Source: United Press International
Date: 3 March 2006

SSRIs face next-generation replacement

new antidepressants?


WASHINGTON, March 3 (UPI) -- A study released Saturday could pose more bad news for the beleaguered anti-depressant field, but some analysts think the selective serotonin reuptake inhibitors market has run its course anyway and will soon be replaced by triple reuptake inhibitors.

"Triple reuptake inhibitors will be the next blockbusters in major depression," Natalie Taylor, an analyst with Decision Resources, told United Press International. "With their new mechanism of action, they're going to offer a clinical difference in efficacy or in tolerability," Taylor said.

Triple reuptake inhibitors, or TRIs, block the uptake of serotonin, norepinephrine and dopamine.

"SSRIs will still be considered first-line therapies for a couple of years, but TRIs might have what it takes to replace SSRIs from that spot and then they're going to start impacting patient share," Taylor said.

TRIs in the pipeline include GlaxoSmithKline's NS2359 and Merck's dov216303. Both candidates are in phase 2, but GSK's is thought to be slightly ahead of Merck's.

NS2359 could launch in 2009, and peak year sales are projected to exceed $2 billion, Taylor said.

Merck's dov216303, which Merck licensed from Dov pharmaceuticals, could launch a couple of years behind GSK's product in 2011, but it will still be a blockbuster, she said.

"We forecast peak-year sales will be $1.5 to $2 billion," she said. This prediction is only for major depression and does not figure in sales for other indications.

The study released Saturday, which Duke University researchers presented at the American Psychosomatic Society meeting in Denver, found that coronary-artery-disease patients taking anti-depressant drugs, including SSRIs, may have a 55-percent higher risk of death compared to patients not on the medications.

The risk remained even after controlling for confounding factors.

"This finding that antidepressant use was an independent risk factor for mortality in patients with coronary artery disease was quite unexpected," said study co-author Lana Watkins of Duke University Medical Center.

Watkins pointed out that it was uncertain if anti-depressant medications were solely to blame for the increased death risk because the study was not a randomized, placebo-controlled trial. Even so, the risk remained even after accounting for other variables, "so there is something important going on here that we don't fully understand," she added.

Forest, which makes two SSRIs, declined to comment, and GlaxoSmithKline, which manufactures Paxil, told UPI it could not comment until it had a chance to review the published study.

Lilly defended the safety of SSRIs, including its Prozac, on heart function.

"There is considerable data in the public domain in support of the benefits of SSRIs and cardiac function in patients with depression," Lilly spokesman Morry Smulevitz told UPI.

"While we welcome further research on depression, results from Lilly's sponsored Prozac clinical trials indicate that therapeutic doses of Prozac do not have a harmful effect on cardiac conduction, heart rate or blood pressure," Smulevitz added.

Taylor said she doubted the findings would significantly affect the SSRI market. The sector has already taken a big hit from the concern about the link to increased suicide risk. Also, the current findings don't conclusively point to SSRIs as the culprit, so it's likely to be too nebulous to have much of an impact on the field.

In addition, generic competition is stealing a lot of market share from the branded medications, Taylor said. Of the six SSRIs on the market, only two are still on patent: Pfizer's Zoloft and Forest's Celexa. But these too will soon go off patent. Zoloft's patent is scheduled to expire in June, and Celexa loses market exclusivity in 2009, she said.

In the study, Watkins and colleagues analyzed clinical data of more than 900 patients receiving a cardiac angiography procedure. Approximately 19 percent of the patients were taking an anti-depressant, with 66 percent of those on SSRIs.

Over the course of three years, 21.4 percent of the patients on antidepressants had died compared to 12.5 percent of those not on the medications.

Patients on the medications had a 55-percent higher risk of dying even after controlling for age, gender, heart-pumping strength, smoking, heart procedures, other illnesses, severity of depression and education. The difference in death risk between SSRIs and other anti-depressant medications was not statistically significant.

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