The $15 billion market for antidepressants, one of the biggest in the pharmaceuticals industry, is in danger of crumbling as generic competition eats away at existing products and drug companies struggle to develop replacements.

Generic competition has already decimated sales of Prozac, Celexa and other drugs known as selective serotonin reuptake inhibitors, or SSRIs, and last week, Pfizer Inc. lost patent protection on Zoloft, the biggest-selling antidepressant in the United States.

According to market research firm Decision Resources Inc., the U.S. antidepressant market will remain flat over the next three years as generics capture more of the market. By 2010, nearly every top branded antidepressant is likely to face a generic rival.

In the meantime, there are very few branded drugs ready to take the place of those losing patent protection and even fewer that represent a substantive breakthrough, researchers say.

It's possible the depression market could die out like the sedative market did, said Kate Hohenberg, a Decision Resources analyst, referring to drugs such as Valium and Xanax.

According to Hohenberg, nothing revolutionary is likely to emerge until at least 2014, although Sanofi-Aventis has a drug that showed inconclusive results in a U.S. clinical trial and Novartis AG recently acquired U.S. rights to an antidepressant called agomelatine from privately owned French drug company Servier.

The drug has been filed for approval in Europe, but Novartis will need to conduct a clinical trial program in the United States, which could take several years.

Meanwhile, the market is likely to rely on updated versions of existing drugs and, possibly, drugs that combine medicines.

It's not like anything coming up is likely to be a bombshell breakthrough, said Dr. Alexander Glassman, chief of clinical psychopharmacology at New York State Psychiatric

Institute. They're tinkering with the same systems as we're tinkering with now.

Wyeth is currently awaiting approval for an updated version of its antidepressant, Effexor XR, which targets serotonin and an additional brain chemical called norepinephrine.

Sepracor Inc., maker of the sleeping pill Lunesta, is developing what it says is an improved version of Wyeth's updated version of Effexor XR. And both Sepracor and GlaxoSmithKline Plc are developing drugs that combine the attributes of an SSRI with those of GlaxoSmithKline's antidepressant, Wellbutrin, which targets norepinephrine and the neurotransmitter dopamine.

These drugs, known as triple reuptake inhibitors, could help tide the market over until a more novel generation arrives, with Glaxo's drug expected to reach the market in 2009.

Triple reuptake inhibitors are potentially the next generation antidepressant medications, said Cowen & Co. analysts in a recent report.

So far, both GlaxoSmithKline's drug and Sepracor's drug are in mid-stage development, but adding dopamine to the combination could be complicated as dopamine is involved with the brain's reward system and implicated in addiction.

The general rule is that the dirtier the drug the more effective, but the more side effects, said Glassman. The question is, can you find one that does most of the good things and none of the bad things.