| Revision as of 11:41, 3 April 2013 edit121.218.77.212 (talk) →Sexual dysfunction← Previous edit | Revision as of 09:20, 9 April 2013 edit undo114.77.126.170 (talk)No edit summaryTag: blankingNext edit → | ||
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| ssri are things that make you feel good | |||
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| {{See also|Serotonin reuptake inhibitor}} | |||
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| ''' Selective serotonin re-uptake inhibitors''' or '''serotonin-specific reuptake inhibitor'''<ref name="BARLOW">{{Cite book|author=Barlow, David H. Durand, V. Mark |title=Abnormal Psychology: An Integrative Approach |edition=Fifth |page=239 |chapter=Chapter 7: Mood Disorders and Suicide |isbn=0-495-09556-7 |oclc=192055408 |location=Belmont, CA |publisher=Wadsworth Cengage Learning |year=2009}}</ref> ('''SSRIs''') are a class of compounds typically used as ]s in the treatment of ], ]s, and some ]s. | |||
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| SSRIs are believed to increase the ] level of the neurotransmitter ] by ] its ] into the ], increasing the level of ] in the synaptic cleft available to bind to the ]. They have varying degrees of selectivity for the other ]s, with pure SSRIs having only weak affinity for the ] and ]. | |||
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| SSRIs are the first class of ] discovered using the process called '']'', a process that starts with a specific biological target and then creates a molecule designed to affect it.<ref name="PRESCORN2004"/> They are the most widely prescribed antidepressants in many countries.<ref name="PRESCORN2004">{{Cite book|author=Preskorn SH, Ross R, Stanga CY |chapter=Selective Serotonin Reuptake Inhibitors |chapterurl=http://books.google.com/books?id=sO_hArhCxwMC&pg=PA241 |editor=Sheldon H. Preskorn, Hohn P. Feighner, Christina Y. Stanga and Ruth Ross |title=Antidepressants: Past, Present and Future |publisher=Springer |location=Berlin |year=2004 |pages=241–62 |isbn=978-3-540-43054-4}}</ref> The efficacy of SSRIs in mild or moderate cases of depression has been disputed.<ref name="JAMA2010"/><ref name="Kramer">{{cite news|last=Kramer|first=Peter|title=In Defense of Antidepressants|url=http://www.nytimes.com/2011/07/10/opinion/sunday/10antidepressants.html|accessdate=13 July 2011|newspaper=The New York Times|date=7 Sept 2011}}</ref><ref name="Pies">{{Cite journal|author=Ronald Pies, MD|title=Antidepressants Work, Sort of-Our System of Care Does Not|year=2010|pages=101–104|issue=2|month=April |volume=30|journal=Journal of Clinical Psychopharmacology |pmid= 20520282|doi:10.1097/JCP.0b013e3181d52dea}}</ref> | |||
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| ==Medical uses== | |||
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| The main indication for SSRIs is ]. SSRIs are frequently prescribed for ]s, such as ], ]s, ] (OCD), ]s, ] and occasionally, for ] (PTSD). They are also frequently used to treat ], although generally with poor results.<ref>{{cite web|last=Medford|first=Nick|title=Understanding and treating depersonalization disorder|url=http://apt.rcpsych.org/content/11/2/92.full|publisher=Advances in Psychiatric Treatment (2005)|accessdate=2011-11-11}}</ref> | |||
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| ===Depression=== | |||
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| Antidepressants are recommended by the ] (NICE) as a first-line treatment of severe depression and for the treatment of mild-to-moderate depression that persists after conservative measures such as cognitive therapy.<ref name=NICE2009>{{cite web |url=http://www.nice.org.uk/nicemedia/pdf/CG%2090%20QRG%20LR%20FINAL.pdf |title=www.nice.org.uk |format= |work= |accessdate=}}</ref> They recommend against their routine use in those who have chronic health problems and mild depression.<ref name=NICE2009/> There has been controversy regarding the efficacy of antidepressants in treating depression depending on its severity and duration. A comprehensive review conducted by NICE concluded that antidepressants have no advantage over placebo in the treatment of short term mild depression, but that the available evidence supported the use of antidepressants in the treatment of dysthymia and other forms of chronic mild depression.<ref>{{cite book |author= |title=Depression: The NICE Guideline on the Treatment and Management of Depression in Adults (Updated Edition) |publisher=RCPsych Publications |location= |year=2010 |pages= |isbn=1-904671-85-3 |url=http://www.nice.org.uk/nicemedia/live/12329/45896/45896.pdf}}</ref> Two meta-analyses of clinical trials published in 2008 and 2011 found that in mild and moderate depression, the effect of SSRIs is small or none compared to placebo, while in very severe depression the effect of SSRIs is between "relatively small " and "substantial".<ref name="JAMA2010"/><ref name="KIRSCH2008"/> Unlike the NICE study, these studies did not discriminate between the acutely and chronically depressed. The 2008 meta-analysis combined 35 clinical trials submitted to the ] (FDA) before licensing of four newer antidepressants (including the SSRIs paroxetine and ], the non-SSRI antidepressant ], and the SNRI (serotonin and norepinephrine reuptake inhibitor) ]). The authors attributed the relationship between severity and efficacy to a reduction of the placebo effect in severely depressed patients, rather than an increase in the effect of the medication.<ref name="KIRSCH2008">{{Cite journal|author=Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT |title=Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration |journal=PLoS Medicine |volume=5 |issue=2 |pages=e45 |year=2008 |month=February |pmid=18303940 |pmc=2253608 |doi=10.1371/journal.pmed.0050045}}</ref> Some researchers have questioned the statistical basis of this study suggesting that it underestimates the effect size of antidepressants.<ref name="HORDER2010">{{Cite journal|author=Horder J, Matthews P, Waldmann R |title=Placebo, Prozac and PLoS: significant lessons for psychopharmacology |journal=Journal of Psychopharmacology |year=2010 |month=June |pmid=20571143 |doi=10.1177/0269881110372544|volume=25|issue=10|pages=1277–88}}</ref><ref name="FOUNTOULAKIS2010">{{Cite journal|author=Fountoulakis KN, Moller H-J |title=Efficacy of antidepressants: a re-analysis and re-interpretation of the Kirsch data |journal=International Journal of Neuropsychopharmacology|volume=14|issue=3 |pages=1–8 |year=2010 |month=August |pmid=20800012 |doi=10.1017/S1461145710000957}}</ref> A 2010 review reached similar conclusions: in mild and moderate depression, specifically that the effect of SSRI is very small or none compared to placebo, while it is clinically significant in very severe depression.<ref name="JAMA2010">{{Cite journal|doi=10.1001/jama.2009.1943|author=Jay C. Fournier, MA; Robert J. DeRubeis, PhD; Steven D. Hollon, PhD; Sona Dimidjian, PhD; Jay D. Amsterdam, MD; Richard C. Shelton, MD; Jan Fawcett, MD|title=Antidepressant Drug Effects and Depression Severity|year=2010|pages=47–53|issue=1|month=January|volume=303|journal=The Journal of the American Medical Association|url=http://jama.ama-assn.org/cgi/content/short/303/1/47?home|pmid=20051569}}</ref><ref>{{Cite news|title=Antidepressants: Do They "Work" or Don't They?|work=Scientific American|date=March 2, 2010|author=John Kelley|url=http://www.scientificamerican.com/article.cfm?id=antidepressants-do-they-work-or-dont-they}}</ref> However, this analysis included only 6 studies out of the over 2,000 that have been done, involved just 2 medications, and did not involve studies with placebo washout periods typically used as controls.<ref name="Kramer"/><ref name="Pies">{{Cite journal|author=Ronald Pies, MD|title=Antidepressants Work, Sort of-Our System of Care Does Not|year=2010|pages=101–104|issue=2|month=April |volume=30|journal=Journal of Clinical Psychopharmacology |pmid= 20520282|doi:10.1097/JCP.0b013e3181d52dea}}</ref> | |||
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| SSRIs are recommended by NICE over tricyclics due to their superior tolerability.<ref>{{cite web |url=http://www.nice.org.uk/nicemedia/live/12329/45896/45896.pdf |title=www.nice.org.uk |format= |work= |accessdate=}}</ref> One study showed that SSRIs have greater adverse effects than TCAs in the elderly, though the authors caution that more research is needed.<ref name="pmid21810375">{{cite journal |author=Coupland CA, Dhiman P, Barton G, ''et al.'' |title=A study of the safety and harms of antidepressant drugs for older people: a cohort study using a large primary care database |journal=Health Technol Assess |volume=15 |issue=28 |pages=1–202, iii–iv |year=2011 |month=August |pmid=21810375 |doi=10.3310/hta15280 |url=}}</ref> There does not appear to be a substantial differences in efficacy among the various second generation antidepressants (SSRIs and SNRIs).<ref>{{cite journal |author=Gartlehner G, Hansen RA, Morgan LC, ''et al.'' |title=Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: an updated meta-analysis |journal=Ann. Intern. Med. |volume=155 |issue=11 |pages=772–85 |year=2011 |month=December |pmid=22147715 |doi=10.1059/0003-4819-155-11-201112060-00009 |url=}}</ref> | |||
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| ===Generalized anxiety disorder=== | |||
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| SSRIs are recommended by the National Institute for Health and Clinical Excellence (NICE) for the treatment of ] (GAD) that has failed to respond to conservative measures such as education and self-help activities. GAD is a common disorder of which the central feature is excessive worry about a number of different events. Key symptoms include excessive anxiety about multiple events and issues, and difficulty controlling worrisome thoughts that persists for at least 6 months. | |||
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| Antidepressants provide a modest-to-moderate reduction in anxiety in GAD,<ref name="urlwww.nice.org.uk">{{cite web |url=http://www.nice.org.uk/nicemedia/live/13314/52599/52599.pdf |title=www.nice.org.uk |format= |work= |accessdate=2013-02-20}}</ref> and are superior to placebo in treating GAD.<ref name = Kapczinski>{{cite journal |author=Kapczinski F, Lima MS, Souza JS, Schmitt R |title=Antidepressants for generalized anxiety disorder |journal=Cochrane Database Syst Rev |volume= |issue=2 |pages=CD003592 |year=2003 |pmid=12804478 |doi=10.1002/14651858.CD003592 |url=}}</ref> The efficacy of different antidepressants is similar.<ref name="urlwww.nice.org.uk"/><ref name = Kapczinski/> | |||
