Selective Serotonin Reuptake Inhibitors (SSRIs)
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SSRIs inhibit the reuptake of serotonin by serotonin transporters located on presynaptic neurons, resulting in increased synaptic availability of serotonin at postsynaptic receptors. Therefore, the therapeutic action is presumed to result from presynaptic and postsynaptic adaptive mechanisms secondary to reuptake inhibition, and it evolves over several weeks to months of treatment. The desensitization of 5-HT1A autoreceptors in the dorsal raphe nucleus is one potentially important mechanism. The drug agents in the SSRI class do differ in their degree of selectivity for binding to the serotonin transporter (escitalopram > citalopram > sertraline > fluvoxamine > paroxetine > fluoxetine) and their potency of serotonin reuptake inhibition (paroxetine > sertraline > escitalopram > fluoxetine > citalopram > fluvoxamine), but these factors have not been proven to lead to clinically relevant differences in efficacy.
SSRIs do not have a significant affinity for histaminergic, alpha-1 adrenergic, postsynaptic dopamine, GABA, or glutamate receptors nor do they inhibit monoamine oxidase (MAO). The receptor binding activity of SSRIs results in a more favorable safety and adverse event profile compared with first-generation antidepressants such as tricyclics and monoamine oxidase inhibitors. Paroxetine is the only SSRI with clinically relevant anticholinergic effects. These effects may be additive with other anticholinergic medications in any patient, but geriatric adults may be more susceptible to the anticholinergic effects of the drug than younger adults.
Dose Comparisons of SSRIs in the Treatment of Depression
a Longest elimination half-life of all SSRIs; active metabolite with the longest elimination half-life of any SSRI; b Immediate-release form requires twice-daily dosing with daily doses greater than 100 mg/day in adults and 50 mg/day in children; c S-enantiomer of citalopram
Gastrointestinal effects are the most common adverse events in patients receiving SSRI treatment. Nausea is the most common ADR with any SSRI during the first 2 weeks of therapy. It is most often transient and of mild to moderate intensity. Diarrhea, dry mouth, constipation, and vomiting are other common gastrointestinal ADRs. Pooled data from 15 studies comparing the risk of gastrointestinal effects of SSRIs indicated that sertraline had a higher incidence of diarrhea than citalopram, fluoxetine, fluvoxamine, or paroxetine. Administration with food may offset some adverse GI effects, such as nausea.
Sexual dysfunction is commonly reported with the use of serotonergic agents such as SSRIs and may result in treatment discontinuation in some patients. In men, these symptoms may include ejaculatory failure or delay, decreased libido, and/or erectile dysfunction. Women may experience decreased libido and delayed or absent orgasm. Clinicians should discuss sexual function with patients prior to initiating treatment and throughout treatment to identify any changes in sexual function and determine if they are medication-related or attributed to the underlying psychiatric disorder. Patients should also be provided with management strategies and treatment options for symptoms of sexual dysfunction.
Monitor patients taking an SSRI for signs and symptoms of bleeding. Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage). In published observational studies, pregnant patients taking SSRIs, particularly in the month prior to obstetric delivery, were at an increased risk of postpartum hemorrhage. Concurrent use of aspirin, NSAIDs, anticoagulant therapy, thrombolytic therapy, or other medications that enhance bleeding potential may increase the risk of these bleeding complications. Patients should be instructed to promptly report any bleeding events to their health care provider.
Severe dermatologic and hypersensitivity reactions, including anaphylactoid reactions, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported rarely. Manifestations of DRESS typically include pyrexia, rash, facial swelling, and/or lymph node involvement in conjunction with other organ system abnormalities including hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis. Early manifestations of DRESS such as pyrexia and lymph node involvement may be present without evidence of a rash.
SSRIs may cause hyponatremia as a result of the syndrome of inappropriate antidiuretic hormone secretion; serum sodium levels less than 110 mmol/L have been reported. Elderly patients, those receiving diuretics or prone to becoming dehydrated, and those who are otherwise volume-depleted (e.g., hypovolemia) appear to be at greatest risk. The syndrome is reversible upon discontinuation of the causative SSRI.
