Once- Versus Twice-Daily Venlafaxine Therapy in Major Depression: A Randomized, Double-Blind Study

Background: Psychotropic drug dosing regimens are often based on the pharmacokinetic elimination halflife of the compound. This implies that the pharmacokinetic half-life of the drug may be the critical or sole determinant of pharmacodynamic half-life. In the present study, we examined the safety and efficacy of once- versus twice-daily dosing regimens of the immediate-release formulation of venlafaxine, a serotonin and norepinephrine reuptake site blocker with a short elimination half-life.

Method: Forty-eight patients with a diagnosis of DSM-IV major depressive episode were randomly assigned to once-daily (N=25) versus twice-daily (N=23) venlafaxine. Venlafaxine was started at 37.5 mg daily with specified increments up to 225 mg daily. Efficacy was rated using the Hamilton Rating Scale for Depression (HAM-D), the MontgomeryAsberg Depression Rating Scale (MADRS), and the Clinical Global Impressions scale (CGI).

Results: Twenty-one patients in each group completed 6 weeks of treatment. We observed a significant reduction in mean weekly HAM-D and MADRS scores at weeks 1 through 6 for both dosing groups (p<.001). There were no statistically significant differences in mean HAM-D or MADRS scores between dosing groups at any time point. There was, however, a nonsignificant trend for a more rapid reduction in the mean HAM-D score at week 2 (p<.06) and in the mean MADRS score at week 1 (p<.07) and week 2 (p<.09) in the b.i.d. dosing group. Similarly, there was a significant decrease in the CGI score at week 2 (p<.02) in the b.i.d. dosing group. The rate of adverse events was similar between treatment groups; the most common adverse events were transient nausea and headaches.

Conclusion: These results indicate that the immediate-release formulation of venlafaxine may be safe and effective in some patients when used in a once-daily dose regimen. Moreover, the present results suggest that the short elimination half-life of immediate-release venlafaxine should not be the sole determinant for multiple daily dosing and that antidepressant activity may be more profoundly influenced by a drug’s pharmacodynamic half-life than by its pharmacokinetic half-life.