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| ===Obsessive compulsive disorder (OCD)=== | |||
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| SSRIs are recommended for the second line treatment of adult ] patients with mild functional impairment and as first line treatment for those with moderate or severe impairment. In children, SSRIs can be considered as a second line therapy in those with moderate-to-severe impairment, with close monitoring for psychiatric adverse effects.<ref> | |||
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| {{cite web |url=http://www.nice.org.uk/nicemedia/pdf/cg031niceguideline.pdf |title=www.nice.org.uk |format= |work= |accessdate=}}</ref> SSRIs are efficacious in the treatment of OCD; patients treated with SSRIs are about twice as likely to respond to treatment as those treated with placebo.<ref>{{cite journal |author=Arroll B, Elley CR, Fishman T, ''et al.'' |title=Antidepressants versus placebo for depression in primary care |journal=Cochrane Database Syst Rev |volume= |issue=3 |pages=CD007954 |year=2009 |pmid=19588448 |doi=10.1002/14651858.CD007954 |url=}}</ref><ref>{{cite web |url=http://www.medscape.com/viewarticle/570825+ |title=Medscape Log In |format= |work= |accessdate=}}</ref> | |||
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| ===Eating disorders=== | |||
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| Anti-depressants are recommended as an alternative or additional first step to self-help programs in the treatment of ].<ref name="urlwww.nice.org.uk">{{cite web |url=http://www.nice.org.uk/nicemedia/pdf/CG9FullGuideline.pdf |title=www.nice.org.uk |format= |work= |accessdate=}}</ref> SSRIs (fluoxetine in particular) are preferred over other anti-depressants due to their acceptability, tolerability, and superior reduction of symptoms in short term trials. Long term efficacy remains poorly characterized. | |||
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| Similar recommendations apply to ].<ref name="urlwww.nice.org.uk" /> SSRIs provide short term reductions in binge eating behavior, but have not been associated with significant weight loss.<ref name="urlNational Guideline Clearinghouse | Practice guideline for the treatment of patients with eating disorders.">{{cite web |url=http://www.guidelines.gov/content.aspx?id=9318+ |title=National Guideline Clearinghouse | Practice guideline for the treatment of patients with eating disorders. |format= |work= |accessdate=}}</ref> | |||
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| Clinical trials have generated mostly negative results for the use of SSRI's in the treatment of ].<ref name="pmid21414249">{{cite journal |author=Flament MF, Bissada H, Spettigue W |title=Evidence-based pharmacotherapy of eating disorders |journal=Int. J. Neuropsychopharmacol. |volume=15 |issue=2 |pages=189–207 |year=2012 |month=March |pmid=21414249 |doi=10.1017/S1461145711000381 |url=}}</ref> Treatment guidelines from the National Institute of Health and Clinical Excellence<ref name="urlwww.nice.org.uk" /> recommend against the use of SSRIs in this disorder. Those from the American Psychiatric Association note that SSRIs confer no advantage regarding weight gain, but that they may be used for the treatment of co-existing depressive, anxiety, or obsessive-compulsive disorders.<ref name="urlNational Guideline Clearinghouse | Practice guideline for the treatment of patients with eating disorders."/> | |||
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| ===Stroke recovery=== | |||
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| SSRIs have been used in the treatment of ] patients, including those with and without symptoms of depression. A recent meta analysis of randomized, controlled clinical trials found a statistically significant effect of SSRIs on dependence, neurological deficit, depression, and anxiety. There was no statistically significant effect on death, motor deficits, or cognition.<ref>{{cite journal |author=Mead GE, Hsieh CF, Lee R, ''et al.'' |title=Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery |journal=Cochrane Database Syst Rev |volume=11 |issue= |pages=CD009286 |year=2012 |pmid=23152272 |doi=10.1002/14651858.CD009286.pub2 |url=}}</ref> | |||
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| ===Premature ejaculation=== | |||
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| A general disadvantage of SSRIs in treating premature ejaculation is that they require continuous daily treatment to delay ejaculation significantly.<ref name="pmid17983899">{{Cite journal|author=Waldinger MD |title=Premature ejaculation: state of the art |journal=The Urologic Clinics of North America |volume=34 |issue=4 |pages=591–9, vii–viii |year=2007 |month=November |pmid=17983899 |doi=10.1016/j.ucl.2007.08.011}}</ref> For the occasional "on-demand" treatment, a few hours before coitus, ] gave better results than paroxetine in one study,<ref name="pmid15363569">{{Cite journal|author=Waldinger MD, Zwinderman AH, Olivier B |title=On-demand treatment of premature ejaculation with clomipramine and paroxetine: a randomized, double-blind fixed-dose study with stopwatch assessment |journal=European Urology |volume=46 |issue=4 |pages=510–5; discussion 516 |year=2004 |month=October |pmid=15363569 |doi=10.1016/j.eururo.2004.05.005}}</ref> while in another study both sertraline and clomipramine were indistinguishable from the pause–squeeze technique and inferior to paroxetine.<ref name="pmid11313839">{{Cite journal|author=Abdel-Hamid IA, El Naggar EA, El Gilany AH |title=Assessment of as needed use of pharmacotherapy and the pause-squeeze technique in premature ejaculation |journal=International Journal of Impotence Research |volume=13 |issue=1 |pages=41–5 |year=2001 |month=February |pmid=11313839 |doi=10.1038/sj.ijir.3900630}}</ref> The most recent research, conducted in 2007, suggests that on-demand treatment with ] (Viagra) offers a dramatic improvement in ejaculation delay and sexual satisfaction as compared with daily paroxetine,<ref name="pmid17470165">{{Cite journal|author=Wang WF, Wang Y, Minhas S, Ralph DJ |title=Can sildenafil treat primary premature ejaculation? A prospective clinical study |journal=International Journal of Urology |volume=14 |issue=4 |pages=331–5 |year=2007 |month=April |pmid=17470165 |doi=10.1111/j.1442-2042.2007.01606.x}}</ref> with on-demand sertraline, paroxetine or clomipramine,<ref name="pmid11313839"/> and with the pause–squeeze technique.<ref name="pmid11313839"/><ref name="pmid17470165"/> | |||
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| ==Adverse effects== | |||
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| General side effects are mostly present during the first 1–4 weeks while the body adapts to the drug (with the exception of sexual side effects, which tend to occur later in treatment). In fact, it often takes 6–8 weeks for the drug to begin reaching its full potential (the slow onset is considered a downside to treatment with SSRIs). Almost all SSRIs are known to cause one or more of these symptoms: | |||
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| *]/vomiting | |||
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| *drowsiness or ] | |||
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| *] (very common as a short-term side effect) | |||
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| *] | |||
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| *extremely vivid or strange ]s | |||
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| *] | |||
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| *] (pupil dilation) | |||
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| *changes in appetite | |||
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| *] and/or changes in sleep | |||
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| *excessive ] | |||
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| *]/gain (measured by a change in bodyweight of 7 pounds) | |||
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| *increased risk of ]s by 1.7 fold<ref>{{cite journal |author=Wu Q, Bencaz AF, Hentz JG, Crowell MD |title=Selective serotonin reuptake inhibitor treatment and risk of fractures: a meta-analysis of cohort and case-control studies |journal=Osteoporos Int |volume=23 |issue=1 |pages=365–75 |year=2012 |month=January |pmid=21904950 |doi=10.1007/s00198-011-1778-8 |url=}}</ref> | |||
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| *changes in ] (see the next section) | |||
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| *increased feelings of depression and anxiety (which may sometimes provoke ]s) | |||
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| *] | |||
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| *]s | |||
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| *] dysfunction including ], increased or reduced ] | |||
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| *] | |||
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| *] (thoughts of ]) | |||
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| *]<ref>{{cite web|author=September 23, 2012 |url=http://www.emedicinehealth.com/ssris_and_depression/page5_em.htm |title=SSRIs and Depression |publisher=Emedicinehealth.com |date= |accessdate=2012-09-23}}</ref> | |||
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| *] | |||
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| *] | |||
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| *] | |||
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| Many side effects disappear after the adaptation phase, when the antidepressant effects begin to come to prominence. However, despite being called general, the side effects and their durations are highly individual and drug-specific. Usually the treatment is begun with a small dose to see how the patient's body reacts to the drug, after that either the dose can be adjusted (e.g. Prozac in the UK is begun at a 20 mg dose, and then adjusted as necessary to 40 mg or 60 mg). Should the drug prove ineffective, or the side effects intolerable to the patient, another common route is to switch treatment to either another SSRI, or an ].<ref>A landmark study in the use of anti-depressants and their role in step-therapy can be found in the STAR*D trial.</ref> | |||
