The disease is known to doctors as "irrational rationality" because it forces its victims to defy reason while seeming to embrace it. Characters as disparate as Howard Hughes, Lady Macbeth and Freud's sexually conflicted "Rat Man" are among its victims. Today, in every elementary school of 200 pupils or so, three or four youngsters are likely to suffer from it. Howard Hughes' symptoms included an insistence on having a germ-free environment and all his windows permanently sealed. The schoolchildren are more inclined to count cracks in the blacktop (for them, "Step on a crack, break your mother's back" is frighteningly literal) or meticulously arrange their crayons in neat rows, again and again, to avert some imagined catastrophe.

All of them are suffering or have suffered from a mental disease known as obsessive-compulsive disorder (OCD), which torments its victims with clouds of horrific anxieties and forces them, like primitive priests propitiating unknown gods, to indulge in senseless and repetitive rituals. Not long ago, this disease--along with most other so-called mental illnesses--was considered to be a chronic, un-treatable condition, a psychological crippler whose roots lay hidden deep within the brain's mysterious recesses.

But the brain is finally giving up its secrets, and the biggest secret of all is that this 3-lb. maze of nerves and tissue is also a veritable laboratory of chemicals whose workings and interactions largely determine the state of our mental health, down to the latest mood swing. Many mental illnesses once thought to be purely psychological conditions--among them schizophrenia, panic disorder, post-traumatic stress disorder and OCD--turn out to be caused by specific chemical imbalances. Those who suffer from them are racked not by toilet-training traumas or the "unceasing terror and tension of the fetal night" (as an early psychoanalyst put it) but by something as simple--and complex--as an imperfectly mixed chemical cocktail. The Oedipus complex has been reduced to a matter of molecules.

The good news is that many if not most of these brain afflictions can now be remedied by increasingly precise psychoactive drugs. In the past few years, scientists have joined disciplines and come up with a whole new pharmacopoeia of compounds to deal with mental disorders. "Today the psychiatrists who treat patients are working hand in hand with the 'wet-brain guys'--the pharmacologists, chemists and molecular biologists," says Dr. Steven Hyman, director of the National Institute of Mental Health (NIMH) in Bethesda, Maryland. While the effects of earlier psychiatric drugs were discovered largely by trial and error, the latest compounds are aimed at exact targets in the brain. "When you wanted to develop a new drug, you used to copy an old one that worked, add a little twist to the molecule and test it out on patients," explains Dr. Kenneth Davis, chairman of psychiatry at Mount Sinai School of Medicine in New York City. "If you were lucky, you got a drug that worked as well as the old one but had fewer side effects. Now we can be very, specific and say, 'Let's go after the D3 receptor or the D4 receptor.'"

Scientists consider receptors--which are specially tailored protein molecules--and the substances that bind to them to be the critical junction in the ongoing chemical processes that underlie thinking, feeling, dreaming and remembering. For an electrical signal to travel from neuron to neuron in the brain, it must cross a minuscule gap, the synapse, between them. A number of different chemical messengers known as neurotransmitters ferry the signal across the synapse and then lock on to receptors that lie on the membrane of the next nerve cell in line.

Some neurotransmitters induce other neurons to fire; others dampen neuron activity. In either case, once the chemical locks on to the receptor, it sets in motion a cascade of chemical events in the receiving cell. This ongoing dance of neurotransmitters and receptors is the intricate code that brain cells use to communicate with one another.

Many psychoactive drugs--including opiates, the Valium-type compounds and angel dust--mimic the action of neurotransmitters by binding to particular receptors and influencing the neuron's firing. Pharmacologists have acquired the tools to screen new drugs quickly, testing their affinity for particular receptors by cloning, or duplicating, the receptors and then designing molecules that bind to them. So refined are the new techniques that scientists now know of 14 different receptors for serotonin, the ubiquitous chemical messenger that plays a critical role in sleep, mood, depression and anxiety. They have also discerned five different receptor subtypes for dopamine, a neurotransmitter thought to be involved in schizophrenia. By formulating compounds that selectively bind to particular dopamine receptors, for example, drug designers can craft schizophrenia drugs that curb hallucinations without triggering disabling Parkinsonian symptoms.

