Selective serotonin reuptake inhibitor#General side effects

The main indication for SSRIs is major depressive disorder; however, they are frequently prescribed for anxiety disorders, such as social anxiety disorder, generalized anxiety disorder, panic disorder, obsessive–compulsive disorder (OCD), eating disorders, chronic pain, and, in some cases, for posttraumatic stress disorder (PTSD). They are also frequently used to treat depersonalization disorder, although with varying results.{{cite journal | vauthors = Medford N, Sierra M, Baker D, David AS |title=Understanding and treating depersonalisation disorder |journal=Advances in Psychiatric Treatment |volume=11 |issue=2 |pages=92–100 |year=2005 |doi=10.1192/apt.11.2.92 |doi-access=free }}

{{See|Biology of depression}}

Antidepressants were recommended by the UK National Institute for Health and Care Excellence (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 in 2009.{{cite web | author = National Collaborating Centre for Mental Health | url = http://www.nice.org.uk/nicemedia/pdf/CG%2090%20QRG%20LR%20FINAL.pdf | publisher = The National Institute for Health and Care Excellence (NICE) |title = Depression Quick Reference Guide |website= NICE clinical guidelines 90 and 91 | date = October 2009 |url-status=dead |archive-url=https://web.archive.org/web/20130928172709/http://www.nice.org.uk/nicemedia/pdf/CG%2090%20QRG%20LR%20FINAL.pdf |archive-date=September 28, 2013 }} They recommend against their routine use by those who have chronic health problems and mild depression.

There has been controversy regarding the efficacy of SSRIs in treating depression depending on its severity and duration.

• The serotonin "chemical imbalance" theory of depression, proposed in the 1960s,{{Cite web |last1=Moncrieff |first1=Joanna |author-link=Joanna Moncrieff |last2=Horowitz |first2=Mark |date=20 July 2022 |title=Depression is probably not caused by a chemical imbalance in the brain – new study |url=http://theconversation.com/depression-is-probably-not-caused-by-a-chemical-imbalance-in-the-brain-new-study-186672 |access-date=2022-07-21 |website=The Conversation |language=en}} is not supported by the available scientific evidence.{{Cite journal |last1=Moncrieff |first1=Joanna |author-link=Joanna Moncrieff |last2=Cooper |first2=Ruth E. |last3=Stockmann |first3=Tom |last4=Amendola |first4=Simone |last5=Hengartner |first5=Michael P. |last6=Horowitz |first6=Mark A. |date=2022-07-20 |title=The serotonin theory of depression: a systematic umbrella review of the evidence |journal=Molecular Psychiatry |language=en |volume=28 |issue=8 |pages=3243–3256 |doi=10.1038/s41380-022-01661-0 |issn=1476-5578 |pmc=10618090 |pmid=35854107 |s2cid=250646781 |doi-access=free}}
• Two meta-analyses published in 2008 (Kirsch) and 2010 (Fournier) 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". The 2008 meta-analysis combined 35 clinical trials submitted to the Food and Drug Administration (FDA) before licensing of four newer antidepressants (including the SSRIs paroxetine and fluoxetine, the non-SSRI antidepressant nefazodone, and the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine). 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.{{cite journal |vauthors=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 | date = February 2008 | pmid = 18303940 | pmc = 2253608 | doi = 10.1371/journal.pmed.0050045 | doi-access = free }} Some researchers have questioned the statistical basis of this study suggesting that it underestimates the effect size of antidepressants.{{cite journal |vauthors=Horder J, Matthews P, Waldmann R | title = Placebo, Prozac and PLoS: significant lessons for psychopharmacology | journal = Journal of Psychopharmacology | volume = 25 | issue = 10 | pages = 1277–1288 | date = June 2010 | pmid = 20571143 | doi = 10.1177/0269881110372544 | hdl = 2108/54719 | s2cid = 10323933 | hdl-access = free }}{{cite journal |vauthors=Fountoulakis KN, Möller HJ | title = Efficacy of antidepressants: a re-analysis and re-interpretation of the Kirsch data | journal = The International Journal of Neuropsychopharmacology | volume = 14 | issue = 3 | pages = 405–412 | date = August 2010 | pmid = 20800012 | doi = 10.1017/S1461145710000957 | doi-access = free }}
• A 2012 meta-analysis of fluoxetine and venlafaxine concluded that statistically and clinically significant treatment effects were observed for each drug relative to placebo irrespective of baseline depression severity.{{cite journal |vauthors=Gibbons RD, Hur K, Brown CH, Davis JM, Mann JJ | title = Benefits from antidepressants: synthesis of 6-week patient-level outcomes from double-blind placebo-controlled randomized trials of fluoxetine and venlafaxine | journal = Archives of General Psychiatry | volume = 69 | issue = 6 | pages = 572–579 | date = June 2012 | pmid = 22393205 | pmc = 3371295 | doi = 10.1001/archgenpsychiatry.2011.2044 }}
• A 2017 systematic review stated that "SSRIs versus placebo seem to have statistically significant effects on depressive symptoms, but the clinical significance of these effects seems questionable and all trials were at high risk of bias. Furthermore, SSRIs versus placebo significantly increase the risk of both serious and non-serious adverse events. Our results show that the harmful effects of SSRIs versus placebo for major depressive disorder seem to outweigh any potentially small beneficial effects".{{cite journal | vauthors = Jakobsen JC, Katakam KK, Schou A, Hellmuth SG, Stallknecht SE, Leth-Møller K, Iversen M, Banke MB, Petersen IJ, Klingenberg SL, Krogh J, Ebert SE, Timm A, Lindschou J, Gluud C | title = Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis | journal = BMC Psychiatry | volume = 17 | issue = 1 | pages = 58 | date = February 2017 | pmid = 28178949 | pmc = 5299662 | doi = 10.1186/s12888-016-1173-2 | doi-access = free }} Fredrik Hieronymus et al. criticized the review as inaccurate and misleading.{{cite journal | vauthors = Hieronymus F, Lisinski A, Näslund J, Eriksson E | title = Multiple possible inaccuracies cast doubt on a recent report suggesting selective serotonin reuptake inhibitors to be toxic and ineffective | journal = Acta Neuropsychiatrica | volume = 30 | issue = 5 | pages = 244–250 | pmid = 28718394 | doi = 10.1017/neu.2017.23 | year = 2018 | doi-access = free }}
• In 2018, a systematic review and network meta-analysis comparing the efficacy and acceptability of 21 antidepressant drugs showed escitalopram to be one of the most effective. They showed that "In terms of efficacy, all antidepressants were more effective than placebo, with odds ratios (ORs) ranging between 2.13 (95% credible interval [CrI] 1.89–2.41) for amitriptyline and 1.37 (1.16–1.63) for reboxetine."{{cite journal | vauthors = Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner EH, Higgins JP, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JP, Geddes JR | title = Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis | journal = Lancet | volume = 391 | issue = 10128 | pages = 1357–1366 | date = April 2018 | pmid = 29477251 | pmc = 5889788 | doi = 10.1016/S0140-6736(17)32802-7 }} The odds ratios were specifically in terms of response rates (≥50% reduction in observer-rated symptoms). Odds ratios of response rates have been criticized for artificially inflating the apparent size of antidepressant benefits.{{cite journal | vauthors = Kirsch I, Moncrieff J | title = Clinical trials and the response rate illusion | journal = Contemp Clin Trials | volume = 28 | issue = 4 | pages = 348–351 | date = July 2007 | pmid = 17182286 | doi = 10.1016/j.cct.2006.10.012 | url = }}{{cite journal | vauthors = Moncrieff J, Kirsch I | title = Empirically derived criteria cast doubt on the clinical significance of antidepressant-placebo differences | journal = Contemp Clin Trials | volume = 43 | issue = | pages = 60–2 | date = July 2015 | pmid = 25979317 | doi = 10.1016/j.cct.2015.05.005 | url = | quote = The commonly used method of estimating the 'response' to drug treatment in clinical trials of antidepressants (arbitrarily set at a 50% reduction in symptoms), involves the categorisation of continuous data from symptom scales, and therefore does not provide an independent arbiter of clinical significance. Moreover, this method can exaggerate small differences between interventions such as antidepressants and placebo [28], and statisticians note that it can distort data and should be avoided [29], [30]. Response rates in double-blind antidepressant trials are typically about 50% in the drug groups and 35% in the placebo groups (e.g., [31], [32]). This 15% difference is often defended as clinically significant on the grounds that 15% of depressed people who get better on antidepressants would not have gotten better on placebo. However, a 50% reduction in symptoms is close to the mean and median of drug improvement rates in placebo-controlled antidepressant trials [31], [32], [33] and thus near the apex of the distribution curve. Thus, with an SD of 8 in change scores, a 15% difference in response rates is about (an odds ratio of 1.86, a relative risk of 0.77, and an NNT of 7) is exactly what one would expect from a mean 3-point difference in HAM-D scores [28]. Lack of response does not mean that the patient has not improved; it means that the improvement has been less, by as little as one point, than the arbitrary criterion chosen for defining a therapeutic response.}}{{cite journal | vauthors = Hengartner MP | title = Methodological Flaws, Conflicts of Interest, and Scientific Fallacies: Implications for the Evaluation of Antidepressants' Efficacy and Harm | journal = Front Psychiatry | volume = 8 | issue = | pages = 275 | date = 2017 | pmid = 29270136 | pmc = 5725408 | doi = 10.3389/fpsyt.2017.00275 | doi-access = free | url = | quote = Another common flaw is to report efficacy based on drug-placebo differences in response and remission rates (27). To come at binary constructs such as response and remission, continuous symptom rating scales are dichotomized along arbitrary cut-offs. However, methodologists have vigorously advised against the use of dichotomization (28–30) because it produces, among others, systematically inflated effect sizes (31–33).}}

The use of SSRIs in children with depression remains controversial. A 2021 Cochrane review concluded that, for children and adolescents, SSRIs "may reduce depression symptoms in a small and unimportant way compared with placebo."{{cite journal | vauthors = Hetrick SE, McKenzie JE, Bailey AP, Sharma V, Moller CI, Badcock PB, Cox GR, Merry SN, Meader N | title = New generation antidepressants for depression in children and adolescents: a network meta-analysis | journal = The Cochrane Database of Systematic Reviews | volume = 2021 | issue = 5 | pages = CD013674 | date = May 2021 | pmid = 34029378 | pmc = 8143444 | doi = 10.1002/14651858.CD013674.pub2 | collaboration = Cochrane Common Mental Disorders Group }} However, it also noted significant methodological limitations that make drawing definitive conclusions about efficacy difficult. Fluoxetine is the only SSRI authorized for use in children and adolescents with moderate to severe depression in the United Kingdom.{{cite web | url = http://www.nice.org.uk/guidance/ng134 | publisher = The National Institute for Health and Care Excellence (NICE) | title = Depression in children and young people: identification and management | website = NICE guideline NG134 | date = June 2019 | access-date = 2023-01-16 | archive-date = 2022-12-26 | archive-url = https://web.archive.org/web/20221226152142/https://www.nice.org.uk/guidance/ng134 | url-status = live }}

Some SSRIs are effective for social anxiety disorder, although their effects on symptoms is not always robust and their use is sometimes rejected in favor of psychological therapies. Paroxetine was the first drug to be approved for social anxiety disorder and it is considered effective for this disorder; sertraline and fluvoxamine were later approved for it as well.{{Cn|date=March 2025}} Escitalopram and citalopram are used off-label with acceptable efficacy, while fluoxetine is not considered to be effective for this disorder.{{cite journal | vauthors = Canton J, Scott KM, Glue P | title = Optimal treatment of social phobia: systematic review and meta-analysis | journal = Neuropsychiatric Disease and Treatment | volume = 8 | pages = 203–215 | date = 2012 | pmid = 22665997 | pmc = 3363138 | doi = 10.2147/NDT.S23317 | doi-access = free }} The effect sizes (Cohen's d) of SSRIs in terms of improvement on the Liebowitz social anxiety scale in individual published trials of the drugs for social anxiety disorder have ranged from –0.029 to 1.214.{{cite journal | vauthors = Hedges DW, Brown BL, Shwalb DA, Godfrey K, Larcher AM | title = The efficacy of selective serotonin reuptake inhibitors in adult social anxiety disorder: a meta-analysis of double-blind, placebo-controlled trials | journal = J Psychopharmacol | volume = 21 | issue = 1 | pages = 102–11 | date = January 2007 | pmid = 16714326 | doi = 10.1177/0269881106065102 | s2cid = 21795838 | url = }}

PTSD is relatively hard to treat and generally treatment is not highly effective; SSRIs are no exception. They are not very effective for this disorder and only two SSRIs are FDA approved for this condition: paroxetine and sertraline. Paroxetine has slightly higher response and remission rates for PTSD than sertraline, but both are not fully effective for many patients.{{Citation needed|date=November 2020}} Fluoxetine is used off-label, but with mixed results; venlafaxine, an SNRI, is considered somewhat effective, although its use is also off-label. Fluvoxamine, escitalopram and citalopram are not well tested in this disorder. Paroxetine remains the most suitable drug for PTSD as of now, but with limited benefits.{{cite journal | vauthors = Alexander W | title = Pharmacotherapy for Post-traumatic Stress Disorder In Combat Veterans: Focus on Antidepressants and Atypical Antipsychotic Agents | journal = P & T | volume = 37 | issue = 1 | pages = 32–38 | date = January 2012 | pmid = 22346334 | pmc = 3278188 }}

SSRIs are recommended by the National Institute for Health and Care Excellence (NICE) for the treatment of generalized anxiety disorder (GAD) that has failed to respond to conservative measures such as education and self-help activities.{{Cn|date=March 2025}} 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.

Antidepressants provide a modest-to-moderate reduction in anxiety in GAD,{{cite web |date=2011 |title=NICE Generalised anxiety disorder and panic disorder guideline |url=http://www.nice.org.uk/nicemedia/live/13314/52599/52599.pdf |url-status=dead |archive-url=https://web.archive.org/web/20121021044157/http://www.nice.org.uk/nicemedia/live/13314/52599/52599.pdf |archive-date=2012-10-21 |access-date=2013-02-20}} and are superior to placebo in treating GAD. The efficacy of different antidepressants is similar.

