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Plumbing the Depths Of Depression
Scientists Hope A New Tool Will Tap Into the Source Of the Blues

By Neely Tucker
Washington Post Staff Writer
Tuesday, September 26, 2006

Ketamine, sweet ketamine, answer to our glutamatergic dreams. In the long November night of the soul, in the ever-dark downpour of depression, it turns out that there might be a better umbrella than Prozac and Zoloft and Paxil and their serotonin-loving ilk.

Of course, when it comes to antidepressants, nobody really knows anything, anyway, so why not go with ketamine, a mild hallucinogen known to club freaks as Special K?

Yes, yes, break out the male Wistar rats and the injection needles -- researchers at the National Institute of Mental Health announced a study recently in which 18 chronically depressed patients infused with low dosages of ketamine improved within two hours. Seventy-one percent improved within a day, and nearly 30 percent were depression-free by that time. In 24 hours! These were people who had been dealing with depression from three to 47 years. They had failed to respond to just about every drug on the market.

Most of them stayed depression-free for up to a week.

Chronic depression, one of the most common, debilitating diseases known to mankind, blown away like a flower petal on a passing breeze.

Is it not the modern nirvana, the utopia of a neurotic generation, the idea that the demons lurking in the nether regions of the cerebral cortex could just . . . evaporate? Reigning there in the wet muck of the Freudian dark, the gargoyles of the mind took ketamine like a hit of kryptonite.

Doesn't it make Prozac and friends look like punks? The subsequent news stories focused on the speed -- antidepressants generally take two weeks or longer to work -- but the true breakthrough, scientists say, is that ketamine seems to do something entirely new. It focuses on glutamate, a chemical neurotransmitter that is involved in electrical flow among brain cells. It has not been targeted by any other antidepressant medication.

Think of depression as a leaky water faucet in the kitchen of the mind. Prozac and friends start working on the problem back at the water plant and, in about half of the cases, eventually find the problem.

In this trial, glutamate (and the "glutamatergic system") was shown to be a wrench-toting plumber who makes house calls. It got right to the problem.

"It's not quite the director of the orchestra, but it's involved with many other systems in the brain than other antidepressants," said Carlos A. Zarate Jr., chief of the mood disorders research unit at NIMH, and lead author of the study.

"It's early, but this is exciting because this gives us a new target, and it's a heck of a first move on it," said J. Raymond DePaulo Jr., chief of the Department of Psychiatry at Johns Hopkins School of Medicine and one of the nation's preeminent researchers on depression. He was not involved in the ketamine trials. "This is working on . . . a different set of chemicals. It says the malfunction may be in several different parts of the brain. Ketamine has problems with potential negative effects, but we could create 100 drugs to hit this target of glutamate."

If, you know, that is where the demon actually resides.

* * *

Depression: the Jersey dump fire of the mind, being stuck in the urinal of a Charles Bukowski drinking binge, a wet January locked in a closet with Edgar Allan Poe (whose original tombstone read, "Here, at last, he is happy").

It has been documented in various guises -- mania, melancholy, schizophrenia, fatalism, despair, suicide -- since man first took twig to papyrus. It has been regarded as a moral weakness, a sin, evidence of a flawed mind or the required companion to artistic genius. It uses the normal if unhappy thought patterns of sadness, grief, regret, fear and anxiety to scorch the psyche. It has been found in all cultures in all centuries. You think it is alienation, a postmodern creation of the European industrial age, and then you find out that rural Sri Lanka has the world's highest rate of suicide.

The World Health Organization estimates that 121 million people on the planet currently meet the criteria for clinical depression. These are long-lasting loss of energy, patterns of negative thoughts, inability to concentrate, suicidal ideation, insomnia and so on. There is no test, as there is for diabetes or a brain tumor. There is no clear marker separating, say, natural grief and the medical condition.

It's more of a feeling that goes out of control. It's the difference between waiting for the sun to come up, which is sadness, and the knowledge that the sun will never shine again, which is depression.

Wallace Stevens, "The Plain Sense of Things":

It is difficult even to choose the adjective

For this blank cold, this sadness without cause.

The great structure has become a minor house.

No turban walks across the lessened floors.

The greenhouse never so badly needed paint.

The priest in Ecclesiastes:

"I applied my heart to know wisdom, and to know madness and folly. I perceived that this also was a chasing after wind. For in much wisdom is much grief; and he who increases knowledge increases sorrow."

Playwright Eugene Ionesco:

"No society has been able to abolish human sadness, no political system can deliver us from the pain of living, from our fear of death, our thirst for the absolute. It is the human condition that directs the social condition, not vice versa."

The true genius of the disease, of course, is that it is a cognitive disorder that makes clear thinking impossible -- and yet requires insightful self-analysis in order to report the problem to a physician. You have to admit that is pretty ingenious.

Freud revolutionized the psychiatric field and the study of depression with his study of dreams, the taxonomy of id, ego, superego and the unresolved formulations of childhood trauma. Also, sex. You've got Jung, of course, and later the persuasive theory of Aaron T. Beck, the father of cognitive psychotherapy, who argues that depression twists the thinking process into increasingly negative avenues that repeat, over and over again.

