antidepressant

Antidepressants are prescribed to treat major depressive disorder (MDD), anxiety disorders, chronic pain, and some addictions. Antidepressants are often used in combination with one another.

Despite its longstanding prominence in pharmaceutical advertising, the idea that low serotonin levels cause depression is not supported by scientific evidence.{{cite book|vauthors=Whitaker R, Cosgrove L|date=23 April 2015|title=Psychiatry Under the Influence: Institutional Corruption, Social Injury, and Prescriptions for Reform|publisher=Palgrave Macmillan US|url=https://play.google.com/store/books/details?id=QYwEogEACAAJ|isbn=9781137506924}}{{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}}{{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}} Proponents of the monoamine hypothesis of depression recommend choosing an antidepressant which impacts the most prominent symptoms. Under this practice, for example, a person with MDD who is also anxious or irritable would be treated with selective serotonin reuptake inhibitors (SSRIs) or norepinephrine reuptake inhibitors, while a person suffering from loss of energy and enjoyment of life would take a norepinephrine–dopamine reuptake inhibitor.{{cite journal|vauthors=Nutt DJ|title=Relationship of neurotransmitters to the symptoms of major depressive disorder|journal=The Journal of Clinical Psychiatry|volume=69|issue=suppl E1|pages=4–7|date=30 April 2008|pmid=18494537|url=http://www.psychiatrist.com/jcp/article/pages/2008/v69e01/v69e0101.aspx|archive-date=3 August 2020|access-date=3 August 2020|archive-url=https://web.archive.org/web/20200803182514/http://www.psychiatrist.com/JCP/article/Pages/2008/v69e01/v69e0101.aspx|url-status=dead}}

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".{{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}} 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.

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.{{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}}

Reviews of antidepressants generally find that they benefit adults with depression. On the other hand, some contend that most studies on antidepressant medication are confounded by several biases: the lack of an active placebo, which means that many people in the placebo arm of a double-blind study may deduce that they are not getting any true treatment, thus destroying double-blindness; a short follow up after termination of treatment; non-systematic recording of adverse effects; very strict exclusion criteria in samples of patients; studies being paid for by the industry; selective publication of results. This means that the small beneficial effects that are found may not be statistically significant.{{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}}{{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}}{{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}}{{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}}

Among the 21 most commonly prescribed antidepressants, the most effective and well-tolerated are escitalopram, paroxetine, sertraline, agomelatine, and mirtazapine. 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.{{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}}{{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}}{{cite journal|vauthors=Boaden K, Tomlinson A, Cortese S, Cipriani A|title=Antidepressants in Children and Adolescents: Meta-Review of Efficacy, Tolerability and Suicidality in Acute Treatment|journal=Frontiers in Psychiatry|volume=11|pages=717|date=2 September 2020|pmid=32982805|pmc=7493620|doi=10.3389/fpsyt.2020.00717|doi-access=free}}{{cite journal|vauthors=Hetrick SE, McKenzie JE, Bailey AP, Sharma V, Moller CI, Badcock PB, Cox GR, Merry SN, Meader N|title=New generation antidepressants for depression in children and adolescents: a network meta-analysis|journal=The Cochrane Database of Systematic Reviews|volume=2021|issue=5|pages=CD013674|date=May 2021|pmid=34029378|pmc=8143444|doi=10.1002/14651858.CD013674.pub2|collaboration=Cochrane Common Mental Disorders Group}} Sertraline, escitalopram, and duloxetine may also help reduce symptoms.

A 2023 systematic review and meta-analysis of randomized controlled trials of antidepressants for major depressive disorder found that the medications provided only small or doubtful benefits in terms of quality of life.{{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}} 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.{{cite journal|vauthors=Teng T, Zhang Z, Yin B, Guo T, Wang X, Hu J, Ran X, Dai Q, Zhou X|title=Effect of antidepressants on functioning and quality of life outcomes in children and adolescents with major depressive disorder: a systematic review and meta-analysis|journal=Transl Psychiatry|volume=12|issue=1|pages=183|date=May 2022|pmid=35508443|pmc=9068747|doi=10.1038/s41398-022-01951-9}} Quality of life as an outcome measure is often selectively reported in trials of antidepressants.{{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}}

For children and adolescents, fluvoxamine and escitalopram are effective in treating a range of anxiety disorders.{{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}}{{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}} Fluoxetine, sertraline, and paroxetine can also help with managing various forms of anxiety in children and adolescents.

Meta-analyses of published and unpublished trials have found that antidepressants have a placebo-subtracted effect size (standardized mean difference or SMD) in the treatment of anxiety disorders of around 0.3, which equates to a small improvement and is roughly the same magnitude of benefit as their effectiveness in the treatment of depression. 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.{{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}} 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.

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

Some antidepressants are used as a treatment for social anxiety disorder, but their efficacy is not entirely convincing, as only a small proportion of antidepressants showed some effectiveness for this condition. Paroxetine was the first drug to be FDA-approved for this disorder. Its efficacy is considered beneficial, although not everyone responds favorably to the drug. Sertraline and fluvoxamine extended-release were later approved for it as well, while escitalopram is used off-label with acceptable efficiency. However, there is not enough evidence to support citalopram for treating social anxiety disorder, and fluoxetine was no better than a placebo in clinical trials. SSRIs are used as a first-line treatment for social anxiety, but they do not work for everyone. One alternative would be venlafaxine, an SNRI, which has shown benefits for social phobia in five clinical trials against a placebo, while the other SNRIs are not considered particularly useful for this disorder as many of them did not undergo testing for it. {{As of|2008}}, it is unclear if duloxetine and desvenlafaxine can provide benefits for people with social anxiety. However, another class of antidepressants called MAOIs are considered effective for social anxiety, but they come with many unwanted side effects and are rarely used. Phenelzine was shown to be a good treatment option, but its use is limited by dietary restrictions. Moclobemide is a RIMA and showed mixed results, but still received approval in some European countries for social anxiety disorder. TCA antidepressants, such as clomipramine and imipramine, are not considered effective for this anxiety disorder in particular. This leaves out SSRIs such as paroxetine, sertraline, and fluvoxamine CR as acceptable and tolerated treatment options for this disorder.{{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}}{{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}}

