selective serotonin reuptake inhibitor (SSRI)
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Indications
* No major differences in response among SSRIs or SSRIs & atypical antidepressants. Switching for lack of response not indicated[5][14]
# modestly better than placebo for treating depression, OCD, anxiety in children & adolescents[34]
Contraindications
- children, adolescents[10] (caution)
- NO benefit for coronary artery disease (non-indication)[15]
- little evidence of benefit in infertile women[21]
Dosage
- major depression optimal dose[30]
- sertraline 120 mg QD
- fluvoxamine 100 mg QD
- paroxetine 20 mg QD
- fluoxetine 20 mg QD
- citalopram 33.3 mg QD
- escitalopram 16.7 mg QD
- little benefit of high doses, some evidence of harm[36]
Adverse effects
- serotonin syndrome
- GI bleeding* (< 2%)
- SIADH & hyponatremia[6]
- may inhibit growth hormone secretion & thus growth in children[7]
- in utero effects[9][12]
- lower Apgar scores at birth
- delayed fine motor development
- common, but seldom serious[12]
- not associated with stillbirth or infant mortality[22]
- increased risk of autism in offspring of pregnant women using SSRI
- relative risk < 1.61[23]; 2.17[31]
- exposure to SSRI in late pregnancy (>= 20 weeks of gestation) increases risk of pulmonary hypertension in newborns (RR = 2.5)[24]
- increased, but rare congenital anomalies associated with SSRI use in 1st trimester[28]
- increased likelihood of newborn admission to the NICU[33]
- discontinuation of SSRI during pregnancy associated with depression relapse, prematurity, & postpartum depression that may negatively affect a child's development[33]
- may be associated with bone loss[16]
- may increase risk of fracture in perimenopausal women[29]
- exacerbation of parkinsonism[17]
- REM sleep behavioral disorder[26]
- may trigger manic attack in bipolar affective disorder, especially when not combined with lithium carbonate
- increase in stroke risk in post-menopausal women, largely due to an increase in hemorrhagic stroke (consistent with SSRI's antiplatelet effects) (hazzard ratio 1.45)[18]
- increased risk of intracranial hemorrhage in the general population[20] (1 additional case of hemorrhagic stroke per 10,000 patients/year)
- increased risk of mortality when SSRI initiated after stroke[27]
- sexual dysfunction, orgasm disorder
- commonly associated with decreased libido & erectile dysfunction[19]
- substitute with or add bupropion[38]
- higher SSRI doses may be associated with self-harm in children & young adults[25]
- no association is adults > 60 years of age[26]
- increased risk for violence & aggressive behavior?[35]
- withdrawal may occur if abruptly discontinued
- especially with paroxetine, my result in delirium[19]
- increased risk of falls in the elderly 36-39% in first year[37]
* diminished serotonin in platelets due to diminished uptake[3][4][8][13]
* patients with anxiety disorder should be counseled on potential of adverse effects & when they do occur are likely to be benign & shortlived, often a manifestation of the underlying disorder[26]
- drug adverse effects of SSRIs
- drug adverse effects of antidepressants
- drug adverse effects of psychotropic agents
Drug interactions
- tramadol, trazodone, dextromethorphan, or linezolid in combination may increase risk of serotonin syndrome[32]
- triptans in combination probably do not increase risk of serotonin syndrome, although caution & vigilence is recommended[32]
- drug interaction(s) of oral anticoagulants with selective serotonin reuptake inhibitor (SSRI)
- drug interaction(s) of antidepressant in combination with GLP1-agonist
- drug interaction(s) of ondanstetron with SSRIs
- drug interaction(s) of dextromethorphan with SSRIs
- drug interaction(s) of trazodone with SSRIs
- drug interaction(s) of tramadol with SSRIs
- drug interaction(s) of triptans with SSRIs
- drug interaction(s) of anti-platelet agents with SSRIs
- drug interaction(s) of methylene blue with SSRIs
- drug interaction(s) of linezolid with SSRIs
- drug interaction(s) of statins with SSRIs
- drug interaction(s) of hypericum perforatum (Sr John's wort) with SSRI
- drug interaction(s) of tamoxifen with SSRI
- drug interaction(s) of benzodiazepines with antidepressants
- drug interaction(s) of antidepressants with benzodiazepines
- drug interaction(s) of NSAIDs with SSRIs
- drug interaction(s) of NSAIDs with antidepressants
- drug interaction(s) of antidepressant with opiates
- drug interaction(s) of coxib with SSRI
Laboratory
