[NOTE: This article has been posted prior to peer review for use in an active research program. This content will be updated with a peer reviewed version as soon as it is available.]
Hypersensitivity
Some patients may exhibit an allergic reaction to selective serotonin reuptake inhibitors (SSRIs), including rash, hives, angioedema, and anaphylaxis.1-7 Manufacturers advise that patients with a known history of hypersensitivity to SSRIs or any of their inactive ingredients should avoid the use of SSRIs. Hypersensitivity to SSRIs has only been reported in case studies, so the exact incidence is difficult to estimate. In manufacturer clinical trials comprised of thousands of people, there were no reported cases.
Suicidal Ideation
Manufacturer prescribing information warns that large placebo-controlled trials of antidepressant drugs (n of about 77,000) including SSRIs have found that treatment can increase the incidence of suicidal thoughts and behaviors in younger patients.1-7 The estimated incidence among those less than 18 years of age was 14 additional patients per 1,000 patients treated, and for those 18-24 years of age was 5 additional patients per 1,000 patients treated. Among those 25 years or older, use of antidepressant medication decreased the incidence of suicidal thoughts and behaviors. It is unknown whether this risk extends to long-term use as these trials were limited to four months in duration.
Manufacturers recommend that all patients treated with any antidepressant be monitored for worsening of clinical signs and symptoms, including suicidal thoughts and behaviors, especially in the first few months of drug therapy and at times of dose changes.1-7 They further advise that family members and caregivers should be alert to these signs and symptoms and consult the patient’s physician if they notice concerning changes.
Serotonin Syndrome
SSRIs have been shown to precipitate serotonin syndrome, a potentially life-threatening condition that occurs when serotonin levels are excessively high in the body.1-7 Signs and symptoms include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
The risk of serotonin syndrome is increased by concomitant use of serotonergic drugs such as triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort.1-7 Concomitant use of drugs that impair metabolism of serotonin (namely monoamine oxidase inhibitors [MAOIs]) can also increase the risk of serotonin syndrome.
A retrospective cohort study using Veterans Health Administration records from 2008-2012 and commercially insured patient records from 2010-2013 examined the incidence of serotonin syndrome.8 Among those taking one non-MAOI serotonergic medication, the incidence of serotonin syndrome was 1.28 per 1,000 person-years, and for those taking two non-MAOI medications, the incidence was 2.43 per 1,000 (Relative Risk [RR] 1.97, p<0.001). For those taking an MAOI and serotonergic drug in combination, the incidence was 5.22 per 1,000 person-years (RR 3.37, p<0.001).
A 2023 retrospective cohort study of 1,978 overdoses that included SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) found that of the SSRI overdoses (n=1,388), 173 cases led to serotonin toxicity (12.5%). SNRI overdoses (n=590) led to 96 cases of serotonin toxicity (16.3%). The probability of serotonin toxicity increased with increased dose (Odds Ratio [OR] 1.01, 95% CI [0.93-1.10]) and markedly increased with co-ingestion of an MAOI (OR 33.12, 95% CI [7.5-147]). Co-ingestion of an MAOI increased the probability of serotonin toxicity from 12.7% to 83%.9
Bleeding
Drugs that affect serotonin reuptake such as SSRIs increase the risk of bleeding events including ecchymosis, hematoma, epistaxis, petechiae, and hemorrhage.1-7 Concomitant use of SSRIs with other medications known to increase the risk of bleeding (e.g., aspirin, nonsteroidal anti-inflammatory drugs [NSAIDs], antiplatelet drugs, warfarin, anticoagulants) can accentuate this risk.
One analysis of 317,824 elderly patients taking antidepressants between 1992-1998 ranked medications as having high, intermediate, or low levels of serotonin reuptake inhibition based on the magnitude of their effect on serotonin transporter.10 The overall incidence of gastrointestinal bleeding was higher among those in the high serotonin reuptake inhibition group (7.9 events per 1,000 person years for high group vs 6.6 events for low group). Among those also taking NSAIDs, incidence jumped from 5.8 to 16.7 events per 1,000 person years for those in the low group and from 7.0 to 19.3 events for those in the high group. Incidence was similarly higher for those taking anticoagulants (6.3 vs 17.3 in low group, 7.6 vs 14.9 in high group).
