Progress in Neuro-Psychopharmacology and Biological Psychiatry
High-dose of multiple antipsychotics and cognitive function in schizophrenia: The effect of dose-reduction
Introduction
In the past few decades, cognitive dysfunction has been recognized as a fundamental clinical feature of schizophrenia. The severity of cognitive impairment, rather than that of positive symptoms, may have a greater impact on the quality of life in this disease. Thus, improvement of the cognitive function has become an important target for the treatment of schizophrenia (Kasper and Resinger, 2003, Sharma and Antonova, 2003, Meltzer, 2004, Velligan and Miller, 1999). Conventional antipsychotics are effective for treating positive symptoms. However, they seem to lack the ability to improve cognitive function. Previous research has shown that the new generation of antipsychotics (so-called atypical antipsychotics) may offer many clinical benefits including better efficacy on cognitive impairment as compared to conventional antipsychotics (Conley and Kelly, 2002, Harvey et al., 2004, Kasper and Resinger, 2003, Meltzer, 2004, Sharma and Antonova, 2003, Velligan and Miller, 1999).
Notwithstanding, Japanese psychiatrists have a tendency to use multiple conventional antipsychotics simultaneously in chronically and severely ill patients. Accordingly, the total daily dosage of conventional antipsychotics has become extraordinarily high (Takei et al., 2002). Recent studies indicate that high-dose conventional antipsychotics are not very effective and may give rise to more adverse events (Davis and Chen, 2004). These possibly include damage to neurocognitive functions (Harvey et al., 2004). However, there has been no report in Japan examining whether the high-doses of multiple conventional antipsychotic uses aggravate cognitive impairment in schizophrenic patients.
We recently began a clinical trial to reduce the antipsychotic dosage and to establish a single atypical antipsychotic treatment regimen for schizophrenic patients who have been on high-doses of multiple conventional antipsychotics. To begin with, we simply reduced the numbers and the total daily doses of conventional antipsychotics before starting any atypical antipsychotics. We evaluated possible changes in cognitive function in the course of this procedure using the Wisconsin card sorting test (WCST) and continuous performance test (CPT). These two tests were chosen based on prior reports demonstrating good reliability and poor performance in schizophrenic patients (Barch et al., 2001, Goldberg et al., 1987, Servan-Schreiber et al., 1996). The purpose of this study was to determine whether the antipsychotic dose-reduction itself affects the cognitive functions in chronic schizophrenia.
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Subject
Our criteria for selecting subjects were; (1) patients had to be taking two or more conventional antipsychotics, (2) total chlorpromazine (CP)-equivalent antipsychotic doses (calculated according to Inagaki et al., 1999) had to exceed, or equal, 1400 mg/day, and (3) patients had to have been kept on approximately the same antipsychotic prescriptions for more than one year. Seventeen patients (12 male and 5 female) who met DSM-IV criteria (American Psychiatric Association, 1994) for a diagnosis
Antipsychotic dose-reduction and the PANSS score
All the 17 subject patients completed the dose-reduction procedure as planned. The mean total daily antipsychotic dose was reduced approximately by 42% (Table 1). The mean (± SD) of numbers of simultaneously used conventional antipsychotics was reduced from 3.5(± 0.9) to 2.1(± 0.7). The mean (± SD) period required for the dose-reduction was 21.3 ± 10.6 weeks (range: 10–40).
During the dose-reduction periods, some degree of improvement or deterioration in the PANSS subscale scores were observed among
Improved WCST results following the antipsychotic dose-reduction
This study demonstrates that, in schizophrenic patients who had been taking high-dose of multiple antipsychotics, some of the WCST indices significantly improved when numbers and daily doses of conventional antipsychotics were simply reduced. Our subjects, however, failed to increase the number of achieved sorting categories, which is usually regarded as the main benchmark for the evaluation of WCST. Nevertheless, the reduction of perseverative errors and the increase in total correct answers
Conclusions
Japanese psychiatrists prescribing high-doses of multiple conventional antipsychotic regimen should be aware of improvements in WCST performances following antipsychotic dose-reduction, as demonstrated in this study. The data suggest that such treatment has a damaging effect on the neurocognitive function of schizophrenic patients. The data also indicate that a careful dose-reduction would not lead to significant psychotic deterioration. Rather, it may lead to an improvement of the
Acknowledgment
We are grateful to Miss. Megumi Nakamura and Mr. Masatsugu Fujieda for their contributions to the neurocognitive test operations. We are also grateful to Dr. E. Marcotte for careful reading and correction of this manuscript.
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