2005">{{cite journal|vauthors=Lacasse JR|title=Consumer Advertising of Psychiatric Medications Biases the Public Against Nonpharmacological Treatment|journal=Ethical Human Psychology and Psychiatry|date=September 2005|volume=7|issue=3|pages=175–179|issn=1559-4343|eissn=1938-9000|doi=10.1891/1559-4343.7.3.175|pmid=16604742|s2cid=14133908}}</ref> In the case of the pharmaceutical industry, this can be attributed to obvious financial incentives, with the theory creating a bias against [[non-pharmacological treatment]]s for depression.<ref name="Lacasse2005" /><ref name="pmid16268734" /><ref name="LacasseLeo2015" /><ref name="pmid12953623" />

An alternative theory for antidepressant action proposed by certain academics such as [[Irving Kirsch]] and [[Joanna Moncrieff]] is that they work largely or entirely via [[placebo]] mechanisms.<ref name="pmid31249537">{{cite journal|vauthors=Kirsch I|title=Placebo Effect in the Treatment of Depression and Anxiety|journal=Front Psychiatry|volume=10|article-number=407|date=2019|pmid=31249537|pmc=6584108|doi=10.3389/fpsyt.2019.00407|doi-access=free}}</ref><ref name="Kirsch2014">{{cite book|title=Placebo|vauthors=Kirsch I|chapter=The Emperor's New Drugs: Medication and Placebo in the Treatment of Depression|series=Handbook of Experimental Pharmacology|date=2014|volume=225|pages=291–303|publisher=Springer Berlin Heidelberg|issn=0171-2004|eissn=1865-0325|doi=10.1007/978-3-662-44519-8_16|pmid=25304538|isbn=978-3-662-44518-1}}</ref><ref name="Kirsch2010">{{cite book|vauthors=Kirsch I|date=26 January 2010|title=The Emperor's New Drugs: Exploding the Antidepressant Myth|publisher=Basic Books|isbn=978-0-465-02104-8|oclc=1037471689|url=https://books.google.com/books?id=wk-OxcTKyi4C}}</ref><ref name="pmid35100527">{{cite journal|vauthors=Read J, Moncrieff J|title=Depression: why drugs and electricity are not the answer|journal=Psychol Med|volume=52|issue=8|pages=1401–1410|date=June 2022|pmid=35100527|doi=10.1017/S0033291721005031|s2cid=246442707|url=https://repository.uel.ac.uk/download/0fd9663377e02e8033e12c27844d65b5e918406de4d7c7baca5031a8e8ba4c5a/408146/Read%20and%20Moncrieff%20Psych%20Med%20ROAR.pdf}}</ref> This is supported by meta-analyses of [[randomized controlled trial]]s of antidepressants for depression, which consistently show that placebo groups in trials improve about 80 to 90% as much as antidepressant groups on average<ref name="pmid31249537" /><ref name="HengartnerPlöderl2018">{{cite journal|vauthors=Hengartner MP, Plöderl M|title=False Beliefs in Academic Psychiatry: The Case of Antidepressant Drugs|journal=Ethical Human Psychology and Psychiatry|date=July 2018|volume=20|issue=1|pages=6–16|issn=1559-4343|eissn=1938-9000|doi=10.1891/1559-4343.20.1.6|s2cid=149608377}}</ref> and that antidepressants are only marginally more effective for depression than placebos.<ref name="pmid31248914">{{cite journal|vauthors=Munkholm K, Paludan-Müller AS, Boesen K|title=Considering the methodological limitations in the evidence base of antidepressants for depression: a reanalysis of a network meta-analysis|journal=BMJ Open|volume=9|issue=6|article-number=e024886|date=June 2019|pmid=31248914|pmc=6597641|doi=10.1136/bmjopen-2018-024886}}</ref><ref name="pmid32101579">{{cite journal|vauthors=Hengartner MP, Jakobsen JC, Sørensen A, Plöderl M|title=Efficacy of new-generation antidepressants assessed with the Montgomery-Asberg Depression Rating Scale, the gold standard clinician rating scale: A meta-analysis of randomised placebo-controlled trials|journal=PLOS ONE|volume=15|issue=2|article-number=e0229381|date=2020|pmid=32101579|pmc=7043778|doi=10.1371/journal.pone.0229381|bibcode=2020PLoSO..1529381H|doi-access=free}}</ref><ref name="pmid29477251">{{cite journal|vauthors=Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner EH, Higgins JP, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JP, Geddes JR|title=Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis|journal=Lancet|volume=391|issue=10128|pages=1357–1366|date=April 2018|pmid=29477251|pmc=5889788|doi=10.1016/S0140-6736(17)32802-7}}</ref><ref name="pmid35918097">{{cite journal|vauthors=Stone MB, Yaseen ZS, Miller BJ, Richardville K, Kalaria SN, Kirsch I|title=Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis|journal=The BMJ|volume=378|article-number=e067606|date=August 2022|pmid=35918097|pmc=9344377|doi=10.1136/bmj-2021-067606}}</ref><ref name="pmid30386270" /> The difference between antidepressants and placebo corresponds to an [[effect size]] ([[standardized mean difference|SMD]]) of about 0.3, which in turn equates to about a 2- to 3-point additional improvement on the 0–52-point ([[Hamilton Depression Rating Scale|HRSD]]) and 0–60-point ([[Montgomery–Åsberg Depression Rating Scale|MADRS]]) [[depression rating scale]]s used in trials.<ref name="pmid31248914" /><ref name="pmid32101579" /><ref name="pmid29477251" /><ref name="pmid35918097" /><ref name="pmid30386270" /> Differences in effectiveness between different antidepressants are small and not clinically meaningful.<ref name="pmid36638223">{{cite journal|vauthors=Chen EG, Oliver AK, Raz A|title=Irving Kirsch opens a window on antidepressant medications|journal=Am J Clin Hypn|volume=65|issue=3|pages=223–240|date=January 2023|pmid=36638223|doi=10.1080/00029157.2022.2121678|s2cid=255775806}}</ref><ref name="pmid29477251" /> The small advantage of antidepressants over placebo is often [[statistically significant]] and is the basis for their regulatory approval, but is sufficiently modest that its [[clinical significance]] is doubtful.<ref name="pmid25979317">{{cite journal|vauthors=Moncrieff J, Kirsch I|title=Empirically derived criteria cast doubt on the clinical significance of antidepressant-placebo differences|journal=Contemp Clin Trials|volume=43|pages=60–2|date=July 2015|pmid=25979317|doi=10.1016/j.cct.2015.05.005|doi-access=free}}</ref><ref name="pmid33593736">{{cite journal|vauthors=Hengartner MP, Plöderl M|title=Estimates of the minimal important difference to evaluate the clinical significance of antidepressants in the acute treatment of moderate-to-severe depression|journal=BMJ Evid Based Med|volume=27|issue=2|pages=69–73|date=April 2022|pmid=33593736|doi=10.1136/bmjebm-2020-111600|s2cid=231939760}}</ref><ref name="pmid32101579" /><ref name="pmid30386270">{{cite journal|vauthors=Hengartner MP, Plöderl M|title=Statistically Significant Antidepressant-Placebo Differences on Subjective Symptom-Rating Scales Do Not Prove That the Drugs Work: Effect Size and Method Bias Matter!|journal=Front Psychiatry|volume=9|article-number=517|date=2018|pmid=30386270|pmc=6199395|doi=10.3389/fpsyt.2018.00517|doi-access=free}}</ref> Moreover, the small advantage of antidepressants over placebo may simply be a [[methodological artifact]] caused by [[unblinding]] due to the [[psychoactive]] effects and [[side effect]]s of antidepressants, in turn resulting in enhanced placebo effects and apparent antidepressant efficacy.<ref name="pmid31249537" /><ref name="pmid30386270" /><ref name="Kirsch2014" /> Placebos have been found to modify the activity of several brain regions and to increase levels of dopamine and [[endogenous]] [[opioid]]s in the [[reward pathway]]s.<ref name="pmid35078210">{{cite journal|vauthors=Huneke NT, Aslan IH, Fagan H, Phillips N, Tanna R, Cortese S, Garner M, Baldwin DS|title=Functional Neuroimaging Correlates of Placebo Response in Patients With Depressive or Anxiety Disorders: A Systematic Review|journal=Int J Neuropsychopharmacol|volume=25|issue=6|pages=433–447|date=June 2022|pmid=35078210|pmc=9211006|doi=10.1093/ijnp/pyac009}}</ref><ref name="pmid36006479">{{cite journal|vauthors=Brietzke C, Cesario JC, Hettinga FJ, Pires FO|title=The reward for placebos: mechanisms underpinning placebo-induced effects on motor performance|journal=Eur J Appl Physiol|volume=122|issue=11|pages=2321–2329|date=August 2022|pmid=36006479|doi=10.1007/s00421-022-05029-8|s2cid=251809051|url=https://nrl.northumbria.ac.uk/id/eprint/49965/1/Brietzke%20et%20al.%202022%20The%20reward%20of%20placebo_R1.pdf}}</ref><ref name="pmid15874901">{{cite journal|vauthors=Fricchione G, Stefano GB|title=Placebo neural systems: nitric oxide, morphine and the dopamine brain reward and motivation circuitries|journal=Med Sci Monit|volume=11|issue=5|pages=MS54–65|date=May 2005|pmid=15874901}}</ref> It has been argued by Kirsch that although antidepressants may be used efficaciously for depression as [[active placebo]]s, they are limited by significant pharmacological [[side effect]]s and risks, and therefore [[non-pharmaceutical intervention|non-pharmacological therapies]], such as [[psychotherapy]] and lifestyle changes, which can have similar efficacy to antidepressants but do not have their adverse effects, ought to be preferred as treatments in people with depression.<ref name="pmid31554608">{{cite journal|vauthors=Jakobsen JC, Gluud C, Kirsch I|title=Should antidepressants be used for major depressive disorder?|journal=BMJ Evid Based Med|volume=25|issue=4|page=130|date=August 2020|pmid=31554608|pmc=7418603|doi=10.1136/bmjebm-2019-111238}}</ref>