In Canada, SSRIs are a first-line treatment of adult obsessive–compulsive disorder (OCD). In the UK, they are first-line treatment only with moderate to severe functional impairment and as second line treatment for those with mild impairment, though, as of early 2019, this recommendation is being reviewed.{{cite journal | vauthors = Katzman MA, Bleau P, Blier P, Chokka P, Kjernisted K, Van Ameringen M, Antony MM, Bouchard S, Brunet A, Flament M, Grigoriadis S, Mendlowitz S, O'Connor K, Rabheru K, Richter PM, Robichaud M, Walker JR | title = Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders | journal = BMC Psychiatry | volume = 14 | issue = Suppl 1 | pages = S1 | date = 2014-07-02 | pmid = 25081580 | pmc = 4120194 | doi = 10.1186/1471-244X-14-S1-S1 | doi-access = free }} In pediatric populations, a 2024 systematic review found that SSRIs have been found effective in reducing symptoms of obsessive-compulsive disorder (OCD). Their efficacy is further enhanced when combined with behavioral therapies such as exposure and response prevention (ERP).{{Cite report |url=https://effectivehealthcare.ahrq.gov/products/obsessive-compulsive-disorder/research |title=Diagnosis and Management of Obsessive Compulsive Disorders in Children: A Systematic Review |last1=Steele |first1=Dale W. |last2=Caputo |first2=Eduardo L. |last3=Kanaan |first3=Ghid |last4=Zahradnik |first4=Michael L. |last5=Brannon |first5=Elizabeth |last6=Freeman |first6=Jennifer B. |last7=Balk |first7=Ethan M. |last8=Trikalinos |first8=Thomas A. |last9=Adam |first9=Gaelen P. |date=2024-12-06 |publisher=Agency for Healthcare Research and Quality (AHRQ) |doi=10.23970/ahrqepccer276}} In children, SSRIs can be considered a second line therapy in those with moderate-to-severe impairment, with close monitoring for psychiatric adverse effects.{{cite web | url = http://www.nice.org.uk/nicemedia/pdf/cg031niceguideline.pdf | title = Obsessive-compulsive disorder: Core interventions in the treatment of obsessive-compulsive disorder and body dysmorphic disorder | date = November 2005 | access-date = 2013-02-24 | archive-date = 2008-12-06 | archive-url = https://web.archive.org/web/20081206033654/https://www.nice.org.uk/nicemedia/pdf/cg031niceguideline.pdf | url-status = dead }} SSRIs, especially fluvoxamine, which is the first one to be FDA approved for OCD, are efficacious in its treatment; patients treated with SSRIs are about twice as likely to respond to treatment as those treated with placebo.{{cite journal | vauthors = Arroll B, Elley CR, Fishman T, Goodyear-Smith FA, Kenealy T, Blashki G, Kerse N, Macgillivray S | title = Antidepressants versus placebo for depression in primary care | journal = The Cochrane Database of Systematic Reviews | volume = 2009 | issue = 3 | pages = CD007954 | date = July 2009 | pmid = 19588448 | doi = 10.1002/14651858.CD007954 | pmc = 10576545 | veditors = Arroll B }}{{cite web| vauthors = Busko M |date=28 February 2008 |title=Review Finds SSRIs Modestly Effective in Short-Term Treatment of OCD |website=Medscape |url=http://www.medscape.com/viewarticle/570825+|url-status=dead |archive-url=https://web.archive.org/web/20130413110435/http://www.medscape.com/viewarticle/570825 |archive-date=April 13, 2013 }} Efficacy has been demonstrated both in short-term treatment trials of 6 to 24 weeks and in discontinuation trials of 28 to 52 weeks duration.{{cite journal | vauthors = Fineberg NA, Brown A, Reghunandanan S, Pampaloni I | title = Evidence-based pharmacotherapy of obsessive-compulsive disorder | journal = The International Journal of Neuropsychopharmacology | volume = 15 | issue = 8 | pages = 1173–1191 | date = September 2012 | pmid = 22226028 | doi = 10.1017/S1461145711001829 | doi-access = free | hdl = 2299/216 | hdl-access = free }}{{cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019839s070,020990s032lbl.pdf |title=Sertraline prescribing information |access-date=2015-01-30 |archive-date=2015-06-16 |archive-url=https://web.archive.org/web/20150616011817/http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019839s070%2C020990s032lbl.pdf |url-status=live }}{{cite web |url=https://www.apotex.com/us/en/products/downloads/pil/paxil_irtb_ins.pdf |title=Paroxetine prescribing information |access-date=2015-01-30 |archive-date=2015-02-19 |archive-url=https://web.archive.org/web/20150219055046/https://www.apotex.com/us/en/products/downloads/pil/paxil_irtb_ins.pdf |url-status=live }}

Paroxetine CR was superior to placebo on the primary outcome measure.{{Cn|date=March 2025|reason=Also, vague.}} In a 10-week randomized controlled, double-blind trial escitalopram was more effective than placebo.{{cite journal | vauthors = Batelaan NM, Van Balkom AJ, Stein DJ | title = Evidence-based pharmacotherapy of panic disorder: an update | journal = The International Journal of Neuropsychopharmacology | volume = 15 | issue = 3 | pages = 403–415 | date = April 2012 | pmid = 21733234 | doi = 10.1017/S1461145711000800 | doi-access = free }} Fluvoxamine, another SSRI, has shown positive results.{{cite journal | vauthors = Asnis GM, Hameedi FA, Goddard AW, Potkin SG, Black D, Jameel M, Desagani K, Woods SW | title = Fluvoxamine in the treatment of panic disorder: a multi-center, double-blind, placebo-controlled study in outpatients | journal = Psychiatry Research | volume = 103 | issue = 1 | pages = 1–14 | date = August 2001 | pmid = 11472786 | doi = 10.1016/s0165-1781(01)00265-7 | s2cid = 40412606 }} However, evidence for their effectiveness and acceptability is unclear.{{cite journal | vauthors = Bighelli I, Castellazzi M, Cipriani A, Girlanda F, Guaiana G, Koesters M, Turrini G, Furukawa TA, Barbui C | title = Antidepressants versus placebo for panic disorder in adults | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | issue = 4 | pages = CD010676 | date = April 2018 | pmid = 29620793 | pmc = 6494573 | doi = 10.1002/14651858.CD010676.pub2 }}

Antidepressants are recommended as an alternative or additional first step to self-help programs in the treatment of bulimia nervosa.{{cite web |url=http://www.nice.org.uk/nicemedia/pdf/CG9FullGuideline.pdf |title=Eating disorders in over 8s: management |date=January 2004 |website=Clinical guideline [CG9] |publisher=The National Institute for Health and Care Excellence (NICE) |access-date=2013-03-02 |archive-date=2014-03-27 |archive-url=https://web.archive.org/web/20140327055429/http://www.nice.org.uk/nicemedia/pdf/CG9FullGuideline.pdf |url-status=live }} 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.

Similar recommendations apply to binge eating disorder. SSRIs provide short-term reductions in binge eating behavior, but have not been associated with significant weight loss.{{cite web|url=http://www.guidelines.gov/content.aspx?id=9318+|title = Practice guideline for the treatment of patients with eating disorders |website=National Guideline Clearinghouse | publisher = U.S. Department of Health and Human Services |archive-url = https://web.archive.org/web/20130525135033/http://www.guidelines.gov/content.aspx?id=9318+ |archive-date=2013-05-25 |url-status=dead}}

Clinical trials have generated mostly negative results for the use of SSRIs in the treatment of anorexia nervosa.{{cite journal |vauthors=Flament MF, Bissada H, Spettigue W | title = Evidence-based pharmacotherapy of eating disorders | journal = The International Journal of Neuropsychopharmacology | volume = 15 | issue = 2 | pages = 189–207 | date = March 2012 | pmid = 21414249 | doi = 10.1017/S1461145711000381 | doi-access = free }} Treatment guidelines from the National Institute of Health and Clinical Excellence 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 depression, anxiety, or OCD.

SSRIs have been used off-label in the treatment of stroke patients, including those with and without symptoms of depression. A 2021 meta-analysis of randomized controlled clinical trials found no evidence pointing to their routine use to promote recovery following stroke.{{cite journal |last1=Legg |first1=Lynn A. |last2=Rudberg |first2=Ann-Sofie |last3=Hua |first3=Xing |last4=Wu |first4=Simiao |last5=Hackett |first5=Maree L. |last6=Tilney |first6=Russel |last7=Lindgren |first7=Linnea |last8=Kutlubaev |first8=Mansur A. |last9=Hsieh |first9=Cheng-Fang |last10=Barugh |first10=Amanda J. |last11=Hankey |first11=Graeme J. |last12=Lundström |first12=Erik |last13=Dennis |first13=Martin |last14=Mead |first14=Gillian E. |date=2021-11-15 |title=Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery |journal=The Cochrane Database of Systematic Reviews |volume=2021 |issue=11 |pages=CD009286 |doi=10.1002/14651858.CD009286.pub4 |issn=1469-493X |pmc=8592088 |pmid=34780067}}

{{Main|Premature ejaculation}}

SSRIs are effective for the treatment of premature ejaculation. Taking SSRIs on a chronic, daily basis is more effective than taking them prior to sexual activity.{{cite journal | vauthors = Waldinger MD | title = Premature ejaculation: state of the art | journal = The Urologic Clinics of North America | volume = 34 | issue = 4 | pages = 591–599, vii–viii | date = November 2007 | pmid = 17983899 | doi = 10.1016/j.ucl.2007.08.011 }} The increased efficacy of treatment when taking SSRIs on a daily basis is consistent with clinical observations that the therapeutic effects of SSRIs generally take several weeks to emerge.{{cite journal | vauthors = Machado-Vieira R, Baumann J, Wheeler-Castillo C, Latov D, Henter ID, Salvadore G, Zarate CA | title = The Timing of Antidepressant Effects: A Comparison of Diverse Pharmacological and Somatic Treatments | journal = Pharmaceuticals | volume = 3 | issue = 1 | pages = 19–41 | date = January 2010 | pmid = 27713241 | pmc = 3991019 | doi = 10.3390/ph3010019 | doi-access = free }} Sexual dysfunction ranging from decreased libido to anorgasmia is usually considered to be a significantly distressing side effect which may lead to noncompliance in patients receiving SSRIs.{{cite journal | vauthors = Higgins A, Nash M, Lynch AM | title = Antidepressant-associated sexual dysfunction: impact, effects, and treatment | journal = Drug, Healthcare and Patient Safety | volume = 2 | pages = 141–150 | date = September 2010 | pmid = 21701626 | pmc = 3108697 | doi = 10.2147/DHPS.S7634 | doi-access = free }} However, for those with premature ejaculation, this very same side effect becomes the desired effect.

SSRIs such as sertraline have been found to be effective in decreasing anger.{{cite journal | vauthors = Romero-Martínez Á, Murciano-Martí S, Moya-Albiol L | title = Is Sertraline a Good Pharmacological Strategy to Control Anger? Results of a Systematic Review | journal = Behavioral Sciences| volume = 9 | issue = 5 | date = May 2019 | page = 57 | pmid = 31126061 | pmc = 6562745 | doi = 10.3390/bs9050057 | doi-access = free }}

Side effects vary among the individual drugs of this class. They may include akathisia.{{cite journal | vauthors = Stahl SM, Lonnen AJ | title = The Mechanism of Drug-induced Akathsia | journal = CNS Spectrums | year = 2011 | pmid = 21406165 }}{{cite journal | vauthors = Lane RM | title = SSRI-induced extrapyramidal side-effects and akathisia: implications for treatment | journal = Journal of Psychopharmacology | volume = 12 | issue = 2 | pages = 192–214 | year = 1998 | pmid = 9694033 | doi = 10.1177/026988119801200212| s2cid = 20944428 }}{{cite journal | vauthors = Koliscak LP, Makela EH | title = Selective serotonin reuptake inhibitor-induced akathisia | journal = Journal of the American Pharmacists Association| volume = 49 | issue = 2 | pages = e28–36; quiz e37–38 | year = 2009 | pmid = 19289334 | doi = 10.1331/JAPhA.2009.08083 }}{{cite journal | vauthors = Leo RJ | title = Movement disorders associated with the serotonin selective reuptake inhibitors | journal = The Journal of Clinical Psychiatry | volume = 57 | issue = 10 | pages = 449–454 | year = 1996 | pmid = 8909330 | doi = 10.4088/jcp.v57n1002}}

SSRIs can cause various types of sexual dysfunction such as anorgasmia, erectile dysfunction, diminished libido, genital numbness, and sexual anhedonia (pleasureless orgasm).{{cite journal|vauthors=Bahrick AS|year=2008|title=Persistence of Sexual Dysfunction Side Effects after Discontinuation of Antidepressant Medications: Emerging Evidence|url=https://benthamopen.com/ABSTRACT/TOPSYJ-1-42|journal=The Open Psychology Journal|volume=1|pages=42–50|doi=10.2174/1874350100801010042|doi-access=free|access-date=2021-04-15|archive-date=2021-04-15|archive-url=https://web.archive.org/web/20210415192602/https://benthamopen.com/ABSTRACT/TOPSYJ-1-42|url-status=live}} Sexual problems are common with SSRIs.{{cite journal | vauthors = Taylor MJ, Rudkin L, Bullemor-Day P, Lubin J, Chukwujekwu C, Hawton K | title = Strategies for managing sexual dysfunction induced by antidepressant medication | journal = The Cochrane Database of Systematic Reviews | volume = 5 | issue = 5 | pages = CD003382 | date = May 2013 | pmid = 23728643 | doi = 10.1002/14651858.CD003382.pub3 | doi-access = free }} Poor sexual function is one of the most common reasons people stop the medication.{{cite journal | vauthors = Kennedy SH, Rizvi S | title = Sexual dysfunction, depression, and the impact of antidepressants | journal = Journal of Clinical Psychopharmacology | volume = 29 | issue = 2 | pages = 157–164 | date = April 2009 | pmid = 19512977 | doi = 10.1097/jcp.0b013e31819c76e9 | s2cid = 739831 }}

The mechanism by which SSRIs may cause sexual side effects is not well understood {{as of|2021|lc=1}}. The range of possible mechanisms includes (1) nonspecific neurological effects (e.g., sedation) that globally impair behavior including sexual function; (2) specific effects on brain systems mediating sexual function; (3) specific effects on peripheral tissues and organs, such as the penis, that mediate sexual function; and (4) direct or indirect effects on hormones mediating sexual function.{{cite journal | vauthors = Gitlin MJ | title = Psychotropic medications and their effects on sexual function: diagnosis, biology, and treatment approaches | journal = The Journal of Clinical Psychiatry | volume = 55 | issue = 9 | pages = 406–413 | date = September 1994 | pmid = 7929021 }} Management strategies include: for erectile dysfunction the addition of a PDE5 inhibitor such as sildenafil; for decreased libido, possibly adding or switching to bupropion; and for overall sexual dysfunction, switching to nefazodone.{{cite journal | vauthors = Balon R | title = SSRI-Associated Sexual Dysfunction | journal = The American Journal of Psychiatry | volume = 163 | issue = 9 | pages = 1504–1509; quiz 1664 | year = 2006 | pmid = 16946173 | doi = 10.1176/appi.ajp.163.9.1504 }} Buspirone is sometimes used off-label to reduce sexual dysfunction associated with the use of SSRIs.{{cite journal |title=Buspirone |journal=StatPearls |date=17 January 2023 |pmid=30285372 |url=https://www.ncbi.nlm.nih.gov/books/NBK531477/ |vauthors=Wilson TK, Tripp J |access-date=4 August 2024 |archive-date=11 August 2020 |archive-url=https://web.archive.org/web/20200811215632/https://www.ncbi.nlm.nih.gov/books/NBK531477/ |url-status=live }}{{cite journal |vauthors=Trinchieri M, Trinchieri M, Perletti G, Magri V, Stamatiou K, Cai T, Montanari E, Trinchieri A |title=Erectile and Ejaculatory Dysfunction Associated with Use of Psychotropic Drugs: A Systematic Review |journal=The Journal of Sexual Medicine |volume=18 |issue=8 |pages=1354–1363 |date=August 2021 |pmid=34247952 |doi=10.1016/j.jsxm.2021.05.016 |quote=Buspirone, a non-benzodiazepine anxiolytic, have even demonstrated enhancement of sexual function in certain individuals. For this reason, they have been proposed as augmentation agents (antidotes) or substitution agents in patients with emerging sexual dysfunction after treatment with antidepressants.}}{{cite journal |vauthors=Montejo AL, Prieto N, de Alarcón R, Casado-Espada N, de la Iglesia J, Montejo L |title=Management Strategies for Antidepressant-Related Sexual Dysfunction: A Clinical Approach |journal=Journal of Clinical Medicine |volume=8 |issue=10 |date=October 2019 |page=1640 |pmid=31591339 |pmc=6832699 |doi=10.3390/jcm8101640|doi-access=free }}

A number of non-SSRI drugs are not associated with sexual side effects (such as bupropion, mirtazapine, tianeptine, agomelatine, tranylcypromine, and moclobemide{{cite journal | vauthors = Serretti A, Chiesa A | title = Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis | journal = Journal of Clinical Psychopharmacology | volume = 29 | issue = 3 | pages = 259–266 | date = June 2009 | pmid = 19440080 | doi = 10.1097/JCP.0b013e3181a5233f | s2cid = 1663570 }}{{cite journal | vauthors = Clayton AH |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 |access-date=2013-02-19 |archive-date=2020-06-04 |archive-url=https://web.archive.org/web/20200604183420/http://primarypsychiatry.com/antidepressant-associated-sexual-dysfunction-a-potentially-avoidable-therapeutic-challenge/ |url-status=dead }}{{cite journal | vauthors = 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 = 409–416 | date = December 2002 | pmid = 12429073 }}).

