Fast Versus Slow Strategy of Switching Patients With Schizophrenia to Aripiprazole From Other Antipsychotics :

Of the several factors implicated in causing QT interval prolongation and torsades de pointes, errors in the use of medications that may prolong this interval deserve special attention. To systematically summarize the available clinical data on the QT interval and to offer improved recommendations for the use of QT-prolonging medications. We searched MEDLINE from 1966 through 2002 for all English-language articles related to the QT interval. Additional data sources included bibliographies of articles identified on MEDLINE, a survey of experts, and data presented at a meeting of experts on long QT syndrome. We selected for review registries and case series examining clinical outcomes of patients with prolonged QT interval and the effect of different methods of measurement of the QT interval on patient outcomes. Ten studies were identified, of which 6 were included in the analysis. Data quality was determined by publication in the peer-reviewed literature. Optimal measurement of the QT interval is problematic because of lack of standardization and lack of data regarding the best way to adjust for heart rate. Reliable information on the proper use of QT-prolonging medications is scarce. Although a QT interval of at least 500 milliseconds generally has been shown to correlate with a higher risk of torsades de pointes, there is no established threshold below which prolongation of the QT interval is considered free of proarrhythmic risk. The risk of torsades de pointes should be assessed in patients who are about to begin taking a QT-prolonging medication. Although inadequate clinical studies preclude prediction of absolute risk for individual patients, particularly high-risk situations can be defined based on clinical variables. We propose recommendations on proper monitoring of the QT interval in patients receiving QT-prolonging medications. Although the use of QT-prolonging medications can predispose to torsades de pointes, there is a relative paucity of information that can help clinicians and patients make optimal informed decisions about how best to minimize the risk of this serious complication.

Aripiprazole, 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy]-3,4-dihydro-2(1H)-quinolinone, a novel antipsychotic with partial agonist activity at dopamine D2 receptors, bound with high affinity to recombinant human 5-HT(1A) receptors (h5-HT(1A)) in Chinese hamster ovary cell membranes and displayed potent, partial agonism at 5-HT(1A) receptors in a guanosine-5'-O-(3-[(35)S]thio)-triphosphate ([(35)S]GTP gamma S)-binding assay that was blocked completely by a selective 5-HT(1A) receptor antagonist. An interaction with 5-HT(1A) receptors may contribute to the overall efficacy of aripiprazole against symptoms of schizophrenia, including anxiety, depression, cognitive and negative symptoms, and to its favorable side-effect profile. Combined with previous studies demonstrating the potent partial agonism of aripiprazole at dopamine D2 receptors, this study suggests aripiprazole is the first dopamine-serotonin system stabilizer.

Data from two major government-funded studies of comparative antipsychotic effectiveness in schizophrenia contradict the widely prevalent belief that the newer second-generation medications are vastly superior to the older first-generation drugs. This has caused uncertainty among patients, clinicians and policy-makers about the relative utility of first- and second- generation antipsychotic agents in its treatment. To reduce confusion and provide a contextual understanding of the new data, the World Psychiatry Association Section on Pharmacopsychiatry comprehensively reviewed the literature on the comparative effectiveness of different antipsychotic treatments for schizophrenia and developed this update. Utilizing data from the approximately 1,600 randomized controlled trials of antipsychotic treatment in schizophrenia, we applied the two indirect and one direct method to comparing the effectiveness of 62 currently-available antipsychotic agents. The subclasses of 51 first-generation and 11 second-generation antipsychotics were both found to be very heterogeneous, with substantial differences in side-effect profiles among members. Second-generation antipsychotic agents were found to be inconsistently more effective than first-generation agents in alleviating negative, cognitive, and depressive symptoms and had a lower liability to cause tardive dyskinesia; these modest benefits were principally driven by the ability of second-generation antipsychotics to provide equivalent improvement in positive symptoms along with a lower risk of causing extrapyramidal side-effects. Clozapine was found to be more efficacious than other agents in treatment-refractory schizophrenia. There were no consistent differences in efficacy among other second-generation antipsychotic agents; if such differences exist, they are likely small in magnitude. Dosing was found to be a key variable in optimizing effectiveness of both first- and second- generation antipsychotic agents. There was enormous individual variability in antipsychotic response and vulnerability to various adverse effects. In contrast to their relatively similar efficacy in treating positive symptoms, there were substantial differences among both first- and second- generation antipsychotic agents with regard to their propensity to cause extrapyramidal, metabolic and other adverse effects; second-generation agents have a lower liability to cause acute extrapyramidal symptoms and tardive dyskinesia along with a tendency to cause greater metabolic side-effects than first-generation agents. Based on these data about the comparative effectiveness of different antipsychotic treatment options, we summarize elements of current best antipsychotic practice for the treatment of schizophrenia and discuss the role of government and the pharmaceutical industry in obtaining and disseminating information which can facilitate best practice.