The [[placebo response]], or the improvement in scores in the placebo group in clinical trials, is not only due to the [[placebo effect]], but is also due to other phenomena such as [[spontaneous remission]] and [[regression to the mean]].<ref name="pmid31249537" /><ref name="pmid30975717" /> Depression tends to have an episodic course, with people eventually recovering even with no medical intervention, and people tend to seek treatment, as well as enroll in clinical trials, when they are feeling their worst.<ref name="Hengartner2022">{{cite book|vauthors=Hengartner MP|title=Evidence-biased Antidepressant Prescription|date=2022|publisher=Springer International Publishing|doi=10.1007/978-3-030-82587-4|isbn=978-3-030-82586-7|s2cid=245017942}}</ref><ref name="pmid30975717" /> In meta-analyses of trials of depression therapies, Kirsch estimated based on improvement in untreated waiting-list controls that spontaneous remission and regression to the mean only account for about 25% of the improvement in depression scores with antidepressant therapy.<ref name="pmid31249537" /><ref name="pmid22860015">{{cite journal|vauthors=Khan A, Faucett J, Lichtenberg P, Kirsch I, Brown WA|title=A systematic review of comparative efficacy of treatments and controls for depression|journal=PLOS ONE|volume=7|issue=7|article-number=e41778|date=2012|pmid=22860015|pmc=3408478|doi=10.1371/journal.pone.0041778|bibcode=2012PLoSO...741778K|doi-access=free}}</ref><ref name="KirschSapirstein1998">{{cite journal|author=Kirsch, I.|author2=Sapirstein, G|title=Listening to Prozac but hearing placebo: A meta-analysis of antidepressant medication|journal=Prevention and Treatment|volume=1|issue=2|date=26 June 1998|pages=Article 0002a|doi=10.1037/1522-3736.1.1.12a|url=http://journals.apa.org/prevention/volume1/pre0010002a.html|archive-url=https://web.archive.org/web/19980715085305/http://journals.apa.org/prevention/volume1/pre0010002a.html|archive-date=15 July 1998}}</ref><ref name="pmid20170046">{{cite journal|vauthors=Kirsch I|title=Antidepressants and the placebo response|journal=Epidemiol Psychiatr Soc|volume=18|issue=4|pages=318–22|date=2009|pmid=20170046|doi=10.1017/s1121189x00000282|s2cid=2166423}}</ref><ref name="Hengartner2022" /> However, another academic, [[Michael P. Hengartner]], has argued and presented evidence that spontaneous remission and regression to the mean might actually account for most of the improvement in depression scores with antidepressants, and that the substantial placebo effect observed in clinical trials might largely be a methodological artifact.<ref name="pmid30975717">{{cite journal|vauthors=Hengartner MP|title=Is there a genuine placebo effect in acute depression treatments? A reassessment of regression to the mean and spontaneous remission|journal=BMJ Evid Based Med|volume=25|issue=2|pages=46–48|date=April 2020|pmid=30975717|doi=10.1136/bmjebm-2019-111161|s2cid=109941636}}</ref> This suggests that antidepressants may be associated with much less genuine treatment benefit, whether due to the placebo effect or to the antidepressant itself, than has been traditionally assumed.<ref name="pmid30975717" />

It has been proposed that [[psychedelic drug|psychedelic]]s used for therapeutic purposes may act as [[active placebo|active]] "super placebos".<ref name="DupuisVeissière2022">{{cite journal | vauthors = Dupuis D, Veissière S | title = Culture, context, and ethics in the therapeutic use of hallucinogens: Psychedelics as active super-placebos? | journal = Transcult Psychiatry | volume = 59 | issue = 5 | pages = 571–578 | date = October 2022 | pmid = 36263513 | doi = 10.1177/13634615221131465 | url = }}</ref><ref name="vanElkYaden2022">{{cite journal | vauthors = van Elk M, Yaden DB | title = Pharmacological, neural, and psychological mechanisms underlying psychedelics: A critical review | journal = Neurosci Biobehav Rev | volume = 140 | issue = | article-number = 104793 | date = September 2022 | pmid = 35878791 | doi = 10.1016/j.neubiorev.2022.104793 | url = | quote = In addition, the strong prior expectations that many people have about psychedelics directly contribute to the psychedelic experience and as a consequence it has been suggested that psychedelics may act as a 'super-placebo' (Hartogsohn, 2016). Specifically, strong prior expectations (e.g., that a specific intervention will likely trigger a mystical experience) will increase the likelihood of having e.g., a mystical-type experience (Maij et al., 2019), and this placebo-effect is further boosted by the psychedelic-induced suggestibility. | hdl = 1887/3515020 | hdl-access = free }}</ref>

==Types==
{{See also|List of antidepressants}}

===Selective serotonin reuptake inhibitors===
[[File:Paroxetine-2D-skeletal.svg|alt=refer to caption|thumb|2D chemical structure of Paxil ([[Paroxetine]]), a [[selective serotonin reuptake inhibitor]]]]
[[Selective serotonin reuptake inhibitor]]s (SSRIs) are believed to increase the [[extracellular]] level of the [[neurotransmitter]] serotonin by [[Reuptake inhibitor|limiting]] its [[reuptake|reabsorption]] into the [[presynaptic cell]], increasing the level of [[serotonin]] in the [[synaptic cleft]] available to bind to the [[postsynaptic receptor]]. They have varying degrees of selectivity for the other [[monoamine transporter]]s, with pure SSRIs having only weak affinity for the [[norepinephrine transporter|norepinephrine]] and [[dopamine transporter]]s.

SSRIs are the most widely prescribed antidepressants in many countries.<ref name="PRESCORN2004">{{cite book|vauthors=Preskorn SH, Ross R, Stanga CY|chapter=Selective Serotonin Reuptake Inhibitors|chapter-url=https://books.google.com/books?id=sO_hArhCxwMC&pg=PA241|veditors=Preskorn SH, Feighner HP, Stanga CY, Ross R|title=Antidepressants: Past, Present and Future|publisher=Springer|location=Berlin|year=2004|pages=241–62|isbn=978-3-540-43054-4}}</ref> The efficacy of SSRIs in mild or moderate cases of depression has been disputed.<ref name="JAMA2010">{{cite journal|vauthors=Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC, Fawcett J|title=Antidepressant drug effects and depression severity: a patient-level meta-analysis|journal=JAMA|volume=303|issue=1|pages=47–53|date=January 2010|pmid=20051569|pmc=3712503|doi=10.1001/jama.2009.1943}}</ref><ref name="Kramer">{{cite news|vauthors=Kramer P|title=In Defense of Antidepressants|url=https://www.nytimes.com/2011/07/10/opinion/sunday/10antidepressants.html|access-date=13 July 2011|newspaper=The New York Times|date=7 September 2011|url-status=live|archive-url=https://web.archive.org/web/20110712053223/http://www.nytimes.com/2011/07/10/opinion/sunday/10antidepressants.html|archive-date=12 July 2011}}</ref><ref name="Pies">{{cite journal|vauthors=Pies R|title=Antidepressants work, sort of—our system of care does not|journal=Journal of Clinical Psychopharmacology|volume=30|issue=2|pages=101–104|date=April 2010|pmid=20520282|doi=10.1097/JCP.0b013e3181d52dea|url=https://zenodo.org/record/890741}}</ref><ref>{{cite journal|vauthors=Pies RW|title=Antidepressants: Conundrums and Complexities of Efficacy Studies|journal=Journal of Clinical Psychopharmacology|volume=36|issue=1|pages=1–4|date=February 2016|pmid=26658086|doi=10.1097/jcp.0000000000000455|s2cid=28469650|url=https://zenodo.org/record/890747}}</ref>

===Serotonin–norepinephrine reuptake inhibitors===
[[File:Venlafaxine-3D-balls.png|thumb|right|alt=chemical structure of the SNRI drug venlafaxine|The chemical structure of [[venlafaxine]] (Effexor), an [[Serotonin–norepinephrine reuptake inhibitor|SNRI]]]]

[[Serotonin–norepinephrine reuptake inhibitor]]s (SNRIs) are potent inhibitors of the [[reuptake]] of [[serotonin]] and [[norepinephrine]]. These [[neurotransmitter]]s are known to play an important role in mood. SNRIs can be contrasted with the more widely used [[selective serotonin reuptake inhibitor]]s (SSRIs), which act mostly upon serotonin alone.

The human [[serotonin transporter]] (SERT) and [[norepinephrine transporter]] (NET) are [[membrane protein]]s that are responsible for the reuptake of serotonin and norepinephrine. Balanced dual inhibition of [[monoamine]] reuptake may offer advantages over other antidepressants drugs by treating a wider range of symptoms.<ref name="pmid19740668">{{cite journal|vauthors=Cashman JR, Ghirmai S|title=Inhibition of serotonin and norepinephrine reuptake and inhibition of phosphodiesterase by multi-target inhibitors as potential agents for depression|journal=Bioorganic & Medicinal Chemistry|volume=17|issue=19|pages=6890–6897|date=October 2009|pmid=19740668|doi=10.1016/j.bmc.2009.08.025}}</ref>

SNRIs are sometimes also used to treat [[anxiety disorder]]s, [[obsessive–compulsive disorder]] (OCD), [[attention deficit hyperactivity disorder]] (ADHD), chronic [[neuropathic pain]], and [[fibromyalgia syndrome]] (FMS), and for the relief of [[menopause|menopausal]] symptoms.

