After decades of treading water, Big Pharma appears to be making progress in the search for better treatments for depression.
Midstage human testing of new drugs, which attack the mood disorder in different ways, is already under way. Companies from Pfizer Inc. to Sanofi-Aventis are targeting a system of brain chemicals that are involved in the body's response to stress. Also showing potential are drugs that block the brain's pain, sleep and nicotine receptors, and could also influence mood.
Any advances would be welcomed by patients and industry alike. Depression, which has both physical and mental symptoms, affects about one in 10 adult Americans each year. Existing treatments work in only about half of patients, can have unpleasant side effects and have come under fire for possible links to suicidal thoughts. They nonetheless generated more than $12.6 billion in sales for the industry last year, according to the health-care information company Verispan. But drug makers stand to lose a big chunk of that revenue as many of the best-sellers lose patent protection.
The current crop of antidepressants, from the old standby Prozac to the brand-new Cymbalta, largely function the same way. They target a system of neurotransmitters, including the well-known serotonin, by correcting an imbalance that can take place in a small part of the brain. Doctors stumbled on the system's connection to mood in the 1950s while treating tuberculosis, and it has dominated industry thinking ever since.
"It's rather amazing to consider that even with the tremendous amount of research that has been done on depression, existing medications act on proteins from only about 20 of the approximately 15,000 genes in the brain," says Jack Grebb, vice president of neuroscience global clinical research at Bristol-Myers Squibb Co.
That reality pushed doctors toward new thinking. "As a resident, you have a textbook knowledge that antidepressants need two or three weeks to work," says Florian Holsboer, a professor of psychiatry and a director of the Max Planck Institute of Psychiatry in Munich. "I was very disappointed with that in reality and was scratching my head to rethink ideas about the causality of depression." Dr. Holsboer has been working on the stress approach to antidepressant drugs since the 1980s.
Taking on new approaches is clearly risky for pharmaceutical companies. Tinkering with serotonin-based antidepressants is easier for drug makers, and regulatory approval is more predictable. In 2003, Merck & Co. abandoned its study of a drug that was thought to affect mood by blocking a receptor linked to pain. It had failed efficacy tests after about 10 years of research.
Part of the problem is that the biology of depression isn't well understood, even compared with other difficult psychiatric diseases. Animal tests can be inconclusive; after all, scientists can't ask a rat if it feels sad. But small studies, and then slightly larger investigations, have given rise to new ideas about how depression works and how it might be treated.
For instance, there's a growing awareness at the molecular level that stress causes the increased production of a protein called CRF, which in turn triggers the release of hormones, including cortisol. Researchers now believe that excess cortisol can predispose people to depression by damaging nerve-cell connections and suppressing nerve growth.
Blocking the action of CRF on its target, CRF1, could help regulate that imbalance. Bristol-Myers Squibb has a so-called CRF1 antagonist in the middle stages of testing. GlaxoSmithKline PLC, Pfizer, Sanofi-Aventis and Johnson & Johnson are in the earlier stage of human testing on CRF1 drugs.
Vasopressin, a protein like CRF, can also increase cortisol, though more indirectly. Sanofi-Aventis and Wyeth are testing vasopressin antagonists, forms of which were originally developed to fight high blood pressure and heart failure.
Some scientists view depression as a form of emotional pain. That view led Merck to research a drug to act on the receptor NK1, which is involved in the transmission of pain messages among the brain's neurons. When the drug it developed failed to work on depression, researchers from other drug companies turned to the related receptors NK2 and NK3 to see if they also had behavioral effects. Sanofi is now in the final phase of human testing on an antagonist to the NK2 receptor, which researchers think can play a role in emotional behavior and the brain's ability to adjust.
Novartis AG has U.S. rights to a drug, called agomelatine, which is thought to influence mood in part through the sleep-wake cycle. This summer, European Union drug officials declined to approve the drug without long-term data showing its effectiveness. Novartis is optimistic about its regulatory chances in the U.S.; Servier, which has the EU rights to the drug, is collecting more data and plans to resubmit the drug.
In addition to agomelatine, Novartis has a drug in the early stages of human testing that could help regulate part of a major system of neurotransmitters in charge of excitability. That system accounts for nearly half of the neurotransmitters in the brain, but it has only recently become a target for serious drug development because drugs that aren't sufficiently nuanced risk causing seizures or loss of consciousness, says Gerard Sanacora, head of the Depression Research Program at Yale Medical School, who is conducting research on depression and that system, called the glutamate system.
The Novartis drug, in particular, targets the system's metabatropic glutamate receptor 5, which scientists think plays a role in the body's ability to react and adapt and thus is linked to people's response to stress. The drug in development would slow down the overactive response that is thought to exist in some depressed patients.
Meanwhile, smaller pharmaceutical companies are going after novel neurological pathways with older drugs that are thought to work on depression in new ways. Corcept Therapeutics Inc. is studying the effects of the abortion pill, mifepristone, on psychotic depression. The drug is believed to help the body reduce the effects of the elevated and abnormal release patterns of the hormone cortisol that can occur in psychotic depression. But in September the pill failed to beat an antidepressant alone in a Phase III study.
Targacept Inc. just finished a midstage study showing that mecamylamine, an old blood-pressure drug it got from Merck, acts as an antidepressant by working in a way that's related to nicotine addiction in the brain. Just as the nicotine in tobacco can improve a smoker's mood, a nicotine patch can make depressed patients feel better. The idea behind the drug is that blocking the brain's nicotinic receptors will control mood fluctuations.
For now, the CRF1 antagonists seem closest to commercialization. P. Murali Doraiswamy, head of the biological psychiatry division at Duke University, put the chances of CRF1 drugs making it to market at 30%.
CRF1 drugs could still run into some of the hurdles that earlier novel antidepressants faced. Several drug companies have canceled their CRF1 programs, in part because the drug can cause liver toxicity in early tests, among other problems. Bristol-Myers, for example, tabled one of its two CRF1 compounds recently in favor of the one it now has in human testing, and Johnson & Johnson abandoned one of its programs.
Scientists are cautiously optimistic, though. "If even one of these novel drugs makes it to the market, it would be a breath of fresh air for the field," Dr. Doraiswamy says.