depression/ New York Times

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  • Napalmia
  • 10.11.2008 19:33
Depression is no monochromatic black veil, no shared melancholy, as is often claimed. Instead, the disorder is more like a virus that amplifies each sufferer’s particular vulnerabilities, whether anxiety, helplessness, self-doubt, anger or some combination of these. The subjective experience varies from person to person, yet treatment is far from personalized.

Progress has slowed as researchers grapple with one of the most difficult aspects of the disorder: it is impossible to predict who will respond to what therapy, and many sufferers find no relief from anything now available, including medication. While depression appears in many forms, therapeutic options remain worryingly limited.

“We’re at a point where we need to find new treatments, because it’s very clear that the old ones simply don’t work well for many people,” said Dr. Thomas Insel, director of the National Institute of Mental Health. “Our thinking about depression has to change, and it is changing.”

Some people are genetically predisposed to react more strongly than others to life’s inevitable blows. Scientists have traced this susceptibility in part to how the body processes a neural messenger called serotonin, which is linked to mood, and helps cells learn and communicate. For the past 20 years, depression researchers have focused heavily on this connection, both to understand the disorder and find better treatments. A serotonin “deficit” or “imbalance” has become synonymous with depression itself in the public consciousness, an easy catch-all explanation reinforced in drug ads and awareness campaigns.

But it is increasingly clear that serotonin is only one piece of the puzzle. Even when used aggressively by psychiatrists, selective serotonin reuptake inhibitors like Prozac and Zoloft, which prolong the action of the neurotransmitter in the brain, speed recovery in only about half of seriously afflicted patients. In a small number of young people, these drugs seem to backfire, making patients more likely to harm themselves or to think about it.

Indeed, many sufferers of moderate depression may be more likely to recover with talk therapy, particularly cognitive behavior therapy, in which patients learn techniques for defusing their own reflexive, self-defeating thoughts.

Despite the clear need, better therapies for depression have been slow coming. Newer alternatives, like Effexor and Cymbalta, are not S.S.R.I.’s but so-called S.N.R.I.’s; they prolong the activity of a brain messenger called norepinephrine, as well as serotonin. But this extra effect does not seem to make much difference for most patients, and experts consider these drugs to be essentially an extension of S.S.R.I. therapy, not a real departure.

“We really need to find better, more precise targets” for depression drugs, Dr. Insel said.

Assaults on depression based primarily on serotonin have hit a wall, in effect, forcing psychiatrists and researchers to explore entirely new notions about the causes of the disorder and possible options for treatment.

Recently investigators have explored the role of the hippocampus, an area deep in the brain critical to memory formation, in severe depression. They have looked more closely at the activity of the glutamate system, a brain messenger that jump-starts activity along neural networks. And they have used brain imaging to try to pinpoint areas in the brain that flare up or go quiet when people are suffering from spasms of despair.

Brain imaging has already paid off in an unexpected way. In a series of brain-imaging experiments performed at the University of Toronto and at Emory University in Atlanta, Dr. Helen Mayberg, a neurologist, has found that activity in a part of the brain known as Brodman area 25 is strongly associated with the experience of despair.

Brodman area 25 is uncharted territory; before these studies appeared, no one suspected it was linked to depression. But the researchers went one step further, implanting electrodes into the brains of severely and chronically depressed patients in an effort to quiet this area. The results were encouraging. Depression this severe can seem unbreakable, but most of the patients treated — more than a dozen have had the surgery — have improved enough that they have been able to return to work and to reconnect with family, friends and children. Most continue on drug therapy, as well.

It is a radical experiment, but it has made the darkness of depression visible, a first for psychiatry. If there are many different permutations of depression, then imaging techniques like these should soon help doctors differentiate them. Dr. Mayberg’s work already suggests that depression looks different in the brains of people who respond to talk therapy, compared with those who do well on antidepressants.

Scientists also are rethinking the pharmaceutical approach to depression, and in striking ways. Ketamine, a narcotic better known in nightclubs as “Special K,” has shown antidepressant effects in animal studies, but because of its reputation as a street drug it was never taken seriously as a potential therapy.

But last year scientists at the National Institutes of Health reported in a small study that some severely depressed patients recovered within hours after taking the drug intravenously. Most of them remained in improved condition for more than a week. Now the N.I.H. is running a large-scale study to determine how long the therapeutic effect lasts, and in whom.

The sudden scientific interest in ketamine has been criticized as a desperate stab at what has been an unsolvable medical puzzle, the treatment of chronic depression. But there is hope in the paradigm shift that has led to ketamine’s re-evaluation, and a welcome sign of change. The research already has scientists scrambling to find related compounds that don’t have the side effects of ketamine, as well as drugs that could sustain its effects once the initial treatment was stopped.

After reporting results from the 2006 ketamine study, the lead author, Dr. Carlos Zarate, chief of the mood and anxiety disorders research unit of the National Institute of Mental Health, summed up the findings this way: “What the study tells us is that we can break the sound barrier.”

He wasn’t just talking about breaking the hold of a devastating chronic disorder. He was talking about the science of depression itself, which was badly in need of a shake-up.

Publish date: 8/30/07