SSRIs appear to interfere with bone formation and have been associated with an increased incidence of osteoporotic fractures, although a causal relationship has not been proven.
SSRIs, with the exception of paroxetine, have been associated with a modest but statistically significant increase in the QTc interval. The product labels of SSRIs have varying recommendations regarding use in patients with long QT syndrome, risk factors for QT prolongation, and coadministration with other drugs that cause QT prolongation. The product label for citalopram contains the strongest warnings due to cases of torsade de pointes (TdP), ventricular tachycardia, and sudden death occurring with the drug. In addition, the initially approved maximum recommended dose of citalopram was reduced to address the dose-related risk of QT prolongation and TdP. In an analysis of ECGs obtained in 682 patients treated with paroxetine and 415 patients treated with placebo in controlled clinical trials, no clinically significant changes were seen in the ECGs of either group. The manufacturer of fluoxetine recommends caution in patients with risk factors for QT interval prolongation due to postmarketing reports of QT interval prolongation and ventricular arrhythmia including TdP. The majority of available evidence indicates that at therapeutic doses, and in the absence of risk factors, the use of fluvoxamine is not a significant risk factor for the development of QT prolongation; however, there have been postmarketing reports of QT prolongation and TdP and the manufacturer recommends avoiding fluvoxamine in patients with long QT syndrome. Because cases of QT prolongation and TdP have been reported with escitalopram and sertraline, the manufacturers recommend avoiding use with other medications known to prolong the QTc interval. Sertraline is often an SSRI of choice given a fairly large amount of data involving use in depressed patients with comorbid cardiac risk factors (e.g., recent myocardial infarction, unstable angina, chronic heart failure).
After birth, symptoms consistent with a discontinuation syndrome (i.e., poor feeding, hypoglycemia, hypothermia, lethargy or irritability, vomiting, etc.) have been reported in infants exposed to SSRIs in utero, particularly during the third trimester. When treating a pregnant woman with an SSRI during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. If clinically feasible, and taking the drug half-life into consideration, tapering of the serotonergic agent prior to delivery may be considered as an alternative. 
SSRIs are contraindicated in patients receiving MAO inhibitors or within 2 weeks of their discontinuation. Medications with MAOI activity, such as linezolid or intravenous methylene blue, are also contraindicated for use with SSRIs because of an increased risk of serotonin syndrome.
Any use of an SSRI with other serotonergic agents increases the likelihood of serotonergic adverse effects and should be monitored closely. Drugs that have serotonergic properties include opiates, triptans, most antidepressants, amphetamines, St. John's wort, tramadol, lithium, buspirone, and others.
Anticoagulants, antiplatelet drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), and aspirin should be administered with caution to any patient taking an SSRI, especially in the elderly. Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
SSRIs, with the exception of paroxetine, have been associated with a modest but statistically significant increase in the QTc interval. The product labels of these SSRIs have varying recommendations regarding coadministration with other drugs that cause QT prolongation. Because citalopram has been associated with QT interval prolongation, torsade de pointes (TdP), and sudden death, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. If concurrent therapy is considered essential, ECG monitoring is recommended. Additionally, if patients are also receiving a CYP2C19 inhibitor, the maximum recommended daily dose of citalopram is 20 mg due to the risk of QT interval prolongation. The manufacturers of sertraline and escitalopram recommend avoiding coadministration with other drugs that prolong the QT interval. Practitioners should review the potential for drug interactions prior to prescribing concurrent therapies, taking into account risk versus benefit for the individual patient. Pimozide and thioridazine, two antipsychotics with a well-established risk of QT prolongation and TdP, are contraindicated for use with SSRIs due to an increased risk of QT prolongation and TdP, which may be precipitated by SSRI-induced CYP inhibition and/or additive QT-prolonging effects.