Mechanism of action
- SSRI inhibit the serotonin transporter, thus the reuptake of serotonin by serotoninergic neurons
- inhibition of serotonin uptake by platelets can impair platelet aggregation -> may decrease risk of myocardial infarction[4]
- results in a sudden increase in serotonin, predominantly in the somatodendritic area (not axon terminals)
- serotonin interacts with somatodendritic 5HT1A autoreceptors resulting in decreased serotonin release
- with chronic use, somatodendritic autoreceptors desensitize resulting in an increase in serotonin release from axon terminals (2 weeks)
- with increased release of serotonin & continued reuptake block, eventual desensitization of post synaptic receptors occurs
Complications
More general terms
More specific terms
- citalopram (Celexa, nitalapram)
- fluoxetine (Prozac, Sarafem)
- fluvoxamine (Luvox)
- paroxetine (Paxil, Pexeva, Seroxat, Brisdelle)
- sertraline (Zoloft)
- sibutramine (Meridia, Reductil)
- vilazodone (Viibryd)
- zimelidine (Zimeldine, Normud, Zelmid)
Additional terms
- Na+-dependent serotonin transporter; 5HT transporter; 5HTT; solute carrier family 6 member 4 (SLC6A4, HTT, SERT)
- serotonin & norepinephrine reuptake inhibitor (SNRI, dual-acting reuptake inhibitor)
- serotonin syndrome (serotonism)
- serotonin [5HT] receptor
- serotonin [5HT]-1A receptor; 5-hydroxytryptamine receptor 1A; 5-HT-1A; 5-HT1A; serotonin receptor 1A; G-21 (HTR1A, ADRB2RL1, ADRBRL1)
- serotonin; 5-hydroxytryptamine
References
- ↑ Taylor MJ, Freemantle N, Geddes JR, Bhagwagar Z. Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis. Arch Gen Psychiatry. 2006 Nov;63(11):1217-23. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17088502
- ↑ UCLA Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
- ↑ 3.0 3.1 Journal Watch 21(22):179, 2001 van Walraven C et al Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study. BMJ 323:655, 2001 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11566827
- ↑ 4.0 4.1 4.2 Prescriber's Letter 8(11):62 2001 Sauer WH et al Selective serotonin reuptake inhibitors and myocardial infarction. Circulation 104:1894, 2001 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11602490
- ↑ 5.0 5.1 Journal Watch 22(3):20, 2002 Kroenke et al, Similar effectiveness of paroxetine, fluoxetine, and sertraline in primary care: a randomized trial. JAMA 286:2947, 2001 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11743835 Stimon G. Choosing a first-line antidepressant: equal on average does not mean equal for everyone. JAMA 286:3003, 2001 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11743843
- ↑ 6.0 6.1 Prescriber's Letter 9(7):38 2002
- ↑ 7.0 7.1 Journal Watch 22(16):127, 2002 Weintrob N et al Decreased growth during therapy with selective serotonin reuptake inhibitors. Arch Pediatr Adolesc Med 156:696, 2002 PMID: https://www.ncbi.nlm.nih.gov/pubmed/12090838
- ↑ 8.0 8.1 Prescriber's Letter 10(3):14 2003
- ↑ 9.0 9.1 Journal Watch 23(13):106, 2003 Casper RC et al, Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy. J Pediatr 142:402, 2003 PMID: https://www.ncbi.nlm.nih.gov/pubmed/12712058
- ↑ 10.0 10.1 10.2 Journal Watch 24(11):85, 2004 Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet. 2004 Apr 24;363(9418):1341-5. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15110490 Jureidini JN, Doecke CJ, Mansfield PR, Haby MM, Menkes DB, Tonkin AL. Efficacy and safety of antidepressants for children and adolescents. BMJ. 2004 Apr 10;328(7444):879-83. Review. No abstract available. Erratum in: BMJ. 2004 May 15;328(7449):1170. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/15073072 <Internet> http://bmj.bmjjournals.com/cgi/content/full/328/7444/879
- ↑ 11.0 11.1 Journal Watch 25(8):65, 2005 Martinez C, Rietbrock S, Wise L, Ashby D, Chick J, Moseley J, Evans S, Gunnell D. Antidepressant treatment and the risk of fatal and non-fatal self harm in first episode depression: nested case-control study. BMJ. 2005 Feb 19;330(7488):389. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/15718538 <Internet> http://bmj.bmjjournals.com/cgi/content/full/330/7488/389
Gunnell D, Saperia J, Ashby D. 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. BMJ. 2005 Feb 19;330(7488):385. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/15718537 <Internet> http://bmj.bmjjournals.com/cgi/content/full/330/7488/385