SSRIs are a second-line treatment for adult obsessive–compulsive disorder (OCD) with mild functional impairment, and a first-line treatment for those with moderate or severe impairment.{{cite journal|vauthors=Soomro GM, Altman D, Rajagopal S, Oakley-Browne M|date=January 2008|title=Selective serotonin re-uptake inhibitors (SSRIs) versus placebo for obsessive compulsive disorder (OCD)|journal=The Cochrane Database of Systematic Reviews|volume=2008|issue=1|pages=CD001765|doi=10.1002/14651858.CD001765.pub3|pmc=7025764|pmid=18253995}}{{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}}{{cite web|title=Paroxetine prescribing information|url=https://www.apotex.com/us/en/products/downloads/pil/paxil_irtb_ins.pdf|url-status=dead|archive-url=https://web.archive.org/web/20150219055046/https://www.apotex.com/us/en/products/downloads/pil/paxil_irtb_ins.pdf|archive-date=19 February 2015|access-date=30 January 2015}}{{cite web|title=Sertraline prescribing information|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019839s070,020990s032lbl.pdf|url-status=dead|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}}

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

Clomipramine, a TCA drug, is considered effective and useful for OCD.{{Citation |last=Wilson |first=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}} 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.{{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}}

Placebo responses are a large component of the benefit of antidepressants in the treatment of depression and anxiety. However, placebo responses with antidepressants are lower in magnitude in the treatment of OCD compared to depression and anxiety.{{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}} 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.

Antidepressants are one of the treatment options for PTSD. However, their efficacy is not well established. Paroxetine and sertraline have been FDA approved for the treatment of PTSD. Paroxetine has slightly higher response and remission rates than sertraline for this condition. However, neither drug is considered very helpful for a broad patient demographic. Fluoxetine and venlafaxine are used off-label. Fluoxetine has produced unsatisfactory mixed results. Venlafaxine showed response rates of 78%, which is significantly higher than what paroxetine and sertraline achieved. However, it did not address as many symptoms of PTSD as paroxetine and sertraline, in part due to the fact that venlafaxine is an SNRI. This class of drugs inhibits the reuptake of norepinephrine, which may cause anxiety in some patients. Fluvoxamine, escitalopram, and citalopram were not well-tested for this disorder. MAOIs, while some of them may be helpful, are not used much because of their unwanted side effects. This leaves paroxetine and sertraline as acceptable treatment options for some people, although more effective antidepressants are needed.{{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}}

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

Antidepressants are recommended as an alternative or additional first step to self-help programs in the treatment of bulimia nervosa.{{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}} 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.{{cite web|url=https://www.nlm.nih.gov/medlineplus/druginfo/meds/a695033.html|title=Bupropion: MedlinePlus Drug Information|access-date=24 May 2016|url-status=live|archive-url=https://web.archive.org/web/20160508110157/https://www.nlm.nih.gov/medlineplus/druginfo/meds/a695033.html|archive-date=8 May 2016}}

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

Clinical trials have generated mostly negative results for the use of SSRIs in the treatment of anorexia nervosa.{{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}} Treatment guidelines from the National Institute of Health and Care Excellence (NICE) 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.

A 2012 meta-analysis concluded that antidepressant treatment favorably affects pain, health-related quality of life, depression, and sleep in fibromyalgia syndrome. Tricyclics appear to be the most effective class, with moderate effects on pain and sleep, and small effects on fatigue and health-related quality of life. The fraction of people experiencing a 30% pain reduction on tricyclics was 48%, versus 28% on placebo. For SSRIs and SNRIs, the fractions of people experiencing a 30% pain reduction were 36% (20% in the placebo comparator arms) and 42% (32% in the corresponding placebo comparator arms) respectively. Discontinuation of treatment due to side effects was common.{{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}} Antidepressants including amitriptyline, fluoxetine, duloxetine, milnacipran, moclobemide, and pirlindole are recommended by the European League Against Rheumatism (EULAR) for the treatment of fibromyalgia based on "limited evidence".{{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}}

A 2014 meta-analysis from the Cochrane Collaboration found the antidepressant duloxetine to be effective for the treatment of pain resulting from diabetic neuropathy.{{cite journal|vauthors=Lunn MP, Hughes RA, Wiffen PJ|title=Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia|journal=The Cochrane Database of Systematic Reviews|volume=1|issue=1|pages=CD007115|date=January 2014|pmid=24385423|doi=10.1002/14651858.CD007115.pub3|pmc=10711341}} 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.{{cite journal|vauthors=Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ|title=Amitriptyline for neuropathic pain in adults|journal=The Cochrane Database of Systematic Reviews|issue=7|pages=CD008242|date=July 2015|volume=2015|pmid=26146793|pmc=6447238|doi=10.1002/14651858.CD008242.pub3}} 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.

