Duloxetine: clinical efficacy, safety and tolerability in treatment of major depressive disorder

Objective Existing therapies for major depressive disorder (MDD) often fail to provide full remission. Scientific data suggest that drugs which combine both serotonin and norepinephrine reuptake blockade may be more effective in providing better remission rates. Duloxetine, recently approved for the treatment of MDD, is an inhibitor of serotonin and norepinephrine reuptake, with weak effects on dopamine reuptake. This article reviews the literature on duloxetine with regard to its pharmacodynamics, pharmacokinetics and clinical efficacy both at short-(8 to 9 weeks) and long-term (up to 52 weeks) in adults and elderly, as well as safety and tolerability, with particular regard to incidence of adverse effects, gastrointestinal, cardiovascular and sexual tolerability. Methods A search of Medline was performed using the terms "duloxetine" and "major depressive disorder", with no restriction on year. Results In vitro and in vivo studies show high affinity of duloxetine to human serotonin and norepinephrine transporters, with a weak affinity to dopamine transporter or serotoninergic, adrenergic, muscarinic, histaminergic receptors. Duloxetine is extensively metabolized by CYP450 2D6 and 1A2. The drug exhibits linear, dose- dependent pharmacokinetics. No dose adjustment appears to be needed, based on age. Duloxetine has shown efficacy in acute treatment (8 to 9 weeks) in reducing depressive symptoms compared with placebo, and duloxetine recipients have shown significant improvements in global functioning compared with placebo. An adequate response was found even regarding somatic symptoms of depression, especially pain. Response and remission rates have been shown to be comparable to, or greater than, those seen with fluoxetine or paroxetine. Data following long-term treatment (ranging up to 52 weeks), although based primarily on open arm or placebo-controlled studies, suggest that efficacy and tolerability of duloxetine are maintained in chronic treatment. Duloxetine is generally safe and well tolerated, with nausea, dry mouth, and fatigue being the most common treatment-related adverse effects. Nausea occurred early in treatment, with mild to moderate severity, and tended to resolve without discontinuation of duloxetine. Adverse cardiovascular effects do not appear to result in sustained elevations in blood pressure, QTc-interval prolongation, or other electrocardiographic changes. The incidence of acute-phase treatment-related sexual dysfunction in patients receiving duloxetine, in one study, was significantly higher than that observed in patients receiving placebo. However, during long-term treatment, the incidence of dysfunction in patients receiving duloxetine did not differ significantly from that in placebo-treated patients. Table I shows inhibition of norepinephrine transporter (NAT) and serotonin transporter (SERT) binding in vitro by duloxetine and venlafaxine. Table II shows affinity of duloxetine and venlafaxine for human serotonin receptor subtypes, other neuronal receptors and blockade of monoamine oxidase activity. Table III shows selected pharmacokinetic parameters of duloxetine. Table IV shows selected studies on the efficacy of duloxetine in the treatment of major depressive disorder. Table V shows treatment-related adverse events with duloxetine. Conclusions Based on the available evidence, duloxetine is a well-tolerated and effective treatment for MDD in adults and elderly, although more data from long-term studies are needed.