Several studies have suggested that SSRIs may adversely affect semen quality.{{cite journal |vauthors=Xu J, He K, Zhou Y, Zhao L, Lin Y, Huang Z, Xie N, Yue J, Tang Y |title=The effect of SSRIs on Semen quality: A systematic review and meta-analysis |journal=Frontiers in Pharmacology |volume=13 |issue= |pages=911489 |date=2022 |pmid=36188547 |pmc=9519136 |doi=10.3389/fphar.2022.911489|doi-access=free }}{{cite journal |vauthors=Koyuncu H, Serefoglu EC, Ozdemir AT, Hellstrom WJ | title = Deleterious effects of selective serotonin reuptake inhibitor treatment on semen parameters in patients with lifelong premature ejaculation | journal = International Journal of Impotence Research| volume = 24 | issue = 5 | pages = 171–173 | date = September 2012 | pmid = 22573230 | doi = 10.1038/ijir.2012.12 | doi-access = free }}

While trazodone (an antidepressant with alpha adrenergic receptor blockade) is a notorious cause of priapism, cases of priapism have also been reported with certain SSRIs (e.g. fluoxetine, citalopram).{{cite journal | vauthors = Scherzer ND, Reddy AG, Le TV, Chernobylsky D, Hellstrom WJ | title = Unintended Consequences: A Review of Pharmacologically-Induced Priapism | journal = Sexual Medicine Reviews | volume = 7 | issue = 2 | pages = 283–292 | date = April 2019 | pmid = 30503727 | doi = 10.1016/j.sxmr.2018.09.002 | s2cid = 54621798 }}

Post-SSRI sexual dysfunction (PSSD){{cite journal |vauthors=Jannini TB, Lorenzo GD, Bianciardi E, et al |title=Off-label Uses of Selective Serotonin Reuptake Inhibitors (SSRIs) |journal=Curr Neuropharmacol |volume=20 |issue=4 |pages=693–712 |date=2022 |pmid=33998993 |pmc=9878961 |doi=10.2174/1570159X19666210517150418 |type= Review}}{{cite journal |vauthors=Tarchi L, Merola GP, Baccaredda-Boy O, et al |title=Selective serotonin reuptake inhibitors, post-treatment sexual dysfunction and persistent genital arousal disorder: A systematic review |journal=Pharmacoepidemiol Drug Saf |volume=32 |issue=10 |pages=1053–1067 |date=June 2023 |pmid=37294623 |doi=10.1002/pds.5653 |s2cid=259126886 |url=https://onlinelibrary.wiley.com/doi/10.1002/pds.5653 |type=Review |hdl=2158/1317239 |hdl-access=free |access-date=2023-08-15 |archive-date=2023-07-20 |archive-url=https://web.archive.org/web/20230720114319/https://onlinelibrary.wiley.com/doi/10.1002/pds.5653 |url-status=live }} refers to a set of symptoms reported by some people who have taken SSRIs or other serotonin reuptake-inhibiting (SRI) drugs, in which sexual dysfunction symptoms persist for at least three months{{cite journal |vauthors=Marks S |title=A clinical review of antidepressants, their sexual side-effects, post-SSRI sexual dysfunction, and serotonin syndrome |journal=Br J Nurs |volume=32 |issue=14 |pages=678–682 |date=July 2023 |pmid=37495413 |doi=10.12968/bjon.2023.32.14.678 |s2cid=260202178 |url=https://e-space.mmu.ac.uk/632844/13/BJON%20Final%20Proof%20%28Copyright%20Safe%29.pdf |access-date=2024-03-22 |archive-date=2024-03-22 |archive-url=https://web.archive.org/web/20240322212356/https://e-space.mmu.ac.uk/632844/13/BJON%20Final%20Proof%20(Copyright%20Safe).pdf |url-status=live }} after ceasing to take the drug. The status of PSSD as a legitimate and distinct pathology is contentious; several researchers have proposed that it should be recognized as a separate phenomenon from more common SSRI side effects.

The reported symptoms of PSSD include reduced sexual desire or arousal, erectile dysfunction in males or loss of vaginal lubrication in females, persistent premature ejaculation (even in patients without a previous history of the condition),{{cite journal |vauthors=Adson DE, Kotlyar M |title=Premature Ejaculation Associated with Citalopram Withdrawal |journal= Annals of Pharmacotherapy |volume=37 |issue=12 |pages=1804–1806 |date=2003|doi=10.1345/aph.1D214 |pmid=14632589 |type= Review}} difficulty having an orgasm or loss of pleasurable sensation associated with orgasm, and a reduction or loss of sensitivity in the genitals or other erogenous zones. Additional non-sexual symptoms are also commonly described, including emotional numbing, anhedonia, depersonalization or derealization, and cognitive impairment. The duration of PSSD symptoms appears to vary among patients, with some cases resolving in months and others in years or decades; one analysis of patient reports submitted between 1992 and 2021 in the Netherlands listed a case which had reportedly persisted for 23 years.{{cite journal | vauthors = Chinchilla Alfaro K, van Hunsel F, Ekhart C | title = Persistent sexual dysfunction after SSRI withdrawal: a scoping review and presentation of 86 cases from the Netherlands | journal = Expert Opinion on Drug Safety | volume = 21 | issue = 4 | pages = 553–561 | date = April 2022 | pmid = 34791958 | doi = 10.1080/14740338.2022.2007883 | s2cid = 244347777 |type= Review}} The symptoms of PSSD are largely shared with post-finasteride syndrome (PFS) and post-retinoid sexual dysfunction (PRSD), two other poorly-understood conditions which have been suggested to share a common etiology with PSSD despite being associated with different types of medication.{{cite journal | vauthors = Giatti S, Diviccaro S, Panzica G, Melcangi RC | title = Post-finasteride syndrome and post-SSRI sexual dysfunction: two sides of the same coin? | journal = Endocrine | volume = 61 | issue = 2 | pages = 180–193 | date = August 2018 | pmid = 29675596 | doi = 10.1007/s12020-018-1593-5 | s2cid = 4974636 |type= Review}}

Diagnostic criteria for PSSD were proposed in 2022,{{cite journal | vauthors = Healy D, Bahrick A, Bak M, Barbato A, Calabrò RS, Chubak BM, Cosci F, Csoka AB, D'Avanzo B, Diviccaro S, Giatti S, Goldstein I, Graf H, Hellstrom WJ, Irwig MS, Jannini EA, Janssen PK, Khera M, Kumar MT, Le Noury J, Lew-Starowicz M, Linden DE, Lüning C, Mangin D, Melcangi RC, Rodríguez OW, Panicker JN, Patacchini A, Pearlman AM, Pukall CF, Raj S, Reisman Y, Rubin RS, Schreiber R, Shipko S, Vašečková B, Waraich A | title = Diagnostic criteria for enduring sexual dysfunction after treatment with antidepressants, finasteride and isotretinoin | journal = The International Journal of Risk & Safety in Medicine | volume = 33 | issue = 1 | pages = 65–76 | date = 1 January 2022 | pmid = 34719438 | pmc = 8925105 | doi = 10.3233/JRS-210023 }} but as of 2023, there is no agreement on standards for diagnosis. It is considered a distinct phenomenon from antidepressant discontinuation syndrome, post-acute withdrawal syndrome, and major depressive disorder,{{cite journal |vauthors=Bala A, Nguyen HM, Hellstrom WJ |date=January 2018 |title=Post-SSRI Sexual Dysfunction: A Literature Review |journal=Sexual Medicine Reviews |volume=6 |issue=1 |pages=29–34 |doi=10.1016/j.sxmr.2017.07.002 |pmid=28778697 |quote=There is still no definitive treatment for PSSD. Low-power laser irradiation and phototherapy have shown some promising results. |type= Review}} and should be distinguished from sexual dysfunction associated with depression and persistent genital arousal disorder. There are limited treatment options for PSSD as of 2023 and no evidence that any individual approach is effective. The mechanism by which SSRIs may induce PSSD is unclear.{{cite journal |vauthors=Peleg LC, Rabinovitch D, Lavie Y, et al |title=Post-SSRI Sexual Dysfunction (PSSD): Biological Plausibility, Symptoms, Diagnosis, and Presumed Risk Factors |journal=Sex Med Rev |volume=10 |issue=1 |pages=91–98 |date=January 2022 |pmid=34627736 |doi=10.1016/j.sxmr.2021.07.001 |s2cid=238580777 |type=Review}} However, various neurochemical, hormonal, and biochemical changes during SSRI use—such as reduced dopamine levels, increased serotonin, inhibition of nitric oxide synthase, and the blocking of cholinergic and alpha-1 adrenergic receptors—could account for their sexual adverse effects.{{cite journal |vauthors=Keltner DL, McAfee KM, Taylor CL |title=Mechanisms and treatments of SSRI-induced sexual dysfunction |journal=Perspect Psychiatr. Care |volume=38 |issue=3 |pages=111–116 |date=2002 |doi=10.1111/j.1744-6163.2002.tb00665.x |pmid=12385082 |type= Review|doi-access=free }}{{cite journal |vauthors=Damsa C, Bumb A, Bianchi-Demicheli F, Vidailhet P, Sterck R, Andreoli A, Beyenburg S |title=Dopamine-dependent" side effects of selective serotonin reuptake inhibitors: a clinical review |journal=J Clin Psychiatry |volume=65 |issue=8 |pages=1064–1068 |date=2004 |pmid=15323590 |doi=10.4088/jcp.v65n0806 |type= Review}} Additionally, SSRIs may cause peripheral changes by inhibiting serotonin receptors in peripheral nerves,{{cite journal |vauthors=Frohlich P, Meston CM |title=Fluoxetine-induced changes in tactile sensation and sexual functioning among clinically depressed women |journal=J Sex Marital Ther |volume=31 |issue=2 |pages=113–128 |date=2005 |pmid=15859371 |doi=10.1080/00926230590477961 |type= Review}}{{cite journal |vauthors=Clayton AH, Montejo AL |title=Major depressive disorder, antidepressants, and sexual dysfunction |journal=J Clin Psychiatry |volume=67 |pages=33–37 |date=2006 |pmid=16848675 |type= Review}} which may also play a role in PSSD. As of 2023, prevalence is unknown. A 2020 review stated that PSSD is rare, underreported, and "increasingly identified in online communities".{{cite journal |vauthors=Rothmore J |title=Antidepressant-induced sexual dysfunction |journal=Med J Aust |volume=212 |issue=7 |pages=329–334 |date=April 2020 |pmid=32172535 |doi=10.5694/mja2.50522 |s2cid=212728659 |type= Review}} A 2024 study investigating the prevalence of persistent post-treatment genital numbness among sexual and gender minority youth found 13.2% of SSRI users between the ages 15 and 29 reporting the symptom compared to 0.9% who had used other medications.{{Cite journal |last1=Pirani |first1=Yassie |last2=Delgado-Ron |first2=J. Andrés |last3=Marinho |first3=Pedro |last4=Gupta |first4=Amit |last5=Grey |first5=Emily |last6=Watt |first6=Sarah |last7=MacKinnon |first7=Kinnon R. |last8=Salway |first8=Travis |date=2024-09-20 |title=Frequency of self-reported persistent post-treatment genital hypoesthesia among past antidepressant users: a cross-sectional survey of sexual and gender minority youth in Canada and the US |url=https://link.springer.com/article/10.1007/s00127-024-02769-0 |journal=Social Psychiatry and Psychiatric Epidemiology |language=en |doi=10.1007/s00127-024-02769-0 |pmid=39302425 |issn=1433-9285}}

Reports of PSSD have occurred with almost every SSRI (dapoxetine is an exception). In 2019, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency (EMA) recommended that packaging leaflets of selected SSRIs and SNRIs should be amended to include information regarding a possible risk of persistent sexual dysfunction.{{cite book |url= https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-13-16-may-2019-prac-meeting_en.pdf |publisher= European Medicines Agency |date= 11 June 2019 |title= PRAC recommendations on signals: Adopted at the 13-16 May 2019 PRAC meeting |page= 5 |access-date= 19 July 2023 |archive-date= 20 July 2023 |archive-url= https://web.archive.org/web/20230720114322/https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-13-16-may-2019-prac-meeting_en.pdf |url-status= live }} Following the EMA assessment, a safety review by Health Canada "could neither confirm nor rule out a causal link{{spaces}}... which was long lasting in rare cases", but recommended that "healthcare professionals inform patients about the potential risk of long-lasting sexual dysfunction despite discontinuation of treatment".{{cite journal |title= SSRIs, SNRIs: risk of persistent sexual dysfunction |journal = Reactions Weekly |publisher= Springer |volume= 1838 |issue = 5 |date= 16 January 2021 |page = 5 |doi= 10.1007/s40278-021-89324-7|s2cid = 231669986 }} A 2023 review stated that ongoing sexual dysfunction after SSRI discontinuation was possible, but that cause and effect were undetermined. The 2023 review cautioned that reports of sexual dysfunction cannot be generalized to wider practice as they are subject to a "high risk of bias", but agreed with the EMA assessment that cautionary labeling on SSRIs was warranted.

On the 20th of march of 2024, a lawsuit was filed by the organization Public Citizen, representing Dr. Antonei Csoka, against the United States Food and Drug Administration (FDA) for failing to act on a citizen petition submitted in 2018. The petition seeks to have the risk of serious sexual side effects persisting after discontinuation mentioned in the product labels of SSRIs and SNRIs.{{Cite web |title=Csoka v. FDA |url=https://www.citizen.org/litigation/csoka-v-fda/ |access-date=2024-09-15 |website=Public Citizen |language=en}}{{Cite web |date=2024-05-20 |title=FDA Sued Over Inaction on Citizen Petition |url=https://www.citizen.org/news/fda-sued-over-inaction-on-citizen-petition/ |access-date=2024-09-15 |website=Public Citizen |language=en}}

Certain antidepressants may cause emotional blunting, characterized by reduced intensity of both positive and negative emotions as well as symptoms of apathy, indifference, and amotivation.{{cite journal | vauthors = Marazziti D, Mucci F, Tripodi B, Carbone MG, Muscarella A, Falaschi V, Baroni S | title = Emotional Blunting, Cognitive Impairment, Bone Fractures, and Bleeding as Possible Side Effects of Long-Term Use of SSRIs | journal = Clin Neuropsychiatry | volume = 16 | issue = 2 | pages = 75–85 | date = April 2019 | pmid = 34908941 | pmc = 8650205 }}{{cite journal | vauthors = Ma H, Cai M, Wang H | title = Emotional Blunting in Patients With Major Depressive Disorder: A Brief Non-systematic Review of Current Research | journal = Front Psychiatry | volume = 12 | issue = | pages = 792960 | date = 2021 | pmid = 34970173 | pmc = 8712545 | doi = 10.3389/fpsyt.2021.792960 | doi-access = free }} It may be experienced as either beneficial or detrimental depending on the situation.{{cite journal | vauthors = Moncrieff J | title = Antidepressants: misnamed and misrepresented | journal = World Psychiatry | volume = 14 | issue = 3 | pages = 302–303 | date = October 2015 | pmid = 26407780 | pmc = 4592647 | doi = 10.1002/wps.20243 | url = }} Higher doses of antidepressants seem to be more likely to produce emotional blunting than lower doses. It can be decreased by reducing dosage, discontinuing the medication, or switching to a different antidepressant that may have less propensity for causing this side effect. Specifically, this side effect has been particularly associated with serotonergic antidepressants like SSRIs and SNRIs and may be less with atypical antidepressants like bupropion, agomelatine, and vortioxetine.{{cite journal | vauthors = Corruble E, de Bodinat C, Belaïdi C, Goodwin GM | title = Efficacy of agomelatine and escitalopram on depression, subjective sleep and emotional experiences in patients with major depressive disorder: a 24-wk randomized, controlled, double-blind trial | journal = Int J Neuropsychopharmacol | volume = 16 | issue = 10 | pages = 2219–2234 | date = November 2013 | pmid = 23823799 | doi = 10.1017/S1461145713000679 | url = | doi-access = free }}{{cite journal | vauthors = Fagiolini A, Florea I, Loft H, Christensen MC | title = Effectiveness of Vortioxetine on Emotional Blunting in Patients with Major Depressive Disorder with inadequate response to SSRI/SNRI treatment | journal = J Affect Disord | volume = 283 | issue = | pages = 472–479 | date = March 2021 | pmid = 33516560 | doi = 10.1016/j.jad.2020.11.106 | s2cid = 228877905 | url = | hdl = 11365/1137950 | hdl-access = free }}

Confounding the understanding of emotional blunting is the fact that the same symptom can be caused by depression itself, and may instead be a sign of incomplete resolution of depression. However, there is a very large amount of subjective evidence showing that it is increasingly reported after starting the use of antidepressants, suggesting that antidepressants do in fact induce emotional blunting. There does appear to be a positive correlation between depression symptoms (measured by HAD-D) and degree of emotional blunting (measured by OQuESA), but more research is needed to clarify the amount of contribution by depression to this symptom. One possible explanation of this side effect of SSRIs and SNRIs is that they decrease the resting-state functional connectivity of the dorsal medial prefrontal cortex.

