What are the potential side effects of Selective Serotonin Reuptake Inhibitor (SSRI) medications?

Side Effects of SSRI Medications

SSRIs are generally well tolerated, but side effects are common—occurring in approximately 86% of patients—with most emerging within the first few weeks of treatment and many persisting throughout therapy, requiring close monitoring especially for serious adverse effects including suicidal thinking, serotonin syndrome, and sexual dysfunction. 1, 2

Common Side Effects (First Few Weeks)

Most adverse effects emerge within the first few weeks of treatment and include: 1

• Gastrointestinal effects: Nausea, diarrhea, heartburn, dry mouth 1, 3
• Neurological symptoms: Headache, dizziness, tremor, somnolence, insomnia 1
• Other common effects: Vivid dreams, changes in appetite, weight changes (loss or gain), fatigue, nervousness, bruxism, diaphoresis 1

Critical clinical point: While physicians often underestimate side effect frequency, patient-reported data shows 55% experience bothersome side effects, with most persisting beyond initial weeks rather than resolving as commonly assumed. 2

Serious Adverse Effects Requiring Immediate Attention

Suicidal Thinking and Behavior

• All SSRIs carry a black box warning for suicidal thinking and behavior through age 24 years 1
• Pooled absolute risk: 1% for antidepressant-treated youth versus 0.2% for placebo (risk difference 0.7%, NNH = 143) 1
• Close monitoring is mandatory during the first months of treatment and following any dose adjustments 1, 4
• Paroxetine specifically has been associated with increased risk compared to other SSRIs 4

Serotonin Syndrome (Life-Threatening)

Serotonin syndrome can arise within 24-48 hours after combining serotonergic medications or dose increases, characterized by: 1, 3

• Mental status changes: Confusion, agitation, anxiety 1
• Neuromuscular hyperactivity: Tremors, clonus, hyperreflexia, muscle rigidity 1
• Autonomic hyperactivity: Hypertension, tachycardia, arrhythmias, tachypnea, diaphoresis, shivering, vomiting, diarrhea 1
• Advanced symptoms: Fever, seizures, arrhythmias, unconsciousness leading to death 1
• Treatment requires immediate hospitalization, discontinuation of all serotonergic agents, and continuous cardiac monitoring 1, 4

Behavioral Activation/Agitation

• Occurs early in treatment (first month) or with dose increases, more common in younger children than adolescents 1
• Manifests as motor/mental restlessness, insomnia, impulsiveness, talkativeness, disinhibited behavior, aggression 1
• Supports slow up-titration and close monitoring, particularly in younger children 1, 4
• Usually improves quickly after dose decrease or discontinuation 1

Mania/Hypomania

• Rare but serious, typically appearing later in treatment (beyond first month) 1
• Difficult to distinguish from behavioral activation but persists after SSRI discontinuation and requires active pharmacological intervention 1

Persistent Side Effects During Long-Term Treatment

Sexual Dysfunction

• Occurs in approximately 17% of patients and is one of the most bothersome side effects 2, 5
• Includes erectile dysfunction, delayed ejaculation, anorgasmia in adolescents and adults 1, 6
• 83% of patients still experiencing sexual dysfunction at 3 months continue to have symptoms 2

Weight and Metabolic Changes

• Weight gain reported as a common bothersome side effect in 17% of patients 5
• Changes in appetite can lead to either weight loss or gain 1

Sleep Disturbances

• Drowsiness/somnolence affects 17% as a bothersome side effect 2, 5
• Insomnia can also occur, particularly with behavioral activation 1

Other Serious Adverse Effects

Abnormal Bleeding

• Increased risk especially with concomitant aspirin or NSAID use 1
• Rare bleeding events include ecchymosis, hematoma, epistaxis, petechiae, hemorrhage 1
• Altered anticoagulant effects with warfarin require careful monitoring 7

Seizures

• SSRIs should be used cautiously in patients with seizure disorder history 1
• Rare reports of prolonged seizures, particularly with fluoxetine during ECT 7

Discontinuation Syndrome

• Paroxetine and sertraline are most strongly associated with discontinuation syndrome 4, 3
• Symptoms include dizziness, fatigue, headaches, nausea, vomiting, diarrhea, insomnia, anxiety, irritability 3
• Brief taper rather than abrupt cessation minimizes withdrawal symptoms 3

Special Population Considerations

Pregnancy and Neonatal Effects

• Neonates exposed late in third trimester develop complications requiring prolonged hospitalization, respiratory support, and tube feeding 8, 7
• Clinical findings include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, hypoglycemia, tremor, jitteriness, irritability 8, 7
• Increased risk for persistent pulmonary hypertension of the newborn (PPHN), occurring in 1-2 per 1000 live births with substantial morbidity and mortality 8, 7

Pediatric Patients

• Most side effects emerge within first few weeks, with maximal improvement by week 12 or later supporting gradual dose adjustments 1, 4
• Parents, guardians, and patients must be educated in advance about potential side effects, particularly behavioral activation 1, 4

Critical Drug Interactions

• Monoamine oxidase inhibitors (MAOIs) are absolutely contraindicated due to serotonin syndrome risk 4
• Other serotonergic drugs requiring extreme caution: SNRIs, tricyclic antidepressants, atypical antidepressants, opioids, stimulants, dextromethorphan, illicit drugs 4

Clinical Management Pitfalls

• Physicians significantly underestimate side effect occurrence and severity—only 40% of patients report side effects to prescribers despite 86% experiencing them 2, 5
• Most side effects persist rather than resolve—85% still have blurred vision and 83% still have sexual dysfunction at 3 months 2
• Higher doses are associated with more adverse effects, not fewer 3
• A full therapeutic trial requires 8-12 weeks at target dose before determining efficacy; do not switch medications prematurely 6