What are the side effects of venlafaxine (Effexor), a serotonin-norepinephrine reuptake inhibitor (SNRI)?

Side Effects of Venlafaxine

Venlafaxine causes a broad spectrum of side effects ranging from common gastrointestinal and neurological symptoms to serious cardiovascular effects and discontinuation syndrome, with a notably higher risk profile compared to SSRIs. 1, 2

Common Side Effects

Gastrointestinal Effects

• Nausea is the most frequent side effect and the leading cause of treatment discontinuation, occurring more commonly than with SSRIs 3, 1
• Vomiting, diarrhea, constipation, abdominal discomfort, dry mouth, and decreased appetite are frequently reported 4, 3

Neurological Effects

• Dizziness, headache, tremor, insomnia, somnolence, and nervousness occur commonly 4, 3
• Patients may experience fatigue or excessive sleepiness 1

Autonomic Effects

• Diaphoresis (excessive sweating) occurs more frequently with venlafaxine than with many other antidepressants 4, 3
• Dry mouth is a common complaint 1

Sexual Dysfunction

• Abnormal ejaculation/orgasm in men and sexual dysfunction in both sexes have been reported 3, 1

Weight and Appetite Changes

• Dose-dependent weight loss occurs, with 6% of patients losing 5% or more of body weight 1
• Decreased appetite is common 4, 3
• In pediatric patients, weight gain may be less than expected for age and sex 1

Cardiovascular Side Effects

Venlafaxine causes dose-dependent increases in blood pressure, distinguishing it from SSRIs and representing a key safety concern. 4, 5

• Higher risk of sustained hypertension occurs at doses above 300 mg/day, requiring regular monitoring 3
• Increased pulse rate is common 4, 1
• Blood pressure and pulse should be monitored regularly, especially when initiating treatment or adjusting dosage 3, 5
• Venlafaxine overdoses are more frequently fatal than SSRI overdoses, with increased risk of QT interval prolongation and potential for torsades de pointes 2

Serious Adverse Effects

Suicidality

• Increased risk of suicidal thoughts and behavior occurs particularly in children, adolescents, and young adults up to age 24 years 4, 1
• Close monitoring is essential, especially during the first few months of treatment or when doses are changed 1

Serotonin Syndrome

• This potentially life-threatening condition can occur, particularly when combined with MAOIs (which is contraindicated) 4, 3, 1
• Symptoms include agitation, hallucinations, coordination problems, racing heartbeat, blood pressure changes, fever, nausea, vomiting, and muscle rigidity 1

Discontinuation Syndrome

• Abrupt cessation causes withdrawal symptoms including dizziness, electric shock-like sensations, anxiety, confusion, headache, nausea, and insomnia 4, 3, 1
• A slow discontinuation taper is essential to minimize withdrawal symptoms 4, 3, 1
• The frequency of discontinuation symptoms increases with higher doses and longer treatment duration 1

Other Serious Effects

• Seizures may occur, though uncommon 4, 3
• Abnormal bleeding risk increases, especially when combined with warfarin, NSAIDs, or aspirin 1
• Hyponatremia (low sodium levels), particularly in elderly patients 1
• Mania or hypomania episodes 1
• Mydriasis (enlarged pupils) 1
• Rare lung problems including pneumonia 1
• Severe allergic reactions 1

Special Population Considerations

Pregnancy and Breastfeeding

• Exposure during second and third trimesters increases risk of pre-eclampsia and eclampsia 2
• Newborns exposed in the third trimester may experience feeding problems, breathing difficulties, seizures, and jitteriness 1
• Venlafaxine passes into breast milk 1

Pediatric Patients

• Weight gain may be less than expected based on age- and sex-matched peers 1
• Height growth may be reduced during treatment 1

Elderly Patients

• Greater risk for hyponatremia 1

Comparative Safety Profile

Venlafaxine has a higher incidence of adverse effects requiring treatment discontinuation compared to SSRIs, with meta-analyses showing more frequent discontinuation due to adverse effects 2, 6

• Nausea and vomiting occur more frequently than with SSRIs 3
• Cardiovascular adverse effects and fatal overdoses occur at higher rates than with most SSRI antidepressants 2
• Recent meta-analysis of 28 trials showed venlafaxine increased risk of serious adverse events (risk ratio: 2.66), mainly due to sexual dysfunction and anorexia 6

Monitoring Requirements

• Regular monitoring of blood pressure, pulse, height, and weight is essential 4, 5
• No specific laboratory tests are routinely recommended 4
• Electrocardiogram screening for patients older than 40 years with cardiac risk factors 5
• Cholesterol should be checked regularly 1
• Eye pressure monitoring if history of increased eye pressure or risk for narrow-angle glaucoma 1

Critical Drug Interactions

• Concomitant use with MAOIs is absolutely contraindicated due to serotonin syndrome risk 4, 1
• Caution with triptans, other antidepressants, tramadol, anticoagulants, NSAIDs, and tryptophan supplements 1
• Venlafaxine has minimal effect on CYP450 system compared to other antidepressants 4