Another analysis of data from England’s Drug Safety Research Unit’s prescription event monitoring database from 1986-1998 examined any abnormal bleeding event among the first six months of medication use (n=355,014).11 Bleeding events were more common among those taking SSRIs (1.94%) and other psychiatric drugs (2.00%) compared to non-central nervous system drugs (1.81%), however the difference was marginal. The study also didn’t control for concomitant use of other medications, pre-existing conditions, or other potential confounding factors.
Hyponatremia
Very rarely, SSRIs can precipitate hyponatremia.1-7 Signs and symptoms include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe cases of hyponatremia include hallucination, syncope, seizure, coma, respiratory arrest, and death. Severe cases have been associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Patients who are volume depleted or taking diuretics may be at higher risk of developing hyponatremia when taking SSRIs.
A retrospective cohort study using data from the French National Pharmacovigilance Database and French National Health Insurance from 2011-2013 (n=3,749,800) found that among patients taking SSRIs or SNRIs, there were 169 cases of hyponatremia with an incidence rate of 1.64 per 100,000 person years.12
QT Prolongation
SSRIs can cause dose-dependent abnormalities in the QT interval, a cardiography measurement that estimates the time from the cardiac ventricles starting to contract to when they’re finished relaxing for each heartbeat.1-7 Symptoms of cardiac arrhythmias that patients could experience due to QT prolongation include dizziness, palpitations, or syncope. Manufacturers advise that if patients experience any of these signs or symptoms, they should receive physician evaluation and cardiac monitoring.
There are no controlled trials about the effect of SSRIs of QT interval and the associated risks those changes may entail, and retrospective studies and case reports are unable to control for confounding variables, making exact risks impossible to estimate. However, QT abnormalities may be associated serious cardiovascular events such as Torsade de Pointes, ventricular tachycardia, and sudden death.1-7 Because of this, manufacturers recommend that patients with certain conditions avoid the use of SSRIs unless the benefits outweigh the risks for a particular patient. Conditions include congenital long QT syndrome, bradycardia, hypokalemia, hypomagnesemia, recent acute myocardial infarction, and uncompensated heart failure. If a patient with any of these conditions be treated with an SSRI, manufacturers recommend periodic electrocardiogram (ECG) monitoring.
Manufacturers further recommend that SSRIs be avoided in patients who are taking other drugs that prolong the QT interval, such as class 1A antiarrhythmics (e.g., quinidine, procainamide), class III antiarrhythmics (e.g., amiodarone, sotalol), antipsychotics (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medication known to prolong QT interval (e.g., pentamidine, levomethadyl acetate, methadone).1-7 If patients coadminister SSRIs with any of these medications, manufacturers recommend periodic ECG monitoring.
Patients with hypokalemia or hypomagnesemia may have an increased risk of QT prolongation and arrhythmia, so manufacturers recommend that patients at higher risk of electrolyte imbalances undergo periodic monitoring.1-7
Mania
SSRIs may precipitate mania in patients with bipolar disorder being treated for a depressive episode.1-7 Manufacture clinical trials found that mania or hypomania were reported in 0.1% of patients treated with SSRIs.
A study investigated the risk of switches in mood polarity into hypomania and mania during acute (10-week) and continuation trials (up to 1 year) of antidepressant therapy (bupropion, sertraline, or venlafaxine) in bipolar depressive patients (n=159). During acute treatment trials, 11.6% of patients experienced threshold switches to full-duration hypomania, and 9.3% experienced switches to mania. During continuation treatment, these rates increased to 21.8% for hypomania and 14.9% for mania.13
Angle-Closure Glaucoma
In patients with anatomically narrow angles in their eyes may be susceptible to angle closure attack glaucoma when taking SSRIs.1-7 Antidepressant drugs including SSRIs can cause pupillary dilation, which can cause narrow angles to be closed off, blocking the proper drainage of fluid in the eyes and leading to increased pressures. Manufacturers advise against the use of SSRIs in those with untreated anatomically narrow angles.
Angle-closure glaucoma in association with SSRI use has only been reported in case studies, so the exact incidence is difficult to estimate. In manufacturer clinical trials comprised of thousands of people, there were no reported cases.1-7
Seizures
Patients with seizure disorders were excluded from drug trials, so any effect of SSRIs on these types of pre-existing conditions is unknown.1-7 Therefore, manufacturers advise using caution when prescribing SSRIs to those with seizure disorders.