As many as one-third of patients experiencing emotional blunting do not report it as a side effect to their physician.{{cite journal |last1=Kikuchi |first1=T |last2=Iga |first2=JI |last3=Oosawa |first3=M |last4=Hoshino |first4=T |last5=Moriguchi |first5=Y |last6=Izutsu |first6=M |title=A web-based survey on the occurrence of emotional blunting in patients with major depressive disorder in Japan: Patient perceptions and attitudes. |journal=Neuropsychopharmacology Reports |date=June 2024 |volume=44 |issue=2 |pages=321–332 |doi=10.1002/npr2.12417 |pmid=38616339|pmc=11144621 }}

Acute narrow-angle glaucoma is the most common and important ocular side effect of SSRIs, and often goes misdiagnosed.{{cite journal | vauthors = Costagliola C, Parmeggiani F, Semeraro F, Sebastiani A | title = Selective serotonin reuptake inhibitors: a review of its effects on intraocular pressure | journal = Current Neuropharmacology | volume = 6 | issue = 4 | pages = 293–310 | date = December 2008 | pmid = 19587851 | pmc = 2701282 | doi = 10.2174/157015908787386104 }}{{cite journal | vauthors = Lochhead J | title = SSRI-associated optic neuropathy | journal = Eye | volume = 29 | issue = 9 | pages = 1233–1235 | date = September 2015 | pmid = 26139049 | pmc = 4565945 | doi = 10.1038/eye.2015.119 }}

SSRIs do not appear to affect the risk of coronary heart disease (CHD) in those without a previous diagnosis of CHD.{{cite journal |vauthors=Oh SW, Kim J, Myung SK, Hwang SS, Yoon DH | title = Antidepressant Use and Risk of Coronary Heart Disease: Meta-Analysis of Observational Studies | journal = British Journal of Clinical Pharmacology | volume = 78 | issue = 4 | pages = 727–737 | date = Mar 20, 2014 | pmid = 24646010 | doi = 10.1111/bcp.12383 | pmc = 4239967 }} A large cohort study suggested no substantial increase in the risk of cardiac malformations attributable to SSRI usage during the first trimester of pregnancy.{{cite journal |vauthors=Huybrechts KF, Palmsten K, Avorn J, Cohen LS, Holmes LB, Franklin JM, Mogun H, Levin R, Kowal M, Setoguchi S, Hernández-Díaz S | title = Antidepressant Use in Pregnancy and the Risk of Cardiac Defects | journal = New England Journal of Medicine | volume = 370 | issue = 25 | pages = 2397–2407 | year = 2014 | pmid = 24941178 | doi = 10.1056/NEJMoa1312828 | pmc=4062924}} A number of large studies of people without known pre-existing heart disease have reported no EKG changes related to SSRI use.{{cite journal | vauthors = 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 | doi = 10.1001/archfami.7.1.78 }} The recommended maximum daily dose of citalopram and escitalopram was reduced due to concerns with QT prolongation.{{cite journal|last=FDA|title=FDA Drug Safety|journal=FDA|url=https://www.fda.gov/Drugs/DrugSafety/ucm269086.htm|date=December 2018|access-date=2019-12-16|archive-date=2020-10-10|archive-url=https://web.archive.org/web/20201010111755/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-abnormal-heart-rhythms-associated-high-doses-celexa-citalopram/|url-status=live}}[http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON137769 Citalopram and escitalopram: QT interval prolongation{{snd}}new maximum daily dose restrictions (including in elderly patients), contraindications, and warnings] {{Webarchive|url=https://web.archive.org/web/20130306065253/http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON137769 |date=2013-03-06 }}. From Medicines and Healthcare products Regulatory Agency. Article date: December 2011{{cite web |url=http://m.utoledo.edu/med/gme/em/pdfs/ECG_escitalopram.pdf |title=Clinical and ECG Effects of Escitalopram Overdose |access-date=2012-09-23 |archive-date=2013-10-21 |archive-url=https://web.archive.org/web/20131021173824/http://m.utoledo.edu/med/gme/em/pdfs/ECG_escitalopram.pdf |url-status=live }} In overdose, fluoxetine has been reported to cause sinus tachycardia, myocardial infarction, junctional rhythms, and trigeminy. Some authors have suggested electrocardiographic monitoring in patients with severe pre-existing cardiovascular disease who are taking SSRIs.{{cite journal |vauthors=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 = 469–480 | date = Jun 1999 | doi = 10.2174/0929867306666220330184544 | pmid = 10213794 | s2cid = 28057842 }}

In a 2023 study a possible connection between SSRI usage and the onset of mitral valve regurgitation was identified, indicating that SSRIs could hasten the progression of degenerative mitral valve regurgitation (DMR), especially in individuals carrying 5-HTTLPR genotype. The study's authors suggest that genotyping should be performed on people with DMR to evaluate serotonin transporter (SERT) activity. They also urge practitioners to exercise caution when prescribing SSRIs to individuals with a familial history of DMR.{{Cite web |title=Deciphering the Connection of Serotonin to Degenerative Mitral Valve Regurgitation - Advances in Cardiology and Heart Surgery |url=https://www.nyp.org/advances-cardiology/deciphering-the-connection-of-serotonin-to-degenerative-mitral-valve-regurgitation |access-date=2024-02-12 |website=NewYork-Presbyterian |language=en |archive-date=2024-02-12 |archive-url=https://web.archive.org/web/20240212185502/https://www.nyp.org/advances-cardiology/deciphering-the-connection-of-serotonin-to-degenerative-mitral-valve-regurgitation |url-status=live }}{{Cite journal |last1=Castillero |first1=Estibaliz |last2=Fitzpatrick |first2=Emmett |last3=Keeney |first3=Samuel J. |last4=D'Angelo |first4=Alex M. |last5=Pressly |first5=Benjamin B. |last6=Simpson |first6=Michael T. |last7=Kurade |first7=Mangesh |last8=Erwin |first8=W. Clinton |last9=Moreno |first9=Vivian |last10=Camillo |first10=Chiara |last11=Shukla |first11=Halley J. |last12=Inamdar |first12=Vaishali V. |last13=Aghali |first13=Arbi |last14=Grau |first14=Juan B. |last15=Salvati |first15=Elisa |date=2023-01-04 |title=Decreased serotonin transporter activity in the mitral valve contributes to progression of degenerative mitral regurgitation |journal=Science Translational Medicine |language=en |volume=15 |issue=677 |pages=eadc9606 |doi=10.1126/scitranslmed.adc9606 |issn=1946-6234 |pmc=9896655 |pmid=36599005}}{{Cite web |date=2023-01-29 |title=Serotonin can potentially accelerate degenerative mitral regurgitation, study says |url=https://www.news-medical.net/news/20230129/Serotonin-can-potentially-accelerate-degenerative-mitral-regurgitation-study-says.aspx |access-date=2024-02-12 |website=News-Medical |language=en |archive-date=2024-02-12 |archive-url=https://web.archive.org/web/20240212190502/https://www.news-medical.net/news/20230129/Serotonin-can-potentially-accelerate-degenerative-mitral-regurgitation-study-says.aspx |url-status=live }}

SSRIs directly increase the risk of abnormal bleeding by lowering platelet serotonin levels, which are essential to platelet-driven hemostasis.{{cite journal | vauthors = Andrade C, Sharma E | title = Serotonin Reuptake Inhibitors and Risk of Abnormal Bleeding | journal = The Psychiatric Clinics of North America | volume = 39 | issue = 3 | pages = 413–426 | date = September 2016 | pmid = 27514297 | doi = 10.1016/j.psc.2016.04.010 }}

SSRIs interact with anticoagulants, like warfarin, and antiplatelet drugs, like aspirin.{{cite journal | vauthors = Weinrieb RM, Auriacombe M, Lynch KG, Lewis JD | title = Selective serotonin re-uptake inhibitors and the risk of bleeding | journal = Expert Opinion on Drug Safety | volume = 4 | issue = 2 | pages = 337–344 | date = March 2005 | pmid = 15794724 | doi = 10.1517/14740338.4.2.337 | s2cid = 46551382 }}{{cite journal | vauthors = Andrade C, Sandarsh S, Chethan KB, Nagesh KS | title = Serotonin reuptake inhibitor antidepressants and abnormal bleeding: a review for clinicians and a reconsideration of mechanisms | journal = The Journal of Clinical Psychiatry | volume = 71 | issue = 12 | pages = 1565–1575 | date = December 2010 | pmid = 21190637 | doi = 10.4088/JCP.09r05786blu }}{{cite journal | vauthors = de Abajo FJ, García-Rodríguez LA | title = Risk of upper gastrointestinal tract bleeding associated with selective serotonin reuptake inhibitors and venlafaxine therapy: interaction with nonsteroidal anti-inflammatory drugs and effect of acid-suppressing agents | journal = Archives of General Psychiatry | volume = 65 | issue = 7 | pages = 795–803 | date = July 2008 | pmid = 18606952 | doi = 10.1001/archpsyc.65.7.795 | doi-access = free }} This includes an increased risk of GI bleeding, and post operative bleeding. The relative risk of intracranial bleeding is increased, but the absolute risk is very low.{{cite journal | vauthors = Hackam DG, Mrkobrada M | title = Selective serotonin reuptake inhibitors and brain hemorrhage: a meta-analysis | journal = Neurology | volume = 79 | issue = 18 | pages = 1862–1865 | date = October 2012 | pmid = 23077009 | doi = 10.1212/WNL.0b013e318271f848 | s2cid = 11941911 }} SSRIs are known to cause platelet dysfunction.{{cite journal | vauthors = 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 = 113–116 | date = February 2006 | pmid = 16443409 | doi = 10.1016/j.amjmed.2005.03.044 }}{{cite journal | vauthors = 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 | doi = 10.31887/DCNS.2007.9.1/dhalperin }} This risk is greater in those who are also on anticoagulants, antiplatelet agents and NSAIDs (nonsteroidal anti-inflammatory drugs), as well as with the co-existence of underlying diseases such as cirrhosis of the liver or liver failure.{{cite journal | vauthors = de Abajo FJ | title = Effects of selective serotonin reuptake inhibitors on platelet function: mechanisms, clinical outcomes and implications for use in elderly patients | journal = Drugs & Aging | volume = 28 | issue = 5 | pages = 345–367 | date = May 2011 | pmid = 21542658 | doi = 10.2165/11589340-000000000-00000 | s2cid = 116561324 }}

Evidence from longitudinal, cross-sectional, and prospective cohort studies suggests an association between SSRI usage at therapeutic doses and a decrease in bone mineral density, as well as increased fracture risk,{{cite journal | vauthors = Eom CS, Lee HK, Ye S, Park SM, Cho KH | title = Use of selective serotonin reuptake inhibitors and risk of fracture: a systematic review and meta-analysis | journal = Journal of Bone and Mineral Research | volume = 27 | issue = 5 | pages = 1186–1195 | date = May 2012 | pmid = 22258738 | doi = 10.1002/jbmr.1554 | doi-access = free }}{{cite journal | vauthors = Bruyère O, Reginster JY | title = Osteoporosis in patients taking selective serotonin reuptake inhibitors: a focus on fracture outcome | journal = Endocrine | volume = 48 | issue = 1 | pages = 65–68 | date = February 2015 | pmid = 25091520 | doi = 10.1007/s12020-014-0357-0 | s2cid = 32286954 | url = https://zenodo.org/record/845248 | access-date = 2019-07-01 | archive-date = 2020-10-10 | archive-url = https://web.archive.org/web/20201010111808/https://zenodo.org/record/845248/ | url-status = live }}{{cite journal | vauthors = Hant FN, Bolster MB | title = Drugs that may harm bone: Mitigating the risk | journal = Cleveland Clinic Journal of Medicine | volume = 83 | issue = 4 | pages = 281–288 | date = April 2016 | pmid = 27055202 | doi = 10.3949/ccjm.83a.15066 | doi-access = free }}{{cite journal | vauthors = Fernandes BS, Hodge JM, Pasco JA, Berk M, Williams LJ | title = Effects of Depression and Serotonergic Antidepressants on Bone: Mechanisms and Implications for the Treatment of Depression | journal = Drugs & Aging | volume = 33 | issue = 1 | pages = 21–25 | date = January 2016 | pmid = 26547857 | doi = 10.1007/s40266-015-0323-4 | s2cid = 7648524 }} a relationship that appears to persist even with adjuvant bisphosphonate therapy.{{cite journal | vauthors = Nyandege AN, Slattum PW, Harpe SE | title = Risk of fracture and the concomitant use of bisphosphonates with osteoporosis-inducing medications | journal = The Annals of Pharmacotherapy | volume = 49 | issue = 4 | pages = 437–447 | date = April 2015 | pmid = 25667198 | doi = 10.1177/1060028015569594 | s2cid = 20622369 }} However, because the relationship between SSRIs and fractures is based on observational data as opposed to prospective trials, the phenomenon is not definitively causal.{{cite journal | vauthors = Warden SJ, Fuchs RK | title = Do Selective Serotonin Reuptake Inhibitors (SSRIs) Cause Fractures? | journal = Current Osteoporosis Reports | volume = 14 | issue = 5 | pages = 211–218 | date = October 2016 | pmid = 27495351 | doi = 10.1007/s11914-016-0322-3 | s2cid = 5610316 }} There also appears to be an increase in fracture-inducing falls with SSRI use, suggesting the need for increased attention to fall risk in elderly patients using the medication. The loss of bone density does not appear to occur in younger patients taking SSRIs.{{cite journal | vauthors = Winterhalder L, Eser P, Widmer J, Villiger PM, Aeberli D | title = Changes in volumetric BMD of radius and tibia upon antidepressant drug administration in young depressive patients | journal = Journal of Musculoskeletal & Neuronal Interactions | volume = 12 | issue = 4 | pages = 224–229 | date = December 2012 | pmid = 23196265 }}

SSRI and SNRI antidepressants may cause jaw pain/jaw spasm reversible syndrome (although it is not common). Buspirone appears to be successful in treating bruxism on SSRI/SNRI induced jaw clenching.{{cite journal | vauthors = Garrett AR, Hawley JS | title = SSRI-associated bruxism: A systematic review of published case reports | journal = Neurology. Clinical Practice | volume = 8 | issue = 2 | pages = 135–141 | date = April 2018 | pmid = 29708207 | pmc = 5914744 | doi = 10.1212/CPJ.0000000000000433 }}{{cite journal | vauthors = Prisco V, Iannaccone T, Di Grezia G | date = 2017-04-01 | title = Use of buspirone in selective serotonin reuptake inhibitor-induced sleep bruxism | url = http://www.sciencedirect.com/science/article/pii/S0924933817317169 | journal = European Psychiatry | series = Abstract of the 25th European Congress of Psychiatry | volume = 41 | pages = S855 | doi = 10.1016/j.eurpsy.2017.01.1701 | s2cid = 148816505 | issn = 0924-9338 | access-date = 2020-04-18 | archive-date = 2020-10-10 | archive-url = https://web.archive.org/web/20201010111724/https://www.sciencedirect.com/science/article/abs/pii/S0924933817317169/ | url-status = live }}{{cite journal | vauthors = Albayrak Y, Ekinci O | title = Duloxetine-induced nocturnal bruxism resolved by buspirone: case report | journal = Clinical Neuropharmacology | volume = 34 | issue = 4 | pages = 137–138 | year = 2011 | pmid = 21768799 | doi = 10.1097/WNF.0b013e3182227736 }}