===Serotonin modulators and stimulators===
[[Serotonin modulator and stimulator]]s (SMSs), sometimes referred to more simply as "[[serotonin]] modulators", are a type of [[drug]] with a multimodal action specific to the serotonin [[neurotransmitter]] system. To be precise, SMSs simultaneously modulate one or more [[serotonin receptor]]s and inhibit the [[reuptake]] of serotonin. The term was coined in reference to the [[mechanism of action]] of the serotonergic antidepressant [[vortioxetine]], which acts as a [[serotonin reuptake inhibitor]] (SRI), a [[partial agonist]] of the [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]], and [[receptor antagonist|antagonist]] of the [[5-HT3 receptor|5-HT<sub>3</sub>]] and [[5-HT7 receptor|5-HT<sub>7</sub> receptor]]s.<ref name="pmid24391391">{{cite journal|author=Goldenberg MM|title=Pharmaceutical approval update|journal=P T|volume=38|issue=11|pages=705–7|date=November 2013|pmid=24391391|pmc=3875258}}</ref><ref name="AmerPharmAssoc2013">{{cite web|url=http://www.pharmacist.com/vortioxetine-atypical-antidepressant|author=American Pharmacists Association|title=Vortioxetine: Atypical antidepressant|year=2013|url-status=live|archive-url=https://web.archive.org/web/20151120095834/http://www.pharmacist.com/vortioxetine-atypical-antidepressant|archive-date=20 November 2015}}</ref><ref name="LATimes2013">{{cite web|url=https://www.latimes.com/science/sciencenow/la-sci-fda-approval-antidepressant-20130930-story.html|title=FDA approves a new antidepressant: Brintellix|website=Los Angeles Times|year=2013|url-status=live|archive-url=https://web.archive.org/web/20151120162327/http://www.latimes.com/science/sciencenow/la-sci-fda-approval-antidepressant-20130930-story.html|archive-date=20 November 2015}}</ref> However, it can also technically be applied to [[vilazodone]], which is an antidepressant as well and acts as an SRI and 5-HT<sub>1A</sub> receptor partial agonist.<ref name="pmid15740724">{{cite journal|vauthors=Hughes ZA, Starr KR, Langmead CJ, etal|title=Neurochemical evaluation of the novel 5-HT1A receptor partial agonist/serotonin reuptake inhibitor, vilazodone|journal=European Journal of Pharmacology|volume=510|issue=1–2|pages=49–57|date=March 2005|pmid=15740724|doi=10.1016/j.ejphar.2005.01.018}}</ref>

An alternative term is serotonin partial agonist/reuptake inhibitor (SPARI), which can be applied only to vilazodone.<ref>{{cite book|vauthors=Stahl SM|others=with illustrations by Muntner N|title=Stahl's essential psychopharmacology: neuroscientific basis and practical application|date=2013|publisher=Cambridge University Press|location=Cambridge|isbn=978-1-107-68646-5|edition=4th}}</ref>

===Serotonin antagonists and reuptake inhibitors===
[[Serotonin antagonist and reuptake inhibitors]] (SARIs) while mainly used as antidepressants are also [[anxiolytic]]s and [[hypnotic]]s. They act by [[receptor antagonist|antagonizing]] [[serotonin receptor]]s such as [[5-HT2A receptor|5-HT<sub>2A</sub>]] and [[reuptake inhibitor|inhibiting]] the [[reuptake]] of [[serotonin]], [[norepinephrine]], and/or [[dopamine]]. Additionally, most also act as [[alpha-1 adrenergic receptor|α<sub>1</sub>-adrenergic receptor]] antagonists. The majority of the currently marketed SARIs belong to the [[phenylpiperazine]] class of compounds. They include [[trazodone]] and [[nefazodone]].

===Tricyclic antidepressants===
The majority of the [[tricyclic antidepressant]]s (TCAs) act primarily as [[serotonin–norepinephrine reuptake inhibitor]]s (SNRIs) by blocking the [[serotonin transporter]] (SERT) and the [[norepinephrine transporter]] (NET), respectively, which results in an elevation of the [[Synapse|synaptic]] concentrations of these [[neurotransmitter]]s, and therefore an enhancement of [[neurotransmission]].<ref name="pmid9537821">{{cite journal|vauthors=Tatsumi M, Groshan K, Blakely RD, Richelson E|title=Pharmacological profile of antidepressants and related compounds at human monoamine transporters|journal=Eur J Pharmacol|volume=340|issue=2–3|pages=249–258|year=1997|pmid=9537821|doi=10.1016/S0014-2999(97)01393-9}}</ref><ref name="pmid17471183">{{cite journal|author=Gillman PK|title=Tricyclic antidepressant pharmacology and therapeutic drug interactions updated|journal=[[British Journal of Pharmacology]]|volume=151|issue=6|pages=737–48|date=July 2007|pmid=17471183|pmc=2014120|doi=10.1038/sj.bjp.0707253}}</ref> Notably, with the sole exception of [[amineptine]], the TCAs have weak [[affinity (pharmacology)|affinity]] for the [[dopamine transporter]] (DAT), and therefore have low efficacy as [[dopamine reuptake inhibitor]]s (DRIs).<ref name="pmid9537821" />

Although TCAs are sometimes [[medical prescription|prescribed]] for depressive disorders, they have been largely replaced in clinical use in most parts of the world by newer antidepressants such as [[selective serotonin reuptake inhibitor]]s (SSRIs), [[serotonin–norepinephrine reuptake inhibitor]]s (SNRIs), and [[norepinephrine reuptake inhibitor]]s (NRIs). Adverse effects have been found to be of a similar level between TCAs and SSRIs.<ref>{{cite journal|vauthors=Trindade E, Menon D, Topfer LA, Coloma C|title=Adverse effects associated with selective serotonin reuptake inhibitors and tricyclic antidepressants: a meta-analysis|journal=CMAJ|volume=159|issue=10|pages=1245–1252|date=November 1998|pmid=9861221|pmc=1229819}}</ref>

===Tetracyclic antidepressants===
[[Tetracyclic antidepressants]] (TeCAs) are a class of antidepressants that were first introduced in the 1970s. They are named after their [[chemical structure]], which contains four [[cyclic compound|rings of atoms]], and are closely related to [[tricyclic antidepressant]]s (TCAs), which contain three rings of atoms.

===Monoamine oxidase inhibitors===
[[Monoamine oxidase inhibitor]]s (MAOIs) are chemicals that inhibit the activity of the [[monoamine oxidase|monoamine oxidase enzyme family]]. They have a long history of use as medications prescribed for the treatment of [[clinical depression|depression]]. They are particularly effective in treating [[atypical depression]].<ref>{{cite journal|url=http://www.psychiatrictimes.com/major-depressive-disorder/atypical-depression-21st-century-diagnostic-and-treatment-issues|title=Atypical Depression in the 21st Century: Diagnostic and Treatment Issues|journal=[[Psychiatric Times]]|access-date=23 November 2013|author=Cristancho, Mario|date=20 November 2012|volume=28|issue=1|url-status=live|archive-url=https://web.archive.org/web/20131202224433/http://www.psychiatrictimes.com/major-depressive-disorder/atypical-depression-21st-century-diagnostic-and-treatment-issues|archive-date=2 December 2013}}</ref> They are also used in the treatment of [[Parkinson's disease]] and several other disorders.

Because of potentially lethal dietary and drug interactions, MAOIs have historically been reserved as a last line of treatment, used only when other classes of antidepressant drugs (for example [[selective serotonin reuptake inhibitor]]s and [[tricyclic antidepressant]]s) have failed.<ref>{{cite journal|vauthors=Shulman KI, Herrmann N, Walker SE|title=Current place of monoamine oxidase inhibitors in the treatment of depression|journal=CNS Drugs|volume=27|issue=10|pages=789–797|date=October 2013|pmid=23934742|doi=10.1007/s40263-013-0097-3|s2cid=21625538}}</ref>

