Talk:Antidepressants: Difference between revisions

'''Antidepressants''' most commonly refers to family of modern synthetic pharmaceutical agents used for the treatment of major depressive disorder and other conditions, including dysthymia, anxiety disorders, obsessive-compulsive disorder, eating disorders, chronic pain, neuropathic pain and, in some cases, dysmenorrhoea, snoring, migraine, attention-deficit hyperactivity disorder (ADHD), addiction, dependence, and sleep disorders. They may be prescribed alone or in combination with other medications.{{citation needed}}

The most important classes of antidepressants are the [[selective serotonin reuptake inhibitor]]s ('''SSRIs'''), [[serotonin–norepinephrine reuptake inhibitors]] ('''SNRIs'''), [[MAOI|monoamine oxidase inhibitors]] ('''MAOIs'''), reversible monoamine oxidase A inhibitors ('''rMAO-A inhibitors'''), tetracyclic antidepressants ('''TeCAs'''), and noradrenergic and specific serotonergic antidepressant ('''NaSSAs'''). Herbal substances such as St. John's wort is also sometimes used in the treatment of depression<ref>Linde, K., Kriston, L., Rucker, G., Jamil, S., Schumann, I., Meissner, K., . . . Schneider, A. (2015). '''''Efficacy and Acceptability of Pharmacological Treatments for Depressive Disorders in Primary Care: Systematic Review and Network Meta-Analysis.''''' ''The Annals of Family Medicine'', 13(1), 69-79. doi:10.1370/afm.1687</ref><ref>Linde, K., Berner, M. M., & Kriston, L. (2008). St John's wort for major depression. ''Cochrane Database of Systematic Reviews''. doi:10.1002/14651858.cd000448.pub3</ref>

The earliest and probably most widely accepted scientific theory of antidepressant action is the [[monoamine hypothesis]] (which can be traced back to the 1950s), which states that depression is due to an imbalance (most often a deficiency) of the [[monoamine neurotransmitter]]s (namely [[serotonin]], [[norepinephrine]] and [[dopamine]]).<ref name = GG /> It was originally proposed based on the observation that certain hydrazine anti-tuberculosis agents produce antidepressant effects, which was later linked to their inhibitory effects on [[monoamine oxidase]], the enzyme that catalyses the breakdown of the monoamine neurotransmitters.<ref name = GG /> All currently marketed antidepressants have the monoamine hypothesis as their theoretical basis, with the possible exception of [[agomelatine]] which acts on a dual [[Melatonin|melatonergic]]-[[Serotonin|serotonergic]] pathway.<ref name = GG /> Despite the success 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, there are a sizeable portion (>40%) of depressed patients that do not adequately 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 | 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 }}</ref><ref name="glut">{{cite journal |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 the glutamate, neurogenic, [[Epigenetics|epigenetic]], cortisol hypersecretion and inflammatory hypotheses.<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 }}</ref>