The development of drugs for schizophrenia, one of the most perplexing and devastating of all mental illnesses, was an early success story. After several decades as a hopeless research backwater, the schizophrenia field was reborn in 1989, when the U.S. Food and Drug Administration approved a remarkable drug, clozapine (brand name: Clozaril). Made by the Swiss pharmaceutical firm Sandoz, Clozaril was aimed at patients who did not benefit from other drugs. While traditional antipsychotic drugs such as chlorpromazine (Thorazine) and haloperidol (Haldol) work by blocking dopamine reeeptors, Clozaril appears to bind to serotonin reeeptors as well. "It is what we call a dirty drug," says Mount Sinai's Davis. "It probably binds to a whole bunch of receptors. We used to think that was a bad thing. Now we think that's maybe a good thing." Perhaps because of its affinity for serotonin receptors, Clozaril is largely free of the Parkinsonian side effects (the "Thorazine shuffle" and so on) that plague the classic anti-psychotic drugs. It was also the first drug to ameliorate symptoms of schizophrenia that are resistant to other drugs. But Clozaril has a major drawback: a life-threatening side effect called agranulocytosis, a drastic drop in white blood cells that requires patients to undergo expensive weekly blood monitoring.

Now scientists are exploring an entire spectrum of what Dr. Steven Paul, vice president for central-nervous-system research at Eli Lilly, calls "Clozaril wannabes" that they hope will work as well without triggering --agranulocytosis. One of the wannabes, risperidone (Risperdal), made by Belgium-based Janssen Pharmaceutica, entered the market in 1993, and four others are nearing approval by the FDA, including Lilly's Zyprexa and Abbott Labs' Serlect. Meanwhile, further down the drug-development pipeline are a number of third-generation Clozaril cousins, some of which are specifically targeted at the little-known D3 and D4 receptors.

"We're not curing schizophrenia with these new antipsychotics," says Paul. "But we can treat it better. What would happen if we designed a drug that was 10 times better than Clozaril?" Mount Sinai's Davis, on the other hand, thinks future schizophrenia drugs might well be based on altogether different chemical-messenger systems. "There is evidence that schizophrenics have abnormalities in two very common neurotransmitters, GABA [gamma-aminobutyrie acid] and glutamate," he says. "None of the current drugs do anything for the most incapacitating symptom of schizophrenia, the cognitive deficits. Maybe it's time to get off the dopamine merry-go-round we've been on for 40 years."

New drugs have also drastically altered the outlook for panic disorder, a chronic illness characterized by recurrent panic attacks and a lifetime of fear in between. The symptoms of an attack--among them palpitations, breathlessness, sweating, dizziness, tingling sensations, hot flashes or chills, as well as a sense of impending doom-seem so dire and life-threatening that patients frequently turn up in emergency rooms convinced they are having a heart attack or going insane. Thirty percent of the 2.4 million Americans with panic disorder go on to develop agoraphobia, the fear of leaving home lest they succumb to panic on the freeway, in a store or at a concert. Some 20% of patients attempt suicide.

Panic disorder probably results from a "combination of a genetic predisposition and some number of traumatic separations in childhood," according to Dr. Jack Gorman, a Columbia University psychiatrist. But whatever the cause, the brain of a person who suffers from it is different from that of someone who does not. Stimulation studies using the drug yohimbine have revealed an abnormal firing rate in an area of the brain stem called the locus ceruleus, which is rich in cells that release the neurotransmitter norepinephrine, the trigger for human fight-or-flight response. This primal alarm system has obvious survival value--useful for fleeing man-eating tigers and such. But in patients with panic disorder, it appears to kick in at too low a threshold.

A decade ago, many a panic-disorder patient ended up as a tragic, misunderstood recluse. But today panic disorder is one of the most treatable mental illnesses. Studies have shown that 70% of patients benefit from cognitive behavioral therapy, which includes breathing training, "cognitive restructuring" and "exposure therapy." Most patients can be helped by short-acting antianxiety drugs such as Xanax and long-acting antidepressants such as desipramine and imipramine.

The superstar of the hour, however, is the family of antidepressant drugs known as SSRIS (selective serotonin re-uptake inhibitors). There is evidence linking panic disorder to a serotonin deficiency, and these compounds appear to work by boosting serotonin levels. The best known of all this family is Prozac, Eli Lilly's $2.1 billion-a-year baby, which has become a societal catchword for relief from anxiety. But another family member, Paxil (manufactured by SmithKline Beecham), is the first to be approved by the FDA specifically for the treatment of panic disorder. While drug therapy by itself is successful in 70% of eases--the same rate as cognitive behavioral therapy alone-preliminary, unpublished research suggests that the success rate might climb as high as 90% when the treatments are combined. But Gorman cautions that this needs to be studied in more detail.

