International Journal of Psychiatry in Clinical Practice, 2008; 12(3): 180186
ORIGINAL ARTICLE
Effects of amisulpride on the cognitive function of patients with schizophrenia who switched from risperidone
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YU-TING WANG1,4, NAN-YING CHIU3, SHAW-HWA JOU3, YEN KUANG YANG1,2, I HUI LEE1,2, CHING-CHENG WANG3, KAO CHING CHEN1,2 & YI-CHENG LIAO3 1
Department of Psychiatry, National Cheng Kung University Hospital, Tainan, Taiwan, 2Department of Psychiatry, College of Medicine, National Cheng Kung University, Tainan, Taiwan, 3Department of Psychiatry, Changhua Christian Hospital, Changhua, Taiwan, and 4Department of Psychiatry, St. Martin De Porres Hospital, Chiayi, Taiwan
Abstract Objectives. The aims of this 13-week study were to examine the efficacy and safety of amisulpride, and effects on cognitive function in patients with schizophrenia after they switched from risperidone. Methods. Twenty-three patients with schizophrenia whose antipsychotic was switched from risperidone to amisulpride were recruited. The efficacy, safety, and cognitive function were assessed. Results. Significant improvements were noted in the PANSS, CGI-S, and MADRS. The prolactin level, but not any of the remaining laboratory variables, increased significantly. The cognitive function improved significantly, particularly in memory subtests. Conclusions. Switching antipsychotic from risperidone to amisulpride in schizophrenia might have significantly improved not only the efficacy, but also various domains of cognitive function. However, hyperprolactinemia existed and was sometimes even worse.
Key Words: Amisulpride, cognitive function, hyperprolactinemia
Introduction Amisulpride, a substituted benzamide derivative, is an atypical antipsychotic with selective high affinity for the dopamine D2 and D3 receptor subtypes [13]. Since amisulpride is essentially devoid of 5HT2 antagonism, its moderate affinity for striatal D2 receptors and preferential occupancy of limbic cortical D2/ D3 receptors may acccount for its therapeutic efficacy and low liability to induce EPS [4,5]. In contrast to amisulpride, risperidone is a central 5HT2 and dopamine D2 receptor antagonist with relatively higher affinity for 5 HT2 receptors. A review of previous literature revealed that the efficacy of one atypical antipsychotic over another often depends on the primary measure. Atypical antipyschotics have demonstrated equivalence on positive and negative symptoms [69]. Clinically, side-effects are a critical factor in choosing medication. Among the treatment of atypical antipsychotic agents, these following side effects are very common: affect symptoms, hyperprolactinemia, sexual dysfunction, and changes in cognitive function. In addition to positive and negative symptoms, affective impairments are another major feature of
schizophrenia [10]. These affective impairments may be detrimental to the quality of life for patients with schizophrenia [11]. However, few studies have been performed in this regard. Antipsychotic-induced hyperprolactinemia has been reported as the major cause of sexual dysfunction in patients with schizophrenia [12]. However, few studies have examined the effects of hyperprolactinemia associated with amisulpride for treating patient with schizophrenia [13,14]. Cognitive impairment is a cardinal feature in patient with schizophrenia. Their verbal memory, vigilance, and executive function were identified by a recent review to be associated with functional outcome [15]. Matsui et al. [16] reported that compared to healthy population, schizophrenia patients have deficits in organization of story memory, which are related to symptoms such as disorganized thoughts and behavior. Bruder et al. [17] also reported that a subgroup of schizophrenia patients had a specific verbal memory deficit that is not limited to working memory, but extends to learning and recall of verbal material [6]. Compared with typical antipsychotics, atypical antipsychotic like risperidone was demonstrated to be better in
Correspondence: Dr Nan-Ying Chiu, Department of Psychiatry, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua, Taiwan 500. Tel: 886 4 7238595, ext 7170, 1032. Fax: 886 4 7299371. E-mail: [email protected]
(Received 28 June 2007; accepted 12 November 2007) ISSN 1365-1501 print/ISSN 1471-1788 online # 2008 Informa UK Ltd. DOI: 10.1080/13651500701805727
The effect of amisulpride: A switch study improving cognitive functions such as verbal working memory [6] and verbal declarative memory [15]. However, few studies have shown any difference in cognitive improvement between different kinds of atypical antipsychotics, for example, risperidone and amisulpride. The aims of this study were to examine: (1) the clinical efficacy and adverse effects; (2) the affective symptoms; (3) the plasma prolactin level changes and sexual dysfunction; (4) the cognitive changes; in patients with schizophrenia after they switched from risperidone to amisulpride.