Almost any medication involved with serotonin regulation has the potential to cause [[serotonin syndrome|serotonin toxicity]] (also known as ''serotonin syndrome''){{spaced ndash}} an excess of serotonin that can induce mania, restlessness, agitation, [[emotional lability]], insomnia and confusion as its primary symptoms.<ref name="pmid12771076">{{cite journal |vauthors=Birmes P, Coppin D, Schmitt L, Lauque D | title = Serotonin syndrome: a brief review | journal = CMAJ | volume = 168 | issue = 11 | pages = 1439–42 | year = 2003 | pmid = 12771076 | pmc = 155963 | doi =  }}</ref><ref name="pmid15784664">{{cite journal |vauthors=Boyer EW, Shannon M | title = The serotonin syndrome | journal = N. Engl. J. Med. | volume = 352 | issue = 11 | pages = 1112–20 | year = 2005 | pmid = 15784664 | doi = 10.1056/NEJMra041867 | url = http://toxicology.ucsd.edu/art%203%20serotonin%20syndrome.pdf | format = PDF | archiveurl = https://web.archive.org/web/20130618053344/http://toxicology.ucsd.edu/art%203%20serotonin%20syndrome.pdf | archivedate = 18 June 2013 }}</ref> Although the condition is serious, it is not particularly common, generally only appearing at high doses or while on other medications. Assuming proper medical intervention has been taken (within about 24&nbsp;hours) it is rarely fatal.<ref name="pmid10941349">{{cite journal |vauthors=Mason PJ, Morris VA, Balcezak TJ | title = Serotonin syndrome. Presentation of 2 cases and review of the literature | journal = Medicine  | volume = 79 | issue = 4 | pages = 201–9 | year = 2000 | pmid = 10941349 | doi = 10.1097/00005792-200007000-00001 }}</ref><ref name="pmid10818648">{{cite journal |vauthors=Sampson E, Warner JP | title = Serotonin syndrome: potentially fatal but difficult to recognize | journal = Br J Gen Pract | volume = 49 | issue = 448 | pages = 867–8 | year = 1999 | pmid = 10818648 | pmc = 1313553 | doi =  }}</ref>

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

Another possible problem with antidepressants is the chance of antidepressant-induced mania in patients with [[bipolar disorder]]. Many cases of bipolar depression are very similar to those of unipolar depression. Therefore, the patient can be misdiagnosed with unipolar depression and be given antidepressants. Studies have shown that antidepressant-induced mania can occur in 20–40% of bipolar patients.<ref>{{cite journal |vauthors=Goldberg JF, Truman CJ | title = Antidepressant-induced mania: An overview of current controversies | journal = Bipolar Disorders | volume = 5 | issue = 6 | pages = 407–20 | year = 2003 | pmid = 14636364 | doi = 10.1046/j.1399-5618.2003.00067.x }}</ref> For bipolar depression, antidepressants (most frequently SSRIs) can exacerbate or trigger symptoms of [[hypomania]] and [[mania]].<ref name="pmid9387089">{{cite journal | author = Benazzi F | title = Antidepressant-associated hypomania in outpatient depression: a 203-case study in private practice | journal = J Affect Disord | volume = 46 | issue = 1 | pages = 73–7 | year = 1997 | pmid = 9387089 | doi = 10.1016/S0165-0327(97)00082-7 }}</ref>

Studies have shown that the use of antidepressants is correlated with an increased risk of suicidal behaviour and thinking (suicidality) in those aged under 25.<ref name="StoneETAL" /> This problem has been serious enough to warrant government intervention by the US Food and Drug Administration (FDA) to warn of the increased risk of suicidality during antidepressant treatment.<ref name="pmid17485726">{{cite journal |vauthors=Friedman RA, Leon AC | title = Expanding the black box – depression, antidepressants, and the risk of suicide | journal = N. Engl. J. Med. | volume = 356 | issue = 23 | pages = 2343–6 | year = 2007 | pmid = 17485726 | doi = 10.1056/NEJMp078015 }}</ref> According to the FDA, the heightened risk of suicidality is within the first one to two months of treatment.<ref>{{cite web |url=http://www.fda.gov/drugs/drugsafety/informationbydrugclass/ucm096273 |title=Antidepressant Use in Children, Adolescents, and Adults |format= |work= |accessdate=}}</ref><ref>{{cite web |url=http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088660.pdf%E2%80%8E |title=FDA Medication Guide for Antidepressants |accessdate=5 June 2014 }}</ref> The National Institute for Health and Care Excellence (NICE) places the excess risk in the "early stages of treatment".<ref>{{cite web |url=http://www.nice.org.uk/nicemedia/pdf/CG90NICEguideline.pdf |title=www.nice.org.uk |format= |work= |accessdate=}}</ref> A [[meta-analysis]] suggests that the relationship between antidepressant use and suicidal behavior or thoughts is age-dependent.<ref name="StoneETAL" /> Compared to placebo the use of antidepressants is associated with an increase in suicidal behavior or thoughts among those aged under 25 ([[odds ratio|OR]]=1.62). This increase in suicidality approaches that observed in children and adolescents. There is no effect or possibly a mild protective effect among those aged 25 to 64 (OR=0.79). Antidepressant treatment has a protective effect against suicidality among those aged 65 and over (OR=0.37).<ref name="StoneETAL">{{cite journal |vauthors=Stone M, Laughren T, Jones ML, Levenson M, Holland PC, Hughes A, Hammad TA, Temple R, Rochester G | title = Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration | journal = BMJ | volume = 339 | issue =  | pages = b2880 | year = 2009 | pmid = 19671933 | pmc = 2725270 | doi =  10.1136/bmj.b2880| url =  }}</ref><ref name=dhintrev>{{cite journal |vauthors=Healy D, Aldred G | 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 | format = PDF | journal = [[International Review of Psychiatry]] | volume = 17 | issue = | pages = 163–172 | doi=10.1080/09540260500071624}}</ref>