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.{{cite journal|vauthors=Agabio R, Trogu E, Pani PP|title=Antidepressants for the treatment of people with co-occurring depression and alcohol dependence|journal=The Cochrane Database of Systematic Reviews|volume=2018|issue=4|pages=CD008581|date=April 2018|pmid=29688573|pmc=6494437|doi=10.1002/14651858.CD008581.pub2}} Bupropion is used to help people stop smoking. Antidepressants are also used to control some symptoms of narcolepsy.{{cite web|url=https://www.ninds.nih.gov/Disorders/All-Disorders/Narcolepsy-Information-Page|title=Narcolepsy Information Page|date=27 March 2019|website=National Institute of Neurological Disorders and Stroke|access-date=11 April 2020}} Antidepressants may be used to relieve pain in people with active rheumatoid arthritis. However, further research is required.{{cite journal|vauthors=Richards BL, Whittle SL, Buchbinder R|title=Antidepressants for pain management in rheumatoid arthritis|journal=The Cochrane Database of Systematic Reviews|issue=11|pages=CD008920|date=November 2011|pmid=22071859|doi=10.1002/14651858.CD008920.pub2}} 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.{{cite journal|vauthors=Rayner L, Price A, Evans A, Valsraj K, Higginson IJ, Hotopf M|title=Antidepressants for depression in physically ill people|journal=The Cochrane Database of Systematic Reviews|issue=3|pages=CD007503|date=March 2010|pmid=20238354|doi=10.1002/14651858.CD007503.pub2}} Antidepressants have been shown to improve some parts of cognitive functioning for depressed users, such as memory, attention, and processing speed.{{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}}

Certain antidepressants acting as serotonin 5-HT_2A receptor antagonists, such as trazodone and mirtazapine, have been used as hallucinogen antidotes or "trip killers" to block the effects of serotonergic psychedelics like psilocybin and lysergic acid diethylamide (LSD).{{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}}{{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|url-status=dead|archive-date=2025-05-11}}{{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}}

Among individuals treated with a given antidepressant, between 30% and 50% do not show a response.{{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}}{{cite journal|vauthors=Ruhé HG, Huyser J, Swinkels JA, Schene AH|title=Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review|journal=The Journal of Clinical Psychiatry|volume=67|issue=12|pages=1836–1855|date=December 2006|pmid=17194261|doi=10.4088/JCP.v67n1203|url=http://pdfs.semanticscholar.org/02f0/a7fcfd218854147e6c3e52c3f213ab2d95e4.pdf|url-status=dead|s2cid=9758110|archive-url=https://web.archive.org/web/20190216221042/http://pdfs.semanticscholar.org/02f0/a7fcfd218854147e6c3e52c3f213ab2d95e4.pdf|archive-date=16 February 2019}} Approximately one-third of people achieve a full remission, one-third experience a response, and one-third are non-responders. Partial remission is characterized by the presence of poorly defined residual symptoms. These symptoms typically include depressed mood, anxiety, sleep disturbance, fatigue, and diminished interest or pleasure. It is currently unclear which factors predict partial remission. However, it is clear that residual symptoms are powerful predictors of relapse, with relapse rates three to six times higher in people with residual symptoms than in those, who experience full remission.{{cite journal|vauthors=Tranter R, O'Donovan C, Chandarana P, Kennedy S|title=Prevalence and outcome of partial remission in depression|journal=Journal of Psychiatry & Neuroscience|volume=27|issue=4|pages=241–247|date=July 2002|pmid=12174733|pmc=161658}} In addition, antidepressant drugs tend to lose efficacy throughout long-term maintenance therapy.{{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}} 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.{{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}} Several strategies are used in clinical practice to try to overcome these limits and variations.{{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}} They include switching medication, augmentation, and combination.

There is controversy amongst researchers regarding the efficacy and risk-benefit ratio of antidepressants.{{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}}{{cite journal|vauthors=Warren JB|title=The trouble with antidepressants: why the evidence overplays evidence and underplays risks—an essay by John B Warren|journal=The BMJ|date=2020|volume=370|page=m3200|doi=10.1136/bmj.m3200|pmid=32883743|s2cid=221468976}} 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.{{cite journal|vauthors=McCormack J, Korownyk C|title=Effectiveness of antidepressants|journal=The BMJ|date=2018|volume=360|page=k1073|doi=10.1136/bmj.k1073|pmid=29523598|s2cid=3925654}} The aggregate effect of antidepressants typically results in changes below the threshold of clinical significance on depression rating scales. 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.{{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}} Assessments of antidepressants using alternative, more sensitive scales, such as the MADRS, do not result in marked difference from the HDRS and likewise only find a marginal clinical benefit. 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.{{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}} Poor and complex clinical trial design might also account for the small effects seen for antidepressants.{{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}}{{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}} The randomized controlled trials used to approve drugs are short, and may not capture the full effect of antidepressants. Additionally, the placebo effect might be inflated in these trials by frequent clinical consultation, lowering the comparative performance of antidepressants. Critics agree that current clinical trials are poorly-designed, which limits the knowledge on antidepressants.{{cite journal|vauthors=Boesen K, Gøtzsche PC, Ioannidis JP|title=EMA and FDA psychiatric drug trial guidelines: assessment of guideline development and trial design recommendations|journal=Epidemiology and Psychiatric Sciences|date=2021|volume=30|page=e35|doi=10.1017/S2045796021000147|pmid=33926608|pmc=8157504}} 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.{{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}}

Critics of antidepressants maintain that the superiority of antidepressants over placebo is the result of systemic flaws in clinical trials and the research literature.{{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}} 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. Additionally, meta-analyses co-authored by industry employees find more favorable results for antidepressants. 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.{{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}} Although this issue has diminished with time, it remains an obstacle to accurately assessing the efficacy of antidepressants.{{cite journal|vauthors=Turner EH, Cipriani A, Furukawa TA, Salanti G, de Vries YA|title=Selective publication of antidepressant trials and its influence on apparent efficacy: Updated comparisons and meta-analyses of newer versus older trials|journal=PLOS Medicine|date=2022|volume=19|issue=1|page=e1003886|doi=10.1371/journal.pmed.1003886|pmid=35045113|pmc=8769343|doi-access=free}} Misreporting of clinical trial outcomes and of serious adverse events, such as suicide, is common.{{cite journal|vauthors=Hughes S, Cohen D, Jaggi R|title=Differences in reporting serious adverse events in industry sponsored clinical trial registries and journal articles on antidepressant and antipsychotic drugs: a cross-sectional study|journal=BMJ Open|date=2014|volume=4|issue=7|page=e005535|doi=10.1136/bmjopen-2014-005535|pmid=25009136|pmc=4091397}} 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. 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. Some have therefore maintained that antidepressants may only be active placebos. 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.

