Psychiatrists are ridiculed for calling every quirk a mental illness, but new research on genes and the brain suggests they might be right.

By Sharon Begley

He was young for a stroke victim--only 48. But that wasn't what most puzzled neurologist Theodor Landis and neuropsychologist Marianne Regard about the political journalist recuperating at University Hospital in Zurich. Although a lesion in the right frontal part of his brain had made his left side so weak he couldn't walk, the patient didn't complain about being bedridden. He griped instead about the lousy hospital food. In a diary that the researchers asked him to keep, he wrote, "... sex I start to really miss, and it is time for a real hearty dinner, e.g. a good sausage with hash browns or some spaghetti bolognese, or risotto and a breaded cutlet, nicely decorated." After the patient recovered, he returned to work. As a dining columnist.

Of 36 other patients newly preoccupied with fine food, Regard and Landis found 34 with a brain injury exactly where the journalist turned food writer's was. "Gourmand syndrome," they reported last year, can be a sign of neurological damage. In other words, someone who plans vacations based on where he can find the best sea scallops with raisin-caper emulsion, or chases all over town for the perfect foie gras atop corn pancakes, may be (not to put too fine a point on it) brain damaged. The link between a sudden fixation on food and a brain lesion is one more piece of evidence that idiosyncratic behaviors and personality quirks once thought merely "odd" or "interesting" might be, in a sense, mental illnesses, a reflection of an abnormality in the brain and even in the genes. This is the back story: ever since Freud, the number of psychiatric illnesses has soared. The first edition of "The Diagnostic And Statistical Manual Of Mental Disorders" (DSM), published in 1952, listed 60; the second, in 1968, had 145; the fourth and latest version, in 1994, lists 410. Until recently it was easy to blame this psychiatric bracket creep on therapists trying to expand the population of paying clients. But two recent developments make it harder to dismiss. The first is brain imaging. MRI, CT and PET scans that peer into the structure and activity of the brain are turning up real, physical correlates of eccentric behaviors. The second is genetics. Researchers are finding genes that seem to increase the risk of particular mental illnesses. Because virtually all such illnesses are thought to involve several genes, it is tempting to label people who have only one or two of them "a touch" schizophrenic, or "just slightly" paranoid. And since the genes and brain quirks seem pretty common, "ultimately," says Dean Hamer, a leading behavioral geneticist at the National Cancer Institute who is best known for discovering the so-called gay gene, "it might mean that we're all a little bit crazy."

Mental health, in this new view, is a continuum. At one extreme might be a Ted Kaczynski, the Unabomber suspect described by his brother's lawyers as obsessive-compulsive, out of touch with reality, delusional, antisocial and paranoid. At the other end of the spectrum lie what are usually considered normal, even wonderful, human differences. The computer whiz who hasn't a clue how to engage in small talk is, according to the new theory, not merely socially awkward; he suffers from a mild form of autism. The emotionally needy person you can't get off the telephone has a frontal-lobe abnormality. And the originators of religious dietary rules and hand-washing rituals? They had mild obsessive-compulsive disorder.

In their 1997 book "Shadow Syndromes," psychiatrist John Ratey of Harvard Medical School and Catherine Johnson of the National Alliance for Autism Research argue that all sorts of quirky behaviors are actually mild mental illnesses. The athletic megastar who is as cool as ice in the championship game but explodes at a bar is not just a spoiled brat; he is beset by intermittent rage disorder. Men who are unable to talk about their feelings suffer "from an unrecognized adult form of attention deficit disorder" (ADD). Mild ADD also marks the business titan who can't file his taxes on time. The deadbeat dad, who dotes on his children when they visit but who can't seem to remember to send the child-support checks, is neither a louse nor someone chafing at an unfair custody arrangement. He has mild "environmental dependency syndrome": he can't focus on his kids unless he's with them. And the woman who can't abide a husband who fails to help with the house and kids once the two of them return from their jobs may suffer from "a very mild form of obsessive-compulsive disorder." Call it Mental Illness Lite.

