The role of venlafaxine in rational antidepressant therapy.

The antidepressant venlafaxine has a unique chemical structure and neuropharmacologic profile. It significantly inhibits reuptake of both serotonin and norepinephrine and lacks notable muscarinic-cholinergic or alpha-adrenergic effects. Premarketing studies involving more than 2000 patients showed the efficacy of venlafaxine to be significantly greater than placebo at dosages between 75 and 375 mg/day in both outpatients and inpatients. The medication may be administered twice or three times daily. Venlafaxine was found equally effective for patients older and younger than 60 years and in those with psychomotor retardation or agitation; it proved slightly more efficacious than fluoxetine in a comparison study with melancholic inpatients. A promising finding of these studies is the suggestion of a rapid onset of clinical effect for venlafaxine. In some studies, venlafaxine showed a consistent and robust clinical superiority over placebo by Week 1, and in the inpatient study involving melancholic patients, the superiority of venlafaxine was demonstrated as early as Day 4. In general, early responses are seen at the higher dosages. Venlafaxine has also shown promise in treating rigorously defined treatment-refractory depression. The adverse effects of venlafaxine that most often led to discontinuation from a clinical study were nausea (6%), somnolence (3%), insomnia (3%), and dizziness (3%). Although nausea was the most common adverse effect overall, it resolved rapidly--within the first 1 to 3 weeks of therapy. Other adverse events with incidences significantly higher than with placebo were dizziness, constipation, sweating, nervousness, and abnormal ejaculation. The seizure rate and potential for cardiac conduction changes or orthostatic hypotension with venlafaxine were comparable with rates seen with the serotonin selective reuptake inhibitors. A small number of patients experienced dose-dependent blood pressure elevation with venlafaxine in premarketing studies (3% to 5% of those receiving < or = 200 mg/day; 7% of those receiving 201-300 mg/day; 13% of those receiving > 300 mg/day vs. 2% receiving placebo). In general, venlafaxine is well tolerated, and its treatment discontinuation rate is similar to those of the newer antidepressants and superior to discontinuation rates with the first-generation agents.