What are the common side effects and contraindications of Selective Serotonin Reuptake Inhibitors (SSRIs)?

SSRI Side Effects and Contraindications

Common Side Effects

SSRIs are generally well-tolerated but produce a broad range of side effects that are more common and persistent in real-world practice than clinical trials suggest, with most emerging within the first few weeks of treatment. 1

Gastrointestinal and General Effects

• Nausea, diarrhea, dry mouth, and heartburn are among the most frequently reported gastrointestinal symptoms 1
• Sweating, tremors, and dizziness commonly occur across all SSRIs 1
• These effects typically emerge within the first 2 weeks but often persist throughout the first 3 months of treatment 2

Neuropsychiatric Effects

• Insomnia or somnolence (drowsiness) affects approximately 17% of patients and is rated as particularly bothersome 1, 2
• Headache, nervousness, vivid dreams, and fatigue are frequently reported 1
• Behavioral activation/agitation (motor restlessness, impulsiveness, disinhibited behavior, aggression) occurs more commonly in younger children than adolescents and typically emerges early in treatment or with dose increases 1

Sexual Dysfunction

• Sexual side effects (erectile dysfunction, delayed ejaculation, anorgasmia) occur in approximately 17% of patients and are among the most bothersome adverse effects 1, 2
• 83% of patients experiencing sexual dysfunction continue to have symptoms at 3 months, making this one of the most persistent side effects 2

Metabolic and Physical Effects

• Weight changes (gain or loss) and appetite changes are common 1
• Bruxism (teeth grinding) and tremor occur with regular frequency 1

Real-World vs. Clinical Trial Data

• 86% of patients report at least one side effect in real-world settings, with 55% experiencing bothersome side effects—rates significantly higher than clinical trial data suggest 2
• Physicians consistently underestimate both the frequency and severity of side effects, with only 40% of patients reporting their side effects to prescribers 2, 3

Serious Adverse Effects Requiring Monitoring

Suicidality (Black Box Warning)

• All SSRIs carry a black box warning for suicidal thinking and behavior through age 24 years 1
• Pooled absolute risk is 1% for antidepressant-treated youth vs. 0.2% for placebo (risk difference 0.7%, NNH = 143) 1
• Close monitoring is mandatory, especially during the first months of treatment and following dose adjustments 1

Serotonin Syndrome

• Life-threatening condition caused by elevated brain serotonin levels, typically when SSRIs are combined with other serotonergic medications 1
• Symptoms arise within 24-48 hours and include mental status changes (confusion, agitation), neuromuscular hyperactivity (tremors, clonus, hyperreflexia, muscle rigidity), and autonomic hyperactivity (hypertension, tachycardia, diaphoresis) 1
• Advanced symptoms include fever, seizures, arrhythmias, and unconsciousness leading to potential fatalities 1
• Treatment requires immediate hospitalization, discontinuation of all serotonergic agents, and supportive care with continuous cardiac monitoring 1

Mania/Hypomania

• Rare but serious, typically appearing later in treatment (beyond first month) rather than early like behavioral activation 1
• Unlike behavioral activation, mania may persist after SSRI discontinuation and require active pharmacological intervention 1

Bleeding Risk

• Abnormal bleeding can occur, especially with concomitant aspirin or NSAID use 1
• Rare bleeding events include ecchymosis, hematoma, epistaxis, petechiae, and hemorrhage 1
• Altered anticoagulant effects with warfarin require careful monitoring when initiating or discontinuing SSRIs 4

Seizures

• Seizures have been observed with SSRI use; use cautiously in patients with seizure disorder history 1

Hyponatremia

• More commonly reported in elderly patients 5

Other Rare but Serious Effects

• Galactorrhea and hyperprolactinemia can occur, though notably absent from major guideline discussions despite documented cases 6, 5
• Parkinsonism, confusion, hallucinations, and hypotension occur more frequently in elderly patients 5

Contraindications

Absolute Contraindications

• Concomitant use with monoamine oxidase inhibitors (MAOIs) due to risk of serotonin syndrome 1, 4
• Known hypersensitivity to the specific SSRI

Relative Contraindications and Cautions

• Seizure disorders: Use with extreme caution given observed seizure risk 1
• Concomitant use of other serotonergic medications: Significantly increases serotonin syndrome risk 1
• Bleeding disorders or concurrent anticoagulant/antiplatelet therapy: Requires careful monitoring 1, 4
• Bipolar disorder: Risk of precipitating mania/hypomania 1

Drug Interactions

Cytochrome P450 Inhibition

• SSRIs may prolong half-life of other drugs by inhibiting various cytochrome P450 isoenzymes 1
• Fluvoxamine requires particular caution with alprazolam or triazolam 1
• Sertraline has less effect on metabolism of other medications compared to other SSRIs 1

Specific Interactions

• Warfarin: Requires careful monitoring when SSRIs are initiated or discontinued 4
• Electroconvulsive therapy (ECT): Rare reports of prolonged seizures in patients on fluoxetine receiving ECT 4

Special Populations

Pregnancy and Lactation

• Pregnancy Category C: Use only if potential benefit justifies potential risk 7, 4
• Third-trimester exposure: Neonates may develop complications requiring prolonged hospitalization, including respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, hypoglycemia, and withdrawal symptoms 7, 4
• Persistent pulmonary hypertension of newborn (PPHN): Infants exposed to SSRIs in late pregnancy may have increased risk (6-fold higher in one study after 20 weeks gestation) 4
• Nursing: SSRIs are excreted in breast milk; nursing while on SSRIs is not recommended 4
• Discontinuation during pregnancy: Women who discontinue antidepressants during pregnancy show significantly increased relapse of major depression 7, 4

Pediatric Patients

• Behavioral activation/agitation is more common in younger children than adolescents 1
• Efficacy established for OCD in children ages 6-17, but safety and effectiveness for other indications in pediatric populations have not been established 7

Elderly Patients

• Parkinsonism, confusion, hallucinations, euphoria, hyponatremia, bradycardia, and hypotension occur more frequently 5

Clinical Pearls

• Most side effects emerge within the first 2 weeks but persist throughout the first 3 months, contrary to the common belief that they resolve quickly 2
• Only 40% of patients report side effects to their physicians, and physicians consistently underestimate both frequency and severity 2, 3
• Slow up-titration minimizes behavioral activation and helps avoid exceeding optimal dose 1
• Maximal therapeutic improvement typically occurs by week 12 or later, supporting gradual dose adjustments 1