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. They also note that adverse effects, including withdrawal difficulties, are likely underreported, skewing clinicians' ability to make risk-benefit judgements.{{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}}{{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}} Accordingly, they believe antidepressants are overused, particularly for non-severe depression and conditions in which they are not indicated.{{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}} Critics charge that the widespread use and public acceptance of antidepressants is the result of pharmaceutical advertising, research manipulation, and misinformation.

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

{{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. However, a later meta-analysis found no difference between switching to a new drug and staying on the old medication: although 34% of treatment-resistant people responded when switched to the new drug, 40% responded without being switched.{{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}}

For a partial response, the American Psychiatric Association (APA) guidelines suggest augmentation or adding a drug from a different class. These include lithium and thyroid augmentation, dopamine agonists, sex steroids, NRIs, glucocorticoid-specific agents, or the newer anticonvulsants.{{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}}

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.{{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}} Other tests conducted include the use of psychostimulants as an augmentation therapy. Several studies have shown the efficacy of combining modafinil for treatment-resistant people. It has been used to help combat SSRI-associated fatigue.{{cite journal|vauthors=Goss AJ, Kaser M, Costafreda SG, Sahakian BJ, Fu CH|s2cid=13911763|title=Modafinil augmentation therapy in unipolar and bipolar depression: a systematic review and meta-analysis of randomized controlled trials|journal=The Journal of Clinical Psychiatry|volume=74|issue=11|pages=1101–7|year=2013|pmid=24330897|doi=10.4088/JCP.13r08560|url=https://pdfs.semanticscholar.org/754c/e4bb94f6be37d53b562ffe90fcec9a17073b.pdf|archive-url=https://web.archive.org/web/20200215045012/https://pdfs.semanticscholar.org/754c/e4bb94f6be37d53b562ffe90fcec9a17073b.pdf|url-status=dead|archive-date=15 February 2020}}

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.{{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}}

A gradual loss of therapeutic benefit occurs in a minority of people during the course of treatment.{{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}}{{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}} 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.{{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}}{{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}} For patients who wish to stop their antidepressants, engaging in brief psychological interventions such as Preventive Cognitive Therapy{{cite web|title=Voorkom Depressie – Preventieve Cognitieve Therapie|url=https://www.voorkomdepressie.nl/|website=voorkomdepressie.nl}} or mindfulness-based cognitive therapy while tapering down has been found to diminish the risk for relapse.{{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}}

Antidepressants can cause various adverse effects, depending on the individual and the drug in question.{{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}}

Almost any medication involved with serotonin regulation has the potential to cause serotonin toxicity (also known as serotonin syndrome) – an excess of serotonin that can induce mania, restlessness, agitation, emotional lability, insomnia, and confusion as its primary symptoms.{{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}}{{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}} Although the condition is serious, it is not particularly common, generally only appearing at high doses or while on other medications. Assuming proper medical intervention has been taken (within about 24 hours) it is rarely fatal.{{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}}{{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}} Antidepressants appear to increase the risk of diabetes by about 1.3-fold.{{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|pages=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}}

MAOIs tend to have pronounced (sometimes fatal) interactions with a wide variety of medications and over-the-counter drugs. If taken with foods that contain very high levels of tyramine (e.g., mature cheese, cured meats, or yeast extracts), they may cause a potentially lethal hypertensive crisis. At lower doses, the person may only experience a headache due to an increase in blood pressure.{{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}}

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.{{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}}

Tricyclics and SSRI can cause the so-called drug-induced QT prolongation, especially in older adults;{{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}} this condition can degenerate into a specific type of abnormal heart rhythm called Torsades de points, which can potentially lead to sudden cardiac arrest.{{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}}

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

Antidepressants have been associated with an increased risk of dementia in older adults.{{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}}

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.{{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}}{{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}}

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.{{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}} 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,{{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 }}{{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|pages=75|year=2012|pmid=23351929|pmc=3556001|doi=10.1186/2008-2231-20-75|doi-access=free}} and is associated with preterm birth and low birth weight.{{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}}

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.{{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}} A study of fluoxetine-exposed pregnancies found a 12% increase in the risk of major malformations that did not reach statistical significance.{{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}} 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.{{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}} Another study found no increase in cardiovascular birth defects and a 27% increased risk of major malformations in SSRI exposed pregnancies. The FDA advises for the risk of birth defects with the use of paroxetine{{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}} 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.{{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}}

A neonate (infant less than 28 days old) may experience a withdrawal syndrome from abrupt discontinuation of the antidepressant at birth. Antidepressants can be present in varying amounts in breast milk, but their effects on infants are currently unknown.{{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}}

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.{{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|url-status=dead}}

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.{{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}} For bipolar depression, antidepressants (most frequently SSRIs) can exacerbate or trigger symptoms of hypomania and mania.{{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}} Bupropion has been associated with a lower risk of mood switch than other antidepressants.{{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}}