Fergusson D, Doucette S, Glass KC, Shapiro S, Healy D, Hebert P, Hutton B. Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials. BMJ. 2005 Feb 19;330(7488):396. Review. Erratum in: BMJ. 2005 Mar 19;330(7492):653. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/15718539 <Internet> http://bmj.bmjjournals.com/cgi/content/full/330/7488/396
Cipriani A, Barbui C, Geddes JR. Suicide, depression, and antidepressants. BMJ. 2005 Feb 19;330(7488):373-4. No abstract available. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15718515 - ↑ 12.0 12.1 12.2 Journal Watch 25(12):97, 2005 Moses-Kolko EL, Bogen D, Perel J, Bregar A, Uhl K, Levin B, Wisner KL. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA. 2005 May 18;293(19):2372-83. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15900008
- ↑ 13.0 13.1 Prescriber's Letter 12(7): 2005 Selective Serotonin Reuptake Inhibitors (SSRIs) and Antiplatelet Activity Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=210715&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 14.0 14.1 Hansen RA, Gartlehner G, Lohr KN, Gaynes BN, Carey TS. Efficacy and safety of second-generation antidepressants in the treatment of major depressive disorder. Ann Intern Med. 2005 Sep 20;143(6):415-26. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16172440
- ↑ 15.0 15.1 Lespoerance F et al, Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: The Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial. JAMA 2007, 297:367 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17244833
Glassman AH and Bigger JT Antidepressants in coronary artery disease: SSRI reduce depression, but do they save lives? JAMA 2007, 297:411 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17244839 - ↑ 16.0 16.1 Diem SJ et al, Use of Antidepressants and Rates of Hip Bone Loss in Older Women - The Study of Osteoporotic Fractures Arch Intern Med. 2007;167:1240-1245.
Haney EM et al, Association of Low Bone Mineral Density With Selective Serotonin Reuptake Inhibitor Use by Older Men Arch Intern Med. 2007;167:1246-1251 - ↑ 17.0 17.1 Gonul AS and Aksu M SSRI-induced parkinsonism may be an early sign of future Parkinson's disease. J Clin Psychiatry 1999, 60:410 PMID: https://www.ncbi.nlm.nih.gov/pubmed/10401924
Anonymous Extrpyramidal effects of SSRI antidepressants Prescrire 2001, 10:118 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11718183
Vajda FJ and Solinas C Current approaches to management of depression in Parkinson's disease. J Clin Neurosci 2005, 12:739 PMID: https://www.ncbi.nlm.nih.gov/pubmed/15911816 - ↑ 18.0 18.1 Smoller JW et al Antidepressant Use and Risk of Incident Cardiovascular Morbidity and Mortality Among Postmenopausal Women in the Women's Health Initiative Study Arch Intern Med. 2009;169(22):2128-2139. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/20008698 <Internet> http://archinte.ama-assn.org/cgi/content/short/169/22/2128
- ↑ 19.0 19.1 19.2 Medical Knowledge Self Assessment Program (MKSAP) 15, 19 American College of Physicians, Philadelphia 2009, 2021
- ↑ 20.0 20.1 Hackam DG et al Selective serotonin reuptake inhibitors and brain hemorrhage A meta-analysis Neurology. October 17, 2012 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23077009 <Internet> http://www.neurology.org/content/early/2012/10/17/WNL.0b013e318271f848.abstract
McGrath ER and O'Donnell MJ. Estimating treatment effects in observational studies. Neurology 2012 Oct 30; 79:1844. PMID: https://www.ncbi.nlm.nih.gov/pubmed/23077011 - ↑ 21.0 21.1 Domar AD et al The risks of selective serotonin reuptake inhibitor use in infertile women: a review of the impact on fertility, pregnancy, neonatal health and beyond. Hum. Reprod. Oct 31, 2012 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23117129 <Internet> http://humrep.oxfordjournals.org/content/early/2012/10/31/humrep.des383.abstract
- ↑ 22.0 22.1 Stephansson O et al Selective serotonin reuptake inhibitors during pregnancy and risk of stillbirth and infant mortality. JAMA. 2013 Jan 2;309(1):48-54 PMID: https://www.ncbi.nlm.nih.gov/pubmed/23280224
- ↑ 23.0 23.1 Hviid A et al. Use of selective serotonin reuptake inhibitors during pregnancy and risk of autism. N Engl J Med 2013 Dec 19; 369:2406 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24350950 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1301449
- ↑ 24.0 24.1 Grigoriadis S et al Prenatal exposure to antidepressants and persistent pulmonary hypertension of the newborn: systematic review and meta-analysis. BMJ 2014;348:f6932 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24429387 <Internet> http://www.bmj.com/content/348/bmj.f6932