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Subjects and methods Subjects Prior to the study, the protocol was approved by the local Institutional Review Board and informed consent was obtained from the participants. Twenty-three subjects who met the criteria of DSM-IV-TR for schizophrenia were recruited from the outpatient psychiatric clinics at the Changhua Christian Hospital and the National Cheng Kung University Hospital in Taiwan. Four subjects dropped out because of the following reasons, respectively: (1) the subject titrated drug dose by herself due to weight gain; (2) exacerbation of
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psychotic symptoms; (3) agitation; and (4) agitation along with schizophrenia exacerbation. The subjects’ demographic data are shown in Table I. All participants had initially received risperidone within the 16 mg/day range for at least 3 months before the study. The patients with partial improvement were considered eligible cases for our study. ‘‘Partial improvement’’ was defined as having a Clinical Global Impression-Severity Score (CGI-S) of 14. If the patients’ CGI-S scores were 12, they may also experience troublesome side effects attributable to the current treatment regimen. The exclusion criteria included: (1) pregnant or lactating women; (2) patients treated with anticonvulsants, antidepressant, or mood stabilizing agents; (3) patients with specific systemic disease or other medical conditions that may interfere with the evaluation of the therapeutic response or the safety of amisulpride; (4) patients with high suicidal risk; (5) patients with any substance abuse or dependence; (6) patients who had been previous treated with amisulpride; and (7) patients with drug treatment resistance. This was a 13-week, open label, non-randomized, single-treatment, flexible-dose study of oral amisulpride (1001200 mg/day). Patients’ antipsychotic was switched from risperidone to amisulpride by a fixed strategy. That is, the institution of amisulpride
Table I. Demographic data and daily doses of antipsychotics.
No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Mean9SD 1
Sex F M F F F M F M F F F F M M F F M F M M M M M
Duration of Duration of Age illness antipsychotics (years old) (years) therapy (years) 32.3 44 22.8 20.8 27.8 36.3 24.3 30 22.1 28.9 47.2 21 29.8 19.8 40.7 42.7 47 35 22.4 34 46.9 42.7 23.9 3299.4
7 14 4 3 10 2 4 14 8 13 18 1.5 14 3 25 13 21 10 7 10 20 25 2 10.497.6
6 14 0.5 3 10 2 4 14 8 12 11 0.5 10 3 16 13 21 10 25 2 6.796.2
Pre-switching Daily dose of daily dose of risperidone amisulpride at the end of study Completed study Yes Yes Yes No1 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No2 Yes Yes Yes No3 No4 Yes Yes Yes
mg/day
frequency
3 4 3 2 1 3 1 2 2 2 2 3 4 2 5 2 2 5 4 2 6 4 4 2.991.3
HS BID HS HS QD HS QD HS QD QD HS HS HS HS BID QD HS HS HS HS HS HS HS
The subject titrated drug dose by herself due to the adverse event of weight gain. Exacerbation of psychotic symptoms. 3 Agitation. 4 Agitation. Schizophrenia exacerbation. 2
mg/day 400 200 400 400 400 600 200 100 200 200 200 200 600 100 400 200 200 400 400 400 400 300 200 304.29141.4
frequency BID QD HS HS HS HS HS QD HS QD QD HS BID QD HS QD QD QD QD BID HS HS HS
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treatment was gradually achieved and risperidone was discontinued within 1 week (from Day 0 to Day 7). After the 7-day switching period, the patients received amisulpride alone for the next 12 weeks (Day 8 to Day 91). Measurements Most of the tests described below were performed twice, namely before and after switching, while the efficacy and safety measures were checked four times, (on Day 0, Day 7, Day 35, and Day 91).