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| ] or ] is a possible side effect. Users with some type of ] are at a much higher risk, however SSRI-induced mania in patients previously diagnosed with unipolar depression can trigger a bipolar episode; however, according to DSM IV-TR, the diagnosis of bipolar disorder requires that the individuals symptoms must not stem from medication side effects, toxins, drug abuse, or another general medical condition. | |||
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| ===Sexual dysfunction=== | |||
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| SSRIs can cause various types of ] such as ], ], and diminished ].<ref>{{cite book | last = Coleman | first = E. | authorlink = Eli Coleman | editor1-last = Grant | editor1-first = Jon E. | editor1-link = | editor2-last = Potenza | editor2-first = Marc N. | editor2-link = | title = The Oxford Handbook of Impulse Control Disorders | url = http://books.google.ru/books?id=WjgPfD-tgEMC&lpg=PA277&hl=ru&pg=PA375#v=onepage&q&f=false | edition = | series = | year = 2011 | publisher = ] | location = ] | page = 385 | pages = | nopp = | at = | chapter = Chapter 28. Impulsive/compulsive sexual behavior: Assessment and treatment }}</ref> Initial studies found sexual side effects not significantly different from placebo, but since these studies relied on unprompted reporting, the frequency was probably underestimated. In more recent studies, doctors have specifically asked about sexual difficulties, and found that they are present in between 17% and 41%<ref>{{Cite journal|author=Hu XH, Bull SA, Hunkeler EM, ''et al.'' |title=Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate |journal=The Journal of Clinical Psychiatry |volume=65 |issue=7 |pages=959–65 |year=2004 |month=July |pmid=15291685 |url=http://article.psychiatrist.com/?ContentType=START&ID=10000968 |doi=10.4088/JCP.v65n0712}}</ref><ref>{{Cite journal|author=Landén M, Högberg P, Thase ME |title=Incidence of sexual side effects in refractory depression during treatment with citalopram or paroxetine |journal=The Journal of Clinical Psychiatry |volume=66 |issue=1 |pages=100–6 |year=2005 |month=January |pmid=15669895 |doi=10.4088/JCP.v66n0114}}</ref> of patients, although the lack of placebo control in these studies means they are likely underestimates. This is because release of extracellular concentrations of serotonin in the brain decreases dopamine and norepinephrine leading to erectile and/or sexual dysfunction. | |||
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| Release of postsynaptic 5-HT<sub>2</sub> and 5-HT<sub>3</sub> receptors decreases ] and ] release from the ]. A number of drugs are not associated with sexual side effects (such as ], ], ], ], ], ], ], ] and ],<ref>{{Cite journal| last = Clayton |first = Anita H. |title=Antidepressant-Associated Sexual Dysfunction: A Potentially Avoidable Therapeutic Challenge |journal=Primary Psychiatry |volume=10 |issue=1 |pages=55–61 |year=2003 |url = http://www.primarypsychiatry.com/aspx/articledetail.aspx?articleid=1362}}</ref><ref>{{Cite journal|author=Kanaly KA, Berman JR |title=Sexual side effects of SSRI medications: potential treatment strategies for SSRI-induced female sexual dysfunction |journal=Current Women's Health Reports |volume=2 |issue=6 |pages=409–16 |year=2002 |month=December |pmid=12429073}}</ref> some of which are also not associated with weight gain). As a result, sexual dysfunction caused by SSRIs can sometimes be treated by several different medications including: ], ] and ] among others.{{cn|date=March 2013}} | |||
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| A small number of case reports have appeared in the literature suggesting that in rare cases, sexual dysfunction may persist after discontinuing treatment.<ref>{{cite journal |author=Csoka AB, Bahrick AS, Mehtonen O-P |title=Persistent Sexual Dysfunction after Discontinuation of Selective Serotonin Reuptake Inhibitors (SSRIs) |journal=J Sex Med. |volume=5 |issue= 1|pages=227–33 |year=2008 |doi= 10.1111/j.1743-6109.2007.00630.x|url=http://www.blackwell-synergy.com/doi/abs/10.1111/j.1743-6109.2007.00630.x |pmid=18173768}}</ref> | |||
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| On the other hand, the effect of SSRIs to slow down sexual stimulation may be used as treatment; SSRIs have been proposed as a drug to treat ].<ref>{{Cite journal|author=Waldinger MD, Olivier B |title=Utility of selective serotonin reuptake inhibitors in premature ejaculation |journal=Current Opinion in Investigational Drugs |volume=5 |issue=7 |pages=743–7 |year=2004 |month=July |pmid=15298071}}</ref> The ] herbaceous biennial plant ] (also known as "maca") was found to be effective for alleviating SSRI-induced sexual dysfunction on a small double-blind, randomized, parallel group dose-finding pilot study.<ref>{{cite journal |author=Dording CM, Fisher L, Papakostas G, ''et al.'' |title=A double-blind, randomized, pilot dose-finding study of maca root (L. meyenii) for the management of SSRI-induced sexual dysfunction |journal=CNS Neurosci Ther |volume=14 |issue=3 |pages=182–91 |year=2008 |pmid=18801111 |doi=10.1111/j.1755-5949.2008.00052.x |url=}}</ref> | |||
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| ===Cardiovascular=== | |||
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| Cardiovascular side effects are very rare with SSRI use, with a reported ] of less than 0.0003 percent.<ref>{{cite web|first=Grace Brooke |last=Huffman |title=Cardiac effects in patients using SSRI antidepressants - selective serotonin reuptake inhibitor - Tips from Other Journals |work=] |month=August |year=1997 |url=http://the-medical-dictionary.com/bromazepam_article_8.htm}}</ref> SSRIs inhibit cardiac and vascular ], ] and ]s and prolong ]s.<ref>{{Cite journal|author=Pacher P, Kecskemeti V |title=Cardiovascular Side Effects of New Antidepressants and Antipsychotics: New Drugs, old Concerns? |journal=Current Pharmaceutical Design |volume=10 |issue=20 |pages=2463–75 |year=2004 |pmid=15320756 |pmc=2493295 |doi=10.2174/1381612043383872}}</ref> A number of large studies of patients without known pre-existing heart disease have reported no ] changes related to SSRI use.<ref name="afpssri">{{Cite journal|author=Goldberg RJ |title=Selective serotonin reuptake inhibitors: infrequent medical adverse effects |journal=Archives of Family Medicine |volume=7 |issue=1 |pages=78–84 |year=1998 |pmid=9443704 |url=http://archfami.ama-assn.org/cgi/pmidlookup?view=long&pmid=9443704 |doi=10.1001/archfami.7.1.78}}</ref> More recently, however, concerns about cardiac problems have led to a reduction in the recommended maximum dose of two types of SSRI's. The recommended maximum daily dose of ] was reduced to 40 mg. for most people and 20 mg. for those older than age 60 and some others.<ref>{{cite web|last=FDA|title=FDA Drug Safety|url=http://www.fda.gov/Drugs/DrugSafety/ucm269086.htm}}</ref> The recommended maximum daily dose of ] was reduced to 10 mg. for those older than age 65; the maximum daily dose for most other people remained unchanged at 20 mg.<ref></nowiki>]</ref><ref>{{cite web|url=http://m.utoledo.edu/med/gme/em/pdfs/ECG_escitalopram.pdf |title=ref2 |format=PDF |date= |accessdate=2012-09-23}}</ref> In overdose, fluoxetine has been reported to cause ], ], ]s and ]. Some authors have suggested ] monitoring in patients with severe pre-existing cardiovascular disease who are taking SSRI's.<ref>{{Cite journal|author=Pacher P, Ungvari Z, Nanasi PP, Furst S, Kecskemeti V |title=Speculations on difference between tricyclic and selective serotonin reuptake inhibitor antidepressants on their cardiac effects. Is there any? |journal=Current Medicinal Chemistry |volume=6 |issue=6 |pages=469–80 |year=1999 |month=June |pmid=10213794}}</ref> | |||
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| ===Discontinuation syndrome=== | |||
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| {{Main|SSRI discontinuation syndrome}} | |||
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| Antidepressants such as SSRIs have some ] producing effects, most notably a ]. Their dependence producing properties (depending on the antidepressant) may not be as significant as other psychotropic drugs such as ]s; however, withdrawal symptoms nonetheless may be quite severe and even debilitating. SSRIs have little ] potential, but discontinuation can produce disturbing withdrawal symptoms that may be indistinguishable from a reoccurrence of the original illness.<ref>{{Cite journal|author=van Broekhoven F, Kan CC, Zitman FG |title=Dependence potential of antidepressants compared to benzodiazepines |journal=Prog. Neuropsychopharmacol. Biol. Psychiatry |volume=26 |issue=5 |pages=939–43 |year=2002 |month=June |pmid=12369270 |doi= 10.1016/S0278-5846(02)00209-9|url=http://linkinghub.elsevier.com/retrieve/pii/S0278-5846(02)00209-9}}</ref> Since ] is a reality, discontinuation should be discussed with a medical practitioner before beginning treatment with this class of drugs. | |||
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| When discontinuing an SSRI or SNRI some doctors may switch the patient to fluoxetine due to its much longer ]. This may avoid many of the severe withdrawal symptoms associated with SSRI/SNRI discontinuation. This can be done either by administering a single 20 mg dose of ] or by beginning on a low dosage of fluoxetine and slowly tapering down. Any SSRI or SNRI may be requested in liquid form, which allows very gradual tapering. Alternatively, a patient wishing to stop taking an SSRI/SNRI may visit a compounding pharmacy where his or her prescription may be re-arranged into progressively smaller dosages. For example the lowest dose of cymbalta that can normally be prescribed is 20 mg in gel capsules; a compounding pharmacist may divide this into doses of 20, 15, 10, 5 and 2.5 mg so that a proper tapered reduction may take place. | |||
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| ===Suicide risk=== | |||
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| ====Children and adolescents==== | |||