- ↑ 25.0 25.1 Roy-Byrne P Higher SSRI Doses Linked to Greater Risk for Self-Harm in Youth. NEJM Journal Watch. May 5, 2014 Massachusetts Medical Society (subscription needed) http://www.jwatch.org
Miller M et al. Antidepressant dose, age, and the risk of deliberate self-harm. JAMA Intern Med 2014 Apr 28 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24782035 <Internet> http://archinte.jamanetwork.com/article.aspx?articleid=1863925
Brent DA and Gibbons R. Initial dose of antidepressant and suicidal behavior in youth: Start low, go slow. JAMA Intern Med 2014 Apr 28 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24781493 <Internet> http://archinte.jamanetwork.com/article.aspx?articleid=1863917 - ↑ 26.0 26.1 26.2 26.3 26.4 Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
- ↑ 27.0 27.1 Ayerbe L et al. Explanatory factors for the increased mortality of stroke patients with depression. Neurology 2014 Nov 25; 83:2007. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25355829 <Internet> http://www.neurology.org/content/83/22/2007
Bartoli F and Paolucci S. Association of depression and SSRIs with mortality after stroke. Neurology 2014 Nov 25; 83:1998. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25355834 <Internet> http://www.neurology.org/content/83/22/1998 - ↑ 28.0 28.1 Furu K et al. Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects: Population based cohort study and sibling design. BMJ 2015 Apr 17; 350:h1798 PMID: https://www.ncbi.nlm.nih.gov/pubmed/25888213
- ↑ 29.0 29.1 Sheu YH et al. SSRI use and risk of fractures among perimenopausal women without mental disorders. Inj Prev 2015 Jun 25 PMID: https://www.ncbi.nlm.nih.gov/pubmed/26113668
- ↑ 30.0 30.1 Jakubovski E et al. Systematic review and meta-analysis: Dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder. Am J Psychiatry 2015 Nov 10; <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/26552940 <Internet> http://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2015.15030331
- ↑ 31.0 31.1 Boukhris T et al Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children. JAMA Pediatr. Published online December 14, 2015 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/26660917 <Internet> http://archpedi.jamanetwork.com/article.aspx?articleid=2476187
King BH Assessing Risk of Autism Spectrum Disorder in Children After Antidepressant Use During Pregnancy. JAMA Pediatr. Published online December 14, 2015 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/26660503 <Internet> http://archpedi.jamanetwork.com/article.aspx?articleid=2476185 - ↑ 32.0 32.1 32.2 Paauw DS Dangerous and Deadly Drug Combinations Medscape. June 30, 2016 http://www.medscape.com/features/slideshow/dangerous-drug-combinations
- ↑ 33.0 33.1 33.2 Norby U, Forsberg L, Wide K et al. Neonatal morbidity after maternal use of antidepressant drugs during pregnancy. Pediatrics 2016 Oct 25; <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/27940758 <Internet> http://pediatrics.aappublications.org/content/early/2016/10/21/peds.2016-0181
- ↑ 34.0 34.1 Locher C, Koechlin H, Zion SR et al Efficacy and Safety of Selective Serotonin Reuptake Inhibitors, Serotonin-Norepinephrine Reuptake Inhibitors, and Placebo for Common Psychiatric Disorders Among Children and Adolescents. A Systematic Review and Meta-analysis. JAMA Psychiatry. Published online August 30, 2017. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28854296 <Internet> http://jamanetwork.com/journals/jamapsychiatry/fullarticle/2652447
Merry SN, Hetrick SE, Stasiak K. Effectiveness and Safety of Antidepressants for Children and Adolescents. Implications for Clinical Practice. JAMA Psychiatry. Published online August 30, 2017. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28854300 <Internet> http://jamanetwork.com/journals/jamapsychiatry/fullarticle/2652446 - ↑ 35.0 35.1 Knoll JL, Pies RW. The SSRI-Violence Link: Myth or Menace? Medscape - Aug 20, 2020. https://www.medscape.com/viewarticle/935846
- ↑ 36.0 36.1 Braun C et al. In search of a dose-response relationship in SSRIs-a systematic review, meta-analysis, and network meta-analysis. Acta Psychiatr Scand 2020 Sep 24; [e-pub] PMID: https://www.ncbi.nlm.nih.gov/pubmed/32970827 https://onlinelibrary.wiley.com/doi/10.1111/acps.13235
- ↑ 37.0 37.1 Haddad YK, Kakara R, Marcum ZA. A comparative analysis of selective serotonin reuptake inhibitors and fall risk in older adults. J Am Geriatr Soc. February 8, 2022. PMID: https://www.ncbi.nlm.nih.gov/pubmed/35132611
- ↑ 38.0 38.1 NEJM Knowledge+