Nonetheless, says Dr. Una McCann, head of the unit on anxiety and affective disorders at the NIMH, "serotonin is obviously not the whole story. If it were, the SSRIS would not take two to four weeks to kick in." Recently, some researchers have begun to eye a naturally occurring chemical called eholecystokinin (CCK), an anxiety-causing compound that binds to receptors in the brain stem as well as the gut. This dual affinity may explain the butterflies-in-the-stomach sensations that often herald panic attacks. CCK-mimicking compounds trigger attacks in panic-disorder patients but not in normal volunteers, so a likely candidate for a new panic-disorder pill would be a drug that blocks CCK.

Other anxiety disorders appear to share a common fear circuitry in the brain and are treated by similar methods. Generalized anxiety disorder, for example, is different from panic disorder in that it does not strike suddenly but follows a predictable pattern of worries and fears. In social phobias, the trigger is an exaggerated dread of public embarrassment. "These people have panic attacks only in specific situations, such as writing a cheek in public, using public rest rooms or eating out," explains McCann.

The multifaceted SSRIS have also dramatically altered the treatment of depression, which remains the most common form of mental illness. Although no more efficacious than traditional anti-depressants, they do not produce many of the unpleasant side effects, such as sedation and weight gain, that have caused thousands of potential patients to shun treatment. "SSRIS have revolutionized, and continue to revolutionize, the comfort levels with which psychiatrists and family practitioners treat depression," says Dr. David Kupfer, chairman of psychiatry at the University of Pittsburgh School of Medicine. "Suddenly, physicians are more willing to prescribe these medications for people who truly need them, and people suffering from a depression are more willing to take them and stay on them."

Even patients who have been chronically depressed for five years or more respond well in 65% to 70% of cases, Kupfer points out, and recent research underlines the importance of remaining on the medications long enough to prevent a relapse. "New studies show that the dosage that got you better will keep you better," he says. "Depression is a chronic, lifelong illness, and we're beginning to think of these drugs as being similar to insulin for diabetes."

Still, a new generation of medications-perhaps tailored to particular serotonin receptors--is urgently needed for the 20% of depressed patients who do not benefit from existing drugs. Researchers hope to come up with compounds that begin acting immediately rather than in a period of weeks. "The Holy Grail of new anti-depressant treatment is rapid onset," asserts Dr. John Ascher, a research physician at Glaxo Wellcome in Research Triangle Park, North Carolina. "We're talking about medicine that takes effect in just a day or two."

Ultimately, scientists would like to figure out how genetic defects cause depression, and then to design drugs to correct whatever has gone awry. Gene mapping would be particularly helpful to people at risk for manic-depressive illness: although lithium and related drugs usually relieve the manic episodes, current antidepressants are often ineffective against the acute depressive ones. Says Aseher: "That's the real frontier."

Obsessive-compulsive disorder, which affects 1% to 3% of Americans, was until recently considered a chronic, untreatable condition. Victims more ordinary than Lady Macbeth and Howard Hughes are haunted by persistent, intrusive thoughts or worries (obsessions), and may spend countless hours performing repetitive rituals (compulsions) such as hand washing, counting, hoarding old clothes, arranging napkins in a meaningless symmetry or checking a hundred times to make sure the electric coffeemaker is turned off. Themes of dirt, contamination or germs rule their thoughts, and other common obsessions center on horrific or violent images, a need for symmetry or exactness, or an exaggerated sense of sin or morality.

A key breakthrough in OCD treatment came about in the late 1980s, when researchers discovered that a particular antidepressant, clomipramine hydrochloride (brand name: Anafranil), relieved obsessions and compulsions as no others did. The presumed secret of its success was its ability to inhibit the reabsorption of serotonin in the brain. A few years later, the advent of the SSRI family made it even more obvious that obsessive-compulsive disorder was at least in part a serotonin problem. Some 75% to 80% of OCD patients today get substantial relief--sometimes complete remission--from one or another member of the SSRIS.

