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The line between typical and atypical (first- and second-generation) antipsychotic medications is becoming ever more blurred, with numerous investigators suggesting that the distinction is no longer valid or useful in designing clinical trials, or even in selecting the best agent to treat an individual patient.

Safety studies drawing attention to serious side effects attributable to drugs that have been traditionally categorized as “atypical” antipsychotics have shaken the long-held paradigm that these drugs, as a class, are safer than “typical” antipsychotics.

In addition, new evidence about the risk of sudden cardiac death with drugs in both classes, along with mounting concern about the long-term consequences of weight gain and metabolic irregularities, has made many experts take a critical look at the safety of second-generation antipsychotics.

The jury is out even about extrapyramidal motor side effects, which were once thought to be less of a risk with second-generation antipsychotics.

A recent study by researchers in the working group, Drugs in Psychiatry (German acronym, AGATE), found heterogeneity in drugs within both classes in terms of rates of extrapyramidal side effects in 6,061 inpatients, leading to the conclusion that the odds of inducing such effects were “not distinguishable” by class (Neuropsychobiology 2008;57:80-7).

The study findings characterized “the misleading dichotomy,” showing that rates of extrapyramidal side effects rose continuously with use of both typical and atypical agents and detailing class-busting performances of specific drugs.

For example, the AGATE researchers reported that the “atypical” drugs amisulpride and zotepine (not approved for use in the United States) and risperidone were indistinguishable from “typical” fluphenazine in terms of the risk of extrapyramidal side effects, whereas perazine, a “typical” antipsychotic available in Europe, had a risk profile lower than most drugs in the “atypical” class.

Preventing the development of potentially irreversible tardive dyskinesia, also presumed to be more likely with atypical antipsychotic medications, also is not as clear-cut as once believed.

A 2009 comparative review of antipsychotic drugs for first-episode schizophrenia revealed that most studies have compared the high-potency typical antipsychotic haloperidol with newer antipsychotics (CNS Drugs 2009;23:837-65).

Dr. Kayvon Salimi, lead author of the review, said in an interview that preclinical findings and clinical experience have indicated that mid- and lower-potency older generation antipsychotic medications might compare well with the newer generation antipsychotics with regard to neurologic effects. This was supported to some degree by the results of the 1,460-patient Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) studies, which should in Dr. Salimi's view be followed by similar well-designed clinical trials aimed at addressing remaining gaps in knowledge about how the drugs compare in terms of efficacy, tolerability, and overall effectiveness.

For example, there is insufficient knowledge to stratify the drugs according to risk for tardive dyskinesia, said Dr. Salimi, associate director of the clinical research unit at Dorothea Dix Hospital in Raleigh, N.C., and a clinician in the Schizophrenia Treatment and Evaluation Program in Chapel Hill, N.C. Both sites are divisions of the department of psychiatry at the University of North Carolina at Chapel Hill.

In addition, more knowledge is needed to better understand how the range of mid- and lower-potency older generation antipsychotics and the newer generation antipsychotics compare with one another when it comes to risk for metabolic impairments such as weight gain, dyslipidemia, and diabetes. “This is critical, because in the context of antipsychotic treatment, metabolic changes can happen quickly and in many cases can be difficult to reverse,” Dr. Salimi said.