This labeling is more than a party game ("He thinks we're whispering about him? He must have mild schizophrenia"). It has consequences. Doctors who blame their patients' peculiarities on biologically based mental illness, rather than seeing them as individual responses to life's circumstances, are quick to prescribe psychoactive drugs. Teenage girls with "body dysmorphic disorder"--deep unhappiness with how they look--are candidates for Prozac even before they develop anorexia or bulimia. So was one of Ratey's patients, a 6-year-old who sobbed uncontrollably every time his overprotective mother left him at school. Nothing stopped the tears: not his mother's giving him a kiss and leaving immediately, not her staying in the classroom briefly, not bringing a favorite toy. Once, a therapist might have explored the reasons for the mother's overprotectiveness. Perhaps she had an unhappy marriage that made her displace all her love onto her son. If so, the son's sobs might have been an unconscious way of cooperating with her needs. But Ratey had a different diagnosis. The mother, he concluded, suffered from a biologically based anxiety disorder and should try BuSpar, an anxiety drug. The little boy? Shadow panic disorder. Ratey prescribed Prozac.

Ratey also treated a 38-year-old mother who felt overwhelmed by rising at 5 a.m. for her full-time office job, commuting, shopping, cleaning and cooking, and caring for her two small children--"more than she could handle with good cheer," write Ratey and Johnson. "Caroline" started exploding in anger, slapped her child and threw a tape player against the wall. Stressed out and overextended like every other working mother she knew, Caroline began taking antidepressants. They helped. She relaxed, eased up on the cooking and felt better able to cope.

Some psychiatrists worry that their colleagues are dispensing brain drugs to treat symptoms rather than causes. Putting teenage girls on Prozac to cure them of their sense that their bodies are imperfect is so much easier, after all, than changing the Barbie culture. Or changing pro sports and its fans so that anger and aggression are not rewarded. Since many people have occasional and temporary symptoms of mental illness--from sadness to exuberance bordering on mania--"it's very difficult to say where mental illness shades into normalcy," admits Dr. Mark Olfson of Columbia University. "And that poses real questions for treatment: when should you prescribe antidepressants? In fact, they've exploded in use and are now prescribed for subclinical symptoms."

Calling deadbeat dads, violent athletes and frustrated housewives mentally ill might seem... crazy. A new book, "Making Us Crazy," by social scientists Herb Kutchins and Stuart Kirk, blasts the DSM for being scientifically unsound, swayed by politics (homosexuality is a mental illness; no, it isn't) and pathologizing everyday behaviors like holding a grudge or worrying about public speaking. "The psychiatric bible has been making us crazy--when we are just human," they argue.

The debate might have remained a standoff. Except that psychiatrists who believe in shadow mental illnesses are, to even their own surprise, getting support from science. "For years clinicians have been seeing people who don't fit the DSM criteria, and realizing that these syndromes don't just cut off abruptly," says Catherine Johnson. "They've gotten accused of empire-building, of drumming up patients. But now geneticists and neuroscientists are finding the exact same things." Or close to it. "It's absolutely going to be the case that geneticists will come to the aid of psychiatrists in this debate," says Stanford University neuroscientist Robert Sapolsky. "The idea of a continuum represents a major cognitive breakthrough for genetics. It suggests that a middling genetic load [of mental-illness genes] gives you a personality disorder, a lighter one gives you a personality quirk and a still lighter one gives you mainstream America."

Researchers found the first hints that mental illness comes in mild forms when they examined relatives of seriously ill people. "So-called schizoid personalities, who are extremely withdrawn, are commoner in families of schizophrenics," says Dr. Jonathan Benjamin of Ben Gurion University in Israel. "And awkward social behavior is more frequent in the biological parents of autistic children." That suggests that while the patient has many mental-illness genes, the relatives have only a few, and thus have "shadow syndromes."