And, about the same time as the Beatles, you had scientists voicing the theory that little chemicals ran around in our brains and made us do things that we'd rather not, Freud be damned. This was of great help to the novels of Kurt Vonnegut if nothing else. Brain biology: being utterly unable to get out of bed, running into the yard pronouncing yourself to be the risen Christ or pulling a shotgun out of the hall closet and looking down the barrel. You could take a pill, man. You could still be just as repressed as you ever were, with your mother who had beaten you with a curtain rod, but you just didn't care so much.

Wasn't that great?

It was like pulling a centuries-old dragon into daylight, where you found out it liked fresh hay and a nice barn. The beast could be tamed.

It happened like this: Doctors studying high blood pressure, or tuberculosis, discovered the medications they were using alleviated (or caused) great changes in their patient's moods. One of the main researchers was Rockville's own Julius Axelrod, who spent most of the 1960s learning how a neurotransmitter named noradrenaline works in the brain. (A scientist at the NIH, he won the Nobel Prize in 1970.)

His big idea was something called the catecholamine hypothesis, and it continues to the granddaddy of all psycho-pharmacology.

The thrust of his studies was the role of norepinephrine, a tiny messenger that goes between one neuron in the brain and the next, in depression. It turns out that a lack of that little messenger in the synapses, the spaces between neurons, tends to result in depression, because it can't tell the next neuron to slow down in whatever it is doing. So that neuron has a tiny crash, a little molecular runaway train, and that results in depression.

The first round of medications focused on norepinephrine, and the next generation focused on another messenger called serotonin. That's what Prozac and friends target -- they're called selective serotonin reuptake inhibitors, because they prevent the serotonin from being sucked back ("reuptaking") into the first neuron, and thus keeps them out there in the happy synapses, which results in a sort of mental sunshine.

Got that?

Of course, no one knows why that works, save for a general analogy that when any machine doesn't work well, it starts to fall apart.

Genetics plays a part in depression, too, as it clearly runs in families -- but there is no single gene responsible, geneticists say. Exercise alleviates some measures of depression. Light therapy in winter. Reducing stress. Manic depressives -- a different category of illness -- respond more to lithium. Psychotics, the most severe form of mental illness, respond to still other drugs.

"Everyone is aware that we don't treat depression that well," says Peter D. Kramer, author of "Listening to Prozac" and clinical professor of psychiatry and human behavior at Brown University. "Prozac wasn't effective at more major depressions, but only with more minor forms of mood disorder. I think the field is very much waiting for the next breakthrough. We'd like to have a few more arrows in the quiver."

No kidding, says Cheryl Murphy, a Las Vegas woman who, at 60, has tried to commit suicide five times. She has a daughter and granddaughter who are bipolar. She says she'll be lucky if those two live another 10 years before they succeed in killing themselves. She describes depression, in a telephone interview, as "having your kid's funeral planned in your mind."

Here's her trip through the back aisles of the pharmacy:

"I was on Zoloft first, for years. I was doing fine. Then I decided I was doing so well I didn't need it. When I tried to go back on it, it didn't work. I tried Prozac, and I wanted to kill everybody. It was like drinking tequila. I tried Wellbutrin, Effexor, numerous others. I'm on Neurontin now. It works more for anxiety than it does for the depression, but it keeps me from going off the deep end."

Now there's this target of glutamate, coming in the form of ketamine. It's a cousin of PCP, though, and is mainly used as an anesthetic for pets -- hence one of its nicknames, "cat Valium." People sometimes break into vet clinics to get it, for use as a club drug.

So no one thinks your family doc is going to be writing you a script for an orange bottle of ketamine anytime soon, but the research is continuing. Zarate, the NIMH director, said the next step will be to develop counter-medications to mask ketamine's side effects, and then on to other medicines that target glutamate. We're talking about years here.

Kay Redfield Jamison, a Washington-based psychologist and author (whose memoir of her own struggles with bipolar disorder was a national bestseller), thinks the research is exciting because it seems to throw much more light on how depression works in the brain.

"It's hard to put into words how painful severe depression is. It's just awful. It's life-threatening, it threatens work and relationships. When you knock out the ability to think clearly, or the energy to get up and do things, you haven't got much left as a human being. . . . The exciting thing here is the proof of principle. There is something that can work very quickly."

As the poets tell us, nothing is going to ever dull the pain of human life, or the depth of grief over the death of loved ones, or psychosis, or our sense of existential alienation in the universe.

"It is important to remember how deeply ingrained depression is in human consciousness," Kramer writes in "Against Depression." But, he notes, it seems perverse to describe as normal a condition that "eats away at the brain."

So perhaps it is the struggle against depression that uniquely human, too, in whatever form that might take -- prayer, art or a popped pill. Perhaps somewhere in the glutamatergic system or in some other wet corner of the brain there is a medication that can hack the vines away and let terribly ill people see the way to the warmth of love, the hope of redemption or even, as the priest in the Old Testament would have said, the tender mercies of the Deity. All those things are real, or can be felt as real, and all of those things are worth living for.

Even Freud knew that.

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