What is the classification and common side effects of Effexor (venlafaxine)?

Venlafaxine Classification and Side Effects

Venlafaxine (Effexor) is a serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant with a significant side effect profile including dose-dependent blood pressure elevation, sexual dysfunction, and discontinuation syndrome that requires careful monitoring and tapering when discontinued.

Classification and Mechanism of Action

• Venlafaxine belongs to the class of selective serotonin-norepinephrine reuptake inhibitors (SSNRIs or SNRIs) 1, 2
• It inhibits the reuptake of both serotonin (5-HT) and norepinephrine (NE), with greater potency for serotonin reuptake inhibition at lower doses 3
• At higher doses, venlafaxine demonstrates a more balanced effect on both serotonin and norepinephrine systems, with a 30-fold difference in binding affinity between the two transporters 3
• Venlafaxine has minimal activity at muscarinic cholinergic, H1 histaminergic, and alpha-1 adrenergic receptors, which differentiates it from tricyclic antidepressants 4

Common Side Effects

Gastrointestinal Effects

• Nausea (37% vs 11% for placebo) - most common side effect and reason for discontinuation 5
• Constipation (15% vs 7% for placebo) 5
• Vomiting (6% vs 2% for placebo) 5
• Dry mouth (22% vs 11% for placebo) 5
• Anorexia and weight loss (11% vs 2% for placebo) 5

Neurological Effects

• Somnolence/sedation (23% vs 9% for placebo) 5
• Dizziness (19% vs 7% for placebo) 5
• Insomnia (18% vs 10% for placebo) 5
• Nervousness (13% vs 6% for placebo) 5
• Anxiety (6% vs 3% for placebo) 5
• Tremor (5% vs 1% for placebo) 5
• Headache - common reason for discontinuation 5

Sexual Dysfunction

• Abnormal ejaculation/orgasm in men (12% vs 2% for placebo) 5
• Impotence in men (6% vs 2% for placebo) 5
• Decreased libido (2% vs <1% for placebo) 5
• Orgasm disturbance in women (2% vs <1% for placebo) 5

Other Common Side Effects

• Sweating (dose-dependent, up to 19.3% at higher doses) 5
• Asthenia/fatigue 5
• Blurred vision (6% vs 2% for placebo) 5
• Yawning (3% vs <1% for placebo) 5

Serious and Concerning Side Effects

Cardiovascular Effects

• Dose-dependent increases in blood pressure - a key distinguishing side effect of venlafaxine compared to SSRIs 1, 2, 6
  • 3-5% of patients on ≤200 mg/day
  • 7% of patients on 201-300 mg/day
  • 13% of patients on >300 mg/day 7
• Increased heart rate (approximately 3 beats per minute compared to placebo) 5
• QT interval prolongation risk, particularly in elderly patients and overdose cases 6

Discontinuation Syndrome

• Abrupt discontinuation can lead to withdrawal symptoms 2, 5
• Requires slow tapering when stopping treatment 2
• More severe discontinuation syndrome than with most SSRIs 6

Other Serious Concerns

• Increased risk of suicidal thoughts and behavior, particularly in children, adolescents, and young adults up to age 24 2, 5
• Serotonin syndrome risk, especially when combined with other serotonergic medications 2, 5
• Increased risk of pre-eclampsia and eclampsia when used during second and third trimesters of pregnancy 6
• Higher fatality rate in overdose compared to SSRIs 6

Dose-Dependent Side Effects

• Several side effects show clear dose dependency, including:
  • Blood pressure elevation 1, 2, 5
  • Nausea 5
  • Sweating 5
  • Dizziness 5
  • Somnolence 5
  • Tremor 5

Monitoring Recommendations

• Regular monitoring of blood pressure and pulse, especially when initiating treatment or adjusting dosage 2, 5
• Screening electrocardiogram recommended for patients older than 40 years with cardiac risk factors 1
• Monitoring for signs of suicidal ideation, particularly in younger patients 2, 5
• Weight monitoring due to potential anorexia and weight loss effects 2

Important Clinical Considerations

• Venlafaxine has a short half-life (3-4 hours), with its active metabolite O-desmethylvenlafaxine (desvenlafaxine) having a half-life of about 10-12 hours 3, 4
• Contraindicated with MAOIs due to risk of serotonin syndrome 5
• Drug interactions with medications metabolized by CYP2D6 should be considered, though venlafaxine itself has relatively few pharmacokinetic drug interactions 3
• Adaptation to some side effects (e.g., nausea, dizziness) may occur within 1-3 weeks of therapy, while others (e.g., sexual dysfunction, dry mouth) may persist 5, 7