{{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. 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.{{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}} According to the FDA, the heightened risk of suicidality occurs within the first one to two months of treatment.{{cite web|url=https://www.fda.gov/drugs/drugsafety/informationbydrugclass/ucm096273|title=Antidepressant Use in Children, Adolescents, and Adults|website=Food and Drug Administration|url-status=dead|archive-url=https://web.archive.org/web/20161219143824/https://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/UCM096273|archive-date=19 December 2016}}{{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|url-status=dead|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}} The National Institute for Health and Care Excellence (NICE) places the excess risk in the "early stages of treatment".{{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}} A meta-analysis suggests that the relationship between antidepressant use and suicidal behavior or thoughts is age-dependent. Compared with placebo, the use of antidepressants is associated with an increase in suicidal behavior or thoughts among those 25 years old or younger (OR=1.62). A review of RCTs and epidemiological studies by Healy and Whitaker found an increase in suicidal acts by a factor of 2.4.{{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|pmid=14517576|pmc=193979}} 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).{{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|pages=b2880|year=2009|pmid=19671933|pmc=2725270|doi=10.1136/bmj.b2880}}{{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|url-status=dead|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}}

Sexual side effects are also common with SSRIs, such as loss of sexual drive, failure to reach orgasm, and erectile dysfunction.{{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}} Although usually reversible, these sexual side-effects can, in rare cases, continue after the drug has been completely withdrawn.{{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}}{{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}}

In a study of 1,022 outpatients, overall sexual dysfunction with all antidepressants averaged 59.1%{{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}} 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{{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}} and can lead to an improvement in all aspects of sexual function.{{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}}

Biochemical mechanisms suggested as causative include increased serotonin, particularly affecting 5-HT₂ and 5-HT₃ receptors; decreased dopamine; decreased norepinephrine; blockade of cholinergic and α₁adrenergic receptors; inhibition of nitric oxide synthetase; and elevation of prolactin levels.{{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}} Mirtazapine is reported to have fewer sexual side effects, most likely because it antagonizes 5-HT₂ and 5-HT₃ receptors and may, in some cases, reverse sexual dysfunction induced by SSRIs by the same mechanism.{{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}}

Bupropion, a weak NDRI and nicotinic antagonist, may be useful in treating reduced libido as a result of SSRI treatment.{{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}}

Certain antidepressants may cause emotional blunting, characterized by a reduced intensity of both positive and negative emotions as well as symptoms of apathy, indifference, and amotivation.{{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}}{{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|pages=792960|date=2021|pmid=34970173|pmc=8712545|doi=10.3389/fpsyt.2021.792960|doi-access=free}}{{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}}{{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}}{{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}}{{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}}{{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}}{{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}}{{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}} It may be experienced as either beneficial or detrimental depending on the situation.{{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}} 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.{{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}}{{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}} Higher doses of antidepressants seem to be more likely to produce emotional blunting than lower doses. 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.

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,{{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-status=dead}}{{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}}{{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}} while others (such as bupropion and venlafaxine) achieve the opposite effect.{{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}}{{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}}

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

A 2021 nationwide cohort study in South Korea observed a link between SSRI use and bone loss, particularly in recent users. The study also stressed the need of further research to better understand these effects.{{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|pages=13461|date=June 2021|pmid=34188108|pmc=8241982|doi=10.1038/s41598-021-92821-9|bibcode=2021NatSR..1113461K}} 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.{{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}} 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.{{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}}

A 2017 meta-analysis found that antidepressants were associated with a significantly increased risk of death (+33%) and new cardiovascular complications (+14%) in the general population.{{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}} Conversely, risks were not greater in people with existing cardiovascular disease.

{{Main|Antidepressant discontinuation syndrome}}

Antidepressant discontinuation syndrome, also called antidepressant withdrawal syndrome, is a condition that can occur following the interruption, reduction, or discontinuation of antidepressant medication. The symptoms may include flu-like symptoms, trouble sleeping, nausea, poor balance, sensory changes, and anxiety.{{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}} The problem usually begins within three days and may last for several months. Rarely psychosis may occur.

A discontinuation syndrome can occur after stopping any antidepressant including selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs). The risk is greater among those who have taken the medication for longer and when the medication in question has a short half-life. The underlying reason for its occurrence is unclear. The diagnosis is based on the symptoms.

Methods of prevention include gradually decreasing the dose among those who wish to stop, though it is possible for symptoms to occur with tapering. Treatment may include restarting the medication and slowly decreasing the dose. People may also be switched to the long-acting antidepressant fluoxetine, which can then be gradually decreased.

Approximately 20–50% of people who suddenly stop an antidepressant develop an antidepressant discontinuation syndrome.{{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}} The condition is generally not serious. Though about half of people with symptoms describe them as severe. Some restart antidepressants due to the severity of the symptoms.

{{Main|Pharmacology of antidepressants}}

Antidepressants act via a large number of different mechanisms of action.{{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}}{{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}}{{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}} This includes serotonin reuptake inhibition (SSRIs, SNRIs, TCAs, vilazodone, vortioxetine), norepinephrine reuptake inhibition (NRIs, SNRIs, TCAs), dopamine reuptake inhibition (bupropion, amineptine, nomifensine), direct modulation of monoamine receptors (vilazodone, vortioxetine, SARIs, agomelatine, TCAs, TeCAs, antipsychotics), monoamine oxidase inhibition (MAOIs), and NMDA receptor antagonism (ketamine, esketamine, dextromethorphan), among others (e.g., brexanolone, tianeptine). Some antidepressants also have additional actions, like sigma receptor modulation (certain SSRIs, TCAs, dextromethorphan) and antagonism of histamine H₁ and muscarinic acetylcholine receptors (TCAs, TeCAs).{{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=9780470515167}}