Schizophrenia offers the classic illustration. Schizophrenics have less gray matter in the frontal cortex, the seat of higher thought, says psychiatrist Tyrone Cannon of the University of Pennsylvania. And in the hippocampus, which helps run memory and emotion, cells are out of place. People with mild schizophrenia, whose symptoms are not severe enough to keep them socially isolated, have mild versions of these brain abnormalities. People with severe schizophrenia, who are unable to distinguish fears and fantasies from reality, have severe versions. "Our twins study suggests that people with two genes out of a hypothetical 10 might have only subtle changes in brain structure and function," says Cannon. "But as you increase the number of genes you pass over the threshold to clinical significance."

One such subtle version is called schizotypal personality. People with this diagnosis tend to be suspicious of others; they prefer isolation and are overoccupied with unusual ideas such as a belief in the paranormal. Their speech is vague and digressive; their dress is eccentric. Studies of families support the idea that milder forms of mental illness result from having 1 or 2 rather than all 9 or 10 genes that contribute to the full-blown illness. "The risk that a sibling of a schizophrenic will have the [same] disease is doubled or tripled" compared with the general population, says NCI's Hamer. "But for a schizotypal personality, the risk to the sibling of a schizophrenic of having this is 10-fold higher. That says that a schizotypal sibling shares fewer of the disease genes than a schizophrenic sibling." Schizotypal personalities may not believe that the CIA has implanted a transmitter in their dental fillings, says Dr. Kenneth Kendler of the Medical College of Virginia, "but they are the ones who, when they walk into a bar, feel that people are looking at and talking about them."

Last year addiction, a mental illness, was found to be on a continuum with a normal personality trait. Researchers discovered an abnormally long version, or allele, of a gene on chromosome 11 (humans have 23 pairs of rod-shaped chromosomes, along which genes are strung like pearls). The allele was found more often in heroin addicts than in nonaddicts. The job of this gene is to produce a receptor--a sort of molecular docking site--for the brain chemical dopamine. Here's where the continuum comes in: the long version of the gene is also common in mentally healthy people who exhibit "novelty-seeking" behavior, according to research groups in Israel and at the National Institutes of Health in 1996. Such people tend to be impulsive, fickle, excitable, quick-tempered and extravagant; they seek thrills and feel exhilarated in novel situations. They are the world's race-car drivers and its explorers. This gene is only one of an estimated 10 or so that determine novelty-seeking, explains Ben Gurion's Benjamin. Someone with 2 or 3 of the 10 might be a little impulsive. Someone with all 10 might be a risk freak--or a heroin addict.

In just the last two years, researchers have discovered several genes that may account for personality quirks and, in combination with other genes, trigger mild or full-blown mental illness:

--In 1996 researchers led by NCI's Hamer identified a gene on chromosome 17 that contributes to neuroticism. This catchall term includes being anxious and sometimes depressed, hostile and impulsive. The gene comes in short and long forms, Hamer explains in "Living With Our Genes," a book due in March. It makes what is called a transporter, a protein that sweeps away the brain chemical serotonin from between neurons. Serotonin, Hamer believes, causes anxiety and depression. The short form of the gene makes less transporter, which is less effective at removing serotonin. One would therefore expect a connection: short gene, more serotonin, more anxiety. That's what the researchers found--the short form of the gene is more common in people who are neurotic (as determined by questionnaires). But this gene accounts for only a tiny amount of the differences in people's genetically determined degree of neurotic behavior. Hamer estimates it at 7 to 9 percent. In other words, there are other neuroticism genes. Having few or many could mean the difference between glancing anxiously at the clock when your teenager is out past her curfew... and being Woody Allen.

--In 1997 researchers linked a gene on chromosome 22 to obsessive-compulsive disorder. OCD is marked by intrusive, upsetting thoughts (the "O"), like not being able to let go of the idea that you forgot to turn off the oven, and repetitive behaviors that interfere with daily life (the "C"), like constant hand-washing. The purported OCD gene makes a sort of bio-vacuum cleaner--an enzyme that gets rid of brain chemicals after they have carried a signal between neurons. Everyone has this enzyme, but the OCD version makes such a wimpy version of it that the brain chemicals keep delivering the same infernal message over and over--a nagging "did you turn off the oven?" Again, several genes are thought to cause OCD. Someone with all of them might be so tied up in worries and obsessions as to be dysfunctional. Someone with one or two might keep a superneat desk.