{{Main|Serotonin syndrome}}

Serotonin syndrome is typically caused by the use of two or more serotonergic drugs, including SSRIs.{{cite journal | vauthors = Volpi-Abadie J, Kaye AM, Kaye AD | title = Serotonin syndrome | journal = The Ochsner Journal | volume = 13 | issue = 4 | pages = 533–540 | date = 2013 | pmid = 24358002 | pmc = 3865832 }} Serotonin syndrome is a condition that can range from mild (most common) to deadly. Mild symptoms may consist of increased heart rate, fever, shivering, sweating, dilated pupils, myoclonus (intermittent jerking or twitching), as well as hyperreflexia.{{cite journal | vauthors = Boyer EW, Shannon M | title = The serotonin syndrome | journal = The New England Journal of Medicine | volume = 352 | issue = 11 | pages = 1112–1120 | date = March 2005 | pmid = 15784664 | doi = 10.1056/nejmra041867 | s2cid = 37959124 }} Concomitant use of SSRIs or SNRIs for depression with a triptan for migraine does not appear to heighten the risk of the serotonin syndrome.{{cite journal | vauthors = Orlova Y, Rizzoli P, Loder E | title = Association of Coprescription of Triptan Antimigraine Drugs and Selective Serotonin Reuptake Inhibitor or Selective Norepinephrine Reuptake Inhibitor Antidepressants With Serotonin Syndrome | journal = JAMA Neurology | volume = 75 | issue = 5 | pages = 566–572 | date = May 2018 | pmid = 29482205 | pmc = 5885255 | doi = 10.1001/jamaneurol.2017.5144 }} Taking monoamine oxidase inhibitors (MAOIs) in combination with SSRIs can be fatal, since MAOIs disrupt monoamine oxidase, an enzyme which is needed to break down serotonin and other neurotransmitters. Without monoamine oxidase, the body is unable to eliminate excess neurotransmitters, allowing them to build up to dangerous levels. The prognosis for recovery in a hospital setting is generally good if serotonin syndrome is correctly identified. Treatment consists of discontinuing any serotonergic drugs and providing supportive care to manage agitation and hyperthermia, usually with benzodiazepines.{{cite book|vauthors=Ferri FF|title=Ferri's Clinical Advisor 2017: 5 Books in 1|date=2016|publisher=Elsevier Health Sciences|isbn=978-0-323-44838-3|pages=1154–1155|url=https://books.google.com/books?id=rRhCDAAAQBAJ&pg=PA1154|language=en|access-date=2021-01-26|archive-date=2023-01-14|archive-url=https://web.archive.org/web/20230114060907/https://books.google.com/books?id=rRhCDAAAQBAJ&pg=PA1154|url-status=live}}

{{main|Antidepressants and suicide risk}}

Meta analyses of short duration randomized clinical trials have found that SSRI use is related to a higher risk of suicidal behavior in children and adolescents.{{cite web | url = https://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 | access-date = 2007-09-22 | vauthors = Stone MB, Jones ML | date = 2006-11-17 | website = Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC) | publisher = FDA | pages = 11–74 | archive-date = 2007-03-16 | archive-url = https://web.archive.org/web/20070316092329/https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf | url-status = live }}{{cite web | url = https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf | title = Statistical Evaluation of Suicidality in Adults Treated with Antidepressants | access-date = 2007-09-22 | vauthors = Levenson M, Holland C | date = 2006-11-17 | website = Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC) | publisher = FDA | pages = 75–140 | archive-date = 2007-03-16 | archive-url = https://web.archive.org/web/20070316092329/https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf | url-status = live }}{{cite journal | vauthors = 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 = 865–872 | date = August 2006 | pmid = 16894062 | doi = 10.1001/archpsyc.63.8.865 | doi-access = free }} For instance, a 2004 U.S. Food and Drug Administration (FDA) analysis of clinical trials on children with major depressive disorder found statistically significant increases of the risks of "possible suicidal ideation and suicidal behavior" by about 80%, and of agitation and hostility by about 130%.{{cite web | url = https://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 | access-date = 2008-05-29 | vauthors = Hammad TA | date = 2004-08-16 | publisher = FDA | pages = 42, 115 | archive-date = 2008-06-25 | archive-url = https://web.archive.org/web/20080625161255/https://www.fda.gov/OHRMS/DOCKETS/ac/04/briefing/2004-4065b1-10-TAB08-Hammads-Review.pdf | url-status = live }} According to the FDA, the heightened risk of suicidality is within the first one to two months of treatment.{{cite web |url=https://www.fda.gov/drugs/drugsafety/informationbydrugclass/ucm096273 | archive-url = https://web.archive.org/web/20170107043034/https://www.fda.gov/drugs/drugsafety/informationbydrugclass/ucm096273 | archive-date = 7 January 2017 | url-status = dead | publisher = U.S. Food and Drug Administration |title=Antidepressant Use in Children, Adolescents, and Adults }}{{cite web |url=https://www.fda.gov/downloads/Drugs/DrugSafety/ucm088660.pdf%E2%80%8E |title=FDA Medication Guide for Antidepressants |website=Food and Drug Administration |access-date=2014-06-05 |archive-date=2014-08-18 |archive-url=https://web.archive.org/web/20140818020916/https://www.fda.gov/downloads/Drugs/DrugSafety/ucm088660.pdf%E2%80%8E |url-status=live }}{{cite journal | vauthors = Cox GR, Callahan P, Churchill R, Hunot V, Merry SN, Parker AG, Hetrick SE | title = Psychological therapies versus antidepressant medication, alone and in combination for depression in children and adolescents | journal = The Cochrane Database of Systematic Reviews | issue = 11 | pages = CD008324 | date = November 2014 | volume = 2014 | pmid = 25433518 | doi = 10.1002/14651858.CD008324.pub3 | pmc = 8556660 }} The National Institute for Health and Care Excellence (NICE) places the excess risk in the "early stages of treatment".{{cite web|url=https://www.nice.org.uk/guidance/CG90|title=Overview | Depression in adults: recognition and management | Guidance | NICE|website=www.nice.org.uk|date=28 October 2009|access-date=30 May 2022|archive-date=31 May 2022|archive-url=https://web.archive.org/web/20220531145902/https://www.nice.org.uk/guidance/cg90|url-status=live}} The European Psychiatric Association places the excess risk in the first two weeks of treatment and, based on a combination of epidemiological, prospective cohort, medical claims, and randomized clinical trial data, concludes that a protective effect dominates after this early period. A 2014 Cochrane review found that at six to nine months, suicidal ideation remained higher in children treated with antidepressants compared to those treated with psychological therapy.

In 2004, the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom judged fluoxetine (Prozac) to be the only antidepressant that offered a favorable risk-benefit ratio in children with depression, though it was also associated with a slight increase in the risk of self-harm and suicidal ideation.{{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 |access-date=2007-09-25 |date=2004-12-01 |publisher=MHRA |archive-date=2008-02-28 |archive-url=https://web.archive.org/web/20080228024705/http://www.mhra.gov.uk/home/groups/pl-p/documents/drugsafetymessage/con019472.pdf |url-status=live }} Only two SSRIs are licensed for use with children in the UK, sertraline (Zoloft) and fluvoxamine (Luvox), for the treatment of obsessive–compulsive disorder. Fluoxetine is not licensed for this use.{{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 |date=2005-09-29 |publisher=MHRA |access-date=2008-05-29 |url-status=dead |archive-url=https://web.archive.org/web/20080802183642/http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON019494 |archive-date=2008-08-02 }}

An 2007 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.{{cite journal | vauthors = Tauscher-Wisniewski S, Nilsson M, Caldwell C, Plewes J, Allen AJ | title = Meta-analysis of aggression and/or hostility-related events in children and adolescents treated with fluoxetine compared with placebo | journal = Journal of Child and Adolescent Psychopharmacology | volume = 17 | issue = 5 | pages = 713–718 | date = October 2007 | pmid = 17979590 | doi = 10.1089/cap.2006.0138 }} There is also evidence that higher rates of SSRI prescriptions are associated with lower rates of suicide in children, though since the evidence is correlational, the true nature of the relationship is unclear.{{cite journal | vauthors = 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 = 1898–1904 | date = November 2006 | pmid = 17074941 | doi = 10.1176/appi.ajp.163.11.1898 | s2cid = 2390497 }} A 2021 Swedish study, using a within-individual design, also found that young people (as well as adults) who have both attempted suicide and been prescribed SSRIs most commonly make the attempt before, rather than after, starting their SSRI prescription.

It is unclear whether SSRIs affect the risk of suicidal behavior in adults.

• 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.{{cite journal |vauthors=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 | date = February 2005 | pmid = 15718537 | pmc = 549105 | doi = 10.1136/bmj.330.7488.385 }}
• A 2005 review observed that suicide attempts are increased in those who use SSRIs as compared to placebo and compared to therapeutic interventions other than tricyclic antidepressants. No difference risk of suicide attempts was detected between SSRIs versus tricyclic antidepressants.{{cite journal |vauthors=Fergusson D, Doucette S, Glass KC, Shapiro S, Healy D, Hebert P, Hutton B | title = Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials | journal = BMJ | volume = 330 | issue = 7488 | page = 396 | date = February 2005 | pmid = 15718539 | pmc = 549110 | doi = 10.1136/bmj.330.7488.396 }}
• A 2006 review suggests that the widespread use of antidepressants in the new "SSRI-era" appears to have led to a 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.{{cite journal |vauthors=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 = Journal of Affective Disorders | volume = 94 | issue = 1–3 | pages = 3–13 | date = August 2006 | pmid = 16712945 | doi = 10.1016/j.jad.2006.04.003 }}
• A 2006 meta-analysis of randomized controlled trials suggests that SSRIs increase suicide ideation compared with placebo. However, the observational studies suggest 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.{{cite journal |vauthors=Hall WD, Lucke J | title = How have the selective serotonin reuptake inhibitor antidepressants affected suicide mortality? | journal = The Australian and New Zealand Journal of Psychiatry | volume = 40 | issue = 11–12 | pages = 941–950 | year = 2006 | pmid = 17054562 | doi = 10.1111/j.1440-1614.2006.01917.x }}
• 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.
• In 2016 a review criticized the effects of the FDA Black Box suicide warning inclusion in the prescription. The authors discussed the suicide rates might increase also as a consequence of the warning.{{cite journal | vauthors = Martínez-Aguayo JC, Arancibia M, Concha S, Madrid E |title=Ten years after the FDA black box warning for antidepressant drugs: A critical narrative review |journal=Archives of Clinical Psychiatry |volume=43 |issue=3 |pages=60–66 |year=2016 | doi=10.1590/0101-60830000000086 |doi-access=free }} A 2019 review makes a similar claim, noting that instead of increasing the use of psychotherapy (as the FDA had hoped), the warning has increased the use of benzodiazepines.{{cite journal |last1=Fornaro |first1=Michele |last2=Anastasia |first2=Annalisa |last3=Valchera |first3=Alessandro |last4=Carano |first4=Alessandro |last5=Orsolini |first5=Laura |last6=Vellante |first6=Federica |last7=Rapini |first7=Gabriella |last8=Olivieri |first8=Luigi |last9=Di Natale |first9=Serena |last10=Perna |first10=Giampaolo |last11=Martinotti |first11=Giovanni |last12=Di Giannantonio |first12=Massimo |last13=De Berardis |first13=Domenico |title=The FDA "Black Box" Warning on Antidepressant Suicide Risk in Young Adults: More Harm Than Benefits? |journal=Frontiers in Psychiatry |date=2019-05-03 |volume=10 |page=294 |doi=10.3389/fpsyt.2019.00294|doi-access=free |pmid=31130881 |pmc=6510161 }}
• A 2021 study on Swedish youth and adults between 2006 and 2013 (n = 538,577) finds that the highest frequency of suicides occurs at 30 days before, rather than after, the beginning of SSRI prescription. This indicates that SSRIs do not increase the risk of suicide and may reduce the risk.{{cite journal |last1=Lagerberg |first1=Tyra |last2=Fazel |first2=Seena |last3=Sjölander |first3=Arvid |last4=Hellner |first4=Clara |last5=Lichtenstein |first5=Paul |last6=Chang |first6=Zheng |title=Selective serotonin reuptake inhibitors and suicidal behaviour: a population-based cohort study |journal=Neuropsychopharmacology |date=March 2022 |volume=47 |issue=4 |pages=817–823 |doi=10.1038/s41386-021-01179-z|pmid=34561608 |pmc=8882171 }}

A 2017 meta-analysis found that antidepressants including SSRIs were associated with significantly increased risk of death (+33%) and new cardiovascular complications (+14%) in the general population.{{cite journal | vauthors = Maslej MM, Bolker BM, Russell MJ, Eaton K, Durisko Z, Hollon SD, Swanson GM, Thomson JA, Mulsant BH, Andrews PW | title = The Mortality and Myocardial Effects of Antidepressants Are Moderated by Preexisting Cardiovascular Disease: A Meta-Analysis | journal = Psychother Psychosom | volume = 86 | issue = 5 | pages = 268–282 | date = 2017 | pmid = 28903117 | doi = 10.1159/000477940 | s2cid = 4830115 | url = }} Conversely, risks were not greater in people with existing cardiovascular disease.

SSRI use in pregnancy has been associated with a variety of risks with varying degrees of proof of causation. As depression is independently associated with negative pregnancy outcomes, determining the extent to which observed associations between antidepressant use and specific adverse outcomes reflects a causative relationship has been difficult in some cases.{{cite journal | vauthors = Malm H | title = Prenatal exposure to selective serotonin reuptake inhibitors and infant outcome | journal = Therapeutic Drug Monitoring | volume = 34 | issue = 6 | pages = 607–614 | date = December 2012 | pmid = 23042258 | doi = 10.1097/FTD.0b013e31826d07ea | s2cid = 22875385 }} In other cases, the attribution of adverse outcomes to antidepressant exposure seems fairly clear.

SSRI use in pregnancy is associated with an increased risk of spontaneous abortion of about 1.7-fold.{{cite journal |vauthors=Rahimi R, Nikfar S, Abdollahi M | title = Pregnancy outcomes following exposure to serotonin reuptake inhibitors: a meta-analysis of clinical trials | journal = Reproductive Toxicology | volume = 22 | issue = 4 | pages = 571–575 | year = 2006 | pmid = 16720091 | doi = 10.1016/j.reprotox.2006.03.019 | bibcode = 2006RepTx..22..571R }}{{cite journal |vauthors=Nikfar S, Rahimi R, Hendoiee N, Abdollahi M | title = Increasing the risk of spontaneous abortion and major malformations in newborns following use of serotonin reuptake inhibitors during pregnancy: A systematic review and updated meta-analysis | journal = DARU Journal of Pharmaceutical Sciences| volume = 20 | issue = 1 | pages = 75 | year = 2012 | pmid = 23351929 | pmc = 3556001 | doi = 10.1186/2008-2231-20-75 | doi-access = free }} Use is also associated with preterm birth.{{cite journal | vauthors = Eke AC, Saccone G, Berghella V | title = Selective serotonin reuptake inhibitor (SSRI) use during pregnancy and risk of preterm birth: a systematic review and meta-analysis | journal = BJOG | volume = 123 | issue = 12 | pages = 1900–1907 | date = November 2016 | pmid = 27239775 | doi = 10.1111/1471-0528.14144 | pmc = 9987176 | doi-access = free }} According to some researches, decreased body weight of the child, intrauterine growth retardation, neonatal adaptive syndrome, and persistent pulmonary hypertension also was noted.{{cite journal | vauthors = Dubovicky M, Belovicova K, Csatlosova K, Bogi E | title = Risks of using SSRI / SNRI antidepressants during pregnancy and lactation | journal = Interdisciplinary Toxicology | volume = 10 | issue = 1 | pages = 30–34 | date = September 2017 | pmid = 30123033 | pmc = 6096863 | doi = 10.1515/intox-2017-0004 }}

A systematic review of the risk of major birth defects in antidepressant-exposed pregnancies found a small increase (3% to 24%) in the risk of major malformations and a risk of cardiovascular birth defects that did not differ from non-exposed pregnancies.{{cite journal |vauthors=Einarson TR, Kennedy D, Einarson A | title = Do findings differ across research design? The case of antidepressant use in pregnancy and malformations | journal = Journal of Population Therapeutics and Clinical Pharmacology | volume = 19 | issue = 2 | pages = e334–348 | year = 2012 | pmid = 22946124 }} {{cite journal |vauthors=Riggin L, Frankel Z, Moretti M, Pupco A, Koren G | title = The fetal safety of fluoxetine: a systematic review and meta-analysis | journal = Journal of Obstetrics and Gynaecology Canada | volume = 35 | issue = 4 | pages = 362–369 | date = April 2013 | pmid = 23660045 | doi = 10.1016/S1701-2163(15)30965-8| doi-access = free }} Other studies have found an increased risk of cardiovascular birth defects among depressed mothers not undergoing SSRI treatment, suggesting the possibility of ascertainment bias, e.g. that worried mothers may pursue more aggressive testing of their infants.{{cite journal |vauthors=Koren G, Nordeng HM | title = Selective serotonin reuptake inhibitors and malformations: case closed? | journal = Seminars in Fetal & Neonatal Medicine | volume = 18 | issue = 1 | pages = 19–22 | date = February 2013 | pmid = 23228547 | doi = 10.1016/j.siny.2012.10.004 }} Another study found no increase in cardiovascular birth defects and a 27% increased risk of major malformations in SSRI exposed pregnancies.

