From the Elusiveness of Schizophrenia,
New Clues to Treatment

By BENEDICT CAREY

In Brief:

• A wide array of genetic glitches may contribute to schizophrenia and explain why individual patients have such varied symptoms and responses to treatment.

• Many patients bounce from medication to medication for years; new thinking about the disease has led to expanded treatment options for some.

• In a growing number of treatment programs, psychiatrists provide to people who have had a first psychotic “break” intensive family-based or individual therapies, using medication only when deemed necessary.

The people who suffer from schizophrenia are hardly the only ones confounded by its symptoms. Scientists are baffled, too, and despite years of study they’ve had little success in explaining how the disorder develops, in whom, and why.

Yet there’s a restless energy among psychiatric researchers now, and it’s in part because of several recent studies that, paradoxically, reveal how insufficient current theories about schizophrenia are. Schizophrenia is not a single problem with a uniform solution, these results suggest. Rather, the disease most likely comprises a variety of related mental disorders, with an underlying biology and symptoms that can differ from person to person.

That shift in thinking has already led to expanded treatment options for some patients, and it is likely to guide research on the disorder for years to come.

Perhaps the most striking demonstration of how biologically diverse schizophrenia may be came in a gene study published in March. An analysis of blood samples revealed that rare and previously undetectable genetic mutations were strongly associated with the development of the disorder.

Doctors have known for years that there was some genetic basis for schizophrenia and that the disorder tends to run in families. But they had long assumed that it was some combination of common gene variations, not rare ones, that worked in concert to put people at risk for schizophrenia. While such dark conspiracies of commonly shared genes might well exist, the new findings suggest that other genetic glitches probably contribute — and that they can be unique to single individuals.

This genetic complexity could help explain why people diagnosed with schizophrenia are themselves such a diverse group. They can be withdrawn, listless, confused; they may also be energetic, social or disarmingly lucid. Their backgrounds differ widely, as do their lives and individual, subjective experiences.

Most critically, their responses to drug treatment vary widely — as another influential report recently made clear.

That study, a large government-financed investigation published in 2005, tracked some 1,500 people with schizophrenia who received the standard treatment: regular doses of powerful antipsychotic drugs like Risperdal, Zyprexa or perphenazine. These medications effectively douse the fires of delusional thinking in many patients, research shows, and calm their restless energy and wilder urges. But they do nothing for the listlessness or withdrawal common to schizophrenia. They also come with serious side effects, from movement disorders to rapid weight gain and metabolic changes that are risk factors for diabetes.

In fact, the 2005 analysis found that the vast majority of patients stopped taking the medication they were prescribed within a year and a half, because it either didn’t work well or had intolerable side effects, and switched to another one. The study found few differences between most of the drugs, whether they were newer, expensive medications or an old generic.

The findings confirmed in a rigorous way what psychiatrists who work in the trenches know from experience: Many patients bounce from medication to medication for years. Some find a drug they can live with; others do not and choose not to take drugs at all.

Psychosis can be miserable — and it says something when people prefer its twisted torments to being on a medication.

The shortcomings of the drugs, in turn, cast doubt on one working theory of the biology behind schizophrenia. The drugs act on the brain by numbing cells to a brain chemical called dopamine, which was thought to be overactive for some reason in people with schizophrenia. Most researchers now regard this so-called “dopamine hypothesis” as simplistic at best.

Drug makers see opportunity in this disillusionment and have been testing compounds that act on other signaling systems in the brain. A chemical messenger called glutamate, the brain’s primary stimulating agent, has become the focus of intense investigation. In a recent trial, for instance, the drug maker Eli Lilly reported that a compound acting on the brain’s glutamate system reduced symptoms of schizophrenia without major side effects. Such hopeful results too often pale under scrutiny, experts caution, and any “glutamate hypothesis” will most likely prove incomplete, too.

Yet, interest in an alternative brain signaling system represents a significant move away from old assumptions that have run aground.

What’s more, the emerging appreciation of schizophrenia as a variable disorder, requiring new and creative thinking, has given rise to an interest in treatments that are not based primarily on medication.

In a growing number of treatment programs, mostly in Europe, psychiatrists have been providing to people who have had a first psychotic “break” intensive family-based or individual therapies, using medication only when deemed necessary. Studies of this approach have shown that a third to a half of patients can manage for years without becoming dependent on medications, though researchers are not yet certain who can do so, or why.

Those questions, among many others, may turn out to have relatively straightforward answers. But for now, it is researchers’ growing openness to the many-headed complexity of schizophrenia that allows such questions to be asked at all.

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