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| Several studies have found that SSRI use is related to a higher risk of suicidal behavior in children and adolescents.<ref name =FDA2>{{cite web| url = http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf | title =Clinical review: relationship between antidepressant drugs and suicidal behavior in adults| accessdate = 2007-09-22 | author = Stone MB, Jones ML | date = 2006-11-17| format =PDF | work = Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC) | publisher = FDA| pages = 11–74}}</ref><ref name =FDA3>{{cite web| url = http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf | title = Statistical Evaluation of Suicidality in Adults Treated with Antidepressants | accessdate = 2007-09-22 | author = Levenson M, Holland C | date = 2006-11-17| format =PDF | work =Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC) | publisher = FDA| pages = 75–140}}</ref><ref name = "Olfson">{{Cite journal|author=Olfson M, Marcus SC, Shaffer D |title=Antidepressant drug therapy and suicide in severely depressed children and adults: A case-control study |journal=Archives of General Psychiatry |volume=63 |issue=8 |pages=865–72 |year=2006 |month=August |pmid=16894062 |doi=10.1001/archpsyc.63.8.865}}</ref> For instance, a 2004 ] (FDA) analysis of ]s on children with ] found statistically significant increases of the risks of "possible ] and suicidal behavior" by about 80%, and of agitation and hostility by about 130%;<ref name =FDA>{{cite web| url = http://www.fda.gov/OHRMS/DOCKETS/ac/04/briefing/2004-4065b1-10-TAB08-Hammads-Review.pdf | title = Review and evaluation of clinical data. Relationship between psychiatric drugs and pediatric suicidal behavior. | accessdate = 2008-05-29 | author = Hammad TA | date = 2004-08-116| format =PDF | publisher = FDA| pages = 42; 115}}</ref> | |||
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| More infrequently, studies have been inconclusive.<ref>{{Cite journal|author=Hetrick S, Merry S, McKenzie J, Sindahl P, Proctor M|editor1-last=Hetrick|editor1-first=Sarah E |title=Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and adolescents |journal=Cochrane Database Syst Rev |volume= |issue=3 |pages=CD004851 |year=2007 |pmid=17636776 |doi=10.1002/14651858.CD004851.pub2 |url=}}</ref> however, a recent comparison of aggression and hostility occurring during treatment with fluoxetine to placebo in children and adolescents found that no significant difference between the fluoxetine group and a placebo group.<ref> Journal of Child and Adolescent Psychopharmacology. October 2007, 17(5): 713-718. {{doi|10.1089/cap.2006.0138}}.</ref> There is also evidence that higher rates of SSRI prescriptions are associated with lower rates of suicide in children, though since the evidence is ]al, the true nature of the relationship is unclear.<ref name="pmid17074941">{{Cite journal|author=Gibbons RD, Hur K, Bhaumik DK, Mann JJ |title=The relationship between antidepressant prescription rates and rate of early adolescent suicide |journal=The American Journal of Psychiatry |volume=163 |issue=11 |pages=1898–904 |year=2006 |month=November |pmid=17074941 |doi=10.1176/appi.ajp.163.11.1898}}</ref> | |||
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| In 2004, the ] (MHRA) in the ] judged fluoxetine (Prozac) to be the only antidepressant that offered a favorable ] in children with depression, though it was also associated with a slight increase in the risk of self-harm and suicidal ideation.<ref>{{cite web|url=http://www.mhra.gov.uk/home/groups/pl-p/documents/drugsafetymessage/con019472.pdf |title=Report of the CSM expert working group on the safety of selective serotonin reuptake inhibitor antidepressants|accessdate=2007-09-25 |date=2004-12-01 |format=PDF |publisher=] }}</ref> Only two SSRIs are licensed for use with children in the UK, ] (Zoloft) and ] (Luvox), and only for the treatment of ]. Fluoxetine is not licensed for this use.<ref name = MHRAoverview>{{cite web| url = http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON019494 |title=Selective Serotonin Reuptake Inhibitors (SSRIs): Overview of regulatory status and CSM advice relating to major depressive disorder (MDD) in children and adolescents including a summary of available safety and efficacy data |author=|authorlink= |coauthors= |date=2005-09-29 |publisher = ] | pages= |accessdate=2008-05-29}}</ref> | |||
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| ====Adults==== | |||
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| It is unclear whether or not SSRIs affect the risk of suicidal behavior for adults. | |||
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| * A 2005 meta-analysis of drug company data found no evidence that SSRIs increased the risk of suicide; however, important protective or hazardous effects could not be excluded.<ref>{{Cite journal|author=Gunnell D, Saperia J, Ashby D |title=Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo controlled, randomised controlled trials submitted to the MHRA's safety review |journal=BMJ |volume=330 |issue=7488 |page=385 |year=2005 |month=February |pmid=15718537 |pmc=549105 |doi=10.1136/bmj.330.7488.385 |url=}}</ref> Also among high-risk adult patients, antidepressant drug treatment does not seem related to suicide attempts and death.<ref name = "Olfson" /> | |||
| * A 2005 review observed that suicide attempts are increased in those who use SSRIs as compared to ] and compared to therapeutic interventions other than ]. No difference risk of suicide attempts was detected between SSRIs versus tricyclic antidepressants.<ref>{{Cite journal|author=Fergusson D, Doucette S, Glass KC, ''et al.'' |title=Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials |journal=BMJ |volume=330 |issue=7488 |page=396 |year=2005 |month=February |pmid=15718539 |pmc=549110 |doi=10.1136/bmj.330.7488.396 |url=}}</ref> | |||
| * On the other hand, a 2006 review suggests that the widespread use of antidepressants in the new "SSRI-era" appear to have led to highly significant decline in suicide rates in most countries with traditionally high baseline suicide rates. The decline is particularly striking for women who, compared with men, seek more help for depression. Recent clinical data on large samples in the US too have revealed a protective effect of antidepressant against suicide.<ref>{{Cite journal|author=Rihmer Z, Akiskal H |title=Do antidepressants t(h)reat(en) depressives? Toward a clinically judicious formulation of the antidepressant-suicidality FDA advisory in light of declining national suicide statistics from many countries |journal=J Affect Disord |volume=94 |issue=1–3 |pages=3–13 |year=2006 |month=August |pmid=16712945 |doi=10.1016/j.jad.2006.04.003 |url=}}</ref> | |||
| *A 2006 meta analysis of random controlled trials suggests that SSRIs increase suicide ideation compared with placebo. However, the observational studies suggests that SSRIs did not increase suicide risk more than older antidepressants. The researchers stated that if SSRIs increase suicide risk in some patients, the number of additional deaths is very small because ecological studies have generally found that suicide mortality has declined (or at least not increased) as SSRI use has increased.<ref>{{Cite journal|author=Hall WD, Lucke J |title=How have the selective serotonin reuptake inhibitor antidepressants affected suicide mortality? |journal=Aust N Z J Psychiatry |volume=40 |issue=11–12 |pages=941–50 |year=2006 |pmid=17054562 |doi=10.1111/j.1440-1614.2006.01917.x |url=}}</ref> | |||
| * An additional meta-analysis by the FDA in 2006 found an age-related effect of SSRI's. Among adults younger than 25 years, results indicated that there was a higher risk for suicidal behavior. For adults between 25 and 64, the effect appears neutral on suicidal behavior but possibly protective for suicidal behavior for adults between the ages of 25 and 64. For adults older than 64, SSRI's seem to reduce the risk of both suicidal behavior.<ref name=FDA2>(page 54)</ref> | |||
| ====Suicide warnings==== | |||
| The FDA findings resulted in a ] on SSRI and other antidepressant medications regarding the increased risk of suicidal behavior in patients younger than 24.<ref>{{cite web|url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108905.htm |title=FDA Proposes New Warnings About Suicidal Thinking, Behavior in Young Adults Who Take Antidepressant Medications|date=2007-05-02 |publisher=] |accessdate=2008-05-29}}</ref> Similar precautionary notice revisions were implemented by the Japanese Ministry of Health.<ref>{{cite web|url=http://www1.mhlw.go.jp/kinkyu/iyaku_j/iyaku_j/anzenseijyouhou/261.pdf |title=www1.mhlw.go.jp |format=PDF |work=Japanese Ministry of Health |language=Japanese}}</ref> In 2004 the ] in the United Kingdom issued a warning about increases in 'insomnia, agitation, weight loss, headache, tremor, loss of appetite, self-harm and suicidal thoughts' when the medications are used with children and adolescents.<ref>{{cite web|url=http://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con019493.pdf|title=Questions and answers: Advice on SSRIs in children from the Committee on Safety of Medicine|format=PDF|work=Medicines and Healthcare products Regulatory Agency}}</ref> | |||
| The introduction of a warning regarding the association between SSRIs and suicide by the FDA in 2004 led to a dramatic decrease in prescriptions of these medications to young people. Originally, there were concerns that the decrease in prescriptions caused by the warnings could increase the number of teenage suicides in the US.<ref name="pmid17728420">{{Cite journal|author=Gibbons RD, Brown CH, Hur K, ''et al.'' |title=Early evidence on the effects of regulators' suicidality warnings on SSRI prescriptions and suicide in children and adolescents |journal=The American Journal of Psychiatry |volume=164 |issue=9 |pages=1356–63 |year=2007 |month=September |pmid=17728420 |doi=10.1176/appi.ajp.2007.07030454}}</ref> However, the most recent data from the US National Center for Health Statistics put these concerns to rest. The suicide rates for persons younger than 25 has actually decreased between 2004 and 2007.{{OR|date=March 2013}} | |||
| <ref>{{Cite journal|author=Xu J, Kochanek KD, Tejada-Vera B |title=Deaths: Preliminary Data for 2007 |journal=National Vital Statistics Reports |volume=58 |issue=1 |pages=29–30 |year=2009 |month=August| url = http://www.cdc.gov/nchs/data/nvsr/nvsr58/nvsr58_01.pdf |format=PDF| accessdate = 2009-09-20}}</ref><ref>{{Cite journal|author=Heron M, Hoyert DL, Murphy SL,''et al.'' |title=Deaths: Final Data for 2006 |journal=National Vital Statistics Reports |volume=57 |issue=14 |page=30 |year=2009 |month=April| url = http://www.cdc.gov/nchs/data/nvsr/nvsr57/nvsr57_14.pdf |format=PDF| accessdate = 2009-09-20}}</ref> | |||
