I know what you're thinking, "This is going to be a Cymbalta vs. Effexor article, and Cymbalta will get another TCR drubbing as it did last year."

Not quite. In fact, there are two major battles to be reviewed: Effexor vs. Cymbalta, but probably more relevant, Effexor vs. Lexapro.

First, a quick review. With the initial approval of Prozac in 1988, the 1990s were the age of the SSRIs. The first SNRI, Effexor (venlafaxine), made its debut in 1995, but this immediate release form bombed, largely because no patient could take a dose without nausea, insomnia, and fatigue, earning the product the early nickname of "side effexor." But in 1998, Effexor XR came to the rescue, as an extended release version that was remarkably well tolerated. In 2001, a Wyeth guardian angel named Michael Thase published the famous "pooled analysis," combining the results of eight Effexor vs. SSRI trials, and reporting a 45% remission rate for Effexor vs. 35% for SSRIs and 25% for placebo (Br J Psychiatry 2001;178:234-241).

Then, along came Lexapro, gaining FDA approval in 2002. TCR did a brief review of Lexapro in 2003 (TCR, January 2003). We reviewed studies comparing it with Celexa, showing that 10 mg of Lexapro proved as effective as 40 mg of Celexa, and was better tolerated. Forest ran with the data, and mounted an ingenious marketing campaign that basically convinced most physicians that Lexapro is the most tolerable SSRI on the market, and that you don't have to sacrifice efficacy for tolerability.

The campaign was so good that the trade journal Medical Marketing & Media gave Forest's Lexapro crew its "marketing team of the year award" for 2003. This reward didn't come cheap. The most recent drug advertising survey reported that Lexapro was the most lavish spender on glossy ads in medical journals, outspending all other drugs in America, whether "psychiatric" or "medical."

Chances are that you, dear reader, have bought into the Lexapro message of high tolerability, since most psychiatrists I talk to seem to believe it. But the data to support this is surprisingly weak. Your local Forest reps have certainly circulated two Forest-funded studies comparing Lexapro with Effexor, which is not the right comparison, since most of us already believe that Effexor less tolerable than SSRIs but we use it because of putatively better efficacy. Nonetheless, one study compared Lexapro 10-20 mg with Effexor XR 75-225 mg, and reported a discontinuation rate of 16% on Effexor vs. 4.1% on Lexapro (J Clin Psychiatry 2004; 65:1190-1196).

The hitch was that the design forced investigators to rapidly titrate Effexor up to 225 by day nine, a nausea- inducing schedule that we community psychiatrists only use when we're desperate to decrease our patient load. So you can throw out those numbers as being irrelevant to usual practice.

The other, saner, study, started patients at 75 mg of Effexor, and allowed investigators to double the dose in two weeks if clinically indicated. The mean doses at week 8 were 12.1 mg for Lexapro and 95.2 mg for Effexor. The dropout rates were 11% for Effexor and 8% for Lexapro--not statistically different. However, the specific side effects of nausea, constipation, and increased sweating were all significantly more common among Effexor patients (Neuropsychobiology 2004; 50:57-64). The bottom line is that Effexor is somewhat less tolerable than Lexapro in typical clinical practice circumstances--but not dramatically less.

More to the point, of course, would be a comparison between Lexapro and an SSRI in terms of side effects. But the only such comparison published is between Lexapro and Celexa. Studies that found that a tiny 10 mg of Lexapro was better tolerated than a hefty 40 mg of Celexa--no big surprise there. These studies were apparently crafted to show up Celexa as it was on the verge of going generic.

What about Effexor's famous efficacy gap? The two head-to-heads between Lexapro and Effexor showed similar efficacy, calling this into question. A larger pooled analysis of Effexor vs. SSRI studies, called the COMPARE study, is nearing publication (preliminary data available from Wyeth Medical Affairs). Instead of only 8 studies, this one includes data from 32 studies, and the Effexor efficacy gap has narrowed to a 41% to 35% advantage (vs. 45% to 35% in the smaller analysis). As with the original study, the most damning critique is that many patients in the SSRI arm may have tried and failed SSRIs in the past. Such patients were not excluded from these studies, and if there were many of them, it would stack the odds in favor of Effexor.

And Cymbalta? It got a nice shot in the arm with a recent FDA approval for treating diabetic neuropathy. How does this relate to depression? It doesn't, although it does put a little more face validity on Lilly's journal- saturating ads encouraging us to ask patients "Where does it hurt?"

In terms of response and remission rates, Cymbalta posts similar numbers to all the existing antidepressants, with reported response rates in the range of 45-50% and remission rates of 31-43% (see TCR Jan 2004 for a full review of this data). The only head-to-head involving Cymbalta compared it with Prozac (fluoxetine), but the study design was stacked in Cymbalta’s favor, since a robust 60 mg a day of Cymbalta was compared with a paltry 20 mg of Prozac (J Clin Psychiatry 2002, 63:225- 231). With regard to side effects, it's probably a little bit better tolerated than Effexor, a little worse than the SSRIs.

Cymbalta is taking a mild hit because of safety data showing that 1% of Cymbalta-treated patients develop elevated liver function tests (LFTs), vs. only 0.2% of patients on placebo (see its package insert for details). Lilly reps have taken to discouraging Cymbalta prescribing in the hard-drinking population for this reason, and TCR recommends occasional monitoring of LFTs in any patient on Cymbalta.

TCR VERDICT: The antidepressant horse race continues!