Heading Off Psychosis Psychiatrists are at odds over a new approach to schizophrenia in which those at risk are given drugs before they fall ill

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At 21, daniel muscat's life would have looked to many young people like fun. He had a bunch of friends, a girlfriend he'd recently moved in with, and he was playing lead guitar in a heavy-metal band that stirred a small but rowdy following in the pubs of inner-city Melbourne. He loved playing the guitar and dreamed of making his living by it. But Muscat had been troubled for years by anxiety-partly caused, he suspects, by a "father who was never there for me"-and now it was building into torment. Alone at home, he'd close the windows and curtains. The prospect of going out became frightening. "I'd tremble as I approached the front door," he says. "I thought I was losing it."

Muscat sought help and was referred to a public mental health clinic in Melbourne. Personal Assistance and Crisis Evaluation (pace) was in 1998 conducting a world-first trial on young people whom it judged to be on the verge of psychotic disorders such as schizophrenia. Three years on, Muscat is married with three children and needs neither medication nor counseling. With apparent successes like him to show, the man behind pace, Professor Patrick McGorry, is convinced that schizophrenia can be prevented with early intervention. "We might not have enough evidence yet to prove it to the world," he says, "but I believe we've already saved a small number of people."

The preventive method still being tried by pace involves a controversial group of drugs known as antipsychotics, or neuroleptics. Since their introduction in the 1950s, these drugs have been linked with a plethora of harmful side effects, such as irreversible movement disorders; some patients have likened their effect to that of a "chemical lobotomy." Most psychiatrists, however, consider neuroleptics essential for treating schizophrenia. Still, the practice of giving them to young people in the name of research-pace has recently begun its second trial and similar projects have sprung up in the U.S.-is provoking some anger. Says David Oaks, the American director of Support Coalition International, a lobby group for the mentally ill: "This is one of the most bizarre and counterproductive human experiments on young people I know about." Others, such as Richard Gosden, author of the recently published Punishing The Patient: How Psychiatrists Misunderstand and Mistreat Schizophrenia (Scribe Publications), identify programs like pace's with attempts by pharmaceutical companies to expand the market for their products.

Some psychiatrists have described untreated schizophrenics as trapped in a strange world which healthy minds visit only in the moments before sleep-one of jumbled fantasies and half-formed ideas. Schizophrenia afflicts one in 100 people and usually strikes in adolescence or early adulthood, robbing sufferers of their powers of reason and planting the seeds of terrifying delusions. Sandy Jeffs was a 23-year-old university student in Melbourne in 1976 when she first experienced psychosis. "I became convinced I was the most evil person in the world," she says. "I wouldn't let people touch me, because if they did I thought they'd be contaminated by my evil."

Jeffs says the disorder led to periods of "torture" over many years. Today she manages her illness with medication, but she knows as well as anyone how schizophrenia can wreck lives and sometimes end them. Scared and confused by their symptoms, ostracized because of their strange behavior or depressed by the effects of drug treatment, 1 in 10 sufferers commits suicide. Jeffs tried to kill herself a decade ago, when she believed the Prime Minister of the day had ordered her to do so over the radio.

The theory behind pace's research is that psychosis has a pre-onset phase, or prodrome, lasting a year or more, during which careful intervention could prevent its development. As one of 59 subjects (aged between 14 and 28) in pace's first trial, Muscat made weekly visits to the clinic for counseling and took a 2-mg daily dose of the antipsychotic drug risperidone for six months. He responded well, he says, relapsing only when he forgot to take the drug. Though he now works as a storeman, music remains his passion and he plans to record a CD of his own jazz-guitar compositions. "Going to pace helped me put everything in perspective," he says. "I'm in control of my life again."

pace's critics-mainly dissident psychiatrists, human rights activists and former psychiatric patients-argue that we don't know enough about schizophrenia to be dabbling in prevention. Pointing to the absence of a lab test to confirm diagnoses of psychosis, critics reject the view of mainstream psychiatry that schizophrenia is a brain disease for which some people have a genetic vulnerability, triggered by stress. Author Gosden, who wrote a Ph.D. thesis on controversies over the cause of schizophrenia, explains schizophrenia as a "mystical emergency"-a search for meaning that requires the help of mystics, not psychiatrists. A more popular alternative view, as espoused by Massachusetts psychiatrist and recovered schizophrenic Daniel Fisher, is that the disorder is "a combination of severe emotional distress and an inability to attain, or maintain, a valued social role."

Whatever the nature of the illness, critics argue, it's almost impossible to identify before it manifests. The pace program, says Support Coalition's Oaks, "amounts to [the experimental] drugging of teens before they are even labeled schizophrenic-the definition of which is vague at best-with a powerful neuroleptic chemical that can cause brain damage, addiction and death." Professor Gordon Parker, head of the school of psychiatry at the University of New South Wales, supports the trials, but he too has reservations. "To give potentially dangerous drugs to people who may never develop psychosis," he says, "raises profound ethical questions."