| ===Pregnancy and breastfeeding=== | |||
| SSRI use during pregnancy is associated with an increased rate of ], ], ], newborn behavioral syndrome, and possibly long term behavioral problems.<ref>{{cite journal|last=Domar|first=A. D.|coauthors=Moragianni, V. A.; Ryley, D. A.; Urato, A. C.|title=The risks of selective serotonin reuptake inhibitor use in infertile women: a review of the impact on fertility, pregnancy, neonatal health and beyond|journal=Human Reproduction|date=31 October 2012|doi=10.1093/humrep/des383}}</ref> The risk of spontaneous abortion is increased about 1.7 fold.<ref>{{cite journal|last=Rahimi|first=Roja|coauthors=Shekoufeh Nikfar, Mohammad Abdollahi|title=Pregnancy outcomes following exposure to serotonin reuptake inhibitors: a meta-analysis of clinical trials|journal=Reproductive Toxicology|year=2006|volume=22|issue=4|pages=571–575|pmid=16720091|doi=10.1016/j.reprotox.2006.03.019}}</ref> | |||
| The FDA issued a statement on July 19, 2006 stating nursing mothers on SSRIs must discuss treatment with their physicians. However, the medical literature on the safety of SSRIs has determined that some SSRIs like Sertraline and Paroxetine are considered safe for breastfeeding.<ref>{{cite web|url=http://www.breastfeeding.org/newsletter/v2i4/page2.html |title=Breastfeeding Update: SDCBC's quarterly newsletter |publisher=Breastfeeding.org |date= |accessdate=2010-07-10}} {{Dead link|date=October 2010|bot=H3llBot}}</ref><ref>{{cite web|url=http://www.kellymom.com/health/meds/antidepressants-hale10-02.html |title=Using Antidepressants in Breastfeeding Mothers |publisher=kellymom.com |date= |accessdate=2010-07-10}}</ref><ref>{{Cite journal|author=Gentile S, Rossi A, Bellantuono C |title=SSRIs during breastfeeding: spotlight on milk-to-plasma ratio |journal=Archives of Women's Mental Health |volume=10 |issue=2 |pages=39–51 |year=2007 |pmid=17294355 |doi=10.1007/s00737-007-0173-0}}</ref> | |||
| Maternal SSRI use may be associated with autism.<ref>{{cite web|author=USA |url=http://www.ncbi.nlm.nih.gov/pubmed/21727247 |title=Antidepressant use during pregnancy and ... [Arch Gen Psychiatry. 2011] - PubMed - NCBI |publisher=Ncbi.nlm.nih.gov |date=2012-05-24 |accessdate=2012-09-23}}</ref> | |||
| ====Neonatal abstinence syndrome==== | |||
| ] is a ] in ]. It has been documented in SSRI treatment. By November 2003, a total of 93 cases of SSRI use associated with either neonatal convulsions or withdrawal syndrome had been reported. Subsequently, the authors of a ] study concluded that doctors should avoid or cautiously manage the prescribing of these drugs to pregnant women with ].<ref> ] - Lancet Press Release. Feb 05 2005</ref> | |||
| ====Neuropsychological changes due to SSRI use in infancy ==== | |||
| Since the early 80's scientists have used a technique called neonatal clomipramine to produce animals used in depression research. If rats are given the tricyclic antidepressant ] when 8–21 days old, they develop behavioural changes in adulthood that resemble depression in humans.<ref name="pmid2183099">{{Cite journal|author=Vogel G, Neill D, Hagler M, Kors D |title=A new animal model of endogenous depression: a summary of present findings |journal=Neuroscience and Biobehavioral Reviews |volume=14 |issue=1 |pages=85–91 |year=1990 |pmid=2183099 |doi=10.1016/S0149-7634(05)80164-2}}</ref><ref name="pmid7902983">{{Cite journal|author=Velazquez-Moctezuma J, Aguilar-Garcia A, Diaz-Ruiz O |title=Behavioral effects of neonatal treatment with clomipramine, scopolamine, and idazoxan in male rats |journal=Pharmacology, Biochemistry, and Behavior |volume=46 |issue=1 |pages=215–7 |year=1993 |month=September |pmid=7902983 |doi=10.1016/0091-3057(93)90343-R}}</ref> In 1997 Lundbeck found that treatment with the SSRI ], which only differs from their product citalopram by two atoms could give similar results as clomipramine.<ref name="pmid9400008">{{Cite journal|author=Hansen HH, Sánchez C, Meier E |title=Neonatal administration of the selective serotonin reuptake inhibitor Lu 10-134-C increases forced swimming-induced immobility in adult rats: a putative animal model of depression? |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=283 |issue=3 |pages=1333–41 |year=1997 |month=December |pmid=9400008 |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9400008}}</ref> Later it was found that neonatal citalopram and escitalopram makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes,<ref name="pmid18385313">{{Cite journal|author=Popa D, Léna C, Alexandre C, Adrien J |title=Lasting syndrome of depression produced by reduction in serotonin uptake during postnatal development: evidence from sleep, stress, and behavior |journal=The Journal of Neuroscience |volume=28 |issue=14 |pages=3546–54 |year=2008 |month=April |pmid=18385313 |doi=10.1523/JNEUROSCI.4006-07.2008}}</ref><ref name="pmid16012532">{{Cite journal|author=Maciag D, Simpson KL, Coppinger D, ''et al.'' |title=Neonatal Antidepressant Exposure has Lasting Effects on Behavior and Serotonin Circuitry |journal=Neuropsychopharmacology |volume=31 |issue=1 |pages=47–57 |year=2006 |month=January |pmid=16012532 |doi=10.1038/sj.npp.1300823|pmc=3118509}}</ref> which are reversed by treatment with antidepressants.<ref name="pmid16483567">{{Cite journal|author=Maciag D, Williams L, Coppinger D, Paul IA |title=Neonatal citalopram exposure produces lasting changes in behavior which are reversed by adult imipramine treatment |journal=European Journal of Pharmacology |volume=532 |issue=3 |pages=265–9 |year=2006 |month=February |pmid=16483567 |pmc=2921633 |doi=10.1016/j.ejphar.2005.12.081}}</ref> | |||
| By treating normal and ] lacking the serotonin transporter with fluoxetine scientists showed that normal emotional reactions in adulthood, like a short latency to escape foot shocks and inclination to explore new environments were dependent on active serotonin transporters during the neonatal period.<ref>{{Cite journal|author=Holden C |title=Neuroscience. Prozac treatment of newborn mice raises anxiety |journal=Science |volume=306 |issue=5697 |page=792 |year=2004 |month=October |pmid=15514122 |doi=10.1126/science.306.5697.792}}</ref><ref>{{Cite journal|author=Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA |title=Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice |journal=Science |volume=306 |issue=5697 |pages=879–81 |year=2004 |month=October |pmid=15514160 |doi=10.1126/science.1101678}}</ref> | |||
| But when young mice were treated with the SNRI desimipramine they developed to normal adults, which suggests that serotonin and noradrenaline have different effects in the developing brain. For humans, the developmental stage sensitive to SSRI:s corresponds with the last trimester to the first years of life. A study showed that 4-year old children perinatally exposed to SSRIs behave normally. However, the young mice and rats also seem normal until they reach puberty and develop behavioural disturbances.<ref>{{Cite journal|author=Ansorge MS, Morelli E, Gingrich JA |title=Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice |journal=The Journal of Neuroscience |volume=28 |issue=1 |pages=199–207 |year=2008 |month=January |pmid=18171937 |doi=10.1523/JNEUROSCI.3973-07.2008}}</ref><ref name="pmid16741203">{{Cite journal|author=Misri S, Reebye P, Kendrick K, ''et al.'' |title=Internalizing behaviors in 4-year-old children exposed in utero to psychotropic medications |journal=The American Journal of Psychiatry |volume=163 |issue=6 |pages=1026–32 |year=2006 |month=June |pmid=16741203 |doi=10.1176/appi.ajp.163.6.1026}}</ref> | |||
| The mechanism is currently unknown, but it seems that early life overstimulation of the 5HT-1 receptor that regulates serotonin production results in low serotonin production after puberty.<ref>{{Cite journal|author=Maciag D, Coppinger D, Paul IA |title=Evidence that the deficit in sexual behavior in adult rats neonatally exposed to citalopram is a consequence of 5-HT1 receptor stimulation during development |journal=Brain Research |volume=1125 |issue=1 |pages=171–5 |year=2006 |month=December |pmid=17101120 |pmc=1762094 |doi=10.1016/j.brainres.2006.10.009}}</ref> | |||
| ====Persistent pulmonary hypertension==== | |||
| Persistent ] (PPHN) is a serious and life-threatening, but rare, lung condition that occurs soon after birth of the newborn. ] with PPHN have high pressure in their lung ]s and are not able to get enough oxygen into their bloodstream. About 1 to 2 babies per 1000 babies born in the U.S. develop PPHN shortly after birth, and often they need intensive ]. One study has found that PPHN is six times more common in babies whose mothers take an SSRI antidepressant after the 20th week of the pregnancy compared to babies whose mothers do not take an antidepressant.<ref>, FDA Public Health Advisory - Treatment Challenges of Depression in Pregnancy</ref> | |||
| A population-based cohort study, which included 1.6 million live births in five Nordic countries, of women with filled SSRI prescriptions later than the 20th week gestation by last menstrual period demonstrated an increased risk of persistent pulmonary hypertension (PPHN) compared to control infants (adjusted RR 2.1, 95% CI 1.5-3). The increased risk of PPHN was of similar magnitude for the SSRI class of drugs (Fluoxetine, Citalopram, Paroxetine, Sertraline, Escitalopram). This study showed that the absolute risk of PPHN would only increase the incidence from 0.1 to 0.3 percent of live-births with late prenatal SSRI exposure.<ref>, Kieler H, Artama M, Engeland A, Ericsson O, Furu K, Gissler M, Nielsen RB, Norgaard M, Stephansson O, Valdimarsdottir U, Zoega H, Haglund B." Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the five Nordic countries" BMJ 2012;344:d8012</ref> | |||
| ===Bleeding tendencies=== | |||
| SSRIs appear to increase the risk of bleeding.<ref name=Wein2005>{{cite journal|last=Weinrieb|first=RM|coauthors=Auriacombe, M; Lynch, KG; Lewis, JD|title=Selective serotonin re-uptake inhibitors and the risk of bleeding.|journal=Expert opinion on drug safety|date=2005 Mar|volume=4|issue=2|pages=337–44|pmid=15794724}}</ref> This includes an increased risk of ], post operative bleeding,<ref name=Wein2005/> and ].<ref>http://www.neurology.org/content/early/2012/10/17/WNL.0b013e318271f848.abstract Selective serotonin reuptake inhibitors and brain hemorrhage</ref> SSRIs are known to cause platelet dysfunction.<ref>{{Cite journal|author=Serebruany VL |title=Selective serotonin reuptake inhibitors and increased bleeding risk: are we missing something? |journal=The American Journal of Medicine |volume=119 |issue=2 |pages=113–6 |year=2006 |month=February |pmid=16443409 |doi=10.1016/j.amjmed.2005.03.044}}</ref><ref>{{Cite journal|author=Halperin D, Reber G |title=Influence of antidepressants on hemostasis |journal=Dialogues in Clinical Neuroscience |volume=9 |issue=1 |pages=47–59 |year=2007 |pmid=17506225|pmc=3181838}}</ref> | |||
