When I was a medical student in the mid-1990s, many of the newer generation antipsychotics used to treat schizophrenia, such as risperidone and olanzapine, were just coming on the market. My psychiatry rotation was at the famed Bellevue Hospital in New York, and half of the unit to which I was assigned was filled with patients in clinical trials of many of those drugs. In many cases, these were double-blinded, placebo controlled trials, but that was a bit of a feint. As we made rounds, we could nearly always tell which patients were taking the new medications. It wasn't whether or not they were still psychotic. They were the ones who were stiff or drooling.

In a nutshell, that's the frustrating story of schizophrenia treatment, an effort, until recently, largely directed at blocking dopamine 2(D2) receptors. Even the most successful of drugs turn out to have side effects ranging from barely tolerable to nearly lethal. It wasn't supposed to be this way. The newer medications of the 1990s and later - collectively referred to as atypical antipsychotics - were designed to avoid the side effects of earlier typical drugs such as Haldol: the Parkinsonian stiffness, the neuroleptic malignant syndrome, the tardive dyskinesia. If these new drugs could target the psychosis-inducing part of the dopamine pathway, or other pathways, while avoiding the side effect-inducing part, they would be a huge advance.

Some did that, although in real-life practice, the doses required to quiet psychosis ended up producing side effects anyway. Take the case of olanzapine. Approved in 1996, its relatively high affinity for serotonin receptors made doctors hopeful that it would avoid many of the typicals' side effects. But it's ended up resulting in weight gain and diabetes among those patients who take it.

As a result, schizophrenia remains a terribly debilitating disease desperately in need of better treatments. It costs the United States $60 billion per year, as the feature on "A very expensive disease" of this special supplement on schizophrenia details. With a remarkably consistent prevalence around the world, it costs health care budgets everywhere many times that. It destroys the lives of those who suffer from it, and of their families.

That's why scientists are looking at different genes ("Pregnancy, chromosomes, and receptors"), receptors, and pathways ("Molecular mysteries") as they engage in research. New imaging modalities are also providing new clues; see "Seeing schizophrenia." This research has already led to new drugs in the pipeline, as the material in the last section of this supplement demonstrates.

It bears mentioning, however, that even if such treatments are successful, drugs are not enough, as Anne Harding found when she visited successful long-term programs in New York (see "Beyond drugs") that are emulated by hundreds nationwide and around the world.

Thanks to our sponsor, Johnson & Johnson Pharmaceutical Research and Development, for their support in funding this supplement. We hope that what you hold in your hands will galvanize more efforts to fight this terrible disease.

Ivan Oransky Deputy Editor