High-dose of multiple antipsychotics and cognitive function in schizophrenia: The effect of dose-reduction

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Abstract

We evaluated the effect of antipsychotic dose-reduction on the neurocognitive function of 17 schizophrenic patients (11 male and 6 female, mean age = 42.4 ± 11.3) who have been taking high-doses of multiple conventional antipsychotics. The mean (± SD) of total daily antipsychotic doses (in mg/day, chlorpromazine-equivalent) was 2253 (± 668) at baseline, which was reduced to 1315 (± 276). Possible changes in neurocognitive function were assessed using Wisconsin card sorting test (WCST) and continuous performance test (CPT). As controls, we examined WCST and CPT in 6 schizophrenic patients (4 male and 2 female, mean age = 47.7 ± 14.2) who had been taking high-doses of multiple antipsychotics (mean daily antipsychotic dose = 1753 ± 165 mg) and declined to change their antipsychotic regimen. In WCST, the mean number of total correct answers significantly increased (53.2 ± 16.3 vs. 63.8 ± 19.6, P = 0.035, Wilcoxon signed rank test); perseverative errors significantly decreased (54.4 ± 27.3 vs. 35.4 ± 20.1, P = 0.013, Wilcoxon signed rank test) after the antipsychotic dose-reduction. In contrast, the control group showed no significant difference between the two WCST performances conducted with a three-month interval. The improvements in WCST performance significantly correlated with the decreases in PANSS negative syndrome score in the subject patients. No significant change was observed in CPT performances in either group. Our preliminary data shows that, in schizophrenic patients taking high-doses of multiple conventional antipsychotics, dose-reduction might lead to improvements in cognitive functions.

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.

Section snippets

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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    In view of the observed deterioration in the FGA group during the longer treatment period, the question arises, might an early dose reduction have mitigated against the delayed negative effects of FGAs on cognition? This has indeed been reported previously (Kawai et al., 2006; Takeuchi et al., 2013), and others report that reduction or discontinuation of antipsychotic treatment was associated with better functional remission rates after seven years (Wunderink et al., 2013). Furthermore, Harrow et al. (2014, 2017) observed fewer psychotic symptoms, less hospital admissions and better work performance in the group without continuous prescription of antipsychotics during 20 years.

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