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Efficacy measures The measures included the Clinical Global Impression-Severity and Improvement (CGI-S and CGI-I) [18], and the Positive and Negative Syndrome Scale (PANSS) [19]. Safety measures The measures included the Barnes Akathisia Scale (BAS) [20], the Abnormal Involuntary Movement Scale (AIMS) [21], the EPS Rating Scale (ESRS) [22], the Simpson-Angus Scale (SAS) [23], the Changes in Sexual Function Questionnaire (CSFQ) [24], and the Quality of Life (QOL28) [25]. In addition, the usage of anticholingeric agent and beta blocker was also recorded during the study period. Affective symptoms assessment The assessment was Montgomery-Asberg Depression Rating Scale. (MADRS) [26]. Laboratory assessments The laboratory assessments included hemoglobin (Hb), hematocrit (HcT), platelets (Pl), red blood cell count (RBC), white blood cell count (WBC), asparatate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), creatine (Cr), alkaline phosphatase (Alk-P), sodium (Na), potassium (K), fasting glucose, fasting lipid profile; prolactin, luteinizing hormone (LH), thyroid stimulating hormone (TSH), and body weight. Cognitive function assessments The assessments included the Wisconsin Card Sorting Test (WCST), the Continuous Performance Test (CPT), and the Wechsler Memory Scale, revised version (WMS-III). Statistics The results are presented as means with standard deviations and/or 95% confidence intervals. All
patients were included in the analysis of the efficacy and the safety measurements using last-observationcarried forward data (LOCF) technique, which helped us to obtain the complete data needed for analysis and decrease the bias resulting from the dropped-out participant. Either repeated-measure ANOVA or paired t tests were performed to analyze the laboratory assessments and the cognitive measures data. The post hoc multiple comparison tests were performed using the levels of the first visit as the reference. Multiple comparisons would decrease the P values. In our study, P values equal to or less than 0.01 were considered significant in order to avoid spuriously significant findings. For the efficacy assessments, we chose to present only PANSS, CGIS and QOL28. For the safety assessments, we presented ESRS only. But ESRS is regarded as insignificant. For the lab data, only prolactin level is presented. Changes in the categorical variables were analyzed using either chi-square or Fisher’s exact test. Sign tests were used to analyze the concomitant medication usage. In the categorical analysis of the laboratory variable, the subset of patients with normal laboratory values for a given variable at the baseline was analyzed according to whether the patients were above or below the normal range at endpoint. The SPSS software (SPSS Inc., Chicago, IL) was used for the statistical analyses. Results The mean dose of risperidone was 2.9 (SD 1.3) mg/day and the mean dose of amisulpride was 304.2 (SD 141.4) mg/day. The doses of trihexyphenidyl and propranolol before switching were 2.70 (SD 1.75, N10) and 20 (SD 11.55, N7) mg/day, respectively, the doses after switching were 1.45 (SD 1.72) and 20 (SD 17.32) mg/day, respectively. The dose of propranolol did not change significantly after switching, either. Significant improvements in the PANSS, the CGI-S, and the MADRS were noted. Some efficacy and safety results are shown in Table II. No significant changes were found in laboratory assessment categories except prolactin increase. Neither did the body weight, the CSFQ, or the QOL 28 show any significant change. The results of the cognitive tests are shown in Table III. Some significant changes were found in the following subtests: logical memory, visual reproduction, logical memory delay, visual reproduction delay recall. Discussion Compared with a previous study, the doses of amisulpride we used were lower, while our amisulpride/risperidone ratio was similar [27]. The low doses of amisulpride in our study maybe attributed
The effect of amisulpride: A switch study
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Table II. Main change in the efficacy/safety assessments and laboratory data during the 13-week amisulpride treatment.