All SSRIs are metabolized by CYP450 enzymes to some extent. Although SSRIs do not have a narrow therapeutic index (NTI), dosage adjustments are recommended during concurrent use of citalopram, a CYP2C19 substrate, and inhibitors of CYP2C19 due to dose-dependent QT prolongation which can occur with citalopram. Other important interactions occur with SSRIs that are potent inhibitors of CYP isoenzymes, including fluoxetine, paroxetine, and fluvoxamine. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, which can cause elevations in plasma concentrations of CYP2D6 substrates. Fluvoxamine is a potent inhibitor of CYP1A2 and CYP2C19; clinically significant interactions may occur with drugs such as warfarin. Although sertraline is a less potent inhibitor of CYP2D6 than fluoxetine or paroxetine, it may be necessary to reduce the dosage of concomitantly administered drugs metabolized by CYP2D6. Because escitalopram has less inhibitory effects on CYP2D6 than paroxetine or fluoxetine, clinically significant drug interactions with CYP2D6 substrates are not as likely to occur. Because escitalopram is metabolized by multiple isoenzymes, inhibition of a single enzyme may not significantly elevate escitalopram concentrations.
The approved labeling for all antidepressants carries a boxed warning of an increased risk of suicidal thoughts and behavior in children and young adults, particularly during the first few months of therapy. Experts state that the apparent increase in suicidality reflected by a greater number of spontaneously reported events is mitigated by the lack of any completed suicides, the decline in overall suicidality on rating scales, and the greater number of patients who benefit from antidepressants than who experience these serious adverse effects. Careful assessment and monitoring of suicidality are warranted in all patients initiating treatment with an SSRI.
SSRIs, with the exception of paroxetine, have been associated with a modest but statistically significant increase in the QTc interval. The product labels of these SSRIs have varying recommendations regarding use in patients with long QT syndrome, risk factors for QT prolongation, and coadministration with other drugs that cause QT prolongation. The product label for citalopram contains the strongest warnings due to cases of torsade de pointes (TdP), ventricular tachycardia, and sudden death occurring with the drug. However, if citalopram therapy is considered essential in patients with risk factors for QT prolongation, baseline and periodic ECG monitoring is recommended. The manufacturer of fluoxetine recommends caution in patients with risk factors for QT interval prolongation due to reports of QT interval prolongation and TdP. The majority of available evidence indicates that at therapeutic doses, and in the absence of risk factors, the use of fluvoxamine is not a significant risk factor for the development of QT prolongation; however, there have been postmarketing reports of QT prolongation and TdP and the manufacturer recommends avoiding fluvoxamine in patients with long QT syndrome. Because cases of QT prolongation and TdP have been reported with escitalopram and sertraline, the manufacturers recommend avoiding use with other medications known to prolong the QTc interval.
The use of antidepressants has been associated with the precipitation of mania or hypomania in susceptible individuals. If a patient develops manic symptoms, the antidepressant should be withheld, and appropriate therapy initiated to treat the manic symptoms. Depression may also be the presenting symptom of a mixed/manic episode of bipolar disorder. Patients should be adequately screened for bipolar disorder prior to initiating an antidepressant. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
Small concentrations of SSRIs have been measured in breast milk; there are no data on the effects of SSRIs on milk production. Benefits of breast-feeding need to be weighed against potential risk of infant drug exposure. There are reports of agitation, irritability, poor feeding, and poor weight gain in infants exposed to fluoxetine through breast milk; this agent has a longer half-life than the other SSRIs and a breastfed child should be monitored for these potential side effects. A pooled analysis found that maternal use of sertraline and paroxetine usually produced undetectable or low drug concentrations in infant serum and, therefore, may be preferred SSRIs during lactation.
A discontinuation syndrome is possible when any SSRI is abruptly discontinued. The most commonly reported discontinuation symptoms include fatigue, abdominal pain, nausea, dizziness/light-headedness, tremor, chill, diaphoresis, and incoordination. Other reported symptoms include impaired memory, insomnia, shock sensations, ringing in the ears, dysphoric mood, irritability, anxiety, confusion, lethargy, emotional lability, hypomania, headaches, and agitation or aggression. In general, these symptoms are more frequent with SSRIs having a shorter half-life (e.g., paroxetine) than a long half-life (e.g., fluoxetine). The discontinuation symptoms usually begin 1 to 3 days after abrupt discontinuation of the SSRI and subside within 1 to 2 weeks, although a delay in the onset of these symptoms may be observed with fluoxetine due to the long half-life of the drug and its active metabolite. A slow, individualized taper is advisable for any SSRI, particularly after chronic use, to minimize discontinuation symptoms.
