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%)
- SSRI do not cause inflammatory changes in the colon[26]
- 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 26.5 Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022 - ↑ 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+