Research May Enable Clinicians To Match Drug With Deficits

Patients who experience the cognitive deficits common with persistent, severe mental illness may benefit from newer, “atypical” antipsychotics. The specific benefit, however, is different for specific drugs.

A new head-to-head comparison of two newer “atypical” antipsychotic medications with the older “standard atypical” clozapine and the older conventional antipsychotic haloperidol has indicated that patients who do not optimally respond to the older standard medications may experience improved memory, attention, or executive functions when switched to the newer medications.

Research teams at four state psychiatric hospitals (two in New York and two in North Carolina) studied just over 100 patients with either schizophrenia or schizoaffective disorder in a double-blind, 14-week clinical trial. The group examined the effects of clozapine, haloperidol, olanzapine, and risperidone on a series of 16 different measures of neurocognitive functioning.

The study was funded by a grant from the National Institutes of Health with additional funding from the University of North Carolina Mental Health and Neuroscience Clinical Research Center and the Foundation for Hope in Raleigh, N.C. The report appears in the June issue of the American Journal of Psychiatry.

“So far, this may be one of the only studies to look at clozapine—which is sort of the signature or archetypal antipsychotic—and compare it with newer compounds like olanzapine and risperidone in a head-to-head way, while also including an alternate, standard, conventional antipsychotic like haloperidol,” lead author Robert M. Bilder, Ph.D., told Psychiatric News. “So we think this is a valuable study that may help to put several things into perspective.”

Bilder is the associate director for human research at the Nathan S. Kline Institute for Psychiatric Research, Center for Advanced Brain Imaging.

In their analysis the researchers broke down the 16 individual neurocognitive measures into four domains in addition to a global score. The four domains were general executive and perceptual organization, declarative verbal learning and memory, processing speed and attention, and simple motor functioning.

Patients in the study taking either olanzapine or risperidone saw improvement in global neurocognitive function that was statistically significant. Both olanzapine and risperidone were found to be superior to haloperidol, but did not differ statistically from each other or from clozapine. Over half of the patients taking the two newer atypical antipsychotics improved enough to see their scores improve at least one half of one standard deviation from the baseline measurements.

“It was quite impressive,” Bilder noted, “at least from one perspective—that the magnitude of change was such that it might be considered a clinically significant improvement, albeit the patients did remain significantly impaired. We shouldn’t undermine our level of concern for these patients, who had severe deficits. But the improvement was the equivalent of about seven-and-a-half IQ points.”

In their study, Bilder continued, one of the “tantalizing leads” that came out of the data was an indication that each of the medications may show benefits in different cognitive domains (see chart). The patients who were treated with risperidone showed statistically significant improvement in the declarative verbal learning and memory domain in comparison with both haloperidol and clozapine. Those receiving olanzapine saw significant improvement in the domains of processing speed and attention and in general executive and perceptual organization. Patients receiving clozapine showed a significant improvement only in the motor performance domain.

The intriguing and exciting implications of the differential effects on domains, according to Bilder, lie in the future study of the different mechanisms of action between clozapine, olanzapine, and risperidone. Although each are said to be “atypical antipsychotics,” each is chemically different from the other and is thought to exert its range of effects through different cellular mechanisms.

“The long-term hope,” Bilder speculated, “is that we might have a rational pharmacotherapy of cognitive deficits where patients with specific deficits might best be treated with specific medications targeted to different mechanisms of action.”

Bilder reiterated that much work will need to be done to achieve such an advanced treatment scheme. The current study stops well short of that goal, he noted. “But our study is one of the first to really begin to differentiate these compounds on differential neurocognitive function.”

The research that will undoubtedly follow, Bilder predicted, is hoped to “shed more light on the specific neuronal and brain systems that are impacted” by various diseases.

“There’s really very little about these cognitive deficits that are specific to schizophrenia,” he added, noting the potential to generalize future results. “All serious mental illnesses tend to share the same kinds of memory, attention, and executive function deficits.”

An abstract of “Neurocognitive Effects of Clozapine, Olanzapine, Risperidone, and Haloperidol in Patients With Chronic Schizophrenia or Schizoaffective Disorder,” is posted on the Web at http://ajp.psychiatryonline.org; search under the June 2002 issue or by article title. ▪