What are the potential side effects of Selective Serotonin Reuptake Inhibitors (SSRIs)?

SSRI Side Effects

Most Common Side Effects

SSRIs share a similar adverse effect profile, with gastrointestinal symptoms (nausea, diarrhea, constipation), neurological symptoms (headache, dizziness, somnolence), and sexual dysfunction being the most frequently reported, with nausea and vomiting being the leading causes of treatment discontinuation. 1

Gastrointestinal Effects

• Nausea, diarrhea, constipation, and heartburn typically emerge within the first few weeks of treatment 1, 2
• Nausea and vomiting are the most common reasons patients stop SSRI therapy 1
• Sertraline has a higher rate of diarrhea compared to other SSRIs 1
• Taking medication with food may help reduce gastrointestinal side effects 2
• Flatulence was reported by 64% of patients in naturalistic settings, highlighting that real-world rates exceed clinical trial data 3

Neurological and Cognitive Effects

• Headache, dizziness, somnolence, insomnia, and tremor are commonly reported 1
• Memory impairment (51%) and decreased concentration (50%) occur frequently in clinical practice 3
• Yawning (47%) and fatigue (45%) are common but often underreported in trials 3

Sexual Dysfunction

• Sexual adverse events (erectile dysfunction, delayed ejaculation, anorgasmia) occur in adolescents and adults but are likely underreported 1
• Paroxetine has higher rates of sexual dysfunction than other SSRIs 1
• Decreased libido is a significant long-term concern 1, 3

Weight and Metabolic Effects

• Weight gain (45%) and changes in appetite are common 1, 3
• Paroxetine and mirtazapine result in higher weight gain than sertraline or venlafaxine 1

Other Common Effects

• Dry mouth (45%), sweating (38%), and light-headedness (43%) are frequently reported 3
• Photosensitivity can occur; patients should use SPF 30+ sunscreen, wear protective clothing, and seek shade during peak UV hours 4

Serious Adverse Effects Requiring Close Monitoring

Suicidality (Black Box Warning)

• All SSRIs carry an FDA black box warning for increased suicidal thinking and behavior through age 24 1
• The absolute risk is 1% with antidepressants versus 0.2% with placebo (risk difference 0.7%, number needed to harm = 143) 1
• SSRIs increase the risk of nonfatal suicide attempts (odds ratio 1.57-2.25) 1
• Close monitoring is essential, especially during the first months of treatment and following dose adjustments 1

Behavioral Activation/Agitation

• Motor or mental restlessness, insomnia, impulsiveness, disinhibited behavior, and aggression can occur early in treatment or with dose increases 1
• More common in younger children than adolescents and in anxiety disorders versus depression 1
• Usually improves quickly after dose reduction or discontinuation 1
• Slow up-titration and close monitoring (particularly in younger children) are critical 1

Mania/Hypomania

• Rare but can occur, typically appearing later in treatment than behavioral activation 1
• May persist after SSRI discontinuation and require active pharmacological intervention 1

Serotonin Syndrome

• A potentially life-threatening condition that should be kept in mind when treating patients with SSRIs 1
• Risk increases when combined with other serotonergic medications 4

Bleeding Risk

• Increased risk of abnormal bleeding, especially with concomitant use of NSAIDs or aspirin 1, 4
• Upper gastrointestinal bleeding is a recognized concern 2
• Patients on warfarin require careful monitoring when starting or stopping SSRIs 5

Other Serious Effects

• Seizures: Use cautiously in patients with seizure history 1
• Hyponatremia: Rare but important to monitor 1
• Cardiovascular effects: Increases in blood pressure, pulse, or heart rate can occur 1
• Hepatotoxicity: Rare but documented 1

Neonatal and Pregnancy Considerations

Third Trimester Exposure

• Neonates exposed to SSRIs late in the third trimester may develop complications requiring prolonged hospitalization, respiratory support, and tube feeding 6, 5
• Clinical findings include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying 6, 5
• These features are consistent with either direct toxic effects or drug discontinuation syndrome 6, 5

Persistent Pulmonary Hypertension of the Newborn (PPHN)

• Infants exposed to SSRIs in pregnancy may have increased risk for PPHN 6, 5
• PPHN occurs in 1-2 per 1000 live births and is associated with substantial neonatal morbidity and mortality 6, 5

Discontinuation Syndrome Risk

• Paroxetine, fluvoxamine, and sertraline have higher risk of discontinuation syndrome 4

Drug-Specific Differences

Escitalopram

• May be better tolerated than sertraline with lower gastrointestinal side effects 2
• Fewer effects on CYP450 isoenzymes, contributing to lower drug interaction profile 2
• Higher incidence of headache, pruritus, memory impairment, decreased concentration, and dizziness compared to sertraline 3

Sertraline

• Higher rate of diarrhea than other SSRIs 1
• Significantly decreased appetite compared to escitalopram 3
• Starting with low doses (25-50 mg/day) reduces gastrointestinal side effects 2

Paroxetine

• Highest rates of sexual dysfunction among SSRIs 1
• Higher weight gain than sertraline 1
• Higher risk of discontinuation syndrome 4

Clinical Monitoring Recommendations

• Monitor gastrointestinal symptoms especially during the first 1-2 weeks of treatment 2
• Close monitoring for suicidality is required, particularly in the first months and after dose adjustments 1
• Educate patients and families in advance about behavioral activation, especially in younger children 1
• Assess for bleeding risk, particularly with concomitant NSAID or aspirin use 1, 4
• Most adverse effects emerge within the first few weeks of treatment 1