Sexual side-effects are also common with SSRIs, such as loss of [[sexual drive]], [[anorgasmia|failure to reach orgasm]], and [[erectile dysfunction]].<ref>{{cite book | name-list-format = vanc |editor-first=Jon E. |editor-last=Grant|editor2-last=Potenza|editor2-first=Marc N. |title=The Oxford handbook of impulse control disorders|year=2012|publisher=Oxford University Press|location=Oxford|isbn=978-0-19-538971-5}}</ref> Although usually reversible, these sexual side-effects can, in rare cases, last for months or years after the drug has been completely withdrawn.<ref name="pmid18173768">{{cite journal |vauthors=Csoka AB, Csoka A, Bahrick A, Mehtonen OP | title = Persistent sexual dysfunction after discontinuation of selective serotonin reuptake inhibitors | journal = J Sex Med | volume = 5 | issue = 1 | pages = 227–33 | year = 2008 | pmid = 18173768 | doi = 10.1111/j.1743-6109.2007.00630.x }}</ref>

In a study of 1022 outpatients, overall sexual dysfunction with all antidepressants averaged 59.1%<ref name="pmid11229449">{{cite journal |vauthors=Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F | title = Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction | journal = J Clin Psychiatry | volume = 62 Suppl 3 | issue =  | pages = 10–21 | year = 2001 | pmid = 11229449 | doi =  }}</ref> with SSRIs values between 57 and 73%, mirtazapine 24%, nefazodone 8%, amineptine 7% and moclobemide 4%. [[Moclobemide]], a selective reversible MAO-A inhibitor, does not cause sexual dysfunction,<ref name="pmid19440080">{{cite journal |vauthors=Serretti A, Chiesa A | title = Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis | journal = J Clin Psychopharmacol | volume = 29 | issue = 3 | pages = 259–66 | year = 2009 | pmid = 19440080 | doi = 10.1097/JCP.0b013e3181a5233f }}</ref> and can actually lead to an improvement in all aspects of sexual function.<ref name="pmid9696909">{{cite journal |vauthors=Chebili S, Abaoub A, Mezouane B, Le Goff JF | title = [Antidepressants and sexual stimulation: the correlation] | language = French | journal = Encephale | volume = 24 | issue = 3 | pages = 180–4 | year = 1998 | pmid = 9696909 | doi =  }}</ref>