New research suggests that milder forms of OCD arise from milder brain abnormalities, too. PET scans, which detect regions of high activity in the brain, have shown that a circuit running from the orbital frontal cortex--the bottom front of the brain, which acts as a sort of error-detection system--is hyperactive in OCD patients, finds Jeffrey Schwartz of UCLA. "It gives you the feeling of being stuck in gear," he says. In people with depression but not OCD, just the outer rim of the orbital frontal cortex is running full tilt. "These people have problems getting ruminations out of their mind," says Schwartz. "It's not a true obsession, but a milder thing"--with a milder brain abnormality.

--In December, researchers at Johns Hopkins University traced a gene for manic-depression to chromosome 18. That makes at least five genes associated with this disease. "It may be that if you have only one gene," says Dr. Francis McMahon, who led the team, "you might be more susceptible to mood elevations that let you meet deadlines through a burst of activity, or lead your business team across the finish line. The gene may be overrepresented among artists and creative types." Actor Robin Williams has described his deep depressions; any fan can see his mania. But someone with all five manic-depression genes might be too buffeted by mood swings to function. Says neuroscientist Dr. Samuel Barondes of UC, San Francisco, "Maybe having one of these genes is really good for you, but having all of them makes you crazy."

Genes associated with mental illness might, in fact, keep society supplied with the personality types it needs. People with schizotypal personality disorder, explains Stanford's Sapolsky, gravitate toward solitary lives. They are lighthouse keepers and fire-tower rangers. Those with a touch of OCD are the dogged employees who don't let go of a task until it is complete. Long ago, they may have been shamans and witch doctors and, perhaps, the men who established religious rituals. Who else could have thought up a Hindu ritual of washing the left hand 10 times, the right one 7 and both 5 more at the beginning of the day? The visions of Joan of Arc, the prophet Muhammad and Saint Paul are suggestive of hallucinations produced by temporal-lobe epilepsy. And in 1990 researchers in Minnesota, studying identical twins, calculated that religious belief is 50 percent genetic. Mercifully, they refrained from calling it the God Gene.

Even if neuroscientists find brain lesions linked to holding grudges or spending too much time on the Internet, and even if geneticists find stretches of DNA linked to being aloof or persistent, that will not prove that biology is destiny. For one thing, the structure and activity patterns of the brain reflect experience, not just the biology one is born with. The 40-year-old who has no interest in his lover's feelings may indeed have "bad brain chemistry." But that chemistry could be the product of a bad relationship with his father, social pressures to be emotionally distant--even a traumatic first date. And Schwartz's work with OCD patients has shown that they can overcome their "brain lock" by "willfully activating healthy circuits to predominate over the unhealthy ones," he says. Even genes that affect behavior by acting on the brain may determine our fate only in part. In a recent study, biologists found that baby rats whose mothers lick them have physically different brain structures from those whose mothers don't. The differences lie in regions that respond to stress. Licked rats handle it better than deprived rats do, suggesting that life's experience shapes the brain even when it comes to a trait as basic as temperament.

The idea that eccentric behaviors may be mild forms of mental illness is so new that its implications for society are unclear. But some scientists already worry about stigmatizing people who carry even a few genes for serious mental illness. Will couples count their respective "crazy genes" before they have children--or abort fetuses with too many of them? Will prospective mates demand to look at each other's brain scans? What will that do to the world's supply of artists and dreamers, adventurers and inventors? "If we discover that there are many genes associated with mental illness," says Hopkins's McMahon, "and that at least some of them are pretty common, it could make us realize that we're all in the same boat." Which suggests that when everyone is crazy, no one will be. So pundits will still get to poke fun at the notion that road rage, gourmand syndrome and other nouveaux disorders are real mental illnesses. But as genetic and neuroscience discoveries add support to the idea that something real, something physical, underlies these and other seemingly trivial ills, it will be harder to laugh.

Newsweek 1/26/98 Lifestyle/Special Report: Is Everybody Crazy?