February 15, 2008

Schizophrenia drug’s dosage drives success

The Vanderbilt physician who in the late 1980s established the antipsychotic drug clozapine as the gold standard for treating patients with treatment-resistant schizophrenia has improved on his own research.

The Vanderbilt physician who in the late 1980s established the antipsychotic drug clozapine as the gold standard for treating patients with treatment-resistant schizophrenia has improved on his own research.

Herbert Meltzer, M.D., director of the Schizophrenia Program in the Department of Psychiatry, and colleagues have shown that the success of clozapine in treating this population was not due to the unique pharmacologic features of the drug itself, but the fact that it was used at higher doses than what is used to treat patients with schizophrenia who respond well to antipsychotic drugs. Clozapine is rarely used for the 70 percent of patients whose psychotic symptoms respond well to a wide array of other antipsychotic drugs.

The study, published in the Jan. 23 issue of The Journal of Clinical Psychiatry and funded by Eli Lilly, included 40 men and women, ages 18 to 58, diagnosed with schizophrenia or schizoaffective disorder, which many think is part of the same spectrum of illness. Patients were recruited from three U.S. outpatient community mental health treatment facilities, including Nashville’s Centerstone Mental Health Center.

The results showed that the drug olanzapine, whose pharmacology is considered closer to clozapine than that of any other drug available, when used at a higher dose than the established norm, is as effective as clozapine in improving psychopathology and cognition in treatment-resistant patients. The study showed that treatment-resistant patients taking higher doses respond more slowly than average patients taking conventional doses. In fact, both need to be given for six months before a good treatment response occurs, compared to six weeks for the average patient at the lower dose range.

Schizophrenia affects more than 2 million American adults, about 1 percent of the population age 18 and older. Approximately 30 percent of them are treatment-resistant, says Meltzer, one of the world’s leading experts on schizophrenia and principal investigator of the study.

“The results provide another option for treatment of those patients,” Meltzer says.

Though it has been the only drug approved for treatment-resistant patients for nearly two decades, clozapine has a serious side effect, agranulocytosis, that requires patients to be monitored closely while they are taking the drug. Agranulocytosis is a blood disorder in which the person has a low level of granulocytes — white blood cells important in fighting infections.

Meltzer said because the side effect can be fatal if untreated, patients who take clozapine must have their white cell count monitored each week for the first year, but less frequently thereafter.

“Because of the risk and hassle, clozapine was never as widely used as it should have been,” Meltzer said. “Instead of 30 percent of patients (those who are treatment-resistant) taking the drug, at most, 5 to 10 percent did.”

Another side effect of both clozapine and olanzapine is weight gain. “Both of these drugs very often produce serious weight gain, sometimes as much as 50 to 100 pounds,” Meltzer said. Patients in this study taking olanzapine gained significantly more weight (16 pounds) than those on clozapine (3 pounds).

“This study shows that olanzapine is a viable option for those truly treatment-resistant patients who won’t or can’t take clozapine, providing you take the dose up to the range we used, which was three to four times the dose now established as the optimal effective dose, and if you take caution to limit the weight gain, which unfortunately may not always be successful,” Meltzer said.

He cautioned that a larger study is needed to confirm his findings that the two drugs are essentially equally effective in treating this group of difficult-to-treat patients.

Meltzer’s next step is studying higher doses of the most widely used drug in the treatment of schizophrenia — risperidone. He and his Vanderbilt colleagues, William Bobo, M.D., and Yuejin Chen, M.D., Ph.D., plan to study the long-acting injectable form of risperidone because it does not produce as much weight gain or other metabolic changes as clozapine and olanzapine, and because there is better compliance with the long-acting form. Meltzer is particularly hoping to attract patients to the study who have failed to respond to standard doses of the drug. He hopes to enroll 160 patients, 80 of those in Nashville.

And during that study, using brain imaging and genetic markers, he and Vanderbilt colleagues Adam Anderson, Ph.D., and Stephan Heckers, M.D., chair of the Department of Psychiatry, will investigate why higher doses are more effective in these patients and why it takes longer to get a response.

At the same time, Meltzer’s lab will be involved in basic research to understand the effects of higher doses and longer duration of treatment with clozapine and related drugs in laboratory animals.

Meltzer said that expanding on his clozapine research from the 1980s has been a “terrific” experience. “I always have said if anything I ever published needed correction, I wanted to be the one to do it.”

Others at Vanderbilt contributing to the study were Bobo, Chen, Ajanta Roy, Ph.D., and Karu Jayathilake, Ph.D.

Meltzer is the Bixler/Johnson/Mays Professor of Psychiatry, professor of Pharmacology and director of the Division of Psychopharmacology.

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