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.{{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}}{{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}} This theory states that depression is due to an imbalance, most often a deficiency, of the monoamine neurotransmitters, namely serotonin, norepinephrine, and/or dopamine. However, serotonin in particular has been implicated, as in the serotonin hypothesis of depression. The monoamine hypothesis was originally proposed based on observations that reserpine, a drug which depletes the monoamine neurotransmitters, produced depressive effects in people, and that certain hydrazine antituberculosis agents like iproniazid, which prevent the breakdown of monoamine neurotransmitters, produced apparent antidepressant effects. Most currently marketed antidepressants, which are monoaminergic in their actions, are theoretically consistent with the monoamine hypothesis. 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.{{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}}{{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}} A number of alternative hypotheses have been proposed, including hypotheses involving glutamate, neurogenesis, epigenetics, cortisol hypersecretion, and inflammation, among others.{{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}}{{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}}

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.{{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}} 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. Other literature had described the lack of support for the theory previously.{{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|pages=e392|date=December 2005|pmid=16268734|pmc=1277931|doi=10.1371/journal.pmed.0020392|doi-access=free}}{{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}} In many of the expert responses to the review, it was stated that the monoamine hypothesis had already long been abandoned by psychiatry.{{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}}{{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}} 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. 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.{{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}} 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. 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.

The serotonin and monoamine hypotheses of depression have been heavily promoted by the pharmaceutical industry (e.g., in advertisements) and by the psychiatric profession at large despite the lack of evidence in support of them.{{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}}{{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|page=100098|issn=2666-5603|doi=10.1016/j.ssmmh.2022.100098|s2cid=248246338|doi-access=free}}{{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}} In the case of the pharmaceutical industry, this can be attributed to obvious financial incentives, with the theory creating a bias against non-pharmacological treatments for depression.

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.{{cite journal|vauthors=Kirsch I|title=Placebo Effect in the Treatment of Depression and Anxiety|journal=Front Psychiatry|volume=10|pages=407|date=2019|pmid=31249537|pmc=6584108|doi=10.3389/fpsyt.2019.00407|doi-access=free}}{{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}}{{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}}{{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}} This is supported by meta-analyses of randomized controlled trials of antidepressants for depression, which consistently show that placebo groups in trials improve about 80 to 90% as much as antidepressant groups on average{{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}} and that antidepressants are only marginally more effective for depression than placebos.{{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|pages=e024886|date=June 2019|pmid=31248914|pmc=6597641|doi=10.1136/bmjopen-2018-024886}}{{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|pages=e0229381|date=2020|pmid=32101579|pmc=7043778|doi=10.1371/journal.pone.0229381|bibcode=2020PLoSO..1529381H|doi-access=free}}{{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}}{{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|pages=e067606|date=August 2022|pmid=35918097|pmc=9344377|doi=10.1136/bmj-2021-067606}} The difference between antidepressants and placebo corresponds to an effect size (SMD) of about 0.3, which in turn equates to about a 2- to 3-point additional improvement on the 0–52-point (HRSD) and 0–60-point (MADRS) depression rating scales used in trials. Differences in effectiveness between different antidepressants are small and not clinically meaningful.{{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}} 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.{{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}}{{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}}{{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|pages=517|date=2018|pmid=30386270|pmc=6199395|doi=10.3389/fpsyt.2018.00517|doi-access=free}} Moreover, the small advantage of antidepressants over placebo may simply be a methodological artifact caused by unblinding due to the psychoactive effects and side effects of antidepressants, in turn resulting in enhanced placebo effects and apparent antidepressant efficacy. Placebos have been found to modify the activity of several brain regions and to increase levels of dopamine and endogenous opioids in the reward pathways.{{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}}{{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}}{{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}} It has been argued by Kirsch that although antidepressants may be used efficaciously for depression as active placebos, they are limited by significant pharmacological side effects and risks, and therefore non-pharmacological therapies, such as psychotherapy and lifestyle changes, which can have similar efficacy to antidepressants but do not have their adverse effects, ought to be preferred as treatments in people with depression.{{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|pages=130|date=August 2020|pmid=31554608|pmc=7418603|doi=10.1136/bmjebm-2019-111238}}

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. 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.{{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}} 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.{{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|pages=e41778|date=2012|pmid=22860015|pmc=3408478|doi=10.1371/journal.pone.0041778|bibcode=2012PLoSO...741778K|doi-access=free}}{{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}}{{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}} 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.{{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}} 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.

It has been proposed that psychedelics used for therapeutic purposes may act as active "super placebos".{{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 = }}{{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 = | pages = 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 }}

{{See also|List of antidepressants}}

File:Paroxetine-2D-skeletal.svg), a selective serotonin reuptake inhibitor]]

Selective serotonin reuptake inhibitors (SSRIs) are believed to increase the extracellular level of the neurotransmitter serotonin by limiting its reabsorption into the presynaptic cell, increasing the level of serotonin in the synaptic cleft available to bind to the postsynaptic receptor. They have varying degrees of selectivity for the other monoamine transporters, with pure SSRIs having only weak affinity for the norepinephrine and dopamine transporters.