MAOIs have been found to be effective in the treatment of [[panic disorder]] with [[agoraphobia]],<ref>{{cite journal|vauthors=Buigues J, Vallejo J|title=Therapeutic response to phenelzine in patients with panic disorder and agoraphobia with panic attacks|journal=The Journal of Clinical Psychiatry|volume=48|issue=2|pages=55–59|date=February 1987|pmid=3542985}}</ref> [[social phobia]],<ref>{{cite journal|vauthors=Liebowitz MR, Schneier F, Campeas R, Hollander E, Hatterer J, Fyer A, Gorman J, Papp L, Davies S, Gully R|title=Phenelzine vs atenolol in social phobia. A placebo-controlled comparison|journal=Archives of General Psychiatry|volume=49|issue=4|pages=290–300|date=April 1992|pmid=1558463|doi=10.1001/archpsyc.49.4.290}}</ref><ref>{{cite journal|vauthors=Versiani M, Nardi AE, Mundim FD, Alves AB, Liebowitz MR, Amrein R|title=Pharmacotherapy of social phobia. A controlled study with moclobemide and phenelzine|journal=The British Journal of Psychiatry|volume=161|issue=3|pages=353–360|date=September 1992|pmid=1393304|doi=10.1192/bjp.161.3.353|s2cid=45341667}}</ref><ref>{{cite journal|vauthors=Heimberg RG, Liebowitz MR, Hope DA, Schneier FR, Holt CS, Welkowitz LA, Juster HR, Campeas R, Bruch MA, Cloitre M, Fallon B, Klein DF|title=Cognitive behavioral group therapy vs phenelzine therapy for social phobia: 12-week outcome|journal=Archives of General Psychiatry|volume=55|issue=12|pages=1133–1141|date=December 1998|pmid=9862558|doi=10.1001/archpsyc.55.12.1133}}</ref> atypical depression<ref>{{cite journal|vauthors=Jarrett RB, Schaffer M, McIntire D, Witt-Browder A, Kraft D, Risser RC|title=Treatment of atypical depression with cognitive therapy or phenelzine: a double-blind, placebo-controlled trial|journal=Archives of General Psychiatry|volume=56|issue=5|pages=431–437|date=May 1999|pmid=10232298|pmc=1475805|doi=10.1001/archpsyc.56.5.431}}</ref><ref>{{cite journal|vauthors=Liebowitz MR, Quitkin FM, Stewart JW, McGrath PJ, Harrison W, Rabkin J, Tricamo E, Markowitz JS, Klein DF|title=Phenelzine v imipramine in atypical depression. A preliminary report|journal=Archives of General Psychiatry|volume=41|issue=7|pages=669–677|date=July 1984|pmid=6375621|doi=10.1001/archpsyc.1984.01790180039005}}</ref> or mixed anxiety and depression, [[bulimia]],<ref>{{cite journal|vauthors=Walsh BT, Stewart JW, Roose SP, Gladis M, Glassman AH|title=Treatment of bulimia with phenelzine. A double-blind, placebo-controlled study|journal=Archives of General Psychiatry|volume=41|issue=11|pages=1105–1109|date=November 1984|pmid=6388524|doi=10.1001/archpsyc.1983.01790220095015}}</ref><ref>{{cite journal|vauthors=Rothschild R, Quitkin HM, Quitkin FM, Stewart JW, Ocepek-Welikson K, McGrath PJ, Tricamo E|title=A double-blind placebo-controlled comparison of phenelzine and imipramine in the treatment of bulimia in atypical depressives|journal=The International Journal of Eating Disorders|volume=15|issue=1|pages=1–9|date=January 1994|pmid=8124322|doi=10.1002/1098-108X(199401)15:1<1::AID-EAT2260150102>3.0.CO;2-E}}</ref><ref>{{cite journal|vauthors=Walsh BT, Stewart JW, Roose SP, Gladis M, Glassman AH|title=A double-blind trial of phenelzine in bulimia|journal=Journal of Psychiatric Research|volume=19|issue=2–3|pages=485–489|year=1985|pmid=3900362|doi=10.1016/0022-3956(85)90058-5}}</ref><ref>{{cite journal|vauthors=Walsh BT, Gladis M, Roose SP, Stewart JW, Stetner F, Glassman AH|title=Phenelzine vs placebo in 50 patients with bulimia|journal=Archives of General Psychiatry|volume=45|issue=5|pages=471–475|date=May 1988|pmid=3282482|doi=10.1001/archpsyc.1988.01800290091011}}</ref> and [[post-traumatic stress disorder]],<ref>{{cite journal|vauthors=Davidson J, Walker JI, Kilts C|title=A pilot study of phenelzine in the treatment of post-traumatic stress disorder|journal=The British Journal of Psychiatry|volume=150|issue=2|pages=252–255|date=February 1987|pmid=3651684|doi=10.1192/bjp.150.2.252|s2cid=10001735}}</ref> as well as [[borderline personality disorder]].<ref>{{cite journal|vauthors=Soloff PH, Cornelius J, George A, Nathan S, Perel JM, Ulrich RF|title=Efficacy of phenelzine and haloperidol in borderline personality disorder|journal=Archives of General Psychiatry|volume=50|issue=5|pages=377–385|date=May 1993|pmid=8489326|doi=10.1001/archpsyc.1993.01820170055007}}</ref> MAOIs appear to be particularly effective in the management of [[Bipolar disorder|bipolar depression]] according to a retrospective-analysis.<ref>{{cite journal|vauthors=Mallinger AG, Frank E, Thase ME, Barwell MM, Diazgranados N, Luckenbaugh DA, Kupfer DJ|title=Revisiting the effectiveness of standard antidepressants in bipolar disorder: are monoamine oxidase inhibitors superior?|journal=Psychopharmacology Bulletin|volume=42|issue=2|pages=64–74|year=2009|pmid=19629023|pmc=3570273}}</ref> There are reports of MAOI efficacy in [[obsessive–compulsive disorder]] (OCD), [[trichotillomania]], [[dysmorphophobia]], and [[avoidant personality disorder]], but these reports are from uncontrolled case reports.<ref name="pmid2248064">{{cite journal|vauthors=Liebowitz MR, Hollander E, Schneier F, Campeas R, Welkowitz L, Hatterer J, Fallon B|title=Reversible and irreversible monoamine oxidase inhibitors in other psychiatric disorders|journal=Acta Psychiatrica Scandinavica. Supplementum|volume=360|pages=29–34|year=1990|pmid=2248064|doi=10.1111/j.1600-0447.1990.tb05321.x|s2cid=30319319}}</ref>

MAOIs can also be used in the treatment of Parkinson's disease by targeting MAO-B in particular (therefore affecting [[dopaminergic neuron]]s), as well as providing an alternative for [[migraine]] [[prophylaxis]]. Inhibition of both MAO-A and MAO-B is used in the treatment of [[clinical depression]] and [[anxiety disorder]]s.

===NMDA receptor antagonists===
[[NMDA receptor antagonist]]s like [[ketamine]] and [[esketamine]] are [[rapid-acting antidepressant]]s and seem to work via [[receptor antagonist|blockade]] of the [[ionotropic glutamate receptor|ionotropic glutamate]] [[NMDA receptor]].<ref name="SpravatoLabel">{{cite web|title=SPRAVATO™ (Esketamine) nasal spray FDA label|publisher=[[Food and Drug Administration]]|date=5 March 2019|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211243lbl.pdf|archive-url=https://web.archive.org/web/20190413131728/https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211243lbl.pdf|archive-date=13 April 2019|access-date=6 March 2019}}</ref> Other NMDA antagonists may also play a role in treating depression. The combination medication [[dextromethorphan/bupropion]] (Auvelity), which contains the NMDA receptor antagonist [[dextromethorphan]], was approved in the United States in 2022 for treating major depressive disorder.<ref name="pmid36301443">{{cite journal|vauthors=Keam SJ|title=Dextromethorphan/Bupropion: First Approval|journal=[[CNS Drugs]]|volume=36|issue=11|pages=1229–1238|date=November 2022|pmid=36301443|doi=10.1007/s40263-022-00968-4|s2cid=253158902|url=https://figshare.com/articles/online_resource/Dextromethorphan_Bupropion_First_Approval/21320970}}</ref><ref name="pmid36943010">{{cite journal|vauthors=Parincu Z, Iosifescu DV|title=Combinations of dextromethorphan for the treatment of mood disorders – a review of the evidence|journal=Expert Review of Neurotherapeutics|volume=23|issue=3|pages=205–212|date=March 2023|pmid=36943010|doi=10.1080/14737175.2023.2192402|s2cid=257638827}}</ref>

===Others===
See the [[list of antidepressants]] and [[management of depression]] for other drugs that are not specifically characterized.

==Adjuncts==
Adjunct medications are an umbrella category of substances that increase the potency or "enhance" antidepressants.<ref>{{cite web|url=http://www.merckmanuals.com/professional/psychiatric_disorders/mood_disorders/depressive_disorders.html?qt=depression&alt=sh#v1028590|website=Merck Manual|title=Depressive Disorders|access-date=30 November 2012|archive-url=https://web.archive.org/web/20131205163219/http://www.merckmanuals.com/professional/psychiatric_disorders/mood_disorders/depressive_disorders.html?qt=depression&alt=sh|archive-date=5 December 2013}}</ref> They work by affecting variables very close to the antidepressant, sometimes affecting a completely different [[mechanism of action]]. This may be attempted when depression treatments have not been successful in the past.

Common types of adjunct medication techniques generally fall into the following categories:

* Two or more antidepressants taken together, from either the same or different classes (affecting the same area of the brain, often at a much higher level).
* An [[antipsychotic]] combined with an antidepressant, particularly [[atypical antipsychotic]]s such as [[aripiprazole]] (Abilify), [[quetiapine]] (Seroquel), [[olanzapine]] (Zyprexa), and [[risperidone]] (Risperdal).<ref name="Maudsley">{{cite book|vauthors=Taylor D, Carol P, Shitij K|title=The Maudsley prescribing guidelines in psychiatry|year=2012|publisher=Wiley-Blackwell|location=West Sussex|isbn=978-0-470-97969-3}}</ref><!--first added https://en.wikipedia.org/w/index.php?title=Antidepressant&diff=prev&oldid=576824896-->
It is unknown if undergoing [[psychological therapy]] at the same time as taking anti-depressants enhances the anti-depressive effect of the medication.<ref>{{cite journal|vauthors=Cox GR, Callahan P, Churchill R, Hunot V, Merry SN, Parker AG, Hetrick SE|title=Psychological therapies versus antidepressant medication, alone and in combination for depression in children and adolescents|journal=The Cochrane Database of Systematic Reviews|volume=2014|issue=11|article-number=CD008324|date=November 2014|pmid=25433518|pmc=8556660|doi=10.1002/14651858.CD008324.pub3|url=http://vuir.vu.edu.au/33744/1/Cox%20et%20al%202012%20Psychological%20therapies%20versus%20antidepressant%20medication%20%28Review%29.pdf|url-status=live|hdl-access=free|hdl=11343/59254|archive-url=https://ghostarchive.org/archive/20221009/http://vuir.vu.edu.au/33744/1/Cox%20et%20al%202012%20Psychological%20therapies%20versus%20antidepressant%20medication%20%28Review%29.pdf|archive-date=9 October 2022}}</ref>

===Less common adjuncts===
[[Lithium (medication)|Lithium]] has been used to augment antidepressant therapy in those who have failed to respond to antidepressants alone.<ref name="pmid10505584">{{cite journal|vauthors=Bauer M, Dopfmer S|s2cid=31979046|year=1999|title=Lithium augmentation in treatment-resistant depression: Meta-analysis of placebo-controlled studies|journal=Journal of Clinical Psychopharmacology|volume=19|issue=5|pages=427–34|pmid=10505584|doi=10.1097/00004714-199910000-00006}}</ref> Furthermore, Lithium dramatically decreases the suicide risk in recurrent depression.<ref name="pmid17388706">{{cite journal|vauthors=Guzzetta F, Tondo L, Centorrino F, Baldessarini RJ|s2cid=10343453|title=Lithium treatment reduces suicide risk in recurrent major depressive disorder|journal=J Clin Psychiatry|volume=68|issue=3|pages=380–83|date=March 2007|pmid=17388706|doi=10.4088/JCP.v68n0304}}</ref> There is some evidence for the addition of a thyroid hormone, [[triiodothyronine]], in patients with normal thyroid function.<ref name="pmid16946176">{{cite journal|vauthors=Nierenberg AA, Fava M, Trivedi MH, Wisniewski SR, Thase ME, McGrath PJ, Alpert JE, Warden D, Luther JF, Niederehe G, Lebowitz B, Shores-Wilson K, Rush AJ|year=2006|title=A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: A STAR*D report|journal=American Journal of Psychiatry|volume=163|issue=9|pages=1519–30|pmid=16946176|doi=10.1176/appi.ajp.163.9.1519}}</ref>