| ===Overdose=== | |||
| {{See also|Serotonin syndrome}} | |||
| SSRIs appear safer in ] when compared with traditional antidepressants, such as the tricyclic antidepressants. This relative safety is supported both by case series and studies of deaths per numbers of prescriptions.<ref name="ClinTox2004-isbister">{{Cite journal| author = Isbister G, Bowe S, Dawson A, Whyte I | title = Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose | journal = J Toxicol Clin Toxicol | volume = 42 | issue = 3 | pages = 277–85 | year = 2004 | pmid = 15362595 | doi = 10.1081/CLT-120037428}}</ref> However, case reports of SSRI poisoning have indicated that severe toxicity can occur<ref name="AmJEmergMed1992-Borys">{{Cite journal| author = Borys D, Setzer S, Ling L, Reisdorf J, Day L, Krenzelok E | title = Acute fluoxetine overdose: a report of 234 cases | journal = Am J Emerg Med | volume = 10 | issue = 2 | pages = 115–20 | year = 1992 | pmid = 1586402 | doi = 10.1016/0735-6757(92)90041-U}}</ref> and deaths have been reported following massive single ingestions,<ref name="Lancet1996-Ostrom">{{Cite journal| author = Oström M, Eriksson A, Thorson J, Spigset O | title = Fatal overdose with citalopram | journal = Lancet | volume = 348 | issue = 9023 | pages = 339–40 | year = 1996 | pmid = 8709713 | doi = 10.1016/S0140-6736(05)64513-8}}</ref> although this is exceedingly uncommon when compared to the tricyclic antidepressants.<ref name="ClinTox2004-isbister"/> | |||
| Because of the wide ] of the SSRIs, most patients will have mild or no symptoms following moderate overdoses. The most commonly reported severe effect following SSRI overdose is ]; serotonin toxicity is usually associated with very high overdoses or multiple drug ingestion.<ref name="DrugSaf1995-Sporer">{{Cite journal| author = Sporer K | title = The serotonin syndrome. Implicated drugs, pathophysiology and management | journal = Drug Saf | volume = 13 | issue = 2 | pages = 94–104 | year = 1995 | pmid = 7576268 | doi = 10.2165/00002018-199513020-00004}}</ref> Other reported significant effects include ], ]s, and ].<ref name="ClinTox2004-isbister"/> | |||
| Treatment for SSRI overdose is mainly based on symptomatic and supportive care. Medical care may be required for agitation, maintenance of the airways, and treatment for serotonin syndrome. ] monitoring is usually indicated to detect any cardiac abnormalities. | |||
| ==Contraindications and drug interaction== | |||
| One major contraindication of SSRIs is the concomitant use of MAOIs (]s). This is likely to cause severe ]. | |||
| People taking SSRIs should also avoid taking ] (an ] diphenylbutylpiperidine derivative). ] hydrochloride (or Ultram, Ultracet) can, in rare cases, produce ]s when taken in conjunction with an SSRI or ]. ] impairment is another contraindication for medications of this type. | |||
| SSRIs may increase blood levels and risk of toxicities of certain medications: | |||
| # highly protein-bound medications like ] (coumadin) and ] | |||
| # ]s like ] (Rythmol) or ] (Tambocor) | |||
| # ]s like ] (Toprol xl) or ] (Inderal) | |||
| # ]s like ] (Elavil, Endep) etc. | |||
| # ] like ] (Imitrex, Imigran) etc. | |||
| # ]s like ] (Xanax) or ] (Valium){{Citation needed|date=December 2010}} | |||
| # ] (Tegretol) | |||
| # ] (Propulsid) | |||
| # ] (Clozaril) | |||
| # ] (Neoral) | |||
| # ] (Haldol) | |||
| # ] (Dilantin) | |||
| # ] (Orap) | |||
| # ] (Theo-dur) | |||
| Certain drugs may increase toxicities of SSRIs: | |||
| # ] and other CNS depressants | |||
| # ] dye | |||
| # ]s (water pills) | |||
| # ] – possibly fatal ] | |||
| # ]s like ] (Sudafed) | |||
| # ] | |||
| # ] (Meridia) | |||
| # ] (ecstasy) | |||
| # ] (ambien)<ref>{{cite web|author=September 23, 2012 |url=http://www.emedicinehealth.com/ssris_and_depression/page4_em.htm |title=SSRIs and Depression |publisher=Emedicinehealth.com |date= |accessdate=2012-09-23}}</ref> | |||
| # ] (cough suppressant) – increased risk of ] | |||
| # ] (synergistic serotoninergic effect said to increase risk of seizure or ]) | |||
| # ] – increased risk of ] | |||
| # herbal ] or ] – increased risk of ] | |||
| Painkillers of the NSAIDs drug family may interfere and reduce efficiency of SSRIs:<ref>{{cite web|url=http://www.healthcentral.com/depression/treatment-579181-5.html |title=Why Painkillers Interfere with Anti-depressants |publisher=Healthcentral.com |date=2011-04-20 |accessdate=2012-09-23}}</ref><ref>{{cite web|author=Solomon H. Snyder |url=http://www.pnas.org/content/early/2011/04/20/1104836108.abstract |title=J.L. Warner-Schmidt et.al "Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans" PNAS 2011 |publisher=Pnas.org |date= |accessdate=2012-09-23}}</ref> | |||
| # ] | |||
| # ] (Advil,Nurofen) | |||
| # ] (Aleve) | |||
| SSRIs also directly interfere with ligands of 5-HT receptors, like the ]s and ]s. SSRIs strongly diminish the effects of ]s (e.g. ] and ]), and ]s (e.g. the ]), and almost completely eliminate the serotonergic effects of ] (e.g. ]). The exact mechanism that causes this interaction is still unclear. {{Citation needed|date=September 2010}} However, ] (found in ]) has no actions at the 5-HT2A serotonin receptor, nor is it known to have affinity for any other sites to date. | |||
| ==List of agents== | |||
| Drugs in this class include (trade names in parentheses): | |||
| * ] (Celexa, Cipramil, Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox, Cital) | |||
| * ] (Priligy) | |||
| * ] (Lexapro, Cipralex, Seroplex, Esertia) | |||
| * ] (Depex, Prozac, Fontex, Seromex, Seronil, Sarafem, Ladose, Motivest, Flutop, Fluctin (EUR), Fluox (NZ), Depress (UZB), Lovan (AUS), Prodep (IND)) | |||
| * ] (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox, Floxyfral) | |||
| * ] (Upstene) (discontinued) | |||
| * ] (Paxil, Seroxat, Sereupin, Aropax, Deroxat, Divarius, Rexetin, Xetanor, Paroxat, Loxamine, Deparoc) | |||
| * ] (Zoloft, Lustral, Serlain, Asentra, Tresleen) | |||
| * ] (Zelmid, Normud) (discontinued) | |||
| {| class="wikitable" style="font-size:smaller; text-align:center" | |||
| |- | |||
| ! colspan="5" | Selective serotonin reuptake inhibitors (SSRIs) | |||
| |- | |||
| | ] | |||
| ] | |||
| | ] | |||
| ] | |||
| | ] | |||
| ] | |||
| | ] | |||
| ] | |||
| | ] | |||
| ] | |||
| |- | |||
| ! colspan="5" | | |||
| |- | |||
| | ] | |||
| ] | |||
| | ] | |||
| ] | |||
| | ] | |||
| ] | |||
| | ] | |||
| ] | |||
| | | |||
| |} | |||
| ===Related agents=== | |||
| SSRIs form a subclass of serotonin uptake inhibitors, which includes other ] inhibitors as well. ]s, ]s and ]s are also ] antidepressants. | |||
| ==Mechanism of action== | |||
| SSRIs are believed to act by inhibiting the reuptake of ] after being released in synapses. How much an individual will respond to this, however, also depends on genetics. In addition, several other mechanisms are suggested for the desired effect, e.g. neuroprotection and anti-inflammatory and immunomodulatory factors. Taken together, SSRI has several advantages compared with ]s (TCA)s and 5-HT-]s. However, the latter might be required in addition to SSRIs in certain situations. | |||
| ===Basic understanding=== | |||
| {{Further|Chemical synapse}} | |||
| In the ], messages are passed between two ] via a ], a small gap between the cells. The (presynaptic) cell that sends the information releases neurotransmitters (including serotonin) into that gap. The neurotransmitters are then recognized by ]s on the surface of the recipient (postsynaptic) cell, which upon this stimulation, in turn, relays the signal. About 10% of the neurotransmitters are lost in this process; the other 90% are released from the receptors and taken up again by ]s into the sending (presynaptic) cell (a process called ''reuptake''). | |||
| To stimulate the recipient cell, SSRIs inhibit the reuptake of serotonin. As a result, the serotonin stays in the synaptic gap longer than it normally would, and may repeatedly stimulate the receptors of the recipient cell. The current model of SSRIs (the ]) assumes that a lower homeostatic level of serotonin is primarily responsible for depression. While this holds in cases of major depression, minor to moderate cases are not as clear cut, and may in fact be caused by excess serotonin in specific areas of the brain. | |||
| Some current research points to more than just a single type of chemical signaling - the classic synapse model - involving serotonin. ] are "helper cells" in the brain that do not participate directly in chemical signaling, but play a part in homeostasis for many chemical levels in the brain. Recent research<ref>{{Cite journal|last=Watson|first=Cheryl et. al.|title=Serotonin Regulation by Astrocytes|journal=The FASEB Journal|url=http://www.fasebj.org/cgi/content/meeting_abstract/23/1_MeetingAbstracts/790.2}}</ref> suggests that serotonin is one of the hormones regulated by astrocytes, and that astrocytes actually uptake, package, and resend serotonin in a way similar to neuronal axons, but do not have corresponding post-synaptic terminals, therefore appearing to function only to control the local levels of serotonin in the cerebrospinal fluid. | |||
| Still more research illustrates that the current model for the antidepressant activity of SSRIs may be misdirected, as a drug that works entirely opposite to SSRIs - ], a selective serotonin reuptake '''enhancer''' - also exhibits antidepressant activity, especially in patients resistant to SSRI therapy. The effect of an SSRE in comparison to an SSRI requires that the nature of serotonin signaling in the areas of the brain related to mood and cognition needs further elucidation. If serotonin firing is regularly phasic (related to brain waves), or rapid and discrete, then SSRIs simply compress the signal potential at affected receptors (bringing down the maximum potential and bring up the minimum) by causing a constant leftover signal (serotonin left in the synaptic gap) coupled with weaker subsequent signals (due to the decrease in presynaptic serotonin available to send new signals). By this hypothetical model, SSREs increase the signal potential separation (min to max) at affected 5-HT sites by reducing the level of free cerebrospinal serotonin and increasing the amount uptaken into axons to send new signals. | |||
