Wyeth’s blockbuster serotonin-norepinephrine re-uptake inhibitor (SNRI), Effexor (venlafaxine), is only 5.9% more effective than older selective serotonin re-uptake inhibitors (SSRIs) such as fluoxetine (Prozac, Eli Lilly) and paroxetine (Seroxat/Paxil, GlaxoSmithKline) at treating depression, a new meta-analysis suggests.

Effexor was found to be statistically superior to SSRIs as a class but only to fluoxetine on a one-to-one basis. The clinical significance of “this modest advantage” seems to be limited for the broad grouping of major depressive disorder, the researchers comment in the journal Biological Psychiatry.

Nonetheless, they suggest, the associated number needed to treat (NNT) of 17 patients to achieve a single benefit with venlafaxine over the SSRIs “may be of public health relevance given the large number of patients treated for depression and the significant burden of illness associated with this disorder”.

In their Comprehensive Analysis of Remission (COMPARE) with venlafaxine versus the SSRIs, a research team led by Charles Nemeroff, from the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine in the US, conducted a meta-analysis of 34 randomised, double-blind clinical trials comparing venlafaxine with SSRI antidepressants (fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram). Three of the team were from Wyeth Research in Collegeville, Pennsylvania.

A total of 4,191 patients were treated with venlafaxine at a mean dose of 151mg per day and 3,621 with SSRIs. Nine of the studies also included a placebo control group (n = 932). The primary outcome measure was intent-to-treat (ITT) remission rates (Hamilton Rating Scale for Depression _7) at week eight of treatment.

The meta-analysis revealed that the overall difference in ITT remission rates was 5.9% in favour of venlafaxine (95% confidence interval [CI]: 0.038–0.081; p < 0.001). Accordingly, the number needed to treat (NNT) to benefit one patient with venlafaxine in preference to the SSRIs was 17 (95% CI: 12–26).
In the nine placebo-controlled studies, the drug-placebo differences were 6% (0.02–0.09) for the SSRIs and 13% (0.09–0.16) for venlafaxine.

Looking at specific SSRIs, the difference between venlafaxine and fluoxetine (mean dose of 37 mg/day; 20 studies) was significant (6.6% [95% CI: 0.030–0.095]).

However, the smaller differences versus paroxetine (mean dose of 25 mg/day; eight studies; 5%), sertraline (mean dose of 127 mg/day; three studies; 3%), and citalopram (mean dose of 38 mg/day; two studies; 4%) did not reach significance. Moreover, attrition rates due to adverse events were higher with venlafaxine (11%) than with SSRI antidepressants (9%).

More for public health
In an editorial comment in Biological Psychiatry, Dr John Krystal concurred that the research outcomes highlight “an advance that may have more importance for public health than for individual doctors and patients”.

If an average doctor were actively treating 200 symptomatic depressed patients and switched all of them from an SSRI to venlafaxine, only 12 patients would be expected to benefit from the switch and this signal “might be very hard for that doctor to detect”, Dr Krystal noted.

On the other hand, he continued, if the entire population of depressed patients in the US –estimated at 7.1% of the total population or more than 21 million people – received a treatment that was 5.9% more effective than the SSRIs, “then it is conceivable that more than one million people would respond to venlafaxine who would not have responded to an SSRI”.

This, then, “may be an example of where optimal use of existing medications may improve public health even when it might not make much difference for individual doctors and patients”, Dr Krystal commented.

In a typical clinical practice “this difference constitutes a barely detectable benefit”, but it “could be meaningful across the large population of depressed patients in the United States”, he said.

The extended-release formulation of Efflexor is facing generic competition in 2010 and Wyeth is currently seeking US approval for a follow-on version, Pristiq (desvenlafaxine).