Psychopharmacologists have also tried adding a [[psychostimulant|stimulant]], in particular, [[D-amphetamine]].<ref>{{cite book|vauthors=Stahl SM|title=The Prescriber's Guide (Stahl's Essential Psychopharmacology)|year=2011|publisher=Cambridge University Press|page=39}}</ref> However, the use of stimulants in cases of treatment-resistant depression is relatively controversial.<ref name="pmid1411740">{{cite journal|vauthors=Kraus MF, Burch EA|title=Methylphenidate hydrochloride as an antidepressant: controversy, case studies, and review|journal=Southern Medical Journal|volume=85|issue=10|pages=985–991|date=October 1992|pmid=1411740|doi=10.1097/00007611-199210000-00012}}</ref><ref name="pmid17338594">{{cite journal|vauthors=Orr K, Taylor D|title=Psychostimulants in the treatment of depression: a review of the evidence|journal=CNS Drugs|volume=21|issue=3|pages=239–257|date=2007|pmid=17338594|doi=10.2165/00023210-200721030-00004|s2cid=35761979}}</ref> A review article published in 2007 found psychostimulants may be effective in treatment-resistant depression with concomitant antidepressant therapy, but a more certain conclusion could not be drawn due to substantial deficiencies in the studies available for consideration, and the somewhat contradictory nature of their results.<!--

commented out 19 November 2013

However, the authors claim psychostimulants are likely to have a higher level of clinical effectiveness under circumstances in which the patient will probably die soon, so rapid relief is of great importance. In this situation, the patient is likely to die before dependence on, or tolerance of, the medication interferes with their care.

note 15 September 2015

This content should likely be incorporated into the article in some form, likely by mentioning the usage for fatigue in cancer (among others), but it's not happening right now, so please leave this commented out content in place as an important reminder for future editors.

--><ref name="pmid17338594" />

==History==
{{See also|Discovery and development of dual serotonin and norepinephrine reuptake inhibitors}}
[[File:Saint John's wort flowers.jpg|thumb|alt=refer to caption|[[Hypericum perforatum|St John's wort]]]]

The idea of an antidepressant, if [[Melancholia|melancholy]] is thought synonymous with depression, existed at least as early as the 1599 pamphlet ''A pil to purge melancholie or, A preparative to a pvrgation: or, Topping, copping, and capping: take either or whether: or, Mash them, and squash them, and dash them, and diddle come derrie come daw them, all together..''. [[Thomas d'Urfey]]'s ''Wit and Mirth: Or [[Pills to Purge Melancholy]]'', the title of a large collection of songs, was published between 1698 and 1720.

Before the 1950s, [[opioid]]s and [[amphetamine-type stimulant|amphetamine]]s were commonly used as antidepressants.<ref name="Weber 1988 255–66">{{cite journal|vauthors=Weber MM, Emrich HM|title=Current and Historical Concepts of Opiate Treatment in Psychiatric Disorders|journal=International Clinical Psychopharmacology|volume=3|issue=3|pages=255–66|year=1988|pmid=3153713|doi=10.1097/00004850-198807000-00007}}</ref><ref name="Amph Uses Dex">{{cite journal|vauthors=Heal DJ, Smith SL, Gosden J, Nutt DJ|title=Amphetamine, past and present – a pharmacological and clinical perspective|journal=J. Psychopharmacol.|volume=27|issue=6|pages=479–96|date=June 2013|pmid=23539642|pmc=3666194|doi=10.1177/0269881113482532}}</ref><ref name="Rasmussen2006">{{cite journal|vauthors=Rasmussen N|title=Making the first anti-depressant: amphetamine in American medicine, 1929-1950|journal=J Hist Med Allied Sci|volume=61|issue=3|pages=288–323|date=July 2006|pmid=16492800|doi=10.1093/jhmas/jrj039}}</ref> [[Amphetamine]] has been described as the first antidepressant.<ref name="Rasmussen2006" /> Use of opioids and amphetamines for depression was later restricted due to their addictive nature and side effects.<ref name="Weber 1988 255–66" /><ref name="Rasmussen2006" /> Extracts from the herb [[Hypericum perforatum|St John's wort]] have been used as a "nerve tonic" to alleviate depression.<ref>{{cite journal|author=Czygan FC|title=Kulturgeschichte und Mystik des Johanniskrauts: Vom 2500 Jahre alten Apotropaikum zum aktuellen Antidepressivum|language=de|journal=Pharmazie in unserer Zeit|volume=32|issue=3|pages=184–90|year=2003|pmid=12784538|doi=10.1002/pauz.200390062|trans-title=From a 2500-year-old apotropic comes a current antidepressive. The cultural history and mistique of St. John's wort}}</ref>

[[Hypericum perforatum|St John's wort]] fell out of favor in most countries through the 19th and 20th centuries, except in [[Germany]], where ''[[Hypericum]]'' extracts were eventually licensed, packaged, and prescribed. Small-scale efficacy trials were carried out in the 1970s and 1980s, and attention grew in the 1990s following a [[meta-analysis]].<ref>{{cite journal|vauthors=Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D|title=St John's wort for depression—an overview and meta-analysis of randomized clinical trials|journal=The BMJ|volume=313|issue=7052|pages=253–258|date=August 1996|pmid=8704532|pmc=2351679|doi=10.1136/bmj.313.7052.253}}</ref> It remains an [[over-the-counter drug|over-the-counter]] (OTC) supplement in most countries. Lead contamination associated with its usage has been seen as concerning, as lead levels in women in the United States taking St. John's wort are elevated by about 20% on average.<ref name="LeadInHerbs">{{cite journal|vauthors=Buettner C, Mukamal KJ, Gardiner P, Davis RB, Phillips RS, Mittleman MA|title=Herbal supplement use and blood lead levels of United States adults|journal=Journal of General Internal Medicine|volume=24|issue=11|pages=1175–1182|date=November 2009|pmid=19575271|pmc=2771230|doi=10.1007/s11606-009-1050-5|ref=LeadInHerbs}}</ref> Research continues to investigate its active component [[hyperforin]], and to further understand its mode of action.<ref>{{cite journal|vauthors=Müller WE|title=Current St John's wort research from mode of action to clinical efficacy|journal=Pharmacological Research|volume=47|issue=2|pages=101–109|date=February 2003|pmid=12543057|doi=10.1016/S1043-6618(02)00266-9}}</ref><ref>{{cite journal|vauthors=Nathan PJ|title=Hypericum perforatum (St John's Wort): a non-selective reuptake inhibitor? A review of the recent advances in its pharmacology|journal=Journal of Psychopharmacology|volume=15|issue=1|pages=47–54|date=March 2001|pmid=11277608|doi=10.1177/026988110101500109|s2cid=36924335}}</ref>

===Isoniazid, iproniazid, and imipramine===
In 1951, [[Irving Selikoff]] and Edward H. Robitzek, working out of [[Sea View Hospital]] on [[Staten Island]], began clinical trials on two new [[tuberculosis|anti-tuberculosis]] agents developed by Hoffman-LaRoche, [[isoniazid]], and [[iproniazid]]. Only patients with a poor [[prognosis]] were initially treated. Nevertheless, their condition improved dramatically. Selikoff and Robitzek noted "a subtle general stimulation ... the patients exhibited renewed vigor and indeed this occasionally served to introduce disciplinary problems."<ref name="pmid14906149">{{cite journal|vauthors=Selikoff IJ, Robitzek EH|title=Tuberculosis Chemotherapy with Hydrazine Derivatives of Isonicotinic Acid|journal=Chest|volume=21|issue=4|pages=385–438|year=1952|pmid=14906149|doi=10.1378/chest.21.4.385}}</ref> The promise of a cure for tuberculosis in the Sea View Hospital trials was excitedly discussed in the mainstream press.

In 1952, learning of the stimulating side effects of isoniazid, the Cincinnati psychiatrist Max Lurie tried it on his patients. In the following year, he and Harry Salzer reported that isoniazid improved depression in two-thirds of their patients, so they then coined the term ''antidepressant'' to refer to its action.<ref name="isbn0-88048-397-0">{{cite book|vauthors=Healy D|veditors=Weissman MM|title=The treatment of depression: bridging the 21st century|url=https://books.google.com/books?id=LAmBVolIG5kC|year=2001|publisher=American Psychiatric Pub|isbn=978-0-88048-397-1|pages=10–11|chapter=The Antidepressant Drama|chapter-url=https://books.google.com/books?id=LAmBVolIG5kC}}</ref> A similar incident took place in Paris, where [[Jean Delay]], head of psychiatry at Sainte-Anne Hospital, heard of this effect from his [[pulmonology]] colleagues at Cochin Hospital. In 1952 (before Lurie and Salzer), Delay, with the resident Jean-Francois Buisson, reported the positive effect of isoniazid on depressed patients.<ref name="Healy96">{{cite book|vauthors=Healy D|title=The psychopharmacologists: interviews|year=1996|publisher=Chapman and Hall|location=London|isbn=978-1-86036-008-4|page=8}}</ref> The mode of antidepressant action of isoniazid is still unclear. It is speculated that its effect is due to the inhibition of [[diamine oxidase]], coupled with a weak inhibition of [[monoamine oxidase A]].<ref name="isbn1-86036-010-6">{{cite book|vauthors=Healy D|title=The Psychopharmacologists|volume=2|publisher=A Hodder Arnold Publication|year=1998|pages=132–4|isbn=978-1-86036-010-7}}</ref>

