What are the side effects of venlafaxine (Effexor)

Side Effects of Venlafaxine

Venlafaxine causes a broad spectrum of side effects ranging from common gastrointestinal and neurological symptoms to serious cardiovascular and psychiatric complications, with nausea being the most frequent reason for discontinuation and dose-dependent blood pressure elevation being a distinguishing safety concern. 1, 2

Common Side Effects

Gastrointestinal Effects

• Nausea is the most common side effect (37% vs 11% placebo), and the leading cause of treatment discontinuation (6% of patients). 1, 2
• Vomiting, diarrhea, constipation (15% vs 7% placebo), abdominal discomfort, dry mouth (22% vs 11% placebo), and decreased appetite (11% vs 2% placebo) are frequently reported. 1, 2
• Nausea typically resolves within 1-3 weeks of therapy despite continued treatment. 3

Neurological and Psychiatric Effects

• Dizziness (19% vs 7% placebo), headache, tremor (5% vs 1% placebo), insomnia (18% vs 10% placebo), somnolence (23% vs 9% placebo), and nervousness (13% vs 6% placebo) are common. 1, 2
• Anxiety (6% vs 3% placebo), agitation, and concentration difficulties (48% in treated patients) occur frequently. 1, 2, 4

Autonomic Effects

• Diaphoresis (sweating) occurs more frequently with venlafaxine than with many other antidepressants (12-19% depending on dose vs 5% placebo). 1, 2
• Dry mouth affects 22% of patients compared to 11% on placebo. 2

Sexual Dysfunction

• Abnormal ejaculation/orgasm occurs in 12% of men on venlafaxine vs 2% on placebo, with dose-dependent increases (12.5% at 375 mg/day). 1, 2
• Impotence (6% vs 2% placebo), decreased libido (2% vs <1% placebo), and orgasm disturbances affect both men and women. 1, 2

Weight and Appetite Changes

• Decreased appetite and weight loss (1% vs 0% placebo) can occur during treatment, particularly at higher doses. 1, 2
• Weight gain (29.6%) was reported in some patients, though venlafaxine has a more favorable weight profile than mirtazapine or paroxetine. 5, 4

Cardiovascular Side Effects

Blood Pressure Elevation

• Venlafaxine causes dose-dependent increases in supine diastolic blood pressure, with clinically significant elevations occurring primarily at doses above 300 mg/day (13% vs 2% placebo). 1, 6, 7
• At doses ≤200 mg/day, sustained hypertension occurs in 3-5% of patients; at 201-300 mg/day in 7%; and at >300 mg/day in 13%. 3, 7
• Blood pressure monitoring is essential before each refill, especially at higher doses and in patients over 40 years with cardiac risk factors. 6
• Mean increases in diastolic blood pressure range from 0.7 to 2.5 mm Hg across all dose groups. 2

Cardiac Effects

• Pulse rate increases by approximately 2-3 beats per minute on average. 2
• QT interval prolongation can occur, potentially leading to torsades de pointes, particularly in overdose situations. 8
• Cardiac conduction abnormalities have been reported in a small number of patients, warranting screening electrocardiogram for patients older than 40 years with cardiac risk factors. 6

Serious Adverse Effects

Suicidal Thoughts and Behavior

• Increased risk of suicidal thoughts and behavior occurs particularly in children, adolescents, and young adults up to age 24 years, especially within the first few months of treatment or when the dose is changed. 1, 2
• Close monitoring for new or worsening depression, anxiety, agitation, panic attacks, irritability, hostility, impulsivity, or suicidal ideation is mandatory. 2

Serotonin Syndrome

• Serotonin syndrome is a potentially life-threatening condition that can occur, particularly when venlafaxine is combined with other serotonergic agents (triptans, SSRIs, SNRIs, tramadol, tryptophan, St. John's Wort). 1, 2
• Symptoms include agitation, hallucinations, coma, coordination problems, muscle twitching, racing heartbeat, high or low blood pressure, sweating, fever, nausea, vomiting, diarrhea, and muscle rigidity. 2
• Concomitant use with MAOIs is contraindicated due to risk of serotonin syndrome. 1

Discontinuation Syndrome

• Abrupt discontinuation causes withdrawal symptoms requiring slow tapering when stopping venlafaxine. 1, 6, 2
• Withdrawal symptoms include anxiety, irritability, fatigue, restlessness, sleep problems, headache, sweating, dizziness, electric shock-like sensations, shaking, confusion, nightmares, vomiting, nausea, and diarrhea. 2

Other Serious Effects

• Seizures may be triggered, though this is uncommon. 1
• Hyponatremia (low sodium levels) can occur, with elderly patients at greater risk, presenting as headache, weakness, unsteadiness, confusion, or memory problems. 2
• Abnormal bleeding risk increases, especially when combined with warfarin, NSAIDs, or aspirin. 2
• Mydriasis (enlarged pupils) and narrow-angle glaucoma can occur, requiring regular eye pressure monitoring in at-risk patients. 2

Dose-Dependent Effects

Several adverse events demonstrate clear dose-dependency, including: 2

• Chills (1.1% placebo, 6.8% at 375 mg/day)
• Hypertension (1.1% placebo, 4.5% at 375 mg/day)
• Anorexia (2.2% placebo, 17% at 375 mg/day)
• Nausea (14.1% placebo, 58% at 375 mg/day)
• Agitation (0% placebo, 4.5% at 375 mg/day)
• Somnolence (4.3% placebo, 26.1% at 375 mg/day)
• Tremor (0% placebo, 10.2% at 375 mg/day)
• Yawning (0% placebo, 8% at 375 mg/day)
• Sweating (5.4% placebo, 19.3% at 375 mg/day)

Special Populations and Monitoring

Pregnancy and Breastfeeding

• Exposure during the second and third trimesters increases the risk of pre-eclampsia and eclampsia. 8
• Newborns whose mothers take venlafaxine in the third trimester may experience feeding and breathing problems, seizures, shaking, jitteriness, or constant crying. 2
• Venlafaxine passes into breast milk. 2

Overdose Risk

• Venlafaxine overdoses are more frequently fatal than SSRI overdoses, making it more dangerous in overdose situations. 8

Required Monitoring

• Blood pressure and pulse at each visit, especially when initiating treatment or adjusting dosage. 6
• Height and weight monitoring in children and adolescents. 2
• Cholesterol levels should be checked regularly as venlafaxine can cause elevated cholesterol. 2

Comparative Safety Profile

• Venlafaxine has a higher incidence of nausea and vomiting than SSRIs. 1
• Treatment discontinuation due to adverse effects is more common with venlafaxine than with SSRI antidepressants (19% overall discontinuation rate). 2, 8
• Venlafaxine carries a higher risk of cardiovascular adverse effects and fatal overdoses than most SSRI antidepressants due to its noradrenergic effects. 8

Common Pitfalls and Caveats

• Do not abruptly discontinue venlafaxine; always taper slowly over weeks to avoid severe withdrawal symptoms. 1, 6, 2
• Do not prescribe venlafaxine without establishing a blood pressure monitoring plan, particularly at doses above 300 mg/day. 6, 7
• Avoid alcohol while taking venlafaxine as it may potentiate sedative effects. 2
• Venlafaxine can cause sleepiness and impair decision-making; patients should not drive or operate heavy machinery until they know how the medication affects them. 2
• When switching from another antidepressant to venlafaxine, taper the initial antidepressant first to avoid side effects. 2