Venlafaxine and SSRI remission data revisited

Thase et al (2001) suggest that venlafaxine is more likely than selective serotonin reuptake inhibitors (SSRIs) to produce remission of depression. Their article continues to be widely cited as evidence of the superiority of venlafaxine over SSRIs. While the authors identify most of the significant limitations of the study, they do not sufficiently address one of the major considerations in interpreting a meta-analysis, namely the limitations of the individual studies whose data are pooled in the analysis.

First, it is worth noting that of the 2117 patients (intention-to-treat (ITT) 2045), the data on over half (1066 patients, ITT 1028) comes from the studies that have not been published as articles in peer-reviewed journals. Indeed, the data on 278 patients, 13% of the data used in the meta-analysis, derives from 2 unpublished studies by the manufacturer of venlafaxine, Wyeth-Ayerst (Study 347 and Study 349, respectively). Thus, one cannot critically assess how such factors as study design (subject recruitment, length of study, outcome measures, dose titration, data collection and analysis, etc.) and drop-out rates may have affected the outcomes.

Moreover, data on some 788 subjects (ITT 762), or about 37% of the meta-analysis population, come from studies published only in abstract form (Salinas et al, 1997; Rudolph et al, 1998), and the results of each must be placed in perspective. The 8-week study with some 323 patients (15% of the meta-analysis pool) by Salinas et al (1997) comparing venlafaxine extended release, paroxetine and placebo found no significant difference between drugs and placebo. In addition, there was a markedly greater discontinuation rate in the paroxetine group than in the venlafaxine 75 mg group (35% v. 20%). In an ITT last-observation-carried-forward analysis, such a difference in discontinuation rates could significantly affect the rates of response and remission.

Another paper published only as an abstract (Rudolph et al, 1998) was a 6-week study with some 460 patients (22% of the meta-analysis subjects) designed to compare speed of response to venlafaxine, fluoxetine and placebo. Can data from such a brief study accurately reflect remission rates at 10 or 12 weeks? Recent work by Quitkin et al (2003) suggests otherwise, as a significant number of non-responders to fluoxetine at 6 weeks may show remission at 12 weeks. Thase et al themselves acknowledge that differences in times to response between venlafaxine and SSRIs may have contributed to their findings.

In addition, Clerc et al (1994) likewise reported a 6-week study, wherein almost twice as many patients taking fluoxetine as those taking venlafaxine (35% v. 18%) dropped out of treatment. Finally, in their study of 301 out-patients (approximately 15% of subjects in meta-analysis), Rudolph & Feiger (1999) reported an almost 50% greater drop-out rate in the fluoxetine group compared with the venlafaxine group (29% v. 19%).

Thus, although the meta-analysis raises the interesting possibility of differential remission rates, one should bear in mind the limitations of the component studies.