Selikoff and Robitzek also experimented with another anti-tuberculosis drug, [[iproniazid]]; it showed a greater psychostimulant effect, but more pronounced toxicity.<ref name="pmid12998444">{{cite journal|vauthors=Robitzek EH, Selikoff IJ, Mamlok E, Tendlau A|title=Isoniazid and Its Isopropyl Derivative in the Therapy of Tuberculosis in Humans: Comparative Therapeutic and Toxicologic Properties|journal=Chest|volume=23|issue=1|pages=1–15|year=1953|pmid=12998444|doi=10.1378/chest.23.1.1}}</ref> Later, Jackson Smith, Gordon Kamman, George E. Crane, and [[Frank Ayd]], described the psychiatric applications of iproniazid. [[Ernst Zeller]] found iproniazid to be a potent [[monoamine oxidase inhibitor]].<ref name="pmid18004120">{{cite journal|vauthors=López-Muñoz F, Alamo C, Juckel G, Assion HJ|title=Half a Century of Antidepressant Drugs|journal=Journal of Clinical Psychopharmacology|volume=27|issue=6|pages=555–9|year=2007|pmid=18004120|doi=10.1097/jcp.0b013e3181bb617}}</ref> Nevertheless, iproniazid remained relatively obscure until [[Nathan S. Kline]], the influential head of research at [[Rockland State Hospital]], began to popularize it in the medical and popular press as a "psychic energizer".<ref name="pmid18004120" /><ref>{{cite news|title=Psychic Energizer|url=http://www.time.com/time/magazine/article/0,9171,862555,00.html|date=15 April 1957|magazine=Time|access-date=28 May 2009|archive-url=https://web.archive.org/web/20130811223331/http://www.time.com/time/magazine/article/0%2C9171%2C862555%2C00.html|archive-date=11 August 2013}}</ref> Roche put a significant marketing effort behind iproniazid.<ref name="pmid18004120" /> Its sales grew until it was recalled in 1961, due to reports of lethal [[hepatotoxicity]].<ref name="pmid18004120" />

The antidepressant effect of a [[tricyclic antidepressant]], a three-ringed compound, was first discovered in 1957 by [[Roland Kuhn]] in a Swiss [[psychiatric hospital]]. [[Antihistamine]] derivatives were used to treat surgical shock and later as [[neuroleptics]]. Although in 1955, [[reserpine]] was shown to be more effective than a placebo in alleviating anxious depression, neuroleptics were being developed as [[sedative]]s and [[antipsychotic]]s.{{medical citation needed|date=March 2013}}

Attempting to improve the effectiveness of [[chlorpromazine]], Kuhn {{emdash}} in conjunction with the [[Geigy]] Pharmaceutical Company {{emdash}} discovered the compound "G 22355", later renamed [[imipramine]]. Imipramine had a beneficial effect on patients with depression who showed mental and [[motor retardation]]. Kuhn described his new compound as a "thymoleptic" "taking hold of the emotions," in contrast with neuroleptics, "taking hold of the nerves" in 1955–56. These gradually became established, resulting in the patent and manufacture in the US in 1951 by Häfliger and SchinderA.<ref>{{cite journal|author=Kuhn R|title=The treatment of depressive states with G 22355 (Imipramine Hydrochloride)|journal=The American Journal of Psychiatry|volume=115|issue=5|pages=459–64|year=1958|pmid=13583250|doi=10.1176/ajp.115.5.459}}</ref>

Antidepressants became [[prescription drug]]s in the 1950s. It was estimated that no more than fifty to one hundred individuals per million had the kind of depression that these new drugs would treat, and pharmaceutical companies were not enthusiastic about marketing for this small market. Sales through the 1960s remained poor compared to the sales of tranquilizers,<ref>{{cite web|title=Tranquilizers|url=http://www.cmcsb.com/tranquil.htm|archive-url=https://web.archive.org/web/20120916074410/http://www.cmcsb.com/tranquil.htm|archive-date=16 September 2012|access-date=20 November 2013|website=Cumberland Mountain Community Services|publisher=cmcsb.com}}</ref>{{Unreliable medical source|date=March 2013}} which were being marketed for different uses.<ref name="3faces">{{cite journal|author=Healy D|year=1999|title=The Three Faces of the Antidepressants: A Critical Commentary on the Clinical-Economic Context of Diagnosis|journal=The Journal of Nervous & Mental Disease|volume=187|issue=3|pages=174–80|doi=10.1097/00005053-199903000-00007|pmid=10086474}}</ref> Imipramine remained in common use and numerous successors were introduced. The use of monoamine oxidase inhibitors (MAOI) increased after the development and introduction of "reversible" forms affecting only the MAO-A subtype of inhibitors, making this drug safer to use.<ref name="3faces" /><ref>{{cite journal|author=Pletscher A|year=1991|title=The discovery of antidepressants: A winding path|journal=Experientia|volume=47|issue=1|pages=4–8|doi=10.1007/BF02041242|pmid=1999242|s2cid=112210}}</ref>

By the 1960s, it was thought that the mode of action of tricyclics was to inhibit norepinephrine reuptake. However, norepinephrine reuptake became associated with stimulating effects. Later tricyclics were thought to affect [[serotonin]] as proposed in 1969 by Carlsson and Lindqvist as well as Lapin and Oxenkrug.{{medical citation needed|date=March 2013}}

===Second-generation antidepressants===
{{Main|Second-generation antidepressants}}

Researchers began a process of [[rational drug design]] to isolate antihistamine-derived compounds that would selectively target these systems. The first such compound to be patented was [[zimelidine]] in 1971, while the first released clinically was [[indalpine]]. [[Fluoxetine]] was approved for commercial use by the US [[Food and Drug Administration]] (FDA) in 1988, becoming the first [[Blockbuster drug|blockbuster]] SSRI. Fluoxetine was developed at [[Eli Lilly and Company]] in the early 1970s by [[Bryan Molloy]], [[Klaus Schmiegel]], [[David T. Wong]], and others.<ref>{{cite journal|author=Domino EF|title=History of modern psychopharmacology: A personal view with an emphasis on antidepressants|journal=Psychosomatic Medicine|volume=61|issue=5|pages=591–8|year=1999|pmid=10511010|doi=10.1097/00006842-199909000-00002|url=http://www.psychosomaticmedicine.org/cgi/pmidlookup?view=long&pmid=10511010}}</ref><ref>{{cite journal|vauthors=Wong DT, Bymaster FP, Horng JS, Molloy BB|title=A new selective inhibitor for uptake of serotonin into synaptosomes of rat brain: 3-(p-trifluoromethylphenoxy). N-methyl-3-phenylpropylamine|journal=The Journal of Pharmacology and Experimental Therapeutics|volume=193|issue=3|pages=804–11|year=1975|doi=10.1016/S0022-3565(25)30202-8 |pmid=1151730|url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=1151730|access-date=24 April 2009|archive-date=19 November 2021|archive-url=https://web.archive.org/web/20211119145719/https://jpet.aspetjournals.org/content/193/3/804.long|url-access=subscription}}</ref> SSRIs became known as "novel antidepressants" along with other newer drugs such as SNRIs and [[Norepinephrine Reuptake Inhibitor|NRIs]] with various selective effects.<ref>{{cite journal|doi=10.1016/0924-9338(96)88597-X|title=Tolerability and safety of novel antidepressants|year=1996|vauthors=Freeman H|journal=European Psychiatry|volume=11|pages=206s|s2cid=144286291}}</ref>

===Rapid-acting antidepressants===
[[Esketamine]] (brand name Spravato), the first rapid-acting antidepressant to be approved for clinical treatment of depression, was introduced for this indication in March 2019 in the United States.<ref name="SpravatoLabel" />

====Research====
A 2016 [[randomized controlled trial]] evaluated the [[#Rapid-acting antidepressants|rapid antidepressant]] effects of the psychedelic [[Ayahuasca]] in treatment-resistant depression with a positive outcome.<ref>{{cite journal|vauthors=Palhano-Fontes F, Barreto D, Onias H, Andrade KC, Novaes MM, Pessoa JA, Mota-Rolim SA, Osório FL, Sanches R, Dos Santos RG, Tófoli LF, de Oliveira Silveira G, Yonamine M, Riba J, Santos FR, Silva-Junior AA, Alchieri JC, Galvão-Coelho NL, Lobão-Soares B, Hallak JE, Arcoverde E, Maia-de-Oliveira JP, Araújo DB|title=Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial|journal=Psychological Medicine|volume=49|issue=4|pages=655–663|date=March 2019|pmid=29903051|pmc=6378413|doi=10.1017/S0033291718001356|doi-access=free}}</ref><ref>{{cite journal|title=Antidepressant Effects of Ayahuasca: a Randomized Placebo Controlled Trial in Treatment Resistant Depression – Full Text View – ClinicalTrials.gov|url=https://clinicaltrials.gov/ct2/show/NCT02914769|website=clinicaltrials.gov|date=15 February 2017|vauthors=de Araujo DB}}</ref> In 2018, the FDA granted Breakthrough Therapy Designation for [[psilocybin]]-assisted therapy for treatment-resistant depression and in 2019, the FDA granted Breakthrough Therapy Designation for psilocybin therapy treating major depressive disorder.<ref>{{cite web|date=22 November 2019|title=FDA grants Breakthrough Therapy Designation to Usona Institute's psilocybin program for major depressive disorder|url=https://www.businesswire.com/news/home/20191122005452/en/FDA-grants-Breakthrough-Therapy-Designation-to-Usona-Institutes-psilocybin-program-for-major-depressive-disorder|access-date=17 September 2020|website=businesswire.com}}</ref>

=== Publication bias and aged research ===
A 2018 systematic review published in [[The Lancet]] comparing the efficacy of 21 different first and second generation antidepressants found that antidepressant drugs tended to perform better and cause less adverse events when they were novel or experimental treatments compared to when they were evaluated again years later.<ref name="Zhou-2020" /> Unpublished data was also associated with smaller positive effect sizes. However, the review did not find evidence of bias associated with industry funded research.

