Going Beyond Prozac

In his 1968 novel "Do Androids Dream of Electric Sheep?" (which inspired the movie "Blade Runner"), Philip K. Dick introduced his hero fighting with his wife over what mood to be in. The couple, living in the dreary California of 2021, is fortunate enough to own a Penfield Mood Organ, a device that allows the user to dial up any desired state of mind. A setting of 382 is tolerance and gratitude; 481 is awareness of hope for a bright future; 888 is the desire to watch TV "no matter what's on it," and setting 3 imparts the desire to dial. They spar over the wife's decision to schedule, twice a month, three hours of hopelessness and despair.

If you could manipulate your moods with that kind of precision, would you want to? If your hopelessness and despair were out of control, you probably would. As helpful as today's antidepressants are, about one third of depression sufferers get little or no relief from them. And because the causes of depression are still so poorly understood, it's often hard to tell whether an intervention is getting to the heart of the problem.

But the science is changing fast. Researchers are amassing new insights into the biology of depression, and the knowledge they're acquiring is almost sure to spawn better treatments. According to the new model, depression stems not from a "chemical imbalance" (too little serotonin, too little norepinephrine) but from unhealthy nerve-cell connections in the regions of the brain that create our emotions. If that's true--and the evidence is compelling--then the real goal of treatment is not to alter the brain's chemistry but to repair its blighted circuitry.

The new paradigm reflects a growing awareness of how chronic distress affects the brain. Our stress-hormone system, which kicks us into action in an emergency, may remain switched on in susceptible people, especially those who were very stressed during childhood. Overexposure to stress hormones slows the growth of nerve fibers in a region of the brain called the hippocampus. This brain center allows us to soak up sensory input, link experience to emotion and store all of it as coherent memories. The hippocampus is typically small in depressed people, with some brain cells lost and some shrunken. Experts suspect it is one of the structures central to the condition.

The idea that depression is linked to stalled nerve-cell growth or faulty connections may explain an old mystery. If antidepressant medications boost neurotransmitter concentrations immediately (which they do), why does it often take six weeks or longer to feel better? Recent experiments in mice tell us that antidepressants stimulate the growth of new hippocampal nerve cells, which form new connections with older nerve cells. This process takes several weeks. If drugs like Prozac ease depression by inadvertently boosting neurogenesis, the thinking goes, drugs designed specifically for that purpose might bring surer relief while causing fewer side effects.

Yes, that is a very tall order, but researchers are already pursuing several possible strategies. One quest is to find a drug to block the action of Substance P, one of the chemical messengers involved in the stress response. Aprepitant, the first Substance P blocker to enter clinical trials, has recently proved worthless as an antidepressant. But other compounds are still under study, and researchers are hoping that one of them will work.

A second possible target for therapy is CRH (corticotropin- releasing hormone), a chemical produced by the hypothalamus, a tiny part of the brain with the huge responsibility of integrating hormones with behavior. CRH starts a cascade that ends with the release (into the bloodstream) of the stress hormone cortisol. Researchers have recently shown that an experimental CRH blocker called R121919 can dampen the stress response, both in lab animals and in depressed patients. That drug was abandoned due to concerns about liver damage, but drugmakers are now developing other CRH blockers--and learning to manipulate still other parts of the stress response.

Drugs that suppress vasopressin--another hormone released under conditions of stress--leave rodents less anxious and more spirited. Drugs that mimic a stress-busting hormone called Neuropeptide Y have similar effects. They may also have the ability to reduce a mouse's desire for alcohol--pointing the way to a possible new biological model for alcoholism. None of these compounds has reached advanced stages of clinical research, but some experts believe they represent the next wave in antidepressants.

It may take us decades to understand the biology of depression. What we need in the meantime is as many unique treatments as we can get. We may not want a mood dialer as close at hand as the TV remote. But for those stuck on the despair channel, the need for new options is urgent. With any luck, these new ideas will soon deliver better ways to tune the only mood organ we have: the brain.