What are the common and serious side effects of selective serotonin reuptake inhibitors (SSRIs) and serotonin‑norepinephrine reuptake inhibitors (SNRIs)?

Side Effects of SSRIs and SNRIs

SSRIs and SNRIs are generally well tolerated, but clinicians must monitor for common gastrointestinal and neuropsychiatric effects in the first weeks, while remaining vigilant for serious adverse events including suicidality (especially in patients under 25 years), serotonin syndrome, sexual dysfunction, and bleeding complications throughout treatment. 1

Common Side Effects (First Few Weeks)

Gastrointestinal and General Symptoms

• Nausea is the most frequent adverse event (occurring in approximately 26% of patients), followed by dry mouth, diarrhea, heartburn, headache, and changes in appetite 1, 2
• Weight changes (loss or gain), fatigue, dizziness, vivid dreams, tremor, bruxism, and diaphoresis commonly emerge within the first weeks of treatment 1
• Somnolence or insomnia may occur, with some SSRIs (particularly sertraline at low doses and fluvoxamine at any dose) requiring twice-daily dosing to manage side effects 1

SNRI-Specific Common Effects

• SNRIs produce more noradrenergic adverse effects than SSRIs, including higher rates of dry mouth, sweating, and constipation due to norepinephrine reuptake inhibition 3
• Venlafaxine causes dose-dependent blood pressure elevation at true SNRI doses, which is less frequent with duloxetine and rare with milnacipran 3

Serious Adverse Events Requiring Close Monitoring

Suicidality (Black Box Warning)

• All SSRIs and SNRIs carry an FDA black box warning for suicidal thinking and behavior through age 24 years 1
• The pooled absolute risk is 1% for antidepressant-treated youth versus 0.2% for placebo (risk difference 0.7%, number needed to harm = 143) 1
• Close monitoring is mandatory during the first months of treatment and following any dosage adjustments, particularly in patients under 25 years 1
• The risk is protective in adults 65 years and older (OR 0.06) 1

Behavioral Activation/Agitation

• Motor or mental restlessness, insomnia, impulsiveness, talkativeness, disinhibited behavior, and aggression occur more commonly in younger children than adolescents and in anxiety disorders compared to depressive disorders 1
• This typically emerges early in treatment (first month), with dose increases, or when SSRIs are combined with drugs that inhibit their metabolism 1
• Slow up-titration and close monitoring are essential, particularly in younger children, with advance education of parents/guardians about this potential effect 1
• Behavioral activation usually improves quickly after dose reduction or discontinuation 1

Mania/Hypomania

• Rare reports of mania/hypomania can be difficult to distinguish from behavioral activation 1
• Mania typically appears later in treatment (beyond the first month) and persists after SSRI discontinuation, requiring active pharmacological intervention rather than simple dose reduction 1

Serotonin Syndrome

• Serotonin syndrome is a potentially life-threatening condition characterized by mental status changes (agitation, confusion), autonomic hyperactivity (fever, tachycardia, tachypnea, diaphoresis, mydriasis), and neuromuscular abnormalities (tremor, clonus, hyperreflexia, hypertonia) 1
• While single SSRI treatment may cause mild to moderate serotonin syndrome, severe cases typically occur when two or more serotonergic drugs are combined 1
• High-risk combinations include SSRIs with other antidepressants (particularly SNRIs with ROR 25.42), MAO inhibitors, tramadol, fentanyl (ROR 41.95), trazodone, triptans, dextromethorphan, and St. John's Wort 4, 5, 6
• Among SSRIs, fluvoxamine has the highest risk (ROR 2.66 compared to other SSRIs), while sertraline and fluoxetine have the most reported cases 6
• Immediate discontinuation of all serotonergic agents is mandatory if serotonin syndrome is suspected, with hospital-based supportive care including benzodiazepines and consideration of cyproheptadine for moderate to severe cases 4

Sexual Dysfunction

• Sexual dysfunction (erectile dysfunction, delayed ejaculation, anorgasmia) occurs in approximately 40% of patients across observational studies 1
• Escitalopram and paroxetine show a trend toward increased risk, while bupropion has decreased risk 1
• Symptoms typically emerge within the first week of treatment 1

Bleeding Complications

• SSRIs and SNRIs increase gastrointestinal bleeding risk (OR 1.2-1.5), with higher risk when combined with antiplatelet agents or NSAIDs 1
• Abnormal bleeding can occur at any time during treatment 1

Seizures

• Seizures have been observed with SSRI use, requiring cautious use in patients with seizure disorder history 1

Hyponatremia

• Hyponatremia occurs in 0.5-12% of older adults (OR 3.3 for SSRIs versus other drug classes), typically within the first month of treatment 1

Cardiovascular Effects

• Citalopram carries a 2012 FDA boxed warning not to exceed 40 mg/day (or 20 mg/day in adults over 60 years) due to dose-dependent QT prolongation 1
• Escitalopram and amitriptyline also cause QT prolongation, typically dependent on coexisting risk factors 1
• Venlafaxine has increased cardiotoxicity in overdose compared to other SNRIs, with differences in overdose toxicity possibly related to this effect 3

Hepatotoxicity

• Duloxetine has reports of serious and potentially fatal hepatotoxicity, which appears unique to duloxetine and not a characteristic of the SNRI class 3
• SSRIs cause asymptomatic mild transaminase elevation in 0.5-3% of patients, typically within six months, with lower risk than tricyclic antidepressants 1

Special Population Considerations

Pregnancy and Neonatal Effects

• Third-trimester SSRI exposure causes neonatal adaptation syndrome in newborns, presenting with continuous crying, irritability, jitteriness, restlessness, tremors, hypertonia, tachypnea, feeding difficulty, sleep disturbance, hypoglycemia, and seizures 1
• Onset ranges from hours to days after birth, usually resolving within 1-2 weeks (though one paroxetine-exposed infant had symptoms persisting through 4 weeks) 1
• The FDA revised its 2006 advisory on persistent pulmonary hypertension of the newborn (PPHN), stating conflicting findings make it unclear whether SSRIs cause PPHN, though a meta-analysis suggested a number needed to harm of 286-351 1
• No adverse neurodevelopmental outcomes have been identified in recent reviews of infants with prenatal SSRI exposure 1

Breastfeeding

• Paroxetine is the only SSRI with consistently low infant-to-maternal plasma concentration ratios (<0.10) 1
• Paroxetine, sertraline, and fluvoxamine provide the infant <10% of the maternal daily dose (weight-normalized), though sertraline and fluvoxamine have some paired ratios >0.10 1
• Fluoxetine and venlafaxine produce the highest infant plasma concentrations 1
• Adverse effects in breastfed infants (irritability, decreased feeding) are documented only in case reports, more often with fluoxetine and citalopram, with little evidence of causal links 1

Critical Clinical Pitfalls

• Misinterpreting early serotonin syndrome symptoms (agitation, tremor) as worsening depression can lead to inappropriate dose escalation and potentially fatal outcomes 5
• Failing to consider over-the-counter medications (dextromethorphan, St. John's Wort) and supplements as serotonin syndrome contributors is a common error 4
• When combining serotonergic medications, start the second agent at low dose, increase slowly, and monitor closely during the first 24-48 hours after any dosage change 4, 5
• The margin of safety in SSRI overdose is greater than other antidepressants, though deaths have been reported following very large ingestions 1