Subject:
Antidepressants

Short Description:
Two New Meta-Analyses Compare Antidepressants

Background:
Two recent meta-analyses compared second-generation antidepressants (SGADs) to each other regarding efficacy and safety. One study (Cipriani A et al., Lancet 2009; online ahead of print), compared 12 SGADs across 117 controlled trials consisting of 25,298 participants. The researchers used data at the end of eight weeks whenever possible and defined treatment response as 50% or greater improvements on the Hamilton Depression Rating Scale (HDRS) and the Montgomery-Asberg Rating Scale (MADRS), or much improved or very much improved on the Clinical Global Impressions Scale (CGI). Two primary statistical methods were used: a) a traditional meta-analysis of studies that directly compared various ADs to each other and b) a set of complex statistical methods that incorporated data from all studies, even those that did not directly compare the medications. For example, to determine the efficacy and safety of Zoloft (sertraline) versus Paxil (paroxetine), they examined a) studies that directly compared the two drugs and b) studies that compared Zoloft or Paxil to other SGADs. Few differences were found in the direct comparisons: most notably, Prozac (fluoxetine) performed worse than Zoloft, Effexor (venlafaxine), and Remeron (mirtazapine). When incorporating data from direct and indirect comparisons of the drugs, the researchers found that Remeron, Lexapro (escitalopram), Effexor, and Zoloft were significantly more efficacious than Cymbalta (duloxetine), Prozac, Luvox (fluvoxamine), and Paxil. Overall, the authors concluded that Zoloft and Lexapro fared best in combined efficacy and tolerability.  The Agency for Healthcare Research and Quality (AHRQ) sponsored a similar comprehensive meta-analysis of SGADs (Garltehner G et al. Ann Intern Med 2008:149;734-750). They found that efficacy differences between newer ADs were negligible, although Remeron had a faster onset of action than Celexa (citalopram), Prozac, Paxil, or Zoloft. They also found that Remeron leads to more weight gain than other medications, that Effexor is linked to higher rates of nausea and vomiting, and that Paxil and Effexor may have the highest rates of discontinuation symptoms. Additionally, Paxil was linked to higher rates of sexual dysfunction than Prozac, Fluvox, Serzone (nefazodone), and Zoloft. Unsurprisingly, Wellbutrin (bupropion) was linked to lower rates of sexual dysfunction than other medications. Both meta-analyses found that Lexapro was more efficacious than Celexa, but the Garltehner et al study concluded that the difference between the two drugs was quite small. 

TCPR's Take:
The Lancet study took more of a “stand” than the AHRQ study, concluding that Zoloft and Lexapro, by slim margins, were the winners in terms of combined efficacy and  tolerability. The AHRQ study was less inclined to name a winner, but did provide some useful (though unsurprising) details about relative side effects of different agents. One can argue that the AHRQ study is the more accurate of the two, since these researchers analyzed more raw data, including response rates, change scores, and individual side effects. The Lancet researchers looked only at response rates and used rates of drop-out from studies as a proxy for adverse events. Neither study appeared to be influenced by conflicts of interest. Contrary to some papers published over the last decade, neither of these comprehensive reviews found Effexor to be more effective than SSRIs. Ultimately, it appears that our antidepressant prescribing decisions must still be based on a mixture of efficacy data, side effects properties, drug-drug interactions, and clinical judgment.