Manufacturer clinical trials for citalopram found that seizures were reported in 0.3% of patients receiving treatment (one patient per 98 years of exposure) compared to 0.5% of patients receiving placebo (one patient per 50 years of exposure).1 Manufacturer clinical trials for fluoxetine found that seizures were reported in 0.1% of patients receiving treatment and 0.2% of patients receiving placebo.3
A study of 151,005 depressed patients found 619 had seizures. The incidence rates per 10,000 person-years were 12.44 (95% CI [10.67-14.21]) for SSRI users, 15.44 (95% CI [8.99-21.89]) for SNRI users, and 8.33 (95% CI [4.68-11.98]) for TCA users. In a comparison of patients that took SSRIs in the past (n=662) to patients currently taking SSRIs (n=872), 15.9% reported having seizures in the first group compared to 27.9% in the current user group. Use of SSRIs was associated with significantly increased odds of seizures compared with non-use (adjusted OR 1.98, 95% CI [1.48-2.66]). Among single antidepressants, use of citalopram (adjusted OR 1.69, 95% CI [1.25–2.28]), sertraline (adjusted OR 2.53, 95% [CI 1.49–4.30]) and fluoxetine (adjusted OR 1.51, 95% CI [1.06–2.16]) was associated with significantly increased odds of seizures compared with non-use14
References
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- Lexapro [package insert]. Chicago, IL: AbbVie Inc.; 2023.
- Prozac [package insert]. Indianapolis, IN: Lilly USA; 2023.
- Fluvocamine Maleate [package insert]. Baudette, MN: ANI Pharmaceuticals; 2023.
- Paxil CR [package insert]. Weston, FL: Apotex Corp; 2023.
- Paxil [package insert]. Weston, FL: Apotex Corp; 2024.
- Zoloft [package insert]. Morgantown, WV: Viatris Specialty; 2023.
- Nguyen CT, Xie L, Alley S, McCarron RM, Baser O, Wang Z. Epidemiology and Economic Burden of Serotonin Syndrome With Concomitant Use of Serotonergic Agents: A Retrospective Study Utilizing Two Large US Claims Databases. Prim Care Companion CNS Disord. Dec 28 2017;19(6)doi:10.4088/PCC.17m02200
- Cooper J, Duffull SB, Isbister GK. Predicting serotonin toxicity in serotonin reuptake inhibitor overdose. Clin Toxicol (Phila). Jan 2023;61(1):22-28. doi:10.1080/15563650.2022.2151455
- van Walraven C, Mamdani MM, Wells PS, Williams JI. Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study. BMJ (Clinical research ed). Sep 22 2001;323(7314):655-8. doi:10.1136/bmj.323.7314.655
- Layton D, Clark DW, Pearce GL, Shakir SA. Is there an association between selective serotonin reuptake inhibitors and risk of abnormal bleeding? Results from a cohort study based on prescription event monitoring in England. Eur J Clin Pharmacol. May 2001;57(2):167-76. doi:10.1007/s002280100263
- Revol R, Rault C, Polard E, Bellet F, Guy C. [Hyponatremia associated with SSRI/NRSI: Descriptive and comparative epidemiological study of the incidence rates of the notified cases from the data of the French National Pharmacovigilance Database and the French National Health Insurance]. Encephale. Jun 2018;44(3):291-296. Les hyponatrémies sous ISRS/IRSNA : étude épidémiologique descriptive et comparative des taux d’incidence de cas notifiés à partir des données de la Banque nationale de pharmacovigilance et de l’Assurance maladie. doi:10.1016/j.encep.2017.09.003
- Leverich GS, Altshuler LL, Frye MA, et al. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry. Feb 2006;163(2):232-9. doi:10.1176/appi.ajp.163.2.232
- Bloechliger M, Ceschi A, Rüegg S, et al. Risk of Seizures Associated with Antidepressant Use in Patients with Depressive Disorder: Follow-up Study with a Nested Case–Control Analysis Using the Clinical Practice Research Datalink. Drug Safety. 2016/04/01 2016;39(4):307-321. doi:10.1007/s40264-015-0363-z
