Editing Antidepressant (section)

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

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

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

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

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

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

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

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

It has been proposed that [[psychedelic drug|psychedelic]]s used for therapeutic purposes may act as [[active placebo|active]] "super placebos".<ref name="DupuisVeissière2022">{{cite journal | vauthors = Dupuis D, Veissière S | title = Culture, context, and ethics in the therapeutic use of hallucinogens: Psychedelics as active super-placebos? | journal = Transcult Psychiatry | volume = 59 | issue = 5 | pages = 571–578 | date = October 2022 | pmid = 36263513 | doi = 10.1177/13634615221131465 | url = }}</ref><ref name="vanElkYaden2022">{{cite journal | vauthors = van Elk M, Yaden DB | title = Pharmacological, neural, and psychological mechanisms underlying psychedelics: A critical review | journal = Neurosci Biobehav Rev | volume = 140 | issue = | 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 }}</ref>