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Atypical Antipsychotics Assessed at ACNP
Do people like the term atypical? This question was asked by David Pickar, M.D., chief of the National Institute of Mental Health's Experimental Therapeutics Branch, who chaired the symposium "Tracking the Next Generation of Antipsychotic Drugs."
"It's a term that has outlived its usefulness," rejoined the symposium moderator, John Kane, M.D., department of psychiatry, Hillside Hospital, Glen Oaks, N.Y. "What about 'novel?'" quipped Nina Schooler, Ph.D., professor of psychiatry and director of the Psychosis Research Program, University of Pittsburgh, amid discussion that quickly achieved consensus that new antipsychotic agents which offer therapeutic advantages over older neuroleptics will, themselves, soon become typical.
Kane then put semantics and categorizations aside, and challenged the psychopharmacologists to conduct investigations of the new compounds that will assist clinicians in choosing an optimal antipsychotic for a particular patient at a particular stage in that patient's illness.
"I think we're going to be increasingly hard-pressed to develop a data base that's going to assist us in answering those questions," Kane said. As the utility of the "typical" neuroleptics is now being questioned, Kane indicated, so should the typical clinical research paradigms be reconsidered.
One limitation of the current antipsychotic research data base, Kane recounted, is that subject populations have invariably comprised patients with chronic, entrenched illness.
"The patient population that we're studying in most of the antipsychotic drug development programs is really one segment of the population," said Kane, who is professor of psychiatry at Albert Einstein College of Medicine. "We have to make some decisions and choices based on the data that are generated by those particular trials."
Kane then recommended investigating the therapeutic potential of atypical antipsychotic compounds in patients experiencing their first onset of illness, before they are exposed to typical neuroleptics. "That has implications," Kane said, "not only in looking at the broad and immediate clinical effects of these drugs, but also setting the stage for actually attempting to study the impact of antipsychotic drugs on the evolution of the illness itself." He elaborated, "The evolution of negative symptoms, deficit state and a variety of other issues really can't be studied in patients given putative atypical compounds when they've already been treated with conventional drugs for 10 or 12 years."
Kane also asserted the continued need for placebo-control arms in antipsychotic clinical trials, while acknowledging the growing concern about the use of placebo in investigating medical conditions for which there is proven, effective treatment (Rothman and Michels). Placebo control is a valuable component of antipsychotic efficacy research, Kane argued, because of the variable, often marginal response associated with schizophrenia.
"Without having these comparative groups," he said, "it's difficult to know the responsiveness of the population you're studying, and we can draw erroneous conclusions about a new compound."
The measures of drug response most frequently employed in antipsychotic trials may also be inadequate, Kane suggested, to discern the scope of therapeutic benefit or track fundamental aspects of a patient's progress. Efficacy measures should extend beyond quantifying symptom reduction to include functional outcomes, Kane recommended.
"We're ultimately interested in where patients end up," he said. "What patients improve slightly or not at all? Were differences found between the new drug and comparators clinically as well as statistically significant?"
Other areas that Kane hopes can be elucidated in future clinical trials include: whether one antipsychotic offers sufficient therapeutic advantage to justify switching from another agent; the extent to which such adverse effects as akinesia and akathisia confound measures of clinical response; the optimal doses of study drugs and comparators from investigations with multiple dosage arms of each; and whether maintenance antipsychotic regimens can be evaluated for long-term efficacy, safety and compliance.
Kane also questioned the use of typical neuroleptic comparators to repeatedly demonstrate the efficacy of new, atypical antipsychotics. After initial studies have shown the therapeutic advantages of a new compound, Kane suggested, subsequent direct comparisons between atypical compounds could yield data that is more helpful to clinicians.
To underscore the extent to which new antipsychotics have demonstrated advantage over older neuroleptics, John M. Davis, M.D., Psychiatric Institute, University of Illinois, Chicago, offered the results of his recent meta-analysis of the olanzapine (Zyprexa)-haloperidol (Haldol) and the risperidone (Risperdal)-haloperidol comparative trials (Davis and others). He included all such studies published or presented prior to this ACNP meeting. He based the drug effect size comparison on the reported Positive and Negative Syndrome Scale (PANSS) and/or Brief Psychiatric Rating Scale (BPRS) score reductions associated with haloperidol or the newer antipsychotics, calculated as: mean reduction (new drug) less mean reduction (haloperidol comparator) divided by pool standard deviation.
For the olanzapine studies, Davis related finding the difference in effect size favoring olanzapine to be highly statistically significant.
"It's established," said Davis, "that olanzapine is better than haloperidol." Davis found the data for risperidone more complicated to evaluate because of the large number of (and occasionally heterogeneous) studies. "But taken in toto," Davis concluded, "I feel risperidone is significantly and quite substantially better than standard neuroleptics."
Where there is such evident advantage over typical neuroleptics, Schooler concurred with Kane that further distinctions between the atypical antipsychotics and their relative advantages in particular subsets of patients can be best ascertained through direct comparison. She suggested that an NIMH collaborative effort could facilitate these comparisons; others indicated that such studies are already underway, including a comparison of olanzapine and risperidone scheduled for presentation later in the ACNP proceedings. The interim report of this olanzapine-risperidone comparison is described below, as are the studies presented during the ACNP meeting which addressed the issues from this symposium of earlier treatment of schizophrenia, the switching of antipsychotic agents to improve response and broadening efficacy measures to include improvement of deficit states and function.
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