Editing Antidepressant (section)

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

The idea of an antidepressant, if [[Melancholia|melancholy]] is thought synonymous with depression, existed at least as early as the 1599 pamphlet ''A pil to purge melancholie or, A 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, [[opioid]]s and [[amphetamine-type stimulant|amphetamine]]s were commonly used as antidepressants.<ref name="Weber 1988 255–66">{{cite journal|vauthors=Weber MM, Emrich HM|title=Current and Historical Concepts of Opiate Treatment in Psychiatric Disorders|journal=International Clinical Psychopharmacology|volume=3|issue=3|pages=255–66|year=1988|pmid=3153713|doi=10.1097/00004850-198807000-00007}}</ref><ref name="Amph Uses Dex">{{cite journal|vauthors=Heal DJ, Smith SL, Gosden J, Nutt DJ|title=Amphetamine, past and present – a pharmacological and clinical perspective|journal=J. Psychopharmacol.|volume=27|issue=6|pages=479–96|date=June 2013|pmid=23539642|pmc=3666194|doi=10.1177/0269881113482532}}</ref><ref name="Rasmussen2006">{{cite journal|vauthors=Rasmussen N|title=Making the first anti-depressant: amphetamine in American medicine, 1929-1950|journal=J Hist Med Allied Sci|volume=61|issue=3|pages=288–323|date=July 2006|pmid=16492800|doi=10.1093/jhmas/jrj039}}</ref> [[Amphetamine]] has been described as the first antidepressant.<ref name="Rasmussen2006" /> Use of opioids and amphetamines for depression was later restricted due to their addictive nature and side effects.<ref name="Weber 1988 255–66" /><ref name="Rasmussen2006" /> Extracts from the herb [[Hypericum perforatum|St John's wort]] have been used as a "nerve tonic" to alleviate depression.<ref>{{cite journal|author=Czygan FC|title=Kulturgeschichte und Mystik des Johanniskrauts: Vom 2500 Jahre alten Apotropaikum zum aktuellen Antidepressivum|language=de|journal=Pharmazie in unserer Zeit|volume=32|issue=3|pages=184–90|year=2003|pmid=12784538|doi=10.1002/pauz.200390062|trans-title=From a 2500-year-old apotropic comes a current antidepressive. The cultural history and mistique of St. John's wort}}</ref>

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

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

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

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

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

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

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

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

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

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

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

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

=== Publication bias and aged research ===
A 2018 systematic review published in [[The Lancet]] comparing the efficacy of 21 different first and second generation antidepressants found that antidepressant drugs tended to perform better and cause less adverse events when they were novel or experimental treatments compared to when they were evaluated again years later.<ref>{{cite journal|vauthors=Zhou X, Teng T, Zhang Y, Del Giovane C, Furukawa TA, Weisz JR, Li X, Cuijpers P, Coghill D, Xiang Y, Hetrick SE, Leucht S, Qin M, Barth J, Ravindran AV, Yang L, Curry J, Fan L, Silva SG, Cipriani A, Xie P|title=Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysis|journal=The Lancet. Psychiatry|volume=7|issue=7|pages=581–601|date=July 2020|pmid=32563306|pmc=7303954|doi=10.1016/S2215-0366(20)30137-1}}</ref> Unpublished data was also associated with smaller positive effect sizes. However, the review did not find evidence of bias associated with industry funded research.