If that makes McGorry a psychiatric zealot, he plays the role unconvincingly. Described by Parker as "in terms of international reputation, one of the top two or three psychiatrists in Australia," McGorry, 48, was influenced as a young man by the writings of the rebel Scottish psychiatrist Ronald D. Laing. McGorry thought he would be unable to bear working in psychiatry when he began studying medicine in the 1970s, but he later resolved to change it from the inside. Calm and softly spoken, he welcomes, he says, "careful and open debate" on pace's work. On a wall in his office in inner-city Melbourne, one picture stands out: a framed photo of a group of 1980s activists triumphantly carrying an ect (electroconvulsive therapy) machine from a psychiatric hospital in Melbourne.

McGorry, a professor of psychiatry at the University of Melbourne, says he feels for those who've been mistreated by psychiatrists, some of whom he blames for giving antipsychotic drugs their bad reputation. In the last 30 years, he says, these drugs have been prescribed "in grossly excessive doses, and people have been turned into zombies by psychiatrists."

In contrast, he says, pace uses only low doses of risperidone, one of the newer (so-called atypical) antipsychotics, which drug companies and most psychiatrists say are less likely to cause serious side effects than their predecessors. In pace's only completed trial, subjects were prescribed an average daily dose of 1.3 mg of risperidone-which McGorry says is much less than psychiatrists prescribe for schizophrenics.

Dr. Richard Prytula, a consultant psychiatrist and psychoanalyst in Melbourne, says that "if the [pace] doses are sufficient to be effective, they'll cause side effects." While some pace subjects have reported adverse reactions-Muscat experienced daytime drowsiness, others nausea and leaking breast milk-they seem to have been spared the more severe side effects associated with neuroleptics. "I'm not saying they're benign," says McGorry of the drugs, "but I don't believe the risk of taking them at [low dose] for six or 12 months is a big deal."

Others are more cautious. American psychiatrist Fisher argues that since atypical neuroleptics have only been around since the 1990s, it's too early to say whether they are safer than the old ones. Even the manufacturers concede that by targeting various neurotransmitters, these drugs have the potential to cause great harm. Risperidone, for example, comes with a page of small-print warnings on side effects, such as the potentially fatal neuroleptic malignant syndrome (an acute toxic reaction to the drugs that occurs in about 1% of patients) and the more common tardive dyskinesia, which is characterized by involuntary movements-sometimes rapid and jerky, sometimes rhythmic-that may be irreversible.

To better target the use of the drug, pace says it has worked on fine-tuning its criteria for choosing trial subjects: they must have some combination of a family history of psychosis and symptoms such as paranoia, auditory hallucinations, social withdrawal and a sudden decline in performance at work or school. Even so, pace cannot be certain that subjects would become psychotic if left untreated-only that there's a 40% risk of their doing so in the next 12 months. Gosden believes even that figure is inflated by flawed criteria. McGorry counters that most preventive treatments are somewhat hit-and-miss-and that antipsychotics are probably less so than other drugs, such as antihypertensives used to thwart stroke.

In pace's first trial, the progress of the 31 subjects who were given risperidone and counseling was compared with that of 28 controls, who received only counseling. In the first group, only three descended into psychosis during six months' treatment, compared with 10 in the second group. These are small numbers, McGorry concedes, "which is why I've been really cautious. I don't want to oversell it. But the risk is that if we don't get the chance to do these studies, the psychiatrists out there are going to be treating these [possibly pre-psychotic] patients with drugs anyway, without evidence to guide them. They're already prescribing them to disturbed kids, throwing them around like lollies." Last October, pace began recruiting for a second trial, which will eventually involve some 200 subjects. The results won't be published before 2004.

The pace experiments have been copied in the U.S., notably at Yale and Harvard universities, where opposition has been more virulent than in Australia-and for good reason. McGorry says some of the American researchers were impatient: "They went at it like a bull at a gate." The problem wasn't that subjects were seriously harmed, McGorry says, but that they were being treated with drugs on unacceptably flimsy grounds.

McGorry has an important ally in sane Australia, the national advocacy group for mental illness sufferers, whose executive director, Barbara Hocking, expresses some reservations about the pace research but says she "definitely" supports it, has the "utmost respect" for those involved and that most of the fears about it relate to "potential problems rather than real ones." Gosden points out that sane and pace have something in common: both are partly funded by drug companies-in pace's case, Janssen-Cilag, makers of risperidone (under the brand name Risperdal). "Pre-psychotic preventive medicine programs should be stopped dead in their tracks," says Gosden. "They have the potential to do enormous harm to human individuality and diversity ... [and are being] driven by funding and lobbying from the pharmaceutical companies." McGorry concedes that pace's link with Janssen-Cilag could invite concerns about influence, but says it was pace which made the approach and that Janssen accepted McGorry's condition that the company could have no role in shaping the research or interpreting the data.

As with most experimental research, the merits of pace's approach may not be clear for some time. "I'm glad somebody is doing it," says N.S.W. University's Parker. "We all need to be aware of the risks, but at least it is being done. So I do not see it as exploitation. And I do not see it as cavalier. I think it's a very carefully thought through, but contentious program." As Muscat strums his guitar at home, he reflects on a life repaired by pace's experimental approach. Given the anguish that schizophrenia causes, not just to sufferers but to their families, many people-dissatisfied with existing treatments-must be hoping that pace's research will prove a breakthrough in the fight against the condition.