Kulin NA, Pastuszak A, Sage SR, et al. Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors. JAMA 1998;279:609-10.
Paxil (paroxetine) tablet package insert. Weston, FL: Apotex Corp.; 2023 Aug.
Celexa (citalopram) tablets package insert. Madison, NJ: Allergan USA, Inc.; 2023 Aug.
Lexapro (escitalopram) package insert. North Chicago, IL: Abbvie, Inc.; 2023 Aug.
Zoloft (sertraline) package insert. Morgantown, WV: Viatris Specialty LLC; 2023 Aug.
Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006;354:579-87.
Prozac (fluoxetine) capsules package insert. Indianapolis, IN: Eli Lilly and Company; 2023 Aug.
Verdel BM, Souverein PC, Egberts TC, et al. Use of antidepressant drugs and risk of osteoporotic and non-osteoporotic fractures. Bone. 2010;47(5):604-9.
Howland RH. Potential adverse effects of discontinuing psychotropic drugs. J Psychosoc Nurs Ment Health Serv 2010;48:11-4.
Pexeva (paroxetine mesylate) package insert. Roswell, GA: Sebela Pharmaceuticals, Inc. 2023 Aug.
Paxil CR (paroxetine) tablets package insert. Weston, FL: Apotex Corp.; 2023 Aug.
Prozac Weekly (fluoxetine hydrochloride delayed-release capsules) package insert. Indianapolis, IN: Lilly USA, LLC; 2017 Mar.
Sarafem (fluoxetine hydrochloride) package insert. Madison, NJ: Allergan USA, Inc; 2021 Sept.
Weissman AM, Levy BT, Hartz AJ, et al. Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants. Am J Psychiatry 2004;161:1066-78.
American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin Number 92: Use of Psychiatric Medications During Pregnancy and Lactation. Obstet Gynecol 2008;105:1001-1020. Reaffirmed 2019.
Wichman CL, Morre KM, Lang TR, et al. Congenital heart disease associated with selective serotonin reuptake inhibitor use during pregnancy. Mayo Clin Proc 2009;84:23-7.
Andrade SE, McPhillips H, Loren D, et al. Antidepressant medication use and risk of persistent pulmonary hypertension of the newborn. Pharmacoepidemiol Drug Safety 2009;18:246-52.
Wilson KL, Zelig CM, Harvey JP, et al. Persistent pulmonary hypertension of the newborn is associated with mode of delivery and not with maternal use of selective serotonin reuptake inhibitors. Am J Perinatol 2011;28:19-24.
Fluvoxamine tablets package insert. Baudette, MN: ANI Pharmaceuticals, Inc.; 2023 Aug.
Birmaher B, Brent D, and the AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry. 2007;46:1503-1526.
Practice Guideline for the treatment of patients with major depressive disorder, 3rd Edition. American Psychiatric Association Press. November 2010.
Luvox CR (fluvoxamine maleate extended-release capsules) package insert. Palo Alto, CA: Jazz Pharmaceuticals, Inc.; 2017 Jan.
Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 2009;373(9665):746-758.
Gartlehner G, Hansen RA, Morgan LC, Thaler K, Lux LJ, Van NM, Mager U, Gaynes BN, Thieda P, Strobelberger M, Lloyd S, Reichenpfader U, Lohr KN. Second-generation antidepressants in the pharmacologic treatment of adult depression: an update of the 2007 Comparative Effectiveness Review. Rockville, MD: Agency for Healthcare Research and Quality (US); December, 2011.
Koen N, Stein DJ. Pharmacotherapy of anxiety disorders: a critical review. Dialogues Clin Neurosci 2011;13:423-437.
Warner CH, Bobo W, Warner C, Reid S, Rachal J. Antidepressant discontinuation syndrome. Am Fam Physician 2006;74:449-456.
Reinhold JA, Mandos LA, Rickels K, et al. Pharmacological treatment of generalized anxiety disorder. Expert Opin Pharmacother 2011;12:2457-67.