The FDA 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.{{cite web|url=http://www.breastfeeding.org/newsletter/v2i4/page2.html |title=Breastfeeding Update: SDCBC's quarterly newsletter |publisher=Breastfeeding.org |access-date=2010-07-10 |url-status=dead |archive-url=https://web.archive.org/web/20090225110030/http://breastfeeding.org/newsletter/v2i4/page2.html |archive-date=February 25, 2009 }}{{cite web |url=http://www.kellymom.com/health/meds/antidepressants-hale10-02.html |title=Using Antidepressants in Breastfeeding Mothers |publisher=kellymom.com |access-date=2010-07-10 |url-status=dead |archive-url=https://web.archive.org/web/20100923205146/http://kellymom.com/health/meds/antidepressants-hale10-02.html |archive-date=2010-09-23 }}{{cite journal |vauthors=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 | s2cid = 757921 }}

Several studies have documented neonatal abstinence syndrome, a syndrome of neurological, gastrointestinal, autonomic, endocrine and/or respiratory symptoms among a large minority of infants with intrauterine exposure. These syndromes are short-lived, but insufficient long-term data is available to determine whether there are long-term effects.{{cite journal |vauthors=Fenger-Grøn J, Thomsen M, Andersen KS, Nielsen RG | title = Paediatric outcomes following intrauterine exposure to serotonin reuptake inhibitors: a systematic review | journal = Danish Medical Bulletin | volume = 58 | issue = 9 | pages = A4303 | date = September 2011 | pmid = 21893008 }}{{cite journal |vauthors=Kieviet N, Dolman KM, Honig A | title = The use of psychotropic medication during pregnancy: how about the newborn? | journal = Neuropsychiatric Disease and Treatment | volume = 9 | pages = 1257–1266 | year = 2013 | pmid = 24039427 | pmc = 3770341 | doi = 10.2147/NDT.S36394 | doi-access = free }}

Persistent pulmonary hypertension (PPHN) is a serious and life-threatening, but very rare, lung condition that occurs soon after birth of the newborn. Newborn babies with PPHN have high pressure in their lung blood vessels 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 medical care. It is associated with about a 25% risk of significant long-term neurological deficits.{{EMedicine|article|898437|Persistent Newborn Pulmonary Hypertension}} A 2014 meta analysis found no increased risk of persistent pulmonary hypertension associated with exposure to SSRI's in early pregnancy and a slight increase in risk associates with exposure late in pregnancy; "an estimated 286 to 351 women would need to be treated with an SSRI in late pregnancy to result in an average of one additional case of persistent pulmonary hypertension of the newborn".{{cite journal |vauthors=Grigoriadis S, Vonderporten EH, Mamisashvili L, Tomlinson G, Dennis CL, Koren G, Steiner M, Mousmanis P, Cheung A, Ross LE | title = Prenatal exposure to antidepressants and persistent pulmonary hypertension of the newborn: systematic review and meta-analysis | journal = BMJ | volume = 348 | pages = f6932 | year = 2014 | pmid = 24429387 | pmc = 3898424 | doi = 10.1136/bmj.f6932 }} A review published in 2012 reached conclusions very similar to those of the 2014 study.{{cite journal |vauthors='t Jong GW, Einarson T, Koren G, Einarson A | title = Antidepressant use in pregnancy and persistent pulmonary hypertension of the newborn (PPHN): a systematic review | journal = Reproductive Toxicology | volume = 34 | issue = 3 | pages = 293–297 | date = November 2012 | pmid = 22564982 | doi = 10.1016/j.reprotox.2012.04.015 | bibcode = 2012RepTx..34..293T }}

According to a 2015 review available data found that "some signal exists suggesting that antenatal exposure to SSRIs may increase the risk of ASDs (autism spectrum disorders)"{{cite journal | vauthors = Gentile S | title = Prenatal antidepressant exposure and the risk of autism spectrum disorders in children. Are we looking at the fall of Gods? | journal = Journal of Affective Disorders | volume = 182 | pages = 132–137 | date = August 2015 | pmid = 25985383 | doi = 10.1016/j.jad.2015.04.048 }} even though a large cohort study published in 2013{{cite journal | vauthors = Hviid A, Melbye M, Pasternak B | title = Use of selective serotonin reuptake inhibitors during pregnancy and risk of autism | journal = The New England Journal of Medicine | volume = 369 | issue = 25 | pages = 2406–2415 | date = December 2013 | pmid = 24350950 | doi = 10.1056/NEJMoa1301449 | s2cid = 9064353 | doi-access = free }} and a cohort study using data from Finland's national register between the years 1996 and 2010 and published in 2016 found no significant association between SSRI use and autism in offspring.{{cite journal | vauthors = Malm H, Brown AS, Gissler M, Gyllenberg D, Hinkka-Yli-Salomäki S, McKeague IW, Weissman M, Wickramaratne P, Artama M, Gingrich JA, Sourander A | title = Gestational Exposure to Selective Serotonin Reuptake Inhibitors and Offspring Psychiatric Disorders: A National Register-Based Study | journal = Journal of the American Academy of Child and Adolescent Psychiatry | volume = 55 | issue = 5 | pages = 359–366 | date = May 2016 | pmid = 27126849 | pmc = 4851729 | doi = 10.1016/j.jaac.2016.02.013 | display-authors = etal }} The 2016 Finland study also found no association with ADHD, but did find an association with increased rates of depression diagnoses in early adolescence.

In adults and children with bipolar disorder, SSRIs may cause a bipolar switch from depression into hypomania/mania, mixed states or rapid cycling.Chris Aiken: [https://www.psychiatrictimes.com/view/antidepressants-bipolar-ii-disorder Antidepressants in Bipolar II Disorder], May 14, 2019. In: psychiatrictimes.com When taken with mood stabilizers, the risk of switching is not increased, however when taking SSRIs as a monotherapy, the risk of switching may be twice or three times that of the average.{{cite journal | vauthors = Gitlin MJ | title = Antidepressants in bipolar depression: an enduring controversy | journal = International Journal of Bipolar Disorders | volume = 6 | issue = 1 | pages = 25 | date = December 2018 | pmid = 30506151 | pmc = 6269438 | doi = 10.1186/s40345-018-0133-9 | doi-access = free }}{{cite journal | vauthors = Viktorin A, Lichtenstein P, Thase ME, Larsson H, Lundholm C, Magnusson PK, Landén M | title = The risk of switch to mania in patients with bipolar disorder during treatment with an antidepressant alone and in combination with a mood stabilizer | journal = The American Journal of Psychiatry | volume = 171 | issue = 10 | pages = 1067–1073 | date = October 2014 | pmid = 24935197 | doi = 10.1176/appi.ajp.2014.13111501 | s2cid = 25152608 | hdl = 10616/42159 | url = https://figshare.com/articles/journal_contribution/27292893 | hdl-access = free }} The changes are not often easy to detect and require monitoring by family and mental health professionals.{{cite journal | vauthors = Walkup J, Labellarte M | title = Complications of SSRI treatment | journal = Journal of Child and Adolescent Psychopharmacology | volume = 11 | issue = 1 | pages = 1–4 | date = 2001 | pmid = 11322738 | doi = 10.1089/104454601750143320 }} This switch might happen even with no prior (hypo)manic episodes and might therefore not be foreseen by the psychiatrist.

SSRIs are less likely to cause switching compared to older tricyclic antidepressants.

The following drugs may precipitate serotonin syndrome in people on SSRIs:{{cite journal | vauthors = Ener RA, Meglathery SB, Van Decker WA, Gallagher RM | title = Serotonin syndrome and other serotonergic disorders | journal = Pain Medicine | volume = 4 | issue = 1 | pages = 63–74 | date = March 2003 | pmid = 12873279 | doi = 10.1046/j.1526-4637.2003.03005.x | doi-access = free }}{{cite journal | vauthors = Boyer EW, Shannon M | title = The serotonin syndrome | journal = The New England Journal of Medicine | volume = 352 | issue = 11 | pages = 1112–1120 | date = March 2005 | pmid = 15784664 | doi = 10.1056/NEJMra041867 | s2cid = 37959124 }}

• Linezolid
• Monoamine oxidase inhibitors (MAOIs) including moclobemide, phenelzine, tranylcypromine, selegiline and methylene blue
• Lithium
• Sibutramine
• MDMA (ecstasy)
• Dextromethorphan
• Tramadol
• 5-HTP
• Pethidine/meperidine
• St. John's wort
• Yohimbe
• Tricyclic antidepressants (TCAs)
• Serotonin-norepinephrine reuptake inhibitors (SNRIs)
• Buspirone
• Triptan
• Mirtazapine
• Methylene blue

Painkillers of the NSAIDs drug family may interfere and reduce efficiency of SSRIs and may compound the increased risk of gastrointestinal bleeds caused by SSRI use.{{cite book | vauthors = Taylor D, Carol P, Shitij K | title=The Maudsley prescribing guidelines in psychiatry|year=2012|publisher=Wiley-Blackwell|location=West Sussex|isbn=978-0-470-97969-3}}{{cite journal | vauthors = Warner-Schmidt JL, Vanover KE, Chen EY, Marshall JJ, Greengard P | title = Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 22 | pages = 9262–9267 | date = May 2011 | pmid = 21518864 | pmc = 3107316 | doi = 10.1073/pnas.1104836108 | doi-access = free }} NSAIDs include:

• Aspirin
• Ibuprofen (Advil, Nurofen)
• Naproxen (Aleve)

There are a number of potential pharmacokinetic interactions between the various individual SSRIs and other medications. Most of these arise from the fact that every SSRI has the ability to inhibit certain P450 cytochrome enzymes.{{cite book| vauthors= Brunton L, Chabner B, Knollman B |title=Goodman and Gilman's The Pharmacological Basis of Therapeutics |edition=12th |publisher=McGraw Hill Professional |year=2010 |isbn=978-0-07-162442-8 }}{{cite book | vauthors = Ciraulo DA, Shader RI | title=Pharmacotherapy of Depression | url = https://archive.org/details/pharmacotherapyd00cira | url-access = limited |year=2011 |publisher=Springer |isbn=978-1-60327-435-7 |page=[https://archive.org/details/pharmacotherapyd00cira/page/n61 49] | edition=2nd |doi=10.1007/978-1-60327-435-7 | veditors = Ciraulo DA, Shader RI }}{{cite journal | vauthors = Jeppesen U, Gram LF, Vistisen K, Loft S, Poulsen HE, Brøsen K | title = Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine | journal = European Journal of Clinical Pharmacology | volume = 51 | issue = 1 | pages = 73–78 | year = 1996 | pmid = 8880055 | doi = 10.1007/s002280050163 | s2cid = 19802446 }}

Legend:

0{{snd}}no inhibition

+{{snd}}mild/weak inhibition

++{{snd}}moderate inhibition

+++{{snd}}strong/potent inhibition

The CYP2D6 enzyme is entirely responsible for the metabolism of hydrocodone, codeine{{cite journal | vauthors = Overholser BR, Foster DR | title = Opioid pharmacokinetic drug-drug interactions | journal = The American Journal of Managed Care | volume = 17 | issue = Suppl 11 | pages = S276–287 | date = September 2011 | pmid = 21999760 | url = https://www.ajmc.com/pubMed.php?pii=51946 }} and dihydrocodeine to their active metabolites (hydromorphone, morphine, and dihydromorphine, respectively), which in turn undergo phase 2 glucuronidation. These opioids (and to a lesser extent oxycodone, tramadol, and methadone) have interaction potential with selective serotonin reuptake inhibitors.{{cite web | url = https://www.pdr.net/drug-summary/Paxil-paroxetine-hydrochloride-215.2678 | title = Paroxetine hydrochloride – Drug Summary | publisher = Physicians' Desk Reference, LLC | access-date = 2018-09-17 | archive-date = 2018-09-28 | archive-url = https://web.archive.org/web/20180928172320/http://www.pdr.net/drug-summary/Paxil-paroxetine-hydrochloride-215.2678 | url-status = live }}{{cite journal | vauthors = Smith HS | title = Opioid metabolism | journal = Mayo Clinic Proceedings | volume = 84 | issue = 7 | pages = 613–624 | date = July 2009 | pmid = 19567715 | pmc = 2704133 | doi = 10.4065/84.7.613 }} The concomitant use of some SSRIs (paroxetine and fluoxetine) with codeine may decrease the plasma concentration of active metabolite morphine, which may result in reduced analgesic efficacy.{{cite journal | vauthors = Wiley K, Regan A, McIntyre P | title = Immunisation and pregnancy – who, what, when and why? | journal = Australian Prescriber | volume = 40 | issue = 4 | pages = 122–124 | date = August 2017 | pmid = 28947846 | pmc = 5601969 | doi = 10.18773/austprescr.2017.046 }}{{cite journal | vauthors = Weaver JM | title = New FDA black box warning for codeine: how will this affect dentists? | journal = Anesthesia Progress | volume = 60 | issue = 2 | pages = 35–36 | year = 2013 | pmid = 23763556 | pmc = 3683877 | doi = 10.2344/0003-3006-60.2.35 }}

Another important interaction of certain SSRIs involves paroxetine, a potent inhibitor of CYP2D6, and tamoxifen, an agent used commonly in the treatment and prevention of breast cancer. Tamoxifen is a prodrug that is metabolised by the hepatic cytochrome P450 enzyme system, especially CYP2D6, to its active metabolites. Concomitant use of paroxetine and tamoxifen in women with breast cancer is associated with a higher risk of death, as much as a 91 percent in women who used it the longest.{{cite journal | vauthors = Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, Pritchard KI, Austin PC, Paszat LF | title = Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study | journal = BMJ | volume = 340 | pages = c693 | date = February 2010 | pmid = 20142325 | pmc = 2817754 | doi = 10.1136/bmj.c693 }}

{{See also|Serotonin syndrome}}

SSRIs appear safer in overdose 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.{{cite journal |vauthors=Isbister GK, Bowe SJ, Dawson A, Whyte IM |year=2004 |title=Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose |journal=Journal of Toxicology. Clinical Toxicology |volume=42 |issue=3 |pages=277–285 |doi=10.1081/CLT-120037428 |pmid=15362595 |s2cid=43121327}} However, case reports of SSRI poisoning have indicated that severe toxicity can occur{{cite journal |vauthors=Borys DJ, Setzer SC, Ling LJ, Reisdorf JJ, Day LC, Krenzelok EP |year=1992 |title=Acute fluoxetine overdose: a report of 234 cases |journal=The American Journal of Emergency Medicine |volume=10 |issue=2 |pages=115–120 |doi=10.1016/0735-6757(92)90041-U |pmid=1586402}} and deaths have been reported following massive single ingestions,{{cite journal |vauthors=Oström M, Eriksson A, Thorson J, Spigset O |year=1996 |title=Fatal overdose with citalopram |journal=Lancet |volume=348 |issue=9023 |pages=339–340 |doi=10.1016/S0140-6736(05)64513-8 |pmid=8709713 |s2cid=5287418}} although this is exceedingly uncommon when compared to the tricyclic antidepressants.

