Pharmacology of atypical antipsychotics.

Atypical antipsychotics represent a new group of medications utilized in the treatment of patients with psychosis, primarily schizophrenia. Currently, there are four approved medications that fall under that classification, and they are clozapine, risperidone, olanzapine, and quetiapine. Even though these drugs are classified together and have some similarities, they are also significantly different. The pharmacology of each of these will be discussed. It is the “atypical” pharmacology that makes these drugs potentially useful in patients with Parkinson’s disease (PD). But, what is the definition of “atypical? ” It has not been strictly defined from a pharmacologic standpoint. Clozapine remains the prototype of this class of drugs and that with which all others are compared. Clozapine is distinguished from typical antipsychotic drugs by its strong antipsychotic effect coupled with freedom from extrapyramidal syndromes (EPS). For the sake of discussion, EPS primarily refers to druginduced parkinsonism. That, in essence, is the clinical definition of “atypical. ” A lack of EPS has implications with regard to the negative symptoms of schizophrenia, medication compliance, and the ultimate occurrence of tardive dyskinesia. Clozapine was commercially released in Europe but was withdrawn shortly after 16 patients developed agranulocytosis, and 8 died from infection in Finland in 1975 (1). The drug was also withheld from testing in the United States until the 1980s and was finally approved for use in 1990. In multiple trials for schizophrenia, clozapine has been shown to be as effective or more so than each neuroleptic with which it has been compared, including for negative symptom control (i.e., anhedonia, blunted affect, and motor retardation) (2–6). This is the first time where one antipsychotic agent was found to be superior, from an efficacy standpoint, to another (7). In one study, clozapine was found to improve 30% of treatment-resistant patients with schizophrenia (patients who failed therapy with at least three neuroleptics including 60 mg/d of haloperidol) (6) compared with only 4% with chlorpromazine, creating an important niche for this drug. A similar result came with a comparison to fluphenazine (7,8). In fact, the Food and Drug Administration in the United States has approved clozapine specifically for those resistant patients. In one of these studies (6), all patients were treated with haloperidol and benztropine for 6 weeks, then, in a double blind fashion, randomized to receive chlorpromazine and benztropine or clozapine for 6 weeks (after a 1-week washout). Patients were assessed weekly for EPS with the Simpson-Angus (S-A) scale (a measure of parkinsonism often used in psychiatric studies) and the Abnormal Involuntary Movement scale (AIMS). Despite masking of the side effects with benztropine, the S-A score increased during the openlabel haloperidol portion of the trial. In the washout, there was some improvement, but with chlorpromazine/benztropine, no further improvement occurred. However, in the clozapine group, the S-A score improved significantly. Clozapine patients also showed improvement of tardive dyskinesia on the AIMS score. The resulting superiority of clozapine with regard to antipsychotic efficacy and improved EPS revolutionized the treatment of patients with schizophrenia. This altered the notion that parkinsonism had to emerge if psychosis were to dissipate. Its impact on treatment for psychosis in PD has been equally important. However, enthusiasm for clozapine is tempered by the 1% risk of agranulocytosis and the required WBC monitoring. Patients must have a WBC count weekly for the first 6 months and then every other week for as long as the patient remains on the drug. There are other concerns as well. Recently clozapine therapy has been associated with hyperglycemia, venous thrombosis, and myocarditis (9–11). A variety of pharmacologic properties of clozapine have been sited as possible reasons for its atypical behavior, and they have been the standards from which to measure the atypicality of other agents in this class Presented in part at the Annual Meeting of the American Academy of Neurology, Philadelphia, Pennsylvania, May, 2001. Printed with permission from the American Academy of Neurology. Address correspondence and reprint requests to Stewart A. Factor, DO, Parkinson’s Disease and Movement Disorder Center of Albany Medical Center, 215 Washington Avenue, Albany, NY, USA. Clinical Neuropharmacology Vol. 25, No. 3, pp. 153–157 © 2002 Lippincott Williams & Wilkins, Inc., Philadelphia