SSRIs are the most widely prescribed antidepressants in many countries.{{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}} The efficacy of SSRIs in mild or moderate cases of depression has been disputed.{{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}}{{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}}{{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}}{{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}}

File:Venlafaxine-3D-balls.png (Effexor), an SNRI]]

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

The human serotonin transporter (SERT) and norepinephrine transporter (NET) are membrane proteins that are responsible for the reuptake of serotonin and norepinephrine. Balanced dual inhibition of monoamine reuptake may offer advantages over other antidepressants drugs by treating a wider range of symptoms.{{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}}

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

Serotonin modulator and stimulators (SMSs), sometimes referred to more simply as "serotonin modulators", are a type of drug with a multimodal action specific to the serotonin neurotransmitter system. To be precise, SMSs simultaneously modulate one or more serotonin receptors and inhibit the reuptake of serotonin. The term was coined in reference to the mechanism of action of the serotonergic antidepressant vortioxetine, which acts as a serotonin reuptake inhibitor (SRI), a partial agonist of the 5-HT_1A receptor, and antagonist of the 5-HT₃ and 5-HT₇ receptors.{{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}}{{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}}{{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}} However, it can also technically be applied to vilazodone, which is an antidepressant as well and acts as an SRI and 5-HT_1A receptor partial agonist.{{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}}

An alternative term is serotonin partial agonist/reuptake inhibitor (SPARI), which can be applied only to vilazodone.{{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=978-1107686465|edition=4th}}

Serotonin antagonist and reuptake inhibitors (SARIs) while mainly used as antidepressants are also anxiolytics and hypnotics. They act by antagonizing serotonin receptors such as 5-HT_2A and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. Additionally, most also act as α₁-adrenergic receptor antagonists. The majority of the currently marketed SARIs belong to the phenylpiperazine class of compounds. They include trazodone and nefazodone.

The majority of the tricyclic antidepressants (TCAs) act primarily as serotonin–norepinephrine reuptake inhibitors (SNRIs) by blocking the serotonin transporter (SERT) and the norepinephrine transporter (NET), respectively, which results in an elevation of the synaptic concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission.{{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}}{{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}} Notably, with the sole exception of amineptine, the TCAs have weak affinity for the dopamine transporter (DAT), and therefore have low efficacy as dopamine reuptake inhibitors (DRIs).

Although TCAs are sometimes prescribed for depressive disorders, they have been largely replaced in clinical use in most parts of the world by newer antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and norepinephrine reuptake inhibitors (NRIs). Adverse effects have been found to be of a similar level between TCAs and SSRIs.{{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}}

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

Monoamine oxidase inhibitors (MAOIs) are chemicals that inhibit the activity of the monoamine oxidase enzyme family. They have a long history of use as medications prescribed for the treatment of depression. They are particularly effective in treating atypical depression.{{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}} They are also used in the treatment of Parkinson's disease and several other disorders.

Because of potentially lethal dietary and drug interactions, MAOIs have historically been reserved as a last line of treatment, used only when other classes of antidepressant drugs (for example selective serotonin reuptake inhibitors and tricyclic antidepressants) have failed.{{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}}

MAOIs have been found to be effective in the treatment of panic disorder with agoraphobia,{{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}} social phobia,{{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}}{{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}}{{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}} atypical depression{{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}}{{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}} or mixed anxiety and depression, bulimia,{{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}}{{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}}{{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}}{{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}} and post-traumatic stress disorder,{{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}} as well as borderline personality disorder.{{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}} MAOIs appear to be particularly effective in the management of bipolar depression according to a retrospective-analysis.{{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}} 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.{{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}}

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

NMDA receptor antagonists like ketamine and esketamine are rapid-acting antidepressants and seem to work via blockade of the ionotropic glutamate NMDA receptor.{{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|url-status=dead|archive-date=13 April 2019|access-date=6 March 2019}} 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.{{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}}{{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}}

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

Adjunct medications are an umbrella category of substances that increase the potency or "enhance" antidepressants.{{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}} They work by affecting variables very close to the antidepressant, sometimes affecting a completely different mechanism of action. This may be attempted when depression treatments have not been successful in the past.

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

• Two or more antidepressants taken together, from either the same or different classes (affecting the same area of the brain, often at a much higher level).
• An antipsychotic combined with an antidepressant, particularly atypical antipsychotics such as aripiprazole (Abilify), quetiapine (Seroquel), olanzapine (Zyprexa), and risperidone (Risperdal).{{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}}

It is unknown if undergoing psychological therapy at the same time as taking anti-depressants enhances the anti-depressive effect of the medication.{{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|pages=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}}

Lithium has been used to augment antidepressant therapy in those who have failed to respond to antidepressants alone.{{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}} Furthermore, Lithium dramatically decreases the suicide risk in recurrent depression.{{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}} There is some evidence for the addition of a thyroid hormone, triiodothyronine, in patients with normal thyroid function.{{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}}

Psychopharmacologists have also tried adding a stimulant, in particular, D-amphetamine.{{cite book|vauthors=Stahl SM|title=The Prescriber's Guide (Stahl's Essential Psychopharmacology)|year=2011|publisher=Cambridge University Press|page=39}} However, the use of stimulants in cases of treatment-resistant depression is relatively controversial.{{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}}{{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}} 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.

{{See also|Discovery and development of dual serotonin and norepinephrine reuptake inhibitors}}

File:Saint John's wort flowers.jpg]]

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

Before the 1950s, opioids and amphetamines were commonly used as antidepressants.{{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}}{{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}}{{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}} Amphetamine has been described as the first antidepressant. Use of opioids and amphetamines for depression was later restricted due to their addictive nature and side effects. Extracts from the herb St John's wort have been used as a "nerve tonic" to alleviate depression.{{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}}

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.{{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}} It remains an over-the-counter (OTC) supplement in most countries. Lead contamination associated with its usage has been seen as concerning, as lead levels in women in the United States taking St. John's wort are elevated by about 20% on average.{{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}} Research continues to investigate its active component hyperforin, and to further understand its mode of action.{{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}}{{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}}

In 1951, Irving Selikoff and Edward H. Robitzek, working out of Sea View Hospital on Staten Island, began clinical trials on two new anti-tuberculosis agents developed by Hoffman-LaRoche, isoniazid, and iproniazid. Only patients with a poor prognosis were initially treated. Nevertheless, their condition improved dramatically. Selikoff and Robitzek noted "a subtle general stimulation ... the patients exhibited renewed vigor and indeed this occasionally served to introduce disciplinary problems."{{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}} 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.{{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}} 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.{{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}} 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.{{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}}

Selikoff and Robitzek also experimented with another anti-tuberculosis drug, iproniazid; it showed a greater psychostimulant effect, but more pronounced toxicity.{{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}} 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.{{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}} 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".{{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|url-status=dead}} Roche put a significant marketing effort behind iproniazid. Its sales grew until it was recalled in 1961, due to reports of lethal hepatotoxicity.

