ABSTRACT
Acylated and aroylated hydrazinoclozapines are highly potent dopamine D(1) antagonists that show remarkable selectivity over other dopamine receptors. The most potent compound in this series is the 2,6-dimethoxybenzhydrazide 33 with a D(1)K(i) of 1.6 nM and 212-fold selectivity over D(2) receptor.
Subject(s)
Clozapine/chemistry , Clozapine/pharmacology , Dopamine Antagonists/chemical synthesis , Dopamine Antagonists/pharmacology , Hydrazines/chemistry , Receptors, Dopamine D1/antagonists & inhibitors , Clozapine/chemical synthesis , Clozapine/classification , Dopamine Antagonists/chemistry , Dopamine Antagonists/classification , Dopamine D2 Receptor Antagonists , Molecular Structure , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/metabolism , Structure-Activity RelationshipABSTRACT
OBJECTIVE: To determine the prevalence, trends, and factors associated with antipsychotic polypharmacy categorized according to type of antipsychotic and duration of use and to contrast usage patterns with published treatment guidelines. METHOD: A retrospective cohort study was designed, and Medicaid recipients > or = 16 years of age with a schizophrenia diagnosis (ICD-9-CM = 295.xx) between 1998 and 2000 were identified from the California (20% random sample) and Georgia Medicaid claims databases. Use of anti-psychotic polypharmacy was categorized based on duration (long-term polypharmacy was defined as lasting > 2 months), and long-term use was further categorized based on type of antipsychotic combinations (clozapine, conventional, and atypical). The prevalence, mean duration, and frequency of and yearwise trends in antipsychotic polypharmacy were estimated. A stepwise logistic variable selection procedure was used to identify factors associated with long-term antipsychotic polypharmacy. RESULTS: Of a total of 31,435 persons with schizophrenia, the 1998-2000 prevalence of anti-psychotic polypharmacy was 40% (N = 12,549; mean age = 43 years; white, 47%; female, 48%; mean duration of polypharmacy = 149 days), and long-term antipsychotic polypharmacy prevalence was 23% (N = 7222, mean duration = 236 days). The prevalence of atypical antipsychotic poly-pharmacy increased between 1998 and 2000 (p < .0001). Use of newer atypicals such as quetiapine (OR = 18.32) and older conventionals such as chlorpromazine (OR = 28.87) was strongly associated with long-term antipsychotic polypharmacy. CONCLUSION: Antipsychotic polypharmacy is widely prevalent, is prescribed for long durations, and is an increasing phenomenon among Medicaid-eligible schizophrenia patients, indicating a significant discrepancy with treatment guidelines (which do not advocate the use of any poly-pharmacy except for short-term periods when transitioning patients to new antipsychotics). Further research evaluating the effects of antipsychotic polypharmacy in schizophrenia patients may assist in defining the scope and potential of such use.
