An Integrated Analysis of the Safety and Tolerability of Desvenlafaxine Compared with Placebo in the Treatment of Major Depressive Disorder

Abstract

Introduction: The safety and tolerability profiles of antidepressants can often influence the treatment choices of clinicians treating major depressive disorder. The purpose of this investigation was to characterize the safety and tolerability of desvenlafaxine (administered as desvenlafaxine succinate) in treating depression.Methods: An integrated analysis of all short-term, randomized, double-blind, placebo-controlled registration studies for major depressive disorder (four flexible-dose and five fixed-dose studies) was performed. Adult outpatients with major depressive disorder received desvenla-faxine doses ranging from 50–400 mg/day or placebo for 8 weeks. Treatment-emergent adverse events, laboratory values, vital signs, and discontinuation symptoms were evaluated. In the subset of fixed-dose studies, dose-related effects were analyzed.Results: In the overall population (placebo: n=1,116; desvenlafaxine: n=1,834), adverse events resulted in discontinuations in 3% of placebo-treated patients and 12% of desvenla-faxine-treated patients; in the subset of fixed-dose studies, the rates were 4% with placebo and increased with desvenlafaxine dose (50 mg/ day: 4%; 400 mg/day: 18%). The most common treatment-emergent adverse event was transient nausea that was generally mild to moderate. The most common sexual dysfunction associated with desvenlafaxine treatment was erectile dysfunction in men (7% vs 1% with placebo) and anorgasmia in women (1% and 0%). One desvenlafaxine-treated patient died of a completed suicide; there were four suicide attempts (three desvenlafaxine, one placebo) and eight cases of suicidal ideation (five desvenlafaxine, three placebo) during the on-therapy period. Small but statistically significant changes in mean blood pressure occurred at all desvenlafaxine doses; clinically meaningful changes were observed in 1% of placebo-treated patients and 2% of desvenlafaxine-treated patients. Desvenlafaxine was associated with small but statistically significant mean changes in laboratory assessments, particularly lipid and liver enzyme elevations, and electrocardiograms; few cases of these changes were clinically relevant.Conclusion: Desvenlafaxine in the treatment of major depressive disorder exhibited a safety and tolerability profile generally consistent with the serotonin-norepinephrine reuptake inhibitor class. The most common adverse event was transient nausea. At the recommended therapeutic dose of 50 mg/day, discontinuation due to adverse events was similar to placebo.

Effect of Food on the Pharmacokinetics of Desvenlafaxine in Healthy Subjects

“…Studies investigating desvenlafaxine at lower doses (ie, 50 and 100 mg/d) have demonstrated better tolerability and lower occurrences of AEs [14,15,20].…”

Sexual Dysfunctions in Depression

“…In an early study of 132 patients with depressive disorders, loss of sexual interest (characterized by loss of libido or decrease of sexual desire or potency) was reported by 72% of patients with unipolar disorder and 77% of those with bipolar disorder [15]. Loss of sexual desire may be the presenting complaint in some patients who are found to have significant depressive symptoms only after direct questioning.…”

Getting the balance right: Established and emerging therapies for major depressive disorders

“…143 A strong dose-response effect on tolerability was reported, but both 50 mg and 100 mg doses were well tolerated. 144,177 Discontinuation rates due to adverse events were similar to those with placebo. The most common adverse event was transient mild to moderate nausea.…”

“…108 [134][135][136]140 Higher remission rates of bupropion (46%) vs venlafaxine (33%) and similar responder rates (HAM-D e , MADRS c ) after 6-8 weeks treatment. 143,144 Bupropion may be suitable to augment citalopram and in major depressions. 146,150 Bupropion IR: tremor (22%), menstrual complaints (5%), hypertension and impaired sleep (4%).…”

“…Erectile dysfunction in man and anorgasmia in women were the most common sexual adverse events. 144 The usual dose of venlafaxine IR is 75-375 mg/day and 75-225 mg/day for venlafaxine XR. 46 With rapid venlafaxine dose escalation up to 375 mg/day, onset of efficacy can be achieved after only one week.…”