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

Antidepressants became prescription drugs in the 1950s. It was estimated that no more than fifty to one hundred individuals per million had the kind of depression that these new drugs would treat, and pharmaceutical companies were not enthusiastic about marketing for this small market. Sales through the 1960s remained poor compared to the sales of tranquilizers,{{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}}{{Unreliable medical source|date=March 2013}} which were being marketed for different uses.{{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}} 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.{{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}}

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}}

{{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 SSRI. Fluoxetine was developed at Eli Lilly and Company in the early 1970s by Bryan Molloy, Klaus Schmiegel, David T. Wong, and others.{{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}}{{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-status=dead}} SSRIs became known as "novel antidepressants" along with other newer drugs such as SNRIs and NRIs with various selective effects.{{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}}

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.

A 2016 randomized controlled trial evaluated the rapid antidepressant effects of the psychedelic Ayahuasca in treatment-resistant depression with a positive outcome.{{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}}{{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}} 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.{{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}}

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.{{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}} Unpublished data was also associated with smaller positive effect sizes. However, the review did not find evidence of bias associated with industry funded research.

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.{{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}} 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%.{{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)}} These sources also suggest that aside from the recession, other factors that may influence changes in prescribing rates may include: improvements in diagnosis, a reduction of the stigma surrounding mental health, broader prescribing trends, GP characteristics, geographical location, and housing status. Another factor that may contribute to increasing consumption of antidepressants is the fact that these medications now are used for other conditions including social anxiety and post-traumatic stress disorder.

Between 2005 and 2017, the number of adolescents (12 to 17 years) in England who were prescribed antidepressants has doubled. On the other hand, antidepressant prescriptions for children aged 5–11 in England decreased between 1999 and 2017.{{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}}{{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|pages=e1003215|date=July 2020|pmid=32697803|pmc=7375537|doi=10.1371/journal.pmed.1003215|veditors=Hellner C|doi-access=free}} 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.{{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}}

According to National Institute for Health and Care Excellence (NICE) guidelines, antidepressants for children and adolescents with depression and obsessive-compulsive disorder (OCD) should be prescribed together with therapy and after being assessed by a child and adolescent psychiatrist. However, between 2006 and 2017, only 1 in 4 of 12–17 year-olds who were prescribed an SSRI by their GP had seen a specialist psychiatrist and 1 in 6 has seen a pediatrician. Half of these prescriptions were for depression and 16% for anxiety, the latter not being licensed for treatment with antidepressants.{{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|pages=93|date=April 2020|pmid=32349753|pmc=7191694|doi=10.1186/s12916-020-01560-7|doi-access=free}} 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.{{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}} According to some researchers, strict adherence to treatment guidelines would limit access to effective medication for young people with mental health problems.{{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|pages=150|date=May 2020|pmid=32438910|pmc=7243321|doi=10.1186/s12916-020-01621-x|doi-access=free}}

In the United States, antidepressants were the most commonly prescribed medication in 2013. Of the estimated 16 million "long term" (over 24 months) users, roughly 70 percent are female.{{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}} {{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.{{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}}

File:Sertraline2DACS2.svg]]

United States: The most commonly prescribed antidepressants in the US retail market in 2010 were:{{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}}

Netherlands: In the Netherlands, paroxetine is the most prescribed antidepressant, followed by amitriptyline, citalopram and venlafaxine.{{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|url-status=dead|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}}

{{Main|Adherence (medicine)}}

{{As of|2003}}, worldwide, 30% to 60% of people did not follow their practitioner's instructions about taking their antidepressants,{{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}} 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.{{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}}

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.{{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}}

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.{{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}}{{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}} 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. 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.

Because most antidepressants function by inhibiting the reuptake of neurotransmitters serotonin, dopamine, and norepinephrine{{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}} these drugs can interfere with natural neurotransmitter levels in other organisms impacted by indirect exposure.{{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}} Antidepressants fluoxetine and sertraline have been detected in aquatic organisms residing in effluent-dominated streams.{{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}} 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.{{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}}

Coral reef fish have been demonstrated to modulate aggressive behavior through serotonin.{{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 }} Artificially increasing serotonin levels in crustaceans can temporarily reverse social status and turn subordinates into aggressive and territorial dominant males.{{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}}

Exposure to Fluoxetine has been demonstrated to increase serotonergic activity in fish, subsequently reducing aggressive behavior.{{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}} Perinatal exposure to Fluoxetine at relevant environmental concentrations has been shown to lead to significant modifications of memory processing in 1-month-old cuttlefish.{{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}} 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.{{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}}{{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}}

{{Commons category|Antidepressants}}

• Antidepressants in Japan
• Atypical antidepressant
• Depression and natural therapies
• Depression in childhood and adolescence
• List of investigational antidepressants
• Management of depression

{{Reflist}}

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

{{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:Anaphrodisia

Category:Major depressive disorder

Category:Drug classes defined by psychological effects