What are the common and serious adverse effects of venlafaxine, and how should they be monitored and managed?

Venlafaxine Side Effects

Venlafaxine causes dose-dependent gastrointestinal, neurological, cardiovascular, and sexual side effects, with nausea being the most common reason for discontinuation, and requires careful monitoring for blood pressure elevation and serious withdrawal symptoms upon discontinuation. 1, 2

Common Side Effects

Gastrointestinal Effects

• Nausea is the most frequently reported side effect and the leading cause of treatment discontinuation (6% discontinuation rate), though it typically resolves within 1-3 weeks of therapy 1, 3
• Other GI effects include vomiting, diarrhea, constipation, abdominal discomfort, dry mouth, and decreased appetite 1, 4

Neurological Effects

• Dizziness, headache, tremor, insomnia, somnolence (3% discontinuation rate), and nervousness occur commonly 1, 3
• Sweating (diaphoresis) occurs more frequently with venlafaxine than with many other antidepressants 1

Sexual Dysfunction

• Abnormal ejaculation/orgasm in men and sexual dysfunction in both sexes are well-documented 1, 4
• Meta-analysis shows sexual dysfunction is a leading cause of serious adverse events with venlafaxine 4

Metabolic Effects

• Decreased appetite and weight loss can occur during treatment 1
• Children and adolescents require height and weight monitoring throughout treatment 2
• Elevated cholesterol levels may develop 2

Cardiovascular Side Effects

Venlafaxine causes dose-dependent blood pressure elevation that requires regular monitoring and may necessitate discontinuation. 1, 2

• Blood pressure increases occur in 3-5% of patients at doses ≤200 mg/day, 7% at 201-300 mg/day, and 13% at doses >300 mg/day (compared to 2% with placebo) 3
• Sustained clinical hypertension is more likely at doses above 300 mg/day 1
• Control hypertension before starting treatment and monitor blood pressure regularly throughout therapy 2
• QT interval prolongation can occur, potentially leading to torsades de pointes (a potentially fatal ventricular tachycardia) 5
• Venlafaxine overdoses are more frequently fatal than SSRI overdoses, with higher cardiovascular risk than most selective serotonin reuptake inhibitors 5

Serious Adverse Effects

Suicidality

• Increased risk of suicidal thoughts and behavior, 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
• Watch for new or sudden changes in mood, behavior, actions, thoughts, or feelings 2

Serotonin Syndrome

• This potentially life-threatening condition can occur and presents with agitation, hallucinations, coma, coordination problems, muscle twitching, racing heartbeat, blood pressure changes, sweating, fever, nausea, vomiting, diarrhea, or muscle rigidity 1, 2
• Risk is particularly high when combined with MAOIs—do not use within 2 weeks of MAOI discontinuation or within 7 days after stopping venlafaxine 2

Discontinuation Syndrome

Abrupt discontinuation causes serious withdrawal symptoms requiring slow tapering. 1, 2

• Symptoms include anxiety, irritability, fatigue, restlessness, sleep problems, headache, sweating, dizziness, electric shock-like sensations, shaking, confusion, nightmares, vomiting, nausea, and diarrhea 2
• Venlafaxine is a short-acting agent with particularly marked discontinuation symptoms 6
• A slow discontinuation taper is essential to minimize withdrawal symptoms 1

Other Serious Effects

• Manic/hypomanic episodes: greatly increased energy, severe insomnia, racing thoughts, reckless behavior, unusually grand ideas, excessive happiness or irritability, rapid speech 2
• Hyponatremia (low sodium levels), particularly in elderly patients, presenting with headache, weakness, unsteadiness, confusion, or memory problems 2
• Abnormal bleeding risk, especially when combined with warfarin, NSAIDs, or aspirin 2
• Seizures, though uncommon 1
• Mydriasis (enlarged pupils) 2
• Rare lung disease and pneumonia with worsening shortness of breath, cough, or chest discomfort 2
• Severe allergic reactions with breathing difficulty, facial swelling, or rash 2

Monitoring Requirements

• Regular blood pressure, pulse, and weight monitoring, especially when initiating treatment or adjusting dosage 1
• Height and weight monitoring in children and adolescents 2
• Close observation for suicidal ideation, particularly during the first few months and after dose changes 2

Comparative Safety Profile

• Venlafaxine has a higher incidence of nausea and vomiting than SSRIs 1
• Treatment discontinuation due to adverse effects occurs in 10-20% of patients in clinical trials, compared to 40% with clonidine 6
• Venlafaxine is much safer in overdosage than tricyclic antidepressants but more dangerous than most SSRIs 7, 5
• Meta-analysis of over 70 trials with approximately 7,000 patients shows treatment discontinuation due to adverse effects is more common with venlafaxine than with SSRI antidepressants 5

Special Considerations

• Venlafaxine has weak or no effects on CYP2D6, making it a better alternative than fluoxetine or paroxetine in patients taking tamoxifen 6
• Use in diabetes is limited due to cardiovascular adverse events 1
• Exposure during second and third trimesters of pregnancy increases risk of pre-eclampsia and eclampsia 5
• Contraindicated in uncontrolled narrow-angle glaucoma 2

Dose-Related Effects

Side effects are dose-dependent, with 75 mg identified as the optimum dose balancing efficacy and tolerability. 6

• At 37.5 mg/day: fewer side effects but reduced efficacy 6
• At 75 mg/day: optimal balance of efficacy and tolerability 6
• At 150 mg/day: similar efficacy to 75 mg but more side effects 6
• At doses >300 mg/day: significantly increased risk of sustained hypertension (13% vs 2% placebo) 3