The next wave of antidepressants.(new insights into the biology of depression change goal of treatment)

Miller is editor in chief of the Harvard Mental Health Letter.

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. They spar over the wife's decision to schedule, twice a month, three hours of hopelessness and despair.

Would you want to manipulate your moods with such precision? 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 hard to tell if 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. 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.

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 ...