Baldessarini RJ. Drugs in the Treatment of Psychiatric Disorders: Depression and Anxiety Disorders. In: Hardman JG and Limbird LE, ed. The Pharmacological Basis of Therapeutics 10th International ed. McGraw Hill; 2001:447-484.
Celada P, Puig M, Amargos-Bosch M, et al. The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. J Psychiatry Neurosci 2004;29(4):252-265.
Levkovitz Y, Tedeschini E, Papakostas GI. Efficacy of antidepressants for dysthymia: a meta-analysis of placebo-controlled randomized trials. J Clin Psychiatry 2011;72(4):509-514.
Spina E, Trifiro G, Caraci F. Clinically significant drug interactions with newer antidepressants. CNS Drugs 2012;26(1):39-67.
Pedersen LH, Henriksen TB, Vestergaard M, et al. Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study. BMJ 2009;339:b3569.
Connolly SD, Bernstein GA. Practice parameter for the assessment and treatment of children and adolescents with anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2007;46(2):267-283.
Brisdelle (paroxetine) capsules package insert. Roswell, GA: Sebela Pharmaceuticals, Inc.; 2023 Aug.
Hughes CW, Emslie GJ, Crismon ML. Texas Children's Medication Algorithm Project: update from Texas Consensus Conference Panel on Medication Treatment of Childhood Major Depressive Disorder. J Am Acad Child Adolesc Psychiatry 2007;46:667-686.
Gelenberg AJ, Freeman MP, Mardowitz JC, Rosenbaum JF, Thase ME, Trivedi MH, Van Rhoads RS. Practice guideline for the treatment of patients with major depressive disorder, 3rd ed. Arlington, VA: American Psychiatry Association; 2010 Oct: 1-152. Available at: http://psychiatryonline.org/content.aspx?bookid=28§ionid=1667485. Accessed: Aug 8, 2014.
Lam RW, Kennedy SH, Grigoriadis S, McIntyre RS, Milev R, Ramasubbu R, Parikh SV, Patten SB, Ravindran AV. Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. III. Pharmacotherapy. J Affect Dis 2009;117:S26-S43.
Guideline Development Panel for the Treatment of PTSD in Adults, American Psychological Association. Clinical practice guideline for the treatment of posttraumatic stress disorder (PTSD) in adults. Adopted by the APA in 2017. Am Psychol. 2019;74:596-607.
CredibleMeds. QT drug lists. Available on the World Wide Web at http://www.crediblemeds.org.
Fortinguerra F, Clavenna A, Bonati M. Psychotropic drug use during breastfeeding: a review of the evidence. Pediatrics 2009;124:547-56.
Payne JL. Psychopharmacology in Pregnancy and Breastfeeding. Med Clin North Am. 2019;10:629-650. Review.
Cheung AH, Zuckerbrot RA, Jensen PS, et al. Guidelines for adolescent depression in primary care (GLAD-PC): Part II. Treatment and ongoing management. Pediatrics 2018;141:e20174082.
Food and Drug Administration Adverse Event Reporting System. Potential signals of serious risks/new safety information identified from the FDA adverse event reporting system (FAERS): July - September 2017. Available on the worldwide web at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm592379.htm
The American Geriatrics Society 2019 Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2019;00:1-21.
Nevels RM, Gontkovsky ST, Williams BE. Paroxetine-The Antidepressant from Hell? Probably Not, But Caution Required. Psychopharmacol Bull. 2016;46:77-104. Review.
Beach SR, Kostis WJ, Celano CM, et al. Meta-analysis of selective serotonin reuptake inhibitor-associated QTc prolongation. J Clin Psychiatry 2014;75:e441-e449.
Glassman AH, O'Connor CM, Califf RM, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002;288:701-709.
Beach SR, Celano CM, Sugrue AM, et al. QT prolongation, torsades de pointes, and psychotropic medications: a 5-year update. Psychosomatics 2018;59:105-122.
Wilson E, Lader M. A review of the management of antidepressant discontinuation symptoms. Ther Adv Psychopharmacol 2015;5:357-68.
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