Paroxetine Side Effects
Paroxetine carries significant side effect risks that require careful monitoring, particularly for discontinuation syndrome, sexual dysfunction, and increased suicidal thinking compared to other SSRIs.
Common Side Effects (Occurring in ≥5% of Patients)
The most frequently reported adverse effects with paroxetine include 1:
- Gastrointestinal effects: Nausea (most common reason for discontinuation), dry mouth, constipation, diarrhea, decreased appetite 1
- Neurological effects: Somnolence (23% vs 9% placebo), dizziness (13% vs 6% placebo), insomnia (13% vs 6% placebo), tremor (8% vs 2% placebo), headache 1
- Autonomic effects: Sweating, asthenia (weakness) 1
- Sexual dysfunction: Ejaculatory disturbance (13% in males), impotence (10% in males), female genital disorders (2% in females) 1
Serious and Clinically Significant Side Effects
Discontinuation Syndrome
Paroxetine has the highest risk of discontinuation syndrome among all SSRIs 2. This syndrome is characterized by 2:
- Dizziness, fatigue, lethargy, general malaise
- Myalgias, chills, headaches
- Nausea, vomiting, diarrhea
- Insomnia, imbalance, vertigo
- Sensory disturbances, paresthesias
- Anxiety, irritability, agitation
This occurs following missed doses or acute discontinuation and is notably more severe with paroxetine than with fluvoxamine or sertraline 2.
Suicidality
Paroxetine has been associated with increased risk of suicidal thinking or behavior compared to other SSRIs 2. The FDA requires a boxed warning for suicidal thinking and behavior through age 24 years 2. Key points include:
- Pooled absolute rates: 1% with antidepressants vs 0.2% with placebo 2
- SSRIs as a class show increased risk for nonfatal suicide attempts (odds ratio 1.57-2.25) 2
- Close monitoring is required within the first 1-2 weeks of initiation and after dosage adjustments 2
Sexual Dysfunction
Paroxetine has higher rates of sexual dysfunction than fluoxetine, fluvoxamine, nefazodone, or sertraline 2. This represents a significant quality of life concern that may affect medication adherence.
Drug Interactions
Paroxetine has significant interaction potential 2:
- CYP2D6 inhibition: Paroxetine interacts with drugs metabolized by CYP2D6, including tamoxifen (increases risk of dying from breast cancer over 5 years when combined) 3
- Contraindicated with MAOIs: Risk of serotonin syndrome 2
- Caution with other serotonergic drugs: Including SSRIs, SNRIs, TCAs, tramadol, meperidine, methadone, fentanyl, dextromethorphan, St. John's wort, tryptophan 2
Serotonin Syndrome
Can occur when combining serotonergic medications, with symptoms arising within 24-48 hours 2:
- Mental status changes (confusion, agitation, anxiety)
- Neuromuscular hyperactivity (tremors, clonus, hyperreflexia, muscle rigidity)
- Autonomic hyperactivity (hypertension, tachycardia, arrhythmias, tachypnea, diaphoresis)
- Advanced symptoms: fever, seizures, arrhythmias, unconsciousness, potentially fatal 2
Other Serious Adverse Effects
- Abnormal bleeding: Especially with concomitant NSAIDs or aspirin; includes ecchymosis, hematoma, epistaxis, petechiae, hemorrhage 2
- Behavioral activation/agitation: More common in younger children, may occur early in treatment or with dose increases 2
- Pregnancy risks: Increased risk of birth defects (particularly cardiac), neonatal complications, premature births 1
- Anticholinergic effects: Paroxetine is more anticholinergic than other SSRIs 2
Clinical Management Considerations
Start with subtherapeutic "test" doses to assess tolerability, as initial adverse effects can include anxiety or agitation 2. Increase slowly at 1-2 week intervals for shorter half-life SSRIs 2.
Never discontinue paroxetine abruptly—taper over 10-14 days minimum to limit withdrawal symptoms 2, 1.
Monitor closely for behavioral changes, especially in the first 24-48 hours after starting or adjusting doses of any concomitant serotonergic medication 2.