Recently, positron-emission tomography (PET) scan studies at the UCLA School of Medicine have revealed that either Prozac or cognitive therapy can actually restore normal function in the obsessive-compulsive brain. The scans have documented that OCD patients have abnormal activity in the head of the caudate nucleus, a part of the brain's deep-dwelling basal ganglia, coupled with unusual activity in the orbital prefrontal cortex, just above the eye sockets. The caudate nucleus normally acts as a gatekeeper, determining which thoughts, feelings and behaviors take priority. When it malfunctions, the "worry inputs" generated in the orbital prefrontal region run unchecked, and irrational beliefs become rigid and intractable.

In any case, the worry circuits quieted down after the patients completed 10 weeks of either successful drug treatment or behavior therapy involving exposure and response prevention--demonstrating that either a molecule or a learning experience can materially alter the brain. "What we now know," says the NIMH'S Hyman, "is that anything-whether a drug, a war experience or a talking therapy-changes the way nerve cells talk to each other. In the brain, hardware as well as software is always changing"

In post traumatic stress disorder, the picture of a brain reshaped by experience is even more startling. Only recently, PTSD was deemed an exclusively psychological (not biological) phenomenon. Moreover, many clinicians regarded it as something of a scam, not a real mental illness like schizophrenia. But new medical discoveries, coupled with the wide publicity given to the experiences of Vietnam War veterans in particular, have changed that.

By definition, PTSD victims have suffered a trauma that involved death or serious injury and provoked feelings of intense fear, helplessness and horror that have long outlasted the event. They are hypervigilant, often sleeping with one eye open. "One Vietnam veteran will never stand in the center of the room when he comes here because he is afraid someone will stab him in the back," says Dr. Edna Foa, a psychiatrist at the Medical College of Pennsylvania. Victims are haunted by intrusive, disturbing memories--even entire flashbacks triggered by certain cues. "If I hear a helicopter, it ruins my whole day," said a Vietnam veteran. To avoid any such reminders, PTSD victims may retreat into virtual isolation, and commonly suffer from emotional numbing, fear of intimacy, memory deficits and depression.

One intriguing clue surfaced recently when magnetic-resonance-imaging scans of brains of combat veterans with PTSD were compared with those of civilians who did not have the disorder. Scans of the veterans' brains showed that the right hippocampus, a crescent-shaped structure that plays a key role in memory, was slightly smaller than normal. This may indicate that war, rape or torture actually harms the brain as well as the spirit.

PET scans tell another tale. When eight PTSD victims, civilian and military, volunteered for an experiment at Massachusetts General Hospital in Boston, a PET scan revealed that an area of their brains-the right amygdala, a small, almond-shaped structure--was abnormally active while they were reliving traumatic memories. "The amygdala is the key to the conditioned-fear response in animal studies," explains Dr. Roger Pitman, a psychiatrist at the VA Medical Center in Manchester, New Hampshire. "This study shows us that traumatic memories are activating this 'hot learning center.' It may be that stress hormones burn these memories into the brain, and that is why you have World War II vets still suffering from flash-backs of Iwo Jima."

Yet all this new knowledge has not led to a PTSD pill; unlike the other anxiety disorders, PTSD remains a hard problem to solve. Many medications relieve certain symptoms, such as insomnia, without remedying the underlying disorder. But scientists hope that current research-for example, studies indicating that PTSD patients' memories of disturbing images can be blunted by drugs that block one type of norepinephrine receptor-will produce a generation of medications to treat PTSD.

Is it possible that such studies will come up with a drug that could inoculate soldiers against war shock before they go into battle, or mute the horrifying images within hours, days or weeks? "The logistics would be difficult, but it could be done," says psychiatrist Dr. J. Douglas Bremner of the Veterans Affairs Medical Center in West Haven, Connecticut. "Soldiers suffering from acute-stress reactions on the battlefield are often treated with Valium and other drugs, We now think that acute-stress reaction is the prelude to PTSD. It would be nice to avert PTSD by interrupting the memory-consolidation process before those traumatic memories become pathological."

More secrets of the brain are emerging every day. There is evidence, for instance, that long-term use of antidepressants changes the intracellular environment permanently, even turning certain genes on or off, And new molecular techniques have revealed that individual receptors come in various genetic forms, or polymorphisms. This kind of knowledge opens the gateway to a whole panoply of fresh possibilities. The brain is a vast continent, and scientists have barely landed on its shores.

By JUDITH HOOPER
With reporting by Hannah Bloch/ Washington and Lisa H. Towle/Raleigh