Study Questions 'Real World' Benefits of Newer Antipsychotics
Are the cognitive benefits claimed by manufacturers of second-generation antipsychotics an artificial result of repetitive practice in test conditions?
That's what a randomized trial of risperidone and olanzapine comparing cognitive improvements among first-episode schizophrenia patients and healthy controls suggests. Risperidone is marketed by Janssen Pharmaceutica as Risperdal, and olanzapine is marketed by Eli Lilly and Co. as Zyprexa.
The study, reported in the October Archives of General Psychiatry, found that the cognitive improvements among patients were consistent in magnitude with the “practice effects”—the effects of exposure, familiarity, and procedural learning that naturally occur in test conditions—seen in healthy patients.
“It may be that these drugs are not improving cognition as much as previously thought,” said study author Terry Goldberg, Ph.D.“ Clinicians can't assume that patients are totally normalized in the cognitive domain, and in terms of research it suggests that trials of cognitive-enhancing drugs might include a comparison against healthy controls.”
Goldberg is director of research in neurocognition, psychiatry at Zucker Hillside Hospital/Feinstein Institute in Glen Oaks, N.Y., and a professor of psychiatry at Albert Einstein College of Medicine.
In the study, 104 first-episode schizophrenia patients were randomized to treatment with olanzapine or risperidone. Sixteen cognitive tests were administered at baseline, six weeks, and 16 weeks, and results were compared with performance on the same tests by 84 healthy controls, who were also tested three times.
Neurocognitive tests included measures of working memory and attention, speed, motor function, episodic memory, and executive function.
No differences in effects were observed between the two drugs; both produced dramatic improvements in positive symptoms, with cognitive improvements demonstrated for both drugs on nine of the cognitive measures.
But only two measures demonstrated greater rates of change than those observed in the healthy control group undergoing repeated assessment,.
“We think it's a practice effect,” Goldberg told Psychiatric News. “That's inferential, but if it looks like a duck and quacks like a duck, it's probably a duck.” He added that it is known that schizophrenia patients can demonstrate practice effects; that is, they are capable of learning tasks in a test environment and improving them through repetition.
“Practice effects are better than nothing, but they don't translate out of the laboratory into the real world,” he said. “What this suggests is that the drugs may not really be changing the compromised neurobiology that underlies cognitive deficits.”
William Carpenter, M.D., director of the Maryland Psychiatric Research Center, who has been critical of manufacturers' claims for cognitive effects of second-generation antipsychotics, said the study is persuasive.
“It is critical that we not misjudge the efficacy evidence for any drug tested for cognition in schizophrenia,” Carpenter said.“ Studies to date show either little or no benefit for cognition with the antipsychotic drugs. When a benefit is observed, many explanations other than efficacy have to be considered. Substantial doses of haloperidol have been the common comparator, and superiority of a new drug may simply reflect less adverse effect on cognition.
“This may be why neurocognitive advantages tend to disappear when compared with low-dose haloperidol, or to perphenazine as in the CATIE [Clinical Antipsychotic Trials of Intervention Effectiveness] study,” Carpenter added. “Goldberg's demonstration of improved testing scores simply reflecting learning or practice effects is crucial because of the tendency to interpret any improvement over time as due to drug benefit.”
“Cognitive Improvements After Treatment With Second-Generation Antipsychotic Medication in First-Episode Patients: Is It a Practice Effect?” is posted at<http://archpsyc.ama-assn.org/cgi/content/full/64/10/1115>.▪
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Published online: 16 November 2007
Published in print: November 16, 2007
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The second-generation antipsychotics may not change the compromised neurobiology that underlies cognitive deficits.
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