==Society and culture==

===Prescription trends===

==== United Kingdom ====
In the UK, figures reported in 2010 indicated that the number of antidepressants prescribed by the [[National Health Service]] (NHS) almost doubled over a decade.<ref>{{cite news|vauthors=Davis R|date=11 June 2010|title=Antidepressant Use Rises as Recession Feeds Wave of Worry|newspaper=The Guardian|location=London|url=https://www.theguardian.com/society/2010/jun/11/antidepressant-prescriptions-rise-nhs-recession|url-status=live|access-date=1 July 2010|archive-url=https://web.archive.org/web/20100615165456/http://www.guardian.co.uk/society/2010/jun/11/antidepressant-prescriptions-rise-nhs-recession|archive-date=15 June 2010}}</ref> Further analysis published in 2014 showed that number of antidepressants dispensed annually in the community went up by 25 million in the 14 years between 1998 and 2012, rising from 15 million to 40 million. Nearly 50% of this rise occurred in the four years after the [[Great Recession]], during which time the annual increase in prescriptions rose from 6.7% to 8.5%.<ref>{{cite web|vauthors=Spence R|title=Focus on: Antidepressant prescribing|url=http://www.qualitywatch.org.uk/focus-on/antidepressant-prescribing|url-status=live|archive-url=https://web.archive.org/web/20150204194028/http://www.qualitywatch.org.uk/focus-on/antidepressant-prescribing|archive-date=4 February 2015|access-date=12 January 2015|website=QualityWatch|publisher=QualityWatch (Nuffield Trust/Health Foundation)}}</ref> These sources also suggest that aside from the recession, other factors that may influence changes in prescribing rates may include: improvements in diagnosis, a reduction of the [[Social stigma|stigma]] surrounding mental health, broader prescribing trends, GP characteristics, geographical location, and housing status. Another factor that may contribute to increasing consumption of antidepressants is the fact that these medications now are used for other conditions including [[social anxiety]] and [[post-traumatic stress disorder]].

Between 2005 and 2017, the number of adolescents (12 to 17 years) in England who were prescribed antidepressants has doubled. On the other hand, antidepressant prescriptions for children aged 5–11 in England decreased between 1999 and 2017.<ref>{{cite journal|date=18 November 2020|title=Teenagers' use of antidepressants is rising with variations across regions and ethnic groups|url=https://evidence.nihr.ac.uk/alert/teenagers-use-of-antidepressants-is-rising-with-variations-across-regions-and-ethnic-groups/|journal=NIHR Evidence|type=Plain English summary|publisher=National Institute for Health and Care Research|doi=10.3310/alert_42239|s2cid=240759939|url-access=subscription}}</ref><ref>{{cite journal|vauthors=Jack RH, Hollis C, Coupland C, Morriss R, Knaggs RD, Butler D, Cipriani A, Cortese S, Hippisley-Cox J|title=Incidence and prevalence of primary care antidepressant prescribing in children and young people in England, 1998–2017: A population-based cohort study|journal=PLOS Medicine|volume=17|issue=7|article-number=e1003215|date=July 2020|pmid=32697803|pmc=7375537|doi=10.1371/journal.pmed.1003215|veditors=Hellner C|doi-access=free}}</ref> From April 2015, prescriptions increased for both age groups (for people aged 0 to 17) and peaked during the first COVID lockdown in March 2020.<ref>{{cite web|vauthors=Robinson J|title=Peaks in number of young people prescribed antidepressants coincide with lockdowns|url=https://pharmaceutical-journal.com/article/news/peaks-in-number-of-young-people-prescribed-antidepressants-coincide-with-lockdowns|access-date=4 November 2022|website=The Pharmaceutical Journal|date=23 June 2021}}</ref>

According to [[National Institute for Health and Care Excellence]] (NICE) guidelines, antidepressants for children and adolescents with depression and obsessive-compulsive disorder (OCD) should be prescribed together with therapy and after being assessed by a [[Child and adolescent psychiatry|child and adolescent psychiatrist]]. However, between 2006 and 2017, only 1 in 4 of 12–17 year-olds who were prescribed an SSRI by their GP had seen a specialist psychiatrist and 1 in 6 has seen a pediatrician. Half of these prescriptions were for depression and 16% for anxiety, the latter not being licensed for treatment with antidepressants.<ref name="NIHR-2022"/><ref>{{cite journal|vauthors=Jack RH, Joseph RM, Coupland C, Butler D, Hollis C, Morriss R, Knaggs RD, Cipriani A, Cortese S, Hippisley-Cox J|title=Secondary care specialist visits made by children and young people prescribed antidepressants in primary care: a descriptive study using the QResearch database|journal=BMC Medicine|volume=18|issue=1|article-number=93|date=April 2020|pmid=32349753|pmc=7191694|doi=10.1186/s12916-020-01560-7|doi-access=free}}</ref> Among the suggested possible reasons why GPs are not following the guidelines are the difficulties of accessing talking therapies, long waiting lists, and the urgency of treatment.<ref name="NIHR-2022" /><ref>{{cite web|date=4 November 2022|title=GPs giving antidepressants to children against guidelines|url=https://www.theguardian.com/society/2022/nov/04/gps-giving-antidepressants-to-children-against-guidelines|access-date=5 November 2022|website=The Guardian}}</ref> According to some researchers, strict adherence to treatment guidelines would limit access to effective medication for young people with mental health problems.<ref>{{cite journal|vauthors=Walkup JT, Strawn JR|title=High-quality antidepressant prescribing: please consider whether "perfection is the enemy of progress"|journal=BMC Medicine|volume=18|issue=1|article-number=150|date=May 2020|pmid=32438910|pmc=7243321|doi=10.1186/s12916-020-01621-x|doi-access=free}}</ref>

==== United States ====
In the United States, antidepressants were the most commonly prescribed medication in 2013.<ref name="AJantidepressantstatsUS" /> Of the estimated 16 million "long term" (over 24 months) users, roughly 70 percent are female.<ref name="AJantidepressantstatsUS">{{cite web|vauthors=White R|title=Waking up from sadness: Many find trouble getting off antidepressants|url=http://america.aljazeera.com/articles/2014/1/22/patients-mostly-womenfindtroublegettingoffofantidepressants.html|publisher=Al Jazeera|access-date=8 June 2014|url-status=live|archive-url=https://web.archive.org/web/20140714142717/http://america.aljazeera.com/articles/2014/1/22/patients-mostly-womenfindtroublegettingoffofantidepressants.html|archive-date=14 July 2014}}</ref> {{As of|2017}}, about 16.5% of white people in the United States took antidepressants compared with 5.6% of black people in the United States.<ref name="APP2017">{{cite web|title=By the numbers: Antidepressant use on the rise|url=https://www.apa.org/monitor/2017/11/numbers.aspx|website=apa.org|access-date=1 February 2019}}</ref>

[[File:Sertraline2DACS2.svg|thumb|alt=<!--empty-->|link=<!--empty-->|class=skin-invert-image|Structural formula of the SSRI [[sertraline]]]]

'''United States:''' The most commonly prescribed antidepressants in the US retail market in 2010 were:<ref>{{cite web|title=Top 200 generic drugs by units in 2010|url=http://drugtopics.modernmedicine.com/drugtopics/data/articlestandard//drugtopics/252011/727243/article.pdf|archive-url=https://web.archive.org/web/20121215070930/http://drugtopics.modernmedicine.com/drugtopics/data/articlestandard//drugtopics/252011/727243/article.pdf|archive-date=15 December 2012}}{{cite web|title=Top 200 brand drugs by units in 2010|url=http://drugtopics.modernmedicine.com/drugtopics/data/articlestandard//drugtopics/252011/727256/article.pdf|archive-url=https://web.archive.org/web/20120422181417/http://drugtopics.modernmedicine.com/drugtopics/data/articlestandard//drugtopics/252011/727256/article.pdf|archive-date=22 April 2012}}</ref>

{| class="wikitable sortable"
|-
! scope="col" | '''Drug name'''
! scope="col" | '''Drug class'''
! scope="col" | '''Total prescriptions'''
|-
| [[Sertraline]]
| [[SSRI]]
| 33,409,838
|-
| [[Citalopram]]
| [[SSRI]]
| 27,993,635
|-
| [[Fluoxetine]]
| [[SSRI]]
| 24,473,994
|-
| [[Escitalopram]]
| [[SSRI]]
| 23,000,456
|-
| [[Trazodone]]
| [[Serotonin antagonist and reuptake inhibitor|SARI]]
| 18,786,495
|-
|[[Venlafaxine]] (all formulations)
|[[Serotonin–norepinephrine reuptake inhibitor|SNRI]]
|16,110,606
|-
|[[Bupropion]] (all formulations)
|[[Norepinephrine–dopamine reuptake inhibitor|NDRI]]
|15,792,653
|-
| [[Duloxetine]]
| [[Serotonin–norepinephrine reuptake inhibitor|SNRI]]
| 14,591,949
|-
| [[Paroxetine]]
| [[SSRI]]
| 12,979,366
|-
| [[Amitriptyline]]
| [[Tricyclic antidepressant|TCA]]
| 12,611,254
|-
| [[Venlafaxine]] XR
| [[Serotonin–norepinephrine reuptake inhibitor|SNRI]]
| 7,603,949
|-
| [[Bupropion]] XL
| [[Norepinephrine–dopamine reuptake inhibitor|NDRI]]
| 7,317,814
|-
| [[Mirtazapine]]
| [[Tetracyclic antidepressant|TeCA]]
| 6,308,288
|-
| [[Venlafaxine]] ER
| [[Serotonin–norepinephrine reuptake inhibitor|SNRI]]
| 5,526,132
|-
| [[Bupropion]] SR
| [[Norepinephrine–dopamine reuptake inhibitor|NDRI]]
| 4,588,996
|-
| [[Desvenlafaxine]]
| [[Serotonin–norepinephrine reuptake inhibitor|SNRI]]
| 3,412,354
|-
| [[Nortriptyline]]
| [[Tricyclic antidepressant|TCA]]
| 3,210,476
|-
| [[Bupropion]] ER
| [[Norepinephrine–dopamine reuptake inhibitor|NDRI]]
| 3,132,327
|-
| [[Venlafaxine]]
| [[Serotonin–norepinephrine reuptake inhibitor|SNRI]]
| 2,980,525
|-
| [[Bupropion]]
| [[Norepinephrine–dopamine reuptake inhibitor|NDRI]]
| 753,516
|}