Because of the wide therapeutic index 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 syndrome; serotonin toxicity is usually associated with very high overdoses or multiple drug ingestion.{{cite journal |vauthors=Sporer KA |date=August 1995 |title=The serotonin syndrome. Implicated drugs, pathophysiology and management |journal=Drug Safety |volume=13 |issue=2 |pages=94–104 |doi=10.2165/00002018-199513020-00004 |pmid=7576268 |s2cid=19809259}} Other reported significant effects include coma, seizures, and cardiac toxicity.

Poisoning is also known in animals, and some toxicity information is available for veterinary treatment.{{cite book | vauthors = Gupta R |title=Veterinary Toxicology : Basic and Clinical Principles |publisher=Academic Press |year=2012 |isbn=978-0-12-385926-6 |edition=2 |location=Boston |pages=xii + 1438 |language=English}}

{{Main|SSRI discontinuation syndrome}}

Abrupt discontinuation of SSRIs, especially after prolonged therapy, causes a withdrawal syndrome, which may include symptoms such as nausea and vomiting, headache, dizziness, chills, body aches, paresthesias, insomnia, and brain zaps.{{Cite journal |last=Tamam |first=Lut |last2=Ozpoyraz |first2=Nurgul |date=2002-01-01 |title=Selective serotonin reuptake inhibitor discontinuation syndrome: A review |url=https://link.springer.com/article/10.1007/BF02850015 |journal=Advances in Therapy |language=en |volume=19 |issue=1 |pages=17–26 |doi=10.1007/BF02850015 |issn=1865-8652}} Serotonin reuptake inhibitors should not be abruptly discontinued after extended therapy, and whenever possible, should be tapered over several weeks to minimize discontinuation-related symptoms. SSRI-associated withdrawal symptoms are not typically referred to as a dependence syndrome. However, commentators have noted that such symptoms meet the definition of a physical and psychological dependence syndrome.{{Cite journal |last=Nielsen |first=Margrethe |last2=Hansen |first2=Ebba Holme |last3=Gøtzsche |first3=Peter C. |date=2012 |title=What is the difference between dependence and withdrawal reactions? A comparison of benzodiazepines and selective serotonin re-uptake inhibitors |url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1360-0443.2011.03686.x |journal=Addiction |language=en |volume=107 |issue=5 |pages=900–908 |doi=10.1111/j.1360-0443.2011.03686.x |issn=1360-0443}}

Paroxetine may produce discontinuation-related symptoms at a greater rate than other SSRIs, though qualitatively similar effects have been reported for all SSRIs.{{cite book |vauthors=Gelenberg AJ, Freeman MP, Markowitz JC, Rosenbaum JF, Thase ME, Trivedi MH |url=https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf |title=Practice Guideline for the Treatment of Patients With Major Depressive Disorder |date=October 2010 |publisher=American Psychiatric Association |isbn=978-0-89042-338-7 |edition=third |access-date=2018-07-22 |archive-date=2020-08-07 |archive-url=https://web.archive.org/web/20200807023035/https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf |url-status=live }}{{page needed|date=February 2019}}{{cite journal | vauthors = Renoir T | title = Selective serotonin reuptake inhibitor antidepressant treatment discontinuation syndrome: a review of the clinical evidence and the possible mechanisms involved | journal = Frontiers in Pharmacology | volume = 4 | pages = 45 | year = 2013 | pmid = 23596418 | pmc = 3627130 | doi = 10.3389/fphar.2013.00045 | doi-access = free }} Discontinuation effects appear to be less for fluoxetine, perhaps owing to its long half-life and the natural tapering effect associated with its slow clearance from the body. One strategy for minimizing SSRI discontinuation symptoms is to switch the patient to fluoxetine and then taper and discontinue the fluoxetine.

{{see also|Pharmacology of antidepressants}}

All SSRIs block the reuptake of serotonin through the serotonin transporter (SERT). This occurs in various anatomical sites, including the presynaptic terminals of serotonergic neurons in the central and peripheral nervous systems, enteric neurons and epithelial cells in the gastrointestinal tract, the pulmonary endothelium, and platelets.{{Citation |last=Beecher |first=Kate |title=Chapter 6 - Anatomy of the Serotonin Transporter |date=2019-01-01 |work=Serotonin |pages=121–133 |editor-last=Pilowsky |editor-first=Paul M |url=https://www.sciencedirect.com/science/article/abs/pii/B9780128000502000061 |access-date=2025-05-02 |place=Boston |publisher=Academic Press |isbn=978-0-12-800050-2 |last2=Belmer |first2=Arnauld |last3=Bartlett |first3=Selena E.}}{{Cite journal |last=Bertrand |first=Paul P. |last2=Bertrand |first2=Rebecca L. |date=2010-02-16 |title=Serotonin release and uptake in the gastrointestinal tract |url=https://www.sciencedirect.com/science/article/abs/pii/S1566070209004251 |journal=Autonomic Neuroscience |series=Visceral Afferents |volume=153 |issue=1 |pages=47–57 |doi=10.1016/j.autneu.2009.08.002 |issn=1566-0702}}

In the central nervous system, the majority of released serotonin is taken up by SERT. When this process is blocked it stays in the synaptic gap longer than it normally would, and may repeatedly stimulate the receptors of the postsynaptic cell. In the short run, this leads to an increase in signaling across synapses in which serotonin serves as the primary neurotransmitter. On chronic dosing, the increased occupancy of post-synaptic serotonin receptors signals the pre-synaptic neuron to synthesize and release less serotonin. Serotonin levels within the synapse drop, then rise again, ultimately leading to downregulation of post-synaptic serotonin receptors.{{cite book | vauthors = Goodman LS, Brunton LL, Chabner B, Knollmann BC | title = Goodman and Gilman's pharmacological basis of therapeutics | year = 2001 | publisher = McGraw-Hill | location = New York | isbn = 978-0-07-162442-8 | pages = 459–461 }} Other, indirect effects may include increased norepinephrine output, increased neuronal cyclic AMP levels, and increased levels of regulatory factors such as BDNF and CREB.Kolb, Bryan and Wishaw Ian. An Introduction to Brain and Behavior. New York: Worth Publishers 2006, Print. Owing to the lack of a widely accepted comprehensive theory of the biology of mood disorders, there is no widely accepted theory of how these changes lead to the mood-elevating and anti-anxiety effects of SSRIs.

Their effects on serotonin blood levels, which take weeks to take effect, appear to be largely responsible for their slow-to-appear psychiatric effects.{{cite journal | vauthors = O'Brien FE, O'Connor RM, Clarke G, Dinan TG, Griffin BT, Cryan JF | title = P-glycoprotein inhibition increases the brain distribution and antidepressant-like activity of escitalopram in rodents | journal = Neuropsychopharmacology | volume = 38 | issue = 11 | pages = 2209–2219 | date = October 2013 | pmid = 23670590 | pmc = 3773671 | doi = 10.1038/npp.2013.120 }}

SSRIs mediate their action largely with high occupancy in a total of all serotonin transporters within the brain and through this slow downstream changes of large brain regions at therapeutic concentrations, whereas MDMA leads to an excess serotonin release in a short run. This could explain the absence of a "high" by antidepressants and in addition the contrary ability of SSRIs in expressing neuroprotective actions to the neurotoxic abilities of MDMA.

There has to be this consideration that also antidepressants should work as central nervous "stimulants" (with this terminus being a right description rudimentary, yet "stimulating" meant in another way as psychostimulants in not providing or sustaining focus or attention due to increased monoamine-availability in the synaptic cleft but an increased released serotonin for controlling ones longterm emotionall conditioned state), in where due to their potent affinityhttps://www.cambridge.org/core/books/abs/physics-pharmacology-and-physiology-for-anaesthetists/affinity-efficacy-and-potency/69301BD1B8583E6905DE4B150AF21C22 which is depicting how strong the tendency of a molecule is speaking about binding to their prefferable receptor-bindingsite (in antidepressants mostly speaking about the targeted serotonin- and noradrenalintransportershttps://pubmed.ncbi.nlm.nih.gov/28847160/) which is in general rule considered remarkabely higher than in statistics for their respective "high-making" relatives (like methylphenidatehttps://pubmed.ncbi.nlm.nih.gov/8786705/), to occupate and inactivate receptortransporters such efficiantly to directly activate downstream-effects most prominently the downregulation of exacerbitable postsynaptic serotonin-5HT2A-and 1A receptorshttps://pmc.ncbi.nlm.nih.gov/articles/PMC3690146/#:~:text=Downregulation%20of%205%2DHT1A%20autoreceptors%20by%20SSRI%20treatment%20over,serotonin%20from%20the%20synaptic%20cleft. as direct effect to this chances as a longterm regulation (then outcalled as therapeutic adwished effect due to its promised mood-elevating habituation).{{cite journal | vauthors = Shadfar S, Kim YG, Katila N, Neupane S, Ojha U, Bhurtel S, Srivastav S, Jeong GS, Park PH, Hong JT, Choi DY | title = Neuroprotective Effects of Antidepressants via Upregulation of Neurotrophic Factors in the MPTP Model of Parkinson's Disease | journal = Molecular Neurobiology | volume = 55 | issue = 1 | pages = 554–566 | date = January 2018 | pmid = 27975170 | doi = 10.1007/s12035-016-0342-0 | s2cid = 3322646 }}

In addition to their actions as reuptake inhibitors of serotonin, some SSRIs are also, coincidentally, ligands of the sigma receptors. Fluvoxamine is an agonist of the σ₁ receptor, while sertraline is an antagonist of the σ₁ receptor, and paroxetine does not significantly interact with the σ₁ receptor. None of the SSRIs have significant affinity for the σ₂ receptor. Fluvoxamine has by far the strongest activity of the SSRIs at the σ₁ receptor. High occupancy of the σ₁ receptor by clinical dosages of fluvoxamine has been observed in the human brain in positron emission tomography (PET) research. It is thought that agonism of the σ₁ receptor by fluvoxamine may have beneficial effects on cognition. In contrast to fluvoxamine, the relevance of the σ₁ receptor in the actions of the other SSRIs is uncertain and questionable due to their very low affinity for the receptor relative to the SERT.{{cite journal | vauthors = Kishimoto A, Todani A, Miura J, Kitagaki T, Hashimoto K | title = The opposite effects of fluvoxamine and sertraline in the treatment of psychotic major depression: a case report | journal = Annals of General Psychiatry | volume = 9 | pages = 23 | date = May 2010 | pmid = 20492642 | pmc = 2881105 | doi = 10.1186/1744-859X-9-23 | doi-access = free }}

The role of inflammation and the immune system in depression has been extensively studied. The evidence supporting this link has been shown in numerous studies over the past ten years. Nationwide studies and meta-analyses of smaller cohort studies have uncovered a correlation between pre-existing inflammatory conditions such as type 1 diabetes, rheumatoid arthritis (RA), or hepatitis, and an increased risk of depression. Data also shows that using pro-inflammatory agents in the treatment of diseases like melanoma can lead to depression. Several meta-analytical studies have found increased levels of proinflammatory cytokines and chemokines in depressed patients.{{cite journal | vauthors = Bafna SL, Patel DJ, Mehta JD | title = Separation of ascorbic acid and 2-keto-L-gulonic acid | journal = Current Neuropharmacology| volume = 61 | issue = 8 | pages = 1333–1334 | date = August 1972 | pmc = 5050394 | doi = 10.2174/1570159X14666151208113700 | pmid = 27640518 }} This link has led scientists to investigate the effects of antidepressants on the immune system.

SSRIs were originally invented with the goal of increasing levels of available serotonin in the extracellular spaces. However, the delayed response between when patients first begin SSRI treatment to when they see effects has led scientists to believe that other molecules are involved in the efficacy of these drugs.{{cite journal | vauthors = Köhler S, Cierpinsky K, Kronenberg G, Adli M | title = The serotonergic system in the neurobiology of depression: Relevance for novel antidepressants | journal = Journal of Psychopharmacology | volume = 30 | issue = 1 | pages = 13–22 | date = January 2016 | pmid = 26464458 | doi = 10.1177/0269881115609072 | s2cid = 21501578 }} To investigate the apparent anti-inflammatory effects of SSRIs, both Kohler et al. and Więdłocha et al. conducted meta-analyses which have shown that after antidepressant treatment the levels of cytokines associated with inflammation are decreased.{{cite journal | vauthors = Köhler CA, Freitas TH, Stubbs B, Maes M, Solmi M, Veronese N, de Andrade NQ, Morris G, Fernandes BS, Brunoni AR, Herrmann N, Raison CL, Miller BJ, Lanctôt KL, Carvalho AF | title = Peripheral Alterations in Cytokine and Chemokine Levels After Antidepressant Drug Treatment for Major Depressive Disorder: Systematic Review and Meta-Analysis | journal = Molecular Neurobiology | volume = 55 | issue = 5 | pages = 4195–4206 | date = May 2018 | pmid = 28612257 | doi = 10.1007/s12035-017-0632-1 | s2cid = 4040496 | url = https://kclpure.kcl.ac.uk/portal/en/publications/peripheral-alterations-in-cytokine-and-chemokine-levels-after-antidepressant-drug-treatment-for-major-depressive-disorder(7fb3d49a-30e3-4cfd-9a1c-df003daf8dad).html | access-date = 2018-09-17 | archive-date = 2020-08-07 | archive-url = https://web.archive.org/web/20200807024106/https://kclpure.kcl.ac.uk/portal/en/publications/peripheral-alterations-in-cytokine-and-chemokine-levels-after-antidepressant-drug-treatment-for-major-depressive-disorder(7fb3d49a-30e3-4cfd-9a1c-df003daf8dad).html | url-status = live }}{{cite journal | vauthors = Więdłocha M, Marcinowicz P, Krupa R, Janoska-Jaździk M, Janus M, Dębowska W, Mosiołek A, Waszkiewicz N, Szulc A | title = Effect of antidepressant treatment on peripheral inflammation markers – A meta-analysis | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 80 | issue = Pt C | pages = 217–226 | date = January 2018 | pmid = 28445690 | doi = 10.1016/j.pnpbp.2017.04.026 | s2cid = 34659323 }} A large cohort study conducted by researchers in the Netherlands investigated the association between depressive disorders, symptoms, and antidepressants with inflammation. The study showed decreased levels of interleukin (IL)-6, a cytokine that has proinflammatory effects, in patients taking SSRIs compared to non-medicated patients.{{cite journal | vauthors = Vogelzangs N, Duivis HE, Beekman AT, Kluft C, Neuteboom J, Hoogendijk W, Smit JH, de Jonge P, Penninx BW | title = Association of depressive disorders, depression characteristics and antidepressant medication with inflammation | journal = Translational Psychiatry | volume = 2 | issue = 2 | pages = e79 | date = February 2012 | pmid = 22832816 | pmc = 3309556 | doi = 10.1038/tp.2012.8 }}

Treatment with SSRIs has shown reduced production of inflammatory cytokines such as IL-1β, tumor necrosis factor (TNF)-α, IL-6, and interferon (IFN)-γ, which leads to a decrease in inflammation levels and subsequently a decrease in the activation level of the immune response.{{cite journal | vauthors = Kalkman HO, Feuerbach D | title = Antidepressant therapies inhibit inflammation and microglial M1-polarization | journal = Pharmacology & Therapeutics | volume = 163 | pages = 82–93 | date = July 2016 | pmid = 27101921 | doi = 10.1016/j.pharmthera.2016.04.001 }} These inflammatory cytokines have been shown to activate microglia which are specialized macrophages that reside in the brain. Macrophages are a subset of immune cells responsible for host defense in the innate immune system. Macrophages can release cytokines and other chemicals to cause an inflammatory response. Peripheral inflammation can induce an inflammatory response in microglia and can cause neuroinflammation. SSRIs inhibit proinflammatory cytokine production which leads to less activation of microglia and peripheral macrophages. SSRIs not only inhibit the production of these proinflammatory cytokines, they also have been shown to upregulate anti-inflammatory cytokines such as IL-10. Taken together, this reduces the overall inflammatory immune response.{{cite journal | vauthors = Nazimek K, Strobel S, Bryniarski P, Kozlowski M, Filipczak-Bryniarska I, Bryniarski K | title = The role of macrophages in anti-inflammatory activity of antidepressant drugs | journal = Immunobiology | volume = 222 | issue = 6 | pages = 823–830 | date = June 2017 | pmid = 27453459 | doi = 10.1016/j.imbio.2016.07.001 }}

In addition to affecting cytokine production, there is evidence that treatment with SSRIs has effects on the proliferation and viability of immune system cells involved in both innate and adaptive immunity. Evidence shows that SSRIs can inhibit proliferation in T-cells, which are important cells for adaptive immunity and can induce inflammation. SSRIs can also induce apoptosis, programmed cell death, in T-cells. The full mechanism of action for the anti-inflammatory effects of SSRIs is not fully known. However, there is evidence for various pathways to have a hand in the mechanism. One such possible mechanism is the increased levels of cyclic adenosine monophosphate (cAMP) as a result of interference with activation of protein kinase A (PKA), a cAMP dependent protein. Other possible pathways include interference with calcium ion channels, or inducing cell death pathways like MAPK{{cite journal | vauthors = Gobin V, Van Steendam K, Denys D, Deforce D | title = Selective serotonin reuptake inhibitors as a novel class of immunosuppressants | journal = International Immunopharmacology | volume = 20 | issue = 1 | pages = 148–156 | date = May 2014 | pmid = 24613205 | doi = 10.1016/j.intimp.2014.02.030 | doi-access = free | hdl = 20.500.11755/f7f0ef07-e0db-45d2-a887-886bfd5de635 | hdl-access = free }} and Notch signaling pathway.{{cite journal | vauthors = Saha M, Rizzo SA, Ramanathan M, Hightower RM, Santostefano KE, Terada N, Finkel RS, Berg JS, Chahin N, Pacak CA, Wagner RE, Alexander MS, Draper I, Kang PB | title = Selective serotonin reuptake inhibitors ameliorate MEGF10 myopathy | journal = Human Molecular Genetics | volume = 28 | issue = 14 | pages = 2365–2377 | date = July 2019 | pmid = 31267131 | pmc = 6606856 | doi = 10.1093/hmg/ddz064 }}

The anti-inflammatory effects of SSRIs have prompted studies of the efficacy of SSRIs in the treatment of autoimmune diseases such as multiple sclerosis, RA, inflammatory bowel diseases, and septic shock. These studies have been performed in animal models but have shown consistent immune regulatory effects. Fluoxetine, an SSRI, has also shown efficacy in animal models of graft vs. host disease. SSRIs have also been used successfully as pain relievers in patients undergoing oncology treatment. The effectiveness of this has been hypothesized to be at least in part due to the anti-inflammatory effects of SSRIs.

