What are the side effects of paroxetine (selective serotonin reuptake inhibitor, SSRI)?

Paroxetine Side Effects

Paroxetine causes a broad range of side effects, with the most common being gastrointestinal symptoms (especially nausea), sexual dysfunction, and central nervous system effects (somnolence, dizziness, insomnia), while carrying serious risks including suicidal thinking in young patients, discontinuation syndrome, and potentially higher suicidality risk compared to other SSRIs. 1, 2

Most Common Side Effects (≥5% incidence)

Gastrointestinal Effects

• Nausea is the most frequent side effect, occurring in patients across all approved indications and leading to treatment discontinuation in 3.2% of depression patients (versus 1.1% placebo) 1
• Dry mouth, constipation, diarrhea, and decreased appetite occur commonly across all conditions 1
• These gastrointestinal symptoms typically emerge within the first few weeks of treatment 3

Sexual Dysfunction

• Ejaculatory disturbance affects 13% of male patients with depression (0% placebo), making it one of the most bothersome adverse effects 1
• Other male genital disorders (anorgasmia, erectile difficulties, delayed ejaculation) occur in 10% of male depression patients 1
• Female genital disorders (anorgasmia, difficulty reaching climax) occur in 2% of female patients 1
• Decreased libido affects 3% of depression patients and is particularly prominent in anxiety disorders 1
• Sexual side effects occur in approximately 17% of all SSRI patients and are rated as particularly bothersome 3

Central Nervous System Effects

• Somnolence affects 23% of depression patients (9% placebo) and leads to discontinuation in 2.3% 1
• Dizziness occurs in 13% (6% placebo) 1
• Insomnia affects 13% (6% placebo) 1
• Tremor occurs in 8% (2% placebo) and leads to discontinuation in 1.1% 1
• Nervousness and anxiety each affect 5% of patients 1

Other Common Effects

• Asthenia (weakness) is prominent across all indications, leading to discontinuation in 1.6% of depression patients 1
• Sweating occurs frequently and leads to discontinuation in 1.0% 1
• Headache, vivid dreams, and fatigue are frequently reported 3
• Bruxism (teeth grinding) occurs with regular frequency 3

Serious Adverse Effects Requiring Close Monitoring

Black Box Warning: Suicidality

• All SSRIs, including paroxetine, carry a black box warning for increased suicidal thinking and behavior in patients through age 24 years 3
• The pooled absolute risk is 1% for antidepressant-treated youth versus 0.2% for placebo (risk difference 0.7%, number needed to harm = 143) 3
• Paroxetine has been specifically associated with increased risk of suicidal thinking or behavior compared to other SSRIs 2
• Close monitoring is mandatory, especially during the first months of treatment and following dose adjustments 2, 3

Discontinuation Syndrome

• Paroxetine is specifically noted as one of the SSRIs most strongly associated with discontinuation syndrome (along with fluvoxamine and sertraline) 2
• This represents a critical prescribing consideration distinguishing paroxetine from other SSRIs 2

Behavioral Activation/Agitation

• Motor or mental restlessness, insomnia, impulsiveness, talkativeness, disinhibited behavior, and aggression can occur early in treatment or with dose increases 2
• This is more common in younger children than adolescents and in anxiety disorders compared to depressive disorders 2
• Typically occurs within the first month of treatment and usually improves quickly after dose reduction or discontinuation 2
• This risk supports slow up-titration and close monitoring, particularly in younger children 2

Mania/Hypomania

• Rare but serious, typically appearing later in treatment (beyond the first month) rather than early like behavioral activation 2, 3
• Unlike behavioral activation, mania may persist after SSRI discontinuation and require active pharmacological intervention 2, 3

Serotonin Syndrome

• Life-threatening condition caused by elevated brain serotonin levels, typically when paroxetine is combined with other serotonergic medications 2, 3
• Symptoms arise within 24-48 hours and include mental status changes (confusion, agitation, anxiety), neuromuscular hyperactivity (tremors, clonus, hyperreflexia, muscle rigidity), and autonomic hyperactivity (hypertension, tachycardia, diaphoresis) 2, 3
• Advanced symptoms include fever, seizures, arrhythmias, and unconsciousness leading to potential fatalities 2, 3
• Treatment requires immediate hospitalization, discontinuation of all serotonergic agents, and supportive care with continuous cardiac monitoring 2, 3

Bleeding Risk

• Abnormal bleeding can occur, especially with concomitant aspirin or NSAID use 2, 3
• Rare bleeding events include ecchymosis, hematoma, epistaxis, petechiae, and hemorrhage 2, 3

Seizures

• Seizures have been observed with SSRI use; use cautiously in patients with seizure disorder history 2, 3

Overdose Profile

• Since U.S. introduction, 342 cases of deliberate or accidental overdose have been reported worldwide, with 48 fatalities (17 involving paroxetine alone) 1
• The largest known ingestion involved 2,000 mg (33 times the maximum recommended daily dose) in a patient who recovered 1
• Common overdose symptoms include somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness 1
• Notable serious overdose effects include convulsions (including status epilepticus), ventricular dysrhythmias (including torsade de pointes), serotonin syndrome, rhabdomyolysis, hepatic dysfunction, acute renal failure, and urinary retention 1
• Paroxetine has a greater margin of safety in overdose compared to tricyclic antidepressants, though deaths have been reported following very large ingestions 2

Critical Drug Interactions

Absolute Contraindications

• Monoamine oxidase inhibitors (MAOIs) including phenelzine, isocarboxazid, moclobemide, isoniazid, and linezolid are absolutely contraindicated due to serotonin syndrome risk 2, 3

Medications Requiring Extreme Caution

• Other serotonergic drugs including SNRIs, tricyclic antidepressants, atypical antidepressants, opioids (tramadol, meperidine, methadone, fentanyl), stimulants, dextromethorphan, and illicit drugs (ecstasy, methamphetamine, cocaine, LSD) 2
• When combining two non-MAOI serotonergic drugs, start the second drug at a low dose, increase slowly, and monitor closely for symptoms, especially in the first 24-48 hours after dosage changes 2

Cytochrome P450 Interactions

• Paroxetine is both a substrate and inhibitor of cytochrome P450 2D6 4
• It may prolong the half-life of other drugs metabolized by this pathway 3
• Caution is needed when patients taking paroxetine might ingest excessive quantities of tricyclic antidepressants, as accumulation of the parent tricyclic and/or active metabolite may increase clinically significant sequelae 1

Special Populations

Children and Adolescents

• Behavioral activation/agitation is more common in younger children than adolescents 2, 3
• Slow up-titration minimizes behavioral activation and helps avoid exceeding optimal dose 3

Elderly Patients

• Higher plasma concentrations and slower elimination are noted in the elderly 4
• Wide inter-individual variation in pharmacokinetics occurs across the age range 4

Renal and Hepatic Impairment

• Elimination is reduced in severe renal and hepatic impairment 4

Clinical Management Considerations

• Most side effects emerge within the first few weeks of treatment and are more common and persistent in real-world practice than clinical trials suggest 3
• Maximal therapeutic improvement typically occurs by week 12 or later, supporting gradual dose adjustments 3
• Parents, guardians, and patients should be educated in advance about potential side effects, particularly behavioral activation 2
• The 20% discontinuation rate in major depressive disorder trials (versus lower rates in anxiety disorders) reflects the significant side effect burden 1