| ===Pharmacodynamics=== | |||
| SSRIs inhibit the reuptake of the neurotransmitter ] (5-hydroxytryptamine or 5-HT) into the presynaptic cell, increasing levels of 5-HT within the ]. | |||
| However, there is one counteracting effect: high serotonin levels will not only activate the ] receptors, but also flood presynaptic ]s, which serve as a feedback sensor for the cell. Activation of the autoreceptors (by ]s like serotonin) triggers a throttling back of serotonin production. The resulting serotonin deficiency persists for some time, as the transporter inhibition occurs downstream to the cause of the deficiency and therefore, is not able to counterbalance the serotonin deficiency. The body adapts gradually to this situation by lowering (]) the sensitivity of the autoreceptors.<ref>{{Cite journal|author=Gobbi M, Crespi D, Foddi MC, ''et al.'' |title=Effects of chronic treatment with fluoxetine and citalopram on 5-HT uptake, 5-HT1B autoreceptors, 5-HT3 and 5-HT4 receptors in rats |journal=Naunyn-Schmiedeberg's Archives of Pharmacology |volume=356 |issue=1 |pages=22–8 |year=1997 |month=July |pmid=9228186 |doi=10.1007/PL00005024}}</ref> | |||
| Another adaptive process provoked by SSRIs is the downregulation of postsynaptic ]. After the use of an SSRI, since there is more serotonin available, the response is to decrease the number of postsynaptic receptors over time and in the long run, this modifies the serotonin/receptor ratio. This downregulation of 5-HT2A occurs when the antidepressant effects of SSRIs become apparent. Also, deceased suicidal and otherwise depressed patients have had more 5-HT2A receptors than normal patients. These considerations suggest that 5-HT2A overactivity is involved in the pathogenesis of depression.<ref name=pmid8788498>{{Cite journal|author=Eison AS, Mullins UL |title=Regulation of central 5-HT2A receptors: a review of in vivo studies |journal=Behavioural Brain Research |volume=73 |issue=1–2 |pages=177–81 |year=1996 |pmid=8788498 |doi=10.1016/0166-4328(96)00092-7}}</ref> | |||
| Most of the serotonin receptors on the surface of the cell are ] inside it. These proteins activate or inhibit ]s, which in turn affect ]s. Transcription factors are proteins that fit to the beginning of a gene and tell the cell to start using it. | |||
| These (slowly proceeding) neurophysiological adaptations of the brain tissue are the reason why usually several weeks of continuous SSRI use is necessary for the antidepressant effect to become fully manifested,<ref name=pmid8788498/> and why increased anxiety is a common side effect in the first few days or weeks of use. | |||
| ===Role in BDNF release=== | |||
| SSRIs act on signal pathways such as cAMP (Cyclic AMP) on the postsynaptic neuronal cell, which leads to the release of Brain Derived Neurotrophic Factor (BDNF). BDNF enhances the growth and survival of cortical neurons and synapses.<ref>Kolb, Bryan and Wishaw Ian. An Introduction to Brain and Behavior. New York: Worth Publishers 2006, Print.</ref> | |||
| ===Pharmacogenetics=== | |||
| {{Further| Pharmacogenetics}} | |||
| Large bodies of research are devoted to using ]s to predict whether patients will respond to SSRIs or have side effects that will cause their ], although these tests are not yet ready for widespread clinical use.<ref>{{Cite journal|author=Rasmussen-Torvik LJ, McAlpine DD |title=Genetic screening for SSRI drug response among those with major depression: great promise and unseen perils |journal=Depression and Anxiety |volume=24 |issue=5 |pages=350–7 |year=2007 |pmid=17096399 |doi=10.1002/da.20251}}</ref> ]s of the ] gene correlated with paroxetine discontinuation due to side effects in a group of elderly patients with major depression, but not ] (a non-SSRI antidepressant) discontinuation.<ref>{{Cite journal|author=Murphy GM, Kremer C, Rodrigues HE, Schatzberg AF |title=Pharmacogenetics of antidepressant medication intolerance |journal=The American Journal of Psychiatry |volume=160 |issue=10 |pages=1830–5 |year=2003 |month=October |pmid=14514498 |url=http://ajp.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=14514498 |doi=10.1176/appi.ajp.160.10.1830}}</ref> | |||
| ===Neuroprotection=== | |||
| Studies have suggested that SSRIs may promote the growth of new ]s or ] in rats.<ref>{{Cite journal|author=Malberg JE, Eisch AJ, Nestler EJ, Duman RS |title=Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus |journal=The Journal of Neuroscience |volume=20 |issue=24 |pages=9104–10 |year=2000 |month=December |pmid=11124987 |url=http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=11124987}}</ref> Also, SSRIs may protect against neurotoxicity caused by other compounds (for instance ]) as well as from depression itself. SSRIs have been found to induce programmed cell death in Burkitt lymphoma and the brain tumors neuroblastoma and glioma with minimal effect on normal tissue.<ref>{{Cite journal|author=Levkovitz Y, Gil-Ad I, Zeldich E, Dayag M, Weizman A |title=Differential induction of apoptosis by antidepressants in glioma and neuroblastoma cell lines: evidence for p-c-Jun, cytochrome c, and caspase-3 involvement |journal=Journal of Molecular Neuroscience |volume=27 |issue=1 |pages=29–42 |year=2005 |pmid=16055945 |doi=10.1385/JMN:27:1:029 |url=}}</ref><ref>{{Cite journal|author=Serafeim A, Holder MJ, Grafton G, ''et al.'' |title=Selective serotonin reuptake inhibitors directly signal for apoptosis in biopsy-like Burkitt lymphoma cells |journal=Blood |volume=101 |issue=8 |pages=3212–9 |year=2003 |month=April |pmid=12515726 |doi=10.1182/blood-2002-07-2044}}</ref> | |||
| ===Anti-inflammatory and immunomodulation=== | |||
| Recent studies show pro-inflammatory ] processes take place during ], ] and ], in addition to ] disease (such as autoimmune ]) and it is possible that symptoms manifest in these psychiatric illnesses are being attenuated by pharmacological effect of antidepressants on the immune system.<ref>{{Cite journal|author=O'Brien SM, Scully P, Scott LV, Dinan TG |title=Cytokine profiles in bipolar affective disorder: focus on acutely ill patients |journal=Journal of Affective Disorders |volume=90 |issue=2–3 |pages=263–7 |year=2006 |month=February |pmid=16410025 |doi=10.1016/j.jad.2005.11.015}}</ref><ref>{{Cite journal|author=Obuchowicz E, Marcinowska A, Herman ZS |title= |language=Polish |journal=Psychiatria Polska |volume=39 |issue=5 |pages=921–36 |year=2005 |pmid=16358592}}</ref><ref>{{Cite journal|author=Hong CJ, Yu YW, Chen TJ, Tsai SJ |title=Interleukin-6 genetic polymorphism and Chinese major depression |journal=Neuropsychobiology |volume=52 |issue=4 |pages=202–5 |year=2005 |pmid=16244501 |doi=10.1159/000089003}}</ref><ref>{{Cite journal|author=Elenkov IJ, Iezzoni DG, Daly A, Harris AG, Chrousos GP |title=Cytokine dysregulation, inflammation and well-being |journal=Neuroimmunomodulation |volume=12 |issue=5 |pages=255–69 |year=2005 |pmid=16166805 |doi=10.1159/000087104}}</ref><ref>{{Cite journal|author=Kubera M, Maes M, Kenis G, Kim YK, Lasoń W |title=Effects of serotonin and serotonergic agonists and antagonists on the production of tumor necrosis factor alpha and interleukin-6 |journal=Psychiatry Research |volume=134 |issue=3 |pages=251–8 |year=2005 |month=April |pmid=15892984 |doi=10.1016/j.psychres.2004.01.014}}</ref> | |||
| SSRIs have demonstrated immunomodulatory and anti-inflammatory effects against pro-inflammatory ] processes, specifically on the regulation of ] (IFN-gamma) and ] (IL-10), as well as ] and ] (IL-6). Antidepressants have also been shown to suppress ] upregulation.<ref>{{Cite journal|author=Diamond M, Kelly JP, Connor TJ |title=Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade |journal=European Neuropsychopharmacology |volume=16 |issue=7 |pages=481–90 |year=2006 |month=October |pmid=16388933 |doi=10.1016/j.euroneuro.2005.11.011}}</ref><ref>{{Cite journal|author=Kubera M, Lin AH, Kenis G, Bosmans E, van Bockstaele D, Maes M |title=Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio |journal=Journal of Clinical Psychopharmacology |volume=21 |issue=2 |pages=199–206 |year=2001 |month=April |pmid=11270917 |doi=10.1097/00004714-200104000-00012}}</ref><ref>{{Cite journal|author=Maes M |title=The immunoregulatory effects of antidepressants |journal=Human Psychopharmacology |volume=16 |issue=1 |pages=95–103 |year=2001 |month=January |pmid=12404604 |doi=10.1002/hup.191}}</ref><ref>{{Cite journal|author=Maes M, Kenis G, Kubera M, De Baets M, Steinbusch H, Bosmans E |title=The negative immunoregulatory effects of fluoxetine in relation to the cAMP-dependent PKA pathway |journal=International Immunopharmacology |volume=5 |issue=3 |pages=609–18 |year=2005 |month=March |pmid=15683856 |doi=10.1016/j.intimp.2004.11.008}}</ref> | |||
| Future serotonergic antidepressants may be made to specifically target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.<ref>{{Cite journal|author=O'Brien SM, Scott LV, Dinan TG |title=Cytokines: abnormalities in major depression and implications for pharmacological treatment |journal=Human Psychopharmacology |volume=19 |issue=6 |pages=397–403 |year=2004 |month=August |pmid=15303243 |doi=10.1002/hup.609}}</ref> | |||
| ===SSRIs versus TCAs=== | |||
| SSRIs are described as ']' because they affect only the reuptake pumps responsible for serotonin, as opposed to earlier antidepressants, which affect other monoamine neurotransmitters as well, and as a result, SSRIs have fewer side effects. | |||
| There appears no significant difference in effectiveness between SSRIs and ]s, which were the most commonly used class of antidepressants before the development of SSRIs.<ref>{{Cite journal|author=Anderson IM |title=Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability |journal=Journal of Affective Disorders |volume=58 |issue=1 |pages=19–36 |year=2000 |month=April |pmid=10760555 |doi=10.1016/S0165-0327(99)00092-0}}</ref> However, SSRIs have the important advantage that their ] is high, and, therefore, they are much more difficult to use as a means to commit ]. Further, they have fewer and milder ]. Tricyclic antidepressant also have a higher risk of serious cardiovascular side effects, which SSRIs lack. | |||
| ===SSRIs versus 5-HT-Prodrugs=== | |||
| {{Further|Prodrugs}} | |||