Biochemical mechanisms suggested as causative include increased serotonin, particularly affecting [[5-HT2 receptor|5-HT₂]] and [[5HT3 receptor|5-HT₃ receptors]]; decreased [[dopamine]]; decreased [[norepinephrine]]; blockade of [[cholinergic receptor|cholinergic]] and [[alpha-1 adrenergic receptor|α₁adrenergic receptors]]; inhibition of [[nitric oxide synthase|nitric oxide synthetase]]; and elevation of [[prolactin]] levels.<ref>{{cite journal |vauthors=Keltner NL, McAfee KM, Taylor CL | title = Biological Perspectives | journal = Perspectives in Psychiatric Care | volume = 38 | issue = 3 | pages = 111–6 | year = 2009 | pmid = 12385082 | doi = 10.1111/j.1744-6163.2002.tb00665.x }}</ref> [[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.<ref name="pmid18278806">{{cite journal |vauthors=Ozmenler NK, Karlidere T, Bozkurt A, Yetkin S, Doruk A, Sutcigil L, Cansever A, Uzun O, Ozgen F, Ozsahin A | title = Mirtazapine augmentation in depressed patients with sexual dysfunction due to selective serotonin reuptake inhibitors | journal = Hum Psychopharmacol | volume = 23 | issue = 4 | pages = 321–6 | year = 2008 | pmid = 18278806 | doi = 10.1002/hup.929 }}</ref>

Antidepressant discontinuation symptoms were first reported with [[imipramine]], the first tricyclic antidepressant (TCA), in the late 1950s, and each new class of antidepressants has brought reports of similar conditions, including [[monoamine oxidase inhibitors]] (MAOIs), SSRIs, and SNRIs.  As of 2001, at least 21 different antidepressants, covering all the major classes, were known to cause discontinuation syndromes.<ref name="DrugSaf2001-Haddad">{{cite journal |author=Haddad, P. |title=Antidepressant discontinuation syndromes |journal=Drug Saf |volume=24 |issue=3 |pages=183–97 |year=2001 |pmid=11347722 |doi=10.2165/00002018-200124030-00003}}</ref>  The problem has been poorly studied, and most of the literature has been case reports or small clinical studies; incidence is hard to determine and controversial.<ref name="DrugSaf2001-Haddad" />

People with discontinuation syndrome have been on an antidepressant for at least four weeks and have recently stopped taking the medication, either abruptly or after a fast taper.<ref name="WarnerAFP">{{cite journal |vauthors=Warner CH, Bobo W, Warner C, Reid S, Rachal J |title=Antidepressant discontinuation syndrome |journal=Am Fam Physician |volume=74 |issue=3 |pages=449–56 |date=August 2006  |pmid=16913164 |doi= |url=}}</ref>  Common symptoms include flu-like symptoms (nausea, vomiting, diarrhea, headaches, sweating), sleep disturbances (insomnia, nightmares, constant sleepiness), sensory/movement disturbances (imbalance, tremors, [[Vertigo (medical)|vertigo]], dizziness, electric-shock-like experiences), mood disturbances ([[dysphoria]], anxiety, agitation) and cognitive disturbances (confusion and hyperarousal).<ref name="WarnerAFP" /><ref name=Haddad2007>{{cite journal |last=Haddad |first=P.M. |last2=Anderson |first2=I.M. |year=2007 |title=Recognising and managing antidepressant discontinuation symptoms |journal=Advances in Psychiatric Treatment |volume=13 |issue=6 |pages=447–457 |doi=10.1192/apt.bp.105.001966}}</ref><ref name=Renoir2013>{{cite journal | author = Renoir T |date=April 2013  | title = Selective serotonin reuptake inhibitor antidepressant treatment discontinuation syndrome: a review of the clinical evidence and the possible mechanisms involved | url = | journal = Front Pharmacol | volume = 4 | issue = | page = 45 | doi = 10.3389/fphar.2013.00045 | pmid = 23596418 | pmc=3627130}}</ref>  Over fifty symptoms have been reported.<ref>{{cite journal |vauthors=Haddad PM, Dursun SM |date=January 2008  | title = Neurological complications of psychiatric drugs: clinical features and management | url = | journal = Hum Psychopharmacol | volume = 23 | issue = Suppl 1| pages = 15–26 | pmid = 18098217 | doi=10.1002/hup.918}}</ref>