'''Netherlands:''' In the Netherlands, [[paroxetine]] is the most prescribed antidepressant, followed by [[amitriptyline]], [[citalopram]] and [[venlafaxine]].<ref>{{cite web|url=http://www.gipdatabank.nl/index.asp?scherm=tabellenFrameSet&infoType=g&tabel=01-basis&item=N06AB|title=GIPdatabank|publisher=Gipdatabank.nl|access-date=6 November 2008|archive-url=https://web.archive.org/web/20081206123718/http://www.gipdatabank.nl/index.asp?scherm=tabellenFrameSet&infoType=g&tabel=01-basis&item=N06AB|archive-date=6 December 2008}}</ref>

===Adherence===
{{Main|Adherence (medicine)}}

{{As of|2003}}, worldwide, 30% to 60% of people did not follow their practitioner's instructions about taking their antidepressants,<ref>{{cite web|url=https://www.who.int/chp/knowledge/publications/adherence_full_report.pdf?ua=1|title=Adherence to Long Term Therapies: Evidence for Action|date=2003|publisher=World Health Organization}}</ref> and {{As of|2013|lc=y}} in the US, it appeared that around 50% of people did not take their antidepressants as directed by their practitioner.<ref name="Kaplan-2013">{{cite journal|vauthors=Kaplan JE, Keeley RD, Engel M, Emsermann C, Brody D|title=Aspects of patient and clinician language predict adherence to antidepressant medication|journal=Journal of the American Board of Family Medicine|volume=26|issue=4|pages=409–420|date=July 2013|pmid=23833156|doi=10.3122/jabfm.2013.04.120201|doi-access=free}}</ref>

When people fail to take their antidepressants, there is a greater risk that the drug will not help, that symptoms get worse, that they miss work or are less productive at work, and that the person may be hospitalized.<ref name="Ho2016">{{cite journal|vauthors=Ho SC, Chong HY, Chaiyakunapruk N, Tangiisuran B, Jacob SA|title=Clinical and economic impact of non-adherence to antidepressants in major depressive disorder: A systematic review|journal=Journal of Affective Disorders|volume=193|pages=1–10|date=March 2016|pmid=26748881|doi=10.1016/j.jad.2015.12.029}}</ref>

===Social science perspective===
Some academics{{Who|date=March 2023}} have highlighted the need to examine the use of antidepressants and other medical treatments in cross-cultural terms, because various cultures prescribe and observe different manifestations, symptoms, meanings, and associations of depression and other medical conditions within their populations.<ref name="Ecks_2005">{{cite journal|author=Ecks S|s2cid=23046695|title=Pharmaceutical Citizenship: Antidepressant Marketing and the Promise of Demarginalization in India|journal=Anthropology & Medicine|year=2005|volume=12|issue=3|pages=239–254|doi=10.1080/13648470500291360|pmid=26873669}}</ref><ref name="Lock_2010">{{cite book|vauthors=Lock M, Nguyen VK|title=An anthropology of biomedicine|url=https://archive.org/details/anthropologybiom00lock|url-access=limited|date=2010|publisher=Wiley-Blackwell|location=Chichester, West Sussex|isbn=978-1-4051-1071-6|edition=1st|chapter="Local Biologies and Human Difference|pages=[https://archive.org/details/anthropologybiom00lock/page/n97 83]–109}}</ref> These cross-cultural discrepancies, it has been argued, then have implications on the perceived efficacy and use of antidepressants and other strategies in the treatment of depression in these different cultures.<ref name="Ecks_2005" /><ref name="Lock_2010" /> In India, antidepressants are largely seen as tools to combat marginality, promising the individual the ability to reintegrate into society through their use—a view and association not observed in the West.<ref name="Ecks_2005" />

===Environmental impacts===
Because most antidepressants function by inhibiting the reuptake of neurotransmitters serotonin, dopamine, and norepinephrine<ref name="pmid17690258">{{cite journal|vauthors=Zhou Z, Zhen J, Karpowich NK, Goetz RM, Law CJ, Reith ME, Wang DN|title=LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake|journal=Science|volume=317|issue=5843|pages=1390–3|year=2007|pmid=17690258|pmc=3711652|doi=10.1126/science.1147614|bibcode=2007Sci...317.1390Z}}</ref> these drugs can interfere with natural neurotransmitter levels in other organisms impacted by indirect exposure.<ref>{{cite book|veditors=Daughton CG, Jones-Lepp TJ|title=Pharmaceuticals and personal care products in the environment: scientific and regulatory issues|year=2001|publisher=American Chemical Society|location=Washington, DC|isbn=978-0-8412-3739-1|chapter=Antidepressants in Aquatic Organisms: A Wide Range of Effects|author=Fong PP|pages=264–281}}</ref> Antidepressants fluoxetine and sertraline have been detected in aquatic organisms residing in effluent-dominated streams.<ref name="pmid15720009">{{cite journal|vauthors=Brooks BW, Chambliss CK, Stanley JK, Ramirez A, Banks KE, Johnson RD, Lewis RJ|title=Determination of select antidepressants in fish from an effluent-dominated stream|journal=Environ. Toxicol. Chem.|volume=24|issue=2|pages=464–9|year=2005|pmid=15720009|doi=10.1897/04-081r.1|bibcode=2005EnvTC..24..464B |s2cid=27420248}}</ref> The presence of antidepressants in surface waters and aquatic organisms has caused concern because ecotoxicological effects on aquatic organisms due to fluoxetine exposure have been demonstrated.<ref name="pmid16257063">{{cite journal|vauthors=Fent K, Weston AA, Caminada D|title=Ecotoxicology of human pharmaceuticals|journal=Aquat. Toxicol.|volume=76|issue=2|pages=122–59|year=2006|pmid=16257063|doi=10.1016/j.aquatox.2005.09.009|bibcode=2006AqTox..76..122F}}</ref>

Coral reef fish have been demonstrated to modulate aggressive behavior through serotonin.<ref>{{cite journal|vauthors=Winberg S, Carter CG, McCarthy JD, He XY, Nilsson GE, Houlihan DF|title=Feeding rank and brain serotonergic activity in rainbow trout ''Onchorhynchus my kiss''|journal=J. Exp. Biol.|volume=179|year=1993|issue=1 |pages=197–211|doi=10.1242/jeb.179.1.197|bibcode=1993JExpB.179..197W }}</ref> Artificially increasing serotonin levels in crustaceans can temporarily reverse social status and turn subordinates into aggressive and territorial dominant males.<ref name="pmid9159179">{{cite journal|vauthors=Huber R, Smith K, Delago A, Isaksson K, Kravitz EA|title=Serotonin and aggressive motivation in crustaceans: altering the decision to retreat|journal=Proc. Natl. Acad. Sci. U.S.A.|volume=94|issue=11|pages=5939–42|year=1997|pmid=9159179|pmc=20885|doi=10.1073/pnas.94.11.5939|bibcode=1997PNAS...94.5939H|doi-access=free}}</ref>

Exposure to Fluoxetine has been demonstrated to increase serotonergic activity in fish, subsequently reducing aggressive behavior.<ref name="pmid12954414">{{cite journal|vauthors=Perreault HA, Semsar K, Godwin J|s2cid=39464936|title=Fluoxetine treatment decreases territorial aggression in a coral reef fish|journal=Physiol. Behav.|volume=79|issue=4–5|pages=719–24|year=2003|pmid=12954414|doi=10.1016/S0031-9384(03)00211-7}}</ref> Perinatal exposure to Fluoxetine at relevant environmental concentrations has been shown to lead to significant modifications of memory processing in 1-month-old cuttlefish.<ref name="pmid23474317">{{cite journal|vauthors=Di Poi C, Darmaillacq AS, Dickel L, Boulouard M, Bellanger C|title=Effects of perinatal exposure to waterborne Fluoxetine on memory processing in the cuttlefish Sepia officinalis|journal=Aquat. Toxicol.|volume=132–133|pages=84–91|year=2013|pmid=23474317|doi=10.1016/j.aquatox.2013.02.004|bibcode=2013AqTox.132...84D}}</ref> This impairment may disadvantage cuttlefish and decrease their survival. Somewhat less than 10% of orally administered Fluoxetine is excreted from humans unchanged or as [[glucuronide]].<ref name="pmid10674711">{{cite journal|vauthors=Hiemke C, Härtter S|title=Pharmacokinetics of selective serotonin reuptake inhibitors|journal=Pharmacology & Therapeutics|volume=85|issue=1|pages=11–28|date=January 2000|pmid=10674711|doi=10.1016/s0163-7258(99)00048-0|url=http://www.science.smith.edu/departments/Biochem/Chm_357/Articles/SSRIs.pdf|archive-url=https://web.archive.org/web/20140523225824/http://www.science.smith.edu/departments/Biochem/Chm_357/Articles/SSRIs.pdf|archive-date=23 May 2014}}</ref><ref name="pmid17160491">{{cite journal|vauthors=Nentwig G|title=Effects of pharmaceuticals on aquatic invertebrates. Part II: the antidepressant drug Fluoxetine|journal=Archives of Environmental Contamination and Toxicology|volume=52|issue=2|pages=163–170|date=February 2007|pmid=17160491|doi=10.1007/s00244-005-7190-7|bibcode=2007ArECT..52..163N|s2cid=22309647}}</ref>

==See also==
{{Commons category|Antidepressants}}

* [[Antidepressants in Japan]]
* [[Atypical antidepressant]]
* [[Depression and natural therapies]]
* [[Depression in childhood and adolescence]]
* [[List of investigational antidepressants]]
* [[Management of depression]]
* [[Single-dose long-acting CNS drug]]

==References==
{{Reflist}}

==Further reading==
* {{cite book|vauthors=Stahl SM|title=Psychopharmacology of Antidepressants|publisher=Informa Healthcare|year=1997|isbn=978-1-85317-513-8}}

==External links==
{{Wiktionary|antidepressant}}
*{{Commons category-inline|Antidepressants}}

{{See also for drug classes defined by psychological effects|Antidepressants}}
{{Antidepressants}}
{{Major drug groups}}
{{Chemical classes of psychoactive drugs}}
{{Authority control}}

[[Category:Anaphrodisiacs]]
[[Category:Antidepressants| ]]
[[Category:Major depressive disorder]]
[[Category:Drugs by psychological effects]]