| Serotonin cannot be administered directly because when ingested orally, it will not cross the ], and therefore would have no effect on brain functions. Also, serotonin would activate ''every'' synapse it reaches, whereas SSRIs only ''enhance a signal'' that is already present, but too weak to come through. The selectivity of the membrane can be reduced for a drug by injecting it in a concentrated sugar solution. The high osmotic pressure of the sugar solution causes the endothelial cells of the capillaries to shrink, which opens gaps between their tight junctions and makes the barrier more permeable. As a result the drug can enter the brain tissue. | |||
| ====SSRIs together with 5-HT-Prodrugs==== | |||
| ] serotonin is made from ], an ]. In 1989, the ] made tryptophan available by ] only, in response to an outbreak of ] caused by impure L-tryptophan supplements sold ]. With current standards, L-tryptophan is again available over the counter in the US as well as supplement ], which is a direct precursor to serotonin. | |||
| ==Society and culture== | |||
| ===Criticism=== | |||
| {{See also|Biopsychiatry controversy|Biological psychiatry}} | |||
| In late 2004 media attention was given to a proposed link between SSRI use and ]. For this reason, the use of SSRIs in pediatric cases of depression is now recognized by the United States FDA as warranting a cautionary statement to the parents of children who may be prescribed SSRIs by a ]. The FDA's currently required packaging insert for SSRIs includes a warning (known as a "black box warning") that a pooled analysis of placebo ] of 9 antidepressant drugs (including multiple SSRIs) resulted in a risk of suicidal behavior that was twice that of ]. At the same time, in adults SSRIs do not increase the risk of suicide.<ref name="pmid15718537">{{Cite journal|author=Gunnell D, Saperia J, Ashby D |title=Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo controlled, randomised controlled trials submitted to the MHRA's safety review |journal=BMJ |volume=330 |issue=7488 |page=385 |year=2005 |pmid=15718537 |doi=10.1136/bmj.330.7488.385 |pmc=549105}}</ref> | |||
| Critics of SSRIs claim that the widely disseminated television and print advertising of SSRIs promotes an inaccurate message, oversimplifying what these medications actually do and deceiving the public.<ref>{{Cite journal|author=Lacasse JR, Leo J |title=Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature |journal=PLoS Medicine |volume=2 |issue=12 |pages=e392 |year=2005 |month=December |pmid=16268734 |pmc=1277931 |doi=10.1371/journal.pmed.0020392}}</ref> | |||
| The criticism stems from questions about the validity of claims that SSRIs work by 'correcting' ]s. Without accurately measuring patients' ] levels to allow for continuous monitoring during treatment, it is impossible to know if one is correctly targeting a deficient neurotransmitter (i.e. correcting an imbalance), reaching a desirable level, or even introducing too much of a particular neurotransmitter. Thus it has been argued that SSRIs can actually cause chemical imbalances and abnormal brain states, as evidenced by the fact that many report problems of sexual dysfunction, whose effects last long after the medication has been discontinued. Hence, it is purported that when a patient discontinues an SSRI, they may have a chemical imbalance due to the rapid cessation of the drug that causes the discontinuation syndrome.<ref>{{Cite journal|author=Moncrieff J, Cohen D |title=Do Antidepressants Cure or Create Abnormal Brain States? |journal=PLoS Medicine |volume=3 |issue=7 |pages=e240 |year=2006 |month=July |pmid=16724872 |pmc=1472553 |doi=10.1371/journal.pmed.0030240}}</ref> | |||
| One possible mechanism is by inhibition of ]rgic neurotransmission.<ref>{{Cite journal|author=Damsa C, Bumb A, Bianchi-Demicheli F, ''et al.'' |title='Dopamine-dependent' side effects of selective serotonin reuptake inhibitors: a clinical review |journal=The Journal of Clinical Psychiatry |volume=65 |issue=8 |pages=1064–8 |year=2004 |month=August |pmid=15323590 |url=http://article.psychiatrist.com/?ContentType=START&ID=10001001 |doi=10.4088/JCP.v65n0806}}</ref> | |||
| Biopsychiatrists believe that, among other factors, the balance of ]s in the ] is a biological regulator of ]. In this theory, emotions within a "normal" spectrum reflect a proper balance of neurochemicals, but abnormally extreme emotions, such as ], reflect an imbalance. Psychiatrists{{Who|date=January 2010}} claim that medications regulate neurotransmitters, and many if not most psychiatrists also claim they treat abnormal personalities by removing a neurochemical excess or replenishing a deficit.{{Citation needed|date=January 2010}} On the other hand, ], a psychologist and neuroscientist, claims that the broad biochemical assertions and assumptions of mainstream psychiatry are not supported by evidence.<ref>{{Cite book|author=Valenstein, Elliot S. |title=Blaming the brain: the truth about drugs and mental health |publisher=Free Press |location=New York |year=1998 |pages= |isbn=0-684-84964-X}}{{Page needed|date=September 2010}}</ref> | |||
| One controversial critic of antidepressants, ], a physician who opposes the overuse of prescription medications to treat patients for mental health issues, predicted ] issues that SSRIs incur on a significant percentage of patients. Another prominent SSRI critic is ]. | |||
| A widely reported meta-analysis combined 35 clinical trials submitted to the ] (FDA) before licensing of four newer antidepressants (including the SSRIs ] and ], and two non-SSRI antidepressants ] and ]). The authors found that although the antidepressants were ] superior to ] they did not exceed the ] criteria for a 'clinically significant' effect. For more detail, see the section "]". | |||
| A study in ] on a possible ] regarding the efficacy of SSRI medications in the treatment of depression suggests that their effectiveness and risk-benefit ratios may be greatly exaggerated. Of 74 studies registered with the United States ], 37 with positive results were published in ]s, while 22 studies with negative results were not published and 11 with negative results were published in a way that conveyed a positive outcome (one positive study was not published and three negative studies were published with results that were portrayed as negative). Overall, 94% of studies actually published were positive outcomes; when published and unpublished studies were included for analysis, the percentage of positive outcomes was 51%.<ref name="pmid18199864">{{Cite journal|author=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 |volume=358 |issue=3 |pages=252–60 |year=2008 |month=January |pmid=18199864 |doi=10.1056/NEJMsa065779}}</ref> | |||
| Although controversial, the existence of an SSRI-related withdrawal syndrome mimicking depression may inflate the therapeutic effect size reported in long-term (more than 6 months) placebo controlled trials of SSRI’s, due to a reliance on randomized discontinuation designs. Discontinuation trials are a variant of the classic 2-arm placebo controlled randomized controlled trials used in shorter placebo controlled studies of SSRI’s.<ref>{{Cite journal|author=Deshauer D, Moher D, Fergusson D, Moher E, Sampson M, Grimshaw J |title=Selective serotonin reuptake inhibitors for unipolar depression: a systematic review of classic long-term randomized controlled trials |journal=CMAJ |volume=178 |issue=10 |pages=1293–301 |year=2008 |month=May |pmid=18458261 |pmc=2335186 |doi=10.1503/cmaj.071068}}</ref><ref>{{Cite journal|author=Geddes JR, Carney SM, Davies C, ''et al.'' |title=Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review |journal=Lancet |volume=361 |issue=9358 |pages=653–61 |year=2003 |month=February |pmid=12606176 |doi=10.1016/S0140-6736(03)12599-8}}</ref> | |||
| ===Regulation=== | |||
| All SSRIs are approved in the U.S. for use with ] disorders as outlined in the ] (DSM IV). | |||
| Approved uses for SSRIs vary by country and are determined by the overseeing branch of government in charge of regulating drugs. In the U.S., the ] (FDA) approves drugs after trial results have been submitted by the ]. In Europe, drugs can be approved either by the ] for human consumption throughout the ] or by the regulatory agencies of individual countries for use within those countries.{{Citation needed|date=April 2008}}. In Canada, the drug approval process is carried out by ]. | |||
| ===Lawsuits=== | |||
| Hundreds of lawsuits have been filed against drug manufacturers seeking compensation for harm attributed to the use of SSRIs. Suits based on ], for example, often allege failure to adequately warn users of potential side effects. Manufacturers have defended many suits on the merits and settled many others. In 2005, the U.S. FDA asked manufacturers to include black box warnings on antidepressant drug packaging.<ref>Center for Drug Evaluation and Research ''''. Retrieved September 30, 2008.</ref> Though a 2007 study<ref>{{cite web|url=http://ajp.psychiatryonline.org/article.aspx?articleid=98898 |title=Early Evidence on the Effects of Regulators’ Suicidality Warnings on SSRI Prescriptions and Suicide in Children and Adolescents |publisher=Am J Psychiatry|date=2007-09-01 |accessdate=2012-06-19}}</ref> purportedly showed that the black box "warnings discouraged use of antidepressants in children and adolescents and... led to increases in suicide rates as a result of untreated depression" an article in the ''New York Times''<ref>{{cite news|url=http://www.nytimes.com/2007/09/14/us/14suicide.html?_r=1 |title=Experts Question Study on Youth Suicide Rates |publisher=New York Times|date=2007-09-14 |accessdate=2012-06-19}}</ref> that ran two weeks later questioned the results of the study, claiming that the data did not support a causal link between the black box warning and increased rates of suicide. | |||
| ==See also== | |||
| * ] | |||
| * ] (DRI) | |||
| * ] (NRI) | |||
| * ] (NDRI) | |||
| * ] | |||
| * ] (SRI) | |||
| * ] (SNRI) | |||
| * ] (SNDRI) | |||
| ==References== | |||
| {{Reflist|2}} | |||
| ==External links== | |||
| * at ] | |||
| * Barry Yeoman , The Nation at barryyeoman.com | |||
| * {{MeshName|Serotonin+uptake+inhibitors}} | |||
| {{Antidepressants}} | |||
| {{Serotonergics}} | |||
| {{DEFAULTSORT:Selective Serotonin Reuptake Inhibitor}} | |||
| ] | |||
| ] | |||
Revision as of 09:20, 9 April 2013
ssri are things that make you feel good
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