With the explosion of use and interest in SSRIs in the late 1980s and early 1990s, focused especially on [[Prozac#Popular culture|Prozac]], interest grew as well in discontinuation syndromes.<ref>{{cite news |url=https://www.nytimes.com/2007/05/06/magazine/06antidepressant-t.html|work=New York Times |title=Self-Nonmedication |first=Bruce |last=Stutz |date=6 May 2007 |accessdate=24 May 2010}}</ref>  In the late 1990s, some investigators thought that symptoms that emerged when antidepressants were discontinued, might mean that antidepressants were causing [[addiction]], and some used the term "withdrawal syndrome" to describe the symptoms.  Addictive substances cause [[physiological dependence]], so that [[drug withdrawal]] causes suffering.  These theories were abandoned, since addiction leads to [[drug-seeking behavior]], and people taking antidepressants do not exhibit drug-seeking behavior.  The term "withdrawal syndrome" is no longer used with respect to antidepressants, to avoid confusion with problems that arise from addiction.<ref name="WarnerAFP" /><ref>{{cite journal | author = Shelton RC | year = 2006 | title = The nature of the discontinuation syndrome associated with antidepressant drugs | url = | journal = J Clin Psychiatry | volume = 67 | issue = Suppl 4| pages = 3–7 | pmid = 16683856 }}</ref><ref>WHO (2003)  [http://apps.who.int/medicinedocs/fr/d/Js4896e/9.html WHO Expert Committee on Drug Dependence – WHO Technical Report Series, No. 915 – Thirty-third Report]</ref>  There are case reports of antidepressants being abused, but these are rare and are mostly limited to antidepressants with stimulant effects and to people who already had a substance use disorder.<ref>{{cite journal |vauthors=Evans EA, Sullivan MA | date = Aug 2014 | title = Abuse and misuse of antidepressants | url = | journal = Subst Abuse Rehabil | volume = 5 | issue = | pages = 107–20 | doi = 10.2147/SAR.S37917 | pmid = 25187753 }}</ref>  A 2012 comparison of the effects of stopping therapy with [[benzodiazepine]]s and [[SSRI]]s argued that because the symptoms are similar, it makes no sense to say that benzodiazepines are addictive while SSRIs are not.<ref>{{cite journal  |vauthors=Nielsen M, et al.  | date = May 2012 | title = What is the difference between dependence and withdrawal reactions? A comparison of benzodiazepines and selective serotonin re-uptake inhibitors | url = | journal = Addiction | volume = 107 | issue = 5| pages = 900–8 | doi = 10.1111/j.1360-0443.2011.03686.x | pmid = 21992148 }}</ref>  Responses to that review noted that there is no evidence that people who stop taking SSRIs exhibit drug-seeking behavior while people who stop taking benzodiazepines do, and that the drug classes should be considered differently.<ref>{{cite journal | author = Brady K | date = May 2012 | title = Withdrawal or dependence: a matter of context. Comment on: What is the difference between dependence and withdrawal reactions? A comparison of benzodiazepines and selective serotonin re-uptake inhibitors | url = | journal = Addiction | volume = 107 | issue = 5| pages = 910–1 | doi = 10.1111/j.1360-0443.2012.03862.x | pmid = 22471576 }}</ref><ref>{{cite journal | author = Lader M | date = May 2012 | title = Dependence and withdrawal: comparison of the benzodiazepines and selective serotonin re-uptake inhibitors.  Comment on: What is the difference between dependence and withdrawal reactions? A comparison of benzodiazepines and selective serotonin re-uptake inhibitors | url = | journal = Addiction | volume = 107 | issue = 5| pages = 909–10 | doi = 10.1111/j.1360-0443.2011.03736.x | pmid = 22471575 }}</ref>

 

==History of development==

 

==Society and culture==

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*[[Antipsychotics]] (also known as '''neuroleptics''')

* Linde, K., Kriston, L., Rucker, G., Jamil, S., Schumann, I., Meissner, K., . . . Schneider, A. (2015). <u>Efficacy and Acceptability of Pharmacological Treatments for Depressive Disorders in Primary Care: Systematic Review and Network Meta-Analysis.</u> ''The Annals of Family Medicine'', 13(1), 69-79. doi:10.1370/afm.1687