{{Further|Pharmacogenetics}}

Large bodies of research are devoted to using genetic markers to predict whether patients will respond to SSRIs or have side effects that will cause their discontinuation, although these tests are not yet ready for widespread clinical use.{{cite journal |vauthors=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 = 350–357 | year = 2007 | pmid = 17096399 | doi = 10.1002/da.20251 | s2cid = 24257390 | doi-access = free }}

SSRIs are described as 'selective' 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 to be no significant difference in effectiveness between SSRIs and tricyclic antidepressants, which were the most commonly used class of antidepressants before the development of SSRIs.{{cite journal | vauthors = 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 | date = April 2000 | pmid = 10760555 | doi = 10.1016/S0165-0327(99)00092-0 }} However, SSRIs have the important advantage that their toxic dose is high, and, therefore, they are much more difficult to use as a means to commit suicide. Further, they have fewer and milder side effects. Tricyclic antidepressants also have a higher risk of serious cardiovascular side effects, which SSRIs lack.

SSRIs act on signal pathways such as cyclic adenosine monophosphate (cAMP) 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.

SSRIs vary in their pharmacokinetic properties.

File:Neurotransmitter transporters inhibitors.png transporter inhibitors}}]]

• Citalopram (Celexa)
• Escitalopram (Lexapro)
• Fluoxetine (Prozac)
• Fluvoxamine (Luvox)
• Paroxetine (Paxil)
• Sertraline (Zoloft)

{{hidden begin|toggle=left|title={{bg|#CEFFC1|Structures}}}}

{{hidden end}}

• Dapoxetine (Priligy)

{{hidden begin|toggle=left|title={{bg|#CEFFC1|Structures}}}}

{{hidden end}}

• Indalpine (Upstène)
• Zimelidine (Zelmid)

{{hidden begin|toggle=left|title={{bg|#CEFFC1|Structures}}}}

{{hidden end}}

• Alaproclate (GEA-654)
• Centpropazine
• Cericlamine (JO-1017)
• Femoxetine (Malexil; FG-4963)
• Ifoxetine (CGP-15210)
• Omiloxetine
• Panuramine (WY-26002)
• Pirandamine (AY-23713)
• Seproxetine ((S)-norfluoxetine)

{{hidden begin|toggle=left|title={{bg|#CEFFC1|Structures}}}}

{{hidden end}}

Although described as SNRIs, duloxetine (Cymbalta), venlafaxine (Effexor), and desvenlafaxine (Pristiq) are in fact relatively selective as serotonin reuptake inhibitors (SRIs).{{cite journal | vauthors = Shelton RC | year = 2009 | title = Serotonin norepinephrine reuptake inhibitors: similarities and differences | url = http://primarypsychiatry.com/serotonin-norepinephrine-reuptake-inhibitors-similarities-and-differences/ | journal = Primary Psychiatry | volume = 16 | issue = 4 | page = 25 | access-date = 2017-08-26 | archive-date = 2020-08-07 | archive-url = https://web.archive.org/web/20200807032433/http://primarypsychiatry.com/serotonin-norepinephrine-reuptake-inhibitors-similarities-and-differences/ | url-status = live }} They are about at least 10-fold selective for inhibition of serotonin reuptake over norepinephrine reuptake. The selectivity ratios are approximately 1:30 for venlafaxine, 1:10 for duloxetine, and 1:14 for desvenlafaxine.{{cite journal | vauthors = Montgomery SA | title = Tolerability of serotonin norepinephrine reuptake inhibitor antidepressants | journal = CNS Spectrums | volume = 13 | issue = 7 Suppl 11 | pages = 27–33 | date = July 2008 | pmid = 18622372 | doi = 10.1017/s1092852900028297 | s2cid = 24692832 }} At low doses, these SNRIs act mostly as SSRIs; only at higher doses do they also prominently inhibit norepinephrine reuptake.{{cite book | vauthors = Waller DG, Sampson T | title = Medical Pharmacology and Therapeutics E-Book|url=https://books.google.com/books?id=6b0tDwAAQBAJ&pg=PA302|year=2017|publisher=Elsevier Health Sciences|isbn=978-0-7020-7190-4|pages=302–}}{{cite book|vauthors=Kornstein SG, Clayton AH|title=Women's Mental Health, An Issue of Psychiatric Clinics – E-Book|url=https://books.google.com/books?id=5jpHNa19jFUC&pg=PA389|year=2010|publisher=Elsevier Health Sciences|isbn=978-1-4557-0061-5|pages=389–|access-date=2017-08-26|archive-date=2023-01-14|archive-url=https://web.archive.org/web/20230114060906/https://books.google.com/books?id=5jpHNa19jFUC&pg=PA389|url-status=live}} Milnacipran (Ixel, Savella) and its stereoisomer levomilnacipran (Fetzima) are the only widely marketed SNRIs that inhibit serotonin and norepinephrine to similar degrees, both with ratios close to 1:1.{{cite journal | vauthors = Bruno A, Morabito P, Spina E, Muscatello MR | title = The Role of Levomilnacipran in the Management of Major Depressive Disorder: A Comprehensive Review | journal = Current Neuropharmacology | volume = 14 | issue = 2 | pages = 191–199 | year = 2016 | pmid = 26572745 | pmc = 4825949 | doi = 10.2174/1570159x14666151117122458 }}

Vilazodone (Viibryd) and vortioxetine (Trintellix) are SRIs that also act as modulators of serotonin receptors and are described as serotonin modulators and stimulators (SMS).{{cite journal | vauthors = Mandrioli R, Protti M, Mercolini L | title = New-Generation, non-SSRI Antidepressants: Therapeutic Drug Monitoring and Pharmacological Interactions. Part 1: SNRIs, SMSs, SARIs | journal = Current Medicinal Chemistry| volume = 24| issue = 7| pages = 772–792| year = 2018 | pmid = 28707591 | doi = 10.2174/0929867324666170712165042 }} Vilazodone is a 5-HT_1A receptor partial agonist while vortioxetine is a 5-HT_1A receptor agonist and 5-HT₃ and 5-HT₇ receptor antagonist. Litoxetine (SL 81–0385) and lubazodone (YM-992, YM-35995) are similar drugs that were never marketed.{{cite book|vauthors=Ayd FJ|title=Lexicon of Psychiatry, Neurology, and the Neurosciences|url=https://books.google.com/books?id=ea_QVG2BFy8C&pg=PA581|year=2000|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-2468-5|pages=581–|access-date=2017-08-26|archive-date=2023-01-14|archive-url=https://web.archive.org/web/20230114060907/https://books.google.com/books?id=ea_QVG2BFy8C&pg=PA581|url-status=live}}{{cite book|title=Progress in Drug Research|url=https://books.google.com/books?id=-d8FCAAAQBAJ&pg=PA80|year=2012|publisher=Birkhäuser|isbn=978-3-0348-8391-7|pages=80–82}}{{cite journal | vauthors = Moltzen EK, Bang-Andersen B | title = Serotonin reuptake inhibitors: the corner stone in treatment of depression for half a century{{snd}}a medicinal chemistry survey | journal = Current Topics in Medicinal Chemistry| volume = 6 | issue = 17 | pages = 1801–1823 | year = 2006 | pmid = 17017959 | doi = 10.2174/156802606778249810}}{{cite journal |doi=10.1002/1099-1077(200008)15:6<471::AID-HUP211>3.0.CO;2-4 |title=Selective Serotonin Reuptake Inhibitors (SSRIs) Past, Present and Future. Edited by S. Clare Standford, R.G. Landes Company |location=Austin, Texas |year=1999|isbn=1-57059-649-2 |journal=Human Psychopharmacology: Clinical and Experimental |volume=15 |issue=6 |pages=471 | vauthors = Haddad PM }} They are SRIs and litoxetine is also a 5-HT₃ receptor antagonist while lubazodone is also a 5-HT_2A receptor antagonist.

{{See also|Development and discovery of SSRI drugs}}

Zimelidine was introduced in 1982 and was the first SSRI to be sold. Despite its efficacy, statistically significant increase in cases of Guillain–Barré syndrome among treated patients led to its withdrawal in 1983. Fluoxetine, introduced in 1987 is commonly thought the first SSRI to be marketed.

{{See also|Biopsychiatry controversy|Biological psychiatry}}

A study examining publication of results from FDA-evaluated antidepressants concluded that those with favorable results were much more likely to be published than those with negative results.{{cite journal |vauthors=Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R | title = Selective publication of antidepressant trials and its influence on apparent efficacy | journal = The New England Journal of Medicine | volume = 358 | issue = 3 | pages = 252–260 | date = January 2008 | pmid = 18199864 | doi = 10.1056/NEJMsa065779 | citeseerx = 10.1.1.486.455 }} Furthermore, an investigation of 185 meta-analyses on antidepressants found that 79% of them had authors affiliated in some way to pharmaceutical companies and that they were reluctant to report caveats for antidepressants.{{cite journal | vauthors = Ebrahim S, Bance S, Athale A, Malachowski C, Ioannidis JP | title = Meta-analyses with industry involvement are massively published and report no caveats for antidepressants | journal = Journal of Clinical Epidemiology | volume = 70 | pages = 155–163 | date = February 2016 | pmid = 26399904 | doi = 10.1016/j.jclinepi.2015.08.021 }}

David Healy has argued that warning signs were available for many years prior to regulatory authorities moving to put warnings on antidepressant labels that they might cause suicidal thoughts.{{cite journal | vauthors = Healy D, Aldred G | title = Antidepressant drug use & the risk of suicide | journal = International Review of Psychiatry | volume = 17 | issue = 3 | pages = 163–172 | date = June 2005 | pmid = 16194787 | doi = 10.1080/09540260500071624 | author-link = David Healy (psychiatrist) | citeseerx = 10.1.1.482.5522 | s2cid = 6599566 }} At the time these warnings were added, others argued that the evidence for harm remained unpersuasive{{cite journal | vauthors = Lapierre YD | title = Suicidality with selective serotonin reuptake inhibitors: Valid claim? | journal = Journal of Psychiatry & Neuroscience | volume = 28 | issue = 5 | pages = 340–347 | date = September 2003 | pmid = 14517577 | pmc = 193980 }}{{cite journal | vauthors = Khan A, Khan S, Kolts R, Brown WA | title = Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports | journal = The American Journal of Psychiatry | volume = 160 | issue = 4 | pages = 790–792 | date = April 2003 | pmid = 12668373 | doi = 10.1176/appi.ajp.160.4.790 | s2cid = 20755149 }} and others continued to do so after the warnings were added.{{cite journal | vauthors = Kaizar EE, Greenhouse JB, Seltman H, Kelleher K | title = Do antidepressants cause suicidality in children? A Bayesian meta-analysis | journal = Clinical Trials | volume = 3 | issue = 2 | pages = 73–90; discussion 91–8 | year = 2006 | pmid = 16773951 | doi = 10.1191/1740774506cn139oa | s2cid = 41954145 }}{{cite journal | vauthors = Gibbons RD, Brown CH, Hur K, Davis J, Mann JJ | title = Suicidal thoughts and behavior with antidepressant treatment: reanalysis of the randomized placebo-controlled studies of fluoxetine and venlafaxine | journal = Archives of General Psychiatry | volume = 69 | issue = 6 | pages = 580–587 | date = June 2012 | pmid = 22309973 | pmc = 3367101 | doi = 10.1001/archgenpsychiatry.2011.2048 }}

Fluoxetine was investigated as a potential environmental contaminant, but found to have 'limited accumulation' in comparison to other pharmaceutically active compounds.{{cite journal | vauthors = Christou A, Papadavid G, Dalias P, Fotopoulos V, Michael C, Bayona JM, Piña B, Fatta-Kassinos D | title = Ranking of crop plants according to their potential to uptake and accumulate contaminants of emerging concern | journal = Environmental Research | volume = 170 | pages = 422–432 | date = March 2019 | pmid = 30623890 | doi = 10.1016/j.envres.2018.12.048 | publisher = Elsevier BV | s2cid = 58564142 | bibcode = 2019ER....170..422C | hdl = 10261/202657 | hdl-access = free }}

An SSRI (fluoxetine) has been approved for veterinary use in treatment of canine separation anxiety.{{cite journal |last1=Fitzgerald |first1=Kevin T. |last2=Bronstein |first2=Alvin C. |date=February 2013 |title=Selective serotonin reuptake inhibitor exposure |journal=Topics in Companion Animal Medicine |volume=28 |issue=1 |pages=13–17 |doi=10.1053/j.tcam.2013.03.003 |issn=1946-9837 |pmid=23796482}} Like in human medicine, fluoxetine is extensively used off-label in animal medicine. In dogs and cats it is mainly prescribed off-label for behavior problems.{{cite journal |last1=Kaur |first1=G |last2=Voith |first2=VL |last3=Schmidt |first3=PL |title=The use of fluoxetine by veterinarians in dogs and cats: a preliminary survey. |journal=Veterinary Record Open |date=2016 |volume=3 |issue=1 |pages=e000146 |doi=10.1136/vetreco-2015-000146 |pmid=27110371|pmc=4838767 }}

• List of antidepressants
• Noradrenergic and specific serotonergic antidepressant
• Serotonin releasing agent (SRA)
• Serotonin–norepinephrine reuptake inhibitor (SNRI)
• Serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI)
• Dapoxetine

{{Reflist}}

• [http://www.webmd.com/depression/ssris-myths-and-facts-about-antidepressants#1/ WebMD – Selective Serotonin Reuptake Inhibitors]

{{Antidepressants}}

{{Anxiolytics}}

{{OCD pharmacotherapies}}

{{Monoamine reuptake inhibitors}}

{{Sigma receptor modulators}}

{{DEFAULTSORT:Selective Serotonin Reuptake Inhibitor}}

Category:Sigma receptor modulators

Category:Treatment of obsessive–compulsive disorder

Category:Treatment of depression