Psy-World

The triple reuptake inhibitor GSK372475 is neither efficacious nor well tolerated in patients with major depressive disorder.

Although many antidepressants with different mechanisms of action are available, there remains an unmet need for the development of drugs that are effective in patients who do not respond to currently available treatments. Antidepressants most commonly used to treat major depressive disorder (MDD) involve both serotonin (5-HT) and noradrenaline (NA), however there is also a rationale to suggest that dopaminergic (DA) mechanisms might be relevant to antidepressant response. GSK372475 is a triple reuptake inhibitor with approximately equipotent inhibition of 5-HT, NA and DA transporters. Two studies evaluated the efficacy, safety and tolerability of GSK372475 in outpatients (aged 18-64 years) with major depressive episode associated with MDD. The two 10-week randomized, double-blind, parallel group, placebo- and active-controlled trials were followed by a 1-2 week taper phase and 5-8 weeks of follow-up. Patients were randomized in a 1:1:1 ratio in both studies to receive either GSK372475 (1.5-2 mg/d) in Study 1 or GSK372475 (1-1.5 mg/d) in Study 2, venlafaxine XR (150-225 mg/d) in Study 1 or paroxetine (20-30 mg/d) in Study 2, or placebo. In both studies there was no significant difference between GSK372475 and placebo groups on any of the key efficacy endpoints (six-item Bech scale, IDS-Clinician Rated, MADRS). Both of the active controls showed significant improvements for all measures of clinical efficacy when compared with placebo. Dry mouth, headache, insomnia, and nausea were the most common adverse effects (AEs) with GSK372475. Compared with placebo, GSK372475 had a higher percentage of sleep, anxiety-related, gastrointestinal and cardiovascular (tachycardia) AEs in both studies. There were increases from baseline in sitting blood pressure (systolic and diastolic) and heart rate measurements with GSK372475 compared with the active controls and placebo. Withdrawal rates were higher for GSK372475 compared with placebo, venlafaxine XR, or paroxetine. These findings do not support the idea that triple reuptake inhibition is a useful antidepressant mechanism. Learned S, Graff O, Roychowdhury S, Moate R, Krishnan KR, Archer G, Modell JG, Alexander R, Zamuner S, Evoniuk G, Ratti E (2011). Efficacy, safety, and tolerability of a triple reuptake inhibitor GSK372475 in the treatment of patients with major depressive disorder: two randomized, placebo- and active-controlled clinical trials. J Psychopharmacol, Nov 2, doi: 10.1177/0269881111424931 (in press). Updated December 2011