Venlafaxine Extended-Release

Abstract

Venlafaxine inhibits presynaptic reuptake of serotonin (5-hydroxytryptamine; 5-HT) and noradrenaline (norepinephrine). Venlafaxine extended-release (XR) has been investigated in patients with major depression and in patients with major depression with associated anxiety in randomised, double-blind, multicentre trials. A therapeutic response in patients with major depression was evident at week 2 of treatment with venlafaxine XR 75 to 225 mg/day in a placebo-controlled trial. By week 4, the drug was significantly more effective than placebo at reducing both the Hamilton Rating Scale for Depression (HAM-D) and Montgomery-Asberg Depression Rating Scale (MADRS) total scores. Furthermore, cumulative relapse rates were lower among recipients of venlafaxine XR 75 to 225 mg/day than placebo recipients after 3 and 6 months in another trial. Venlafaxine XR 75 to 150 mg/day was significantly more effective than venlafaxine immediate-release (IR) 75 to 150 mg/day or placebo during a 12-week study. Reductions from baseline in all 4 efficacy parameters (HAM-D, MADRS, HAM-D depressed mood item and the Clinical Global Impression Severity of Illness scale) were significantly higher among patients treated with venlafaxine XR than venlafaxine IR or placebo at week 12 (using an intent-to-treat, last observation carried forward analysis) Venlafaxine XR 75 to 225 mg/day was compared with fluoxetine 20 to 60 mg/day in patients with major depression in 2 randomised, double-blind, placebo-controlled, multicentre studies. Remission rates were significantly in favour of venlafaxine XR recipients in one study: 37, 22 and 18% of patients treated with venlafaxine XR, fluoxetine or placebo, respectively, achieved full remission (HAM-D total score ≤7 at end-point). In the other trial, venlafaxine XR and fluoxetine had comparable efficacy in reducing HAM-D and Hamilton Rating Scale for Anxiety (HAM-A) total scores compared with placebo. However, the HAM-A response rate was significantly higher with venlafaxine XR than with fluoxetine at week 12. In a comparative study involving paroxetine, reductions from baseline in HAM-D and MADRS total scores in patients given venlafaxine XR 75 mg/day or paroxetine 20 mg/day for 12 weeks were significant, but no significant differences between treatment groups were evident. Discontinuation rates because of unsatisfactory clinical response were similar among patients treated with venlafaxine XR, fluoxetine or paroxetine. Adverse events pertaining to the digestive (nausea, dry mouth), nervous (dizziness, somnolence, insomnia) and urogenital (abnormal ejaculation) systems as well as sweating were the most frequently reported adverse events during 8 to 12 weeks of treatment in 3 randomised, double-blind, multicentre trials. Comparative studies with fluoxetine and paroxetine demonstrated a similar adverse event profile to venlafaxine XR. Conclusion: Venlafaxine XR has shown efficacy in the treatment of major depression and was at least as effective as fluoxetine or paroxetine and more effective than venlafaxine IR. Furthermore, it is effective at reducing symptoms of anxiety in depressed patients. The incidence of adverse events in recipients of venlafaxine XR is similar to that in patients receiving treatment with well established selective serotonin reuptake inhibitors. As an effective and well tolerated antidepressant, venlafaxine XR should be considered as a first-line pharmacological treatment in patients with major depression. Venlafaxine and its major active metabolite O-desmethylvenlafaxine (ODV) both inhibit presynaptic reuptake of serotonin (5-hydroxytryptamine; 5-HT) and noradrenaline (norepinephrine). Venlafaxine has been referred to previously as a serotonin noradrenergic reuptake inhibitor (SNRI). Venlafaxine also weakly inhibits dopamine reuptake. The drug has no significant affinity for α₁-adrenergic, muscarinic cholinergic, H₁ histaminergic, benzodiazepine or opioid receptors and does not inhibit monoamine oxidase. Venlafaxine 75 to 150 mg/day did not impair psychomotor performance to any clinically significant degree in healthy volunteers. Although the drug impaired vigilance, it did not affect driving ability after administration of 75 to 150 mg/day for 2 weeks. Venlafaxine did not exacerbate the detrimental effects on psychomotor performance when coadministered with diazepam or alcohol. However, the drug markedly suppressed rapid eye movement (REM) sleep and increased wake time in healthy volunteers and patients with depression. Although dosages ≤300 mg/day are not associated with a significant risk of sustained diastolic blood pressure (DBP) elevation, venlafaxine extended-release (XR) may elevate BP in some patients. The absolute bioavailability of venlafaxine XR (≈45%) is not affected by food or the time of administration, and plasma concentrations of the drug are not affected by gender or age. Maximum plasma concentrations of venlafaxine and ODV occur approximately 5.5 and 9 hours, respectively, after administration of venlafaxine XR, and steady-state concentrations are reached within 3 days with ongoing administration. Proportionality between the dose and plasma concentrations of venlafaxine has been demonstrated. Plasma protein binding is minimal for venlafaxine (27%) and ODV (30%). Venlafaxine undergoes extensive cytochrome P450 (CYP) 2D6-mediated first-pass oxidative metabolism to produce ODV. In most individuals, plasma concentrations of ODV are approximately 2- to 3-fold higher than those of the parent drug; in poor metabolisers (determined by genetic polymorphism in CYP2D6 activity), venlafaxine concentrations are higher than ODV concentrations. The terminal elimination half-lives of venlafaxine and ODV are 5 and 11 hours, respectively, and within 48 hours of administration, 87% of a dose of venlafaxine is recovered in urine. Clearance of venlafaxine is reduced and dosage adjustments are warranted in...