Comparative efficacy between venlafaxine and SSRIs: a pooled analysis of patients with depression

Abstract

Background

Serotonergic and adrenergic enhancement may be synergistic and more effective than serotonergic enhancement alone in treating depression. The dual serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine is a dual reuptake inhibitor that may therefore offer greater efficacy than selective serotonin reuptake inhibitors (SSRIs).

Methods

Data from eight randomized, double-blind, controlled studies were pooled to compare efficacy in depressed patients receiving venlafaxine/venlafaxine extended release (XR), SSRIs, or placebo for ≤8 weeks. The mean changes from baseline in the 21-item Hamilton Rating Scale for Depression (HAM-D₂₁), Montgomery–Åsberg Depression Rating Scale (MADRS), and Clinical Global Impressions—Global Improvement (CGI-I) and CGI—Severity of Illness (CGI-S) item scores were compared, as were response rates derived from these scales.

Results

Statistically significant differences in mean HAM-D₂₁ score decrease between venlafaxine (14.5) and SSRIs (12.6) and between the active treatments and placebo (11.3) were observed. Venlafaxine significantly decreased the mean MADRS scores more than SSRIs (17.8 vs. 15.9), and both treatments were significantly better than placebo (12.9). The same pattern of significance for CGI-I, HAM-D₂₁, and MADRS response rates between venlafaxine (71%, 64%, and 67%, respectively), SSRIs (64%, 57%, and 59%, respectively), and placebo (50%, 42%, and 41%, respectively) was observed.

Conclusions

Venlafaxine was significantly more effective than SSRIs in improving depression, perhaps due to enhancing both serotonin and norepinephrine.

Introduction

Traditionally, all antidepressants are assumed to have comparable efficacy in clinical trials of depressed patients American Psychiatric Association 2000, Depression Guideline Panel 1993, April. On the other hand, clinicians have recognized for decades that some patients respond better to one antidepressant than to another, and that combinations of drugs may be more effective than a single drug (Nelson et al 1991). This mismatch between clinical experience and clinical trials has been difficult to reconcile in part because clinical trials in the United States are often designed only to detect differences between an effective antidepressant and placebo, not to detect differences between two antidepressants (Prien 1994).

Recently, differences in antidepressant efficacy between two antidepressants have been demonstrated both prospectively, by increasing the power of the study with large sample sizes, and retrospectively, by pooling several studies in various meta-analyses Anderson 1998, Anderson 2000, Anderson and Tomenson 1994, Ballús et al 2000, Costa e Silva 1998, Danish University Antidepressant Group 1986, Danish University Antidepressant Group 1990, et al et al 1999, for the Venlafaxine 631 Study Group et alfor the Venlafaxine 631 Study Group et al 2000, Poirier and Boyer 1999, Roose et al 1994, Stahl 2000, Tzanakaki et al 2000. This has led to a debate about whether the differences in antidepressant efficacy shown between two antidepressants in a clinical trial are due to differences in the drugs’ mechanisms of therapeutic action, pharmacogenetic differences between patients who respond to one drug versus another, or differences in clinical trial design, such as dose selection for the different drugs. Although there is no consistent evidence of differences in efficacy between antidepressants with predominantly noradrenergic versus serotonergic actions (Nelson 1999), there is an emerging theme that agents with dual noradrenergic and serotonergic actions may be more efficacious than agents with selective serotonergic actions.

Although no study claims superior efficacy of a selective serotonin agent over a “dual-action” agent, numerous Anderson 1998, Anderson 2000, Anderson and Tomenson 1994, Thase et al 2001, but not all (Freemantle et al 2000), studies and meta-analyses show that “dual-action” tricyclic antidepressants, mirtazapine, milnacipran, venlafaxine, and combinations of a serotonergic and noradrenergic agent have superior efficacy over single-action agents Alves et al 1999, Ballús et al 2000, Costa e Silva 1998, Danish University Antidepressant Group 1986, Danish University Antidepressant Group 1990, Diaz-Martinez et al 1998, et al et al 1999, Lopez-Ibor et al 1996, McPartlin et al 1998, for the Venlafaxine 631 Study Group et alfor the Venlafaxine 631 Study Group et al 2000, Nelson et al 1991, Poirier and Boyer 1999, Roose et al 1994, Steffens et al 1997, et al et al 1997, Tzanakaki et al 2000 To test the hypothesis that dual-action agents have antidepressant efficacy superior to single-action agents, we analyzed a large sample of patients derived from pooling several studies of venlafaxine versus one or another of three selective serotonin reuptake inhibitors (SSRIs): fluoxetine, paroxetine, or fluvoxamine.