N
Visit 1 Day 0 M9SD
N
Visit 2 Day 7 M9SD
N
Visit 3 Day 35 M9SD
N
Visit 4 Day 91 M9SD
51.81915.33*** 11.1494.88** 12.4393.86** 24.3097.47*** 3.9191.53 4.1794.46*** 3.0090.85** 4.3591.27
Statistics
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$
Efficacy assessments PANSS 23 PANSS P 23 PANSS N 23 PANSS G 23 PANSS S 23 MADRS 23 CGI-S 23 QOL28 23 Safety assessments Rating scales$ ESRS 23 Laboratory assessments% Prolactin (ng/ml) 21
65.30919.56 14.2295.68 16.3596.07 30.2698.78 4.4891.86 10.7499.53 3.4890.73 4.3091.36
23 23 23 23 23 23 23
60.91918.89* 12.8795.18* 15.6596.03* 28.4398.95* 3.9691.58 7.4898.55** 3.3590.83
23 23 23 23 23 23 23 22
53.30913.25* 11.3094.09* 13.1794.30* 24.9696.72* 3.8791.46 5.6196.75** 2.9190.60* 4.2291.13
23 23 23 23 23 23 23 21
5.0496.09
23
4.3595.36
22
3.2695.02
22
105.27971.5
23
2.1793.33
21 132.77965.92**
F(3,20)8.78, F(3,20)7.02, F(3,20)4.96, F(3,20)8.25, F(3,20)1.75, F(3,20)9.90, F(3,20)7.11, F(3,20)0.16,
PB0.01 PB0.01 PB0.01 PB0.01 P0.19 PB0.001 PB0.01 P0.85
F(3,20)3.80, PB0.05 t 3.86, PB0.001
$
Last-observation-carried forward data (LOCF) technique was used. The post hoc multiple comparison tests were performed and the data of the first visit were as the reference. *P B0.01, **PB0.001 (two-tailed). % Paired t-tests: *PB0.01, **P B0.001 (two-tailed). PANSS, Positive and Negative Syndrome Scale; MADRS, MontgomeryAsberg Depression Rating Scale; CGI, Clinical Global Impression; QOL28, the Quality of Life; ESRS, the EPS Rating Scale.
to the following reasons: (1) the cases we enrolled were relatively clinically stable; and (2) the pre-switch dose of risperidone was also low. Moreover, all of the subjects in our study had received risperidone for at least 3 months before the study and the dose of concomitant anticholinergic drug was not significantly increased during the amisulpride treatment compared to the dose during the risperidone treatment. Thus, the change in efficacy scores, the safety profiles and the cognitive functions after switching may be attributed to the difference between these two medications themselves. Previous head-to-head comparison studies [27,28] showed no significant difference between the improvements in the amisulpride and risperidone
treatment groups, as assessed by reductions from baseline in the PANSS total scores, the PANSS positive and negative subscores, and the CGI severity scores. In our study, the efficacy scores showed significant improvements after switching. The result of our study partially supported the result of previous head-to-head study; we also found that the clinical effect of amisulpride is not inferior to risperidone. Two reasonable explanations for the discrepancy in the results may be: (1) the study design, since our study is a single-arm study, any treatment effect may have been confounded by the possible improvement in the patient by merely participating in the study; and (2) the differences in the clinical conditions of the participants. Peuskens et al. [27] chose the patients in
Table III. The pre- and post- (after a 3-month) amisulpride treatment cognitive measurements.
Psychological tests WMS-III Logical memory Visual reproduction Working memory Delay recall: logical memory Delay recall: visual reproduction WCST Perseverative errors Completed categories CPT Unmask task d? B Mask task D? B
N
Visit 1 Day 0 M9SD
Visit 4 Day 91 M9SD
19 19 19 19 19
6.7993.26 8.9593.15 95.42914.78 7.1693.18 8.9593.17
9.0593.69** 10.5893.31* 97.47912.62 9.2193.81** 11.4293.63**
t 3.29, PB0.001 t 2.9, P 0.01 t 0.9, P 0.38 t 3.32, PB0.001 t 3.86, PB0.001
20 20
14.499.17 2.0591.39
12.4599.06 2.5591.73
t 1.42, P0.17 t 1.45, P0.16
14 14
3.9091.06 2.0090.78
4.0290.98 1.9390.72
t 0.75, P0.46 t 0.25, P0.81
14 14
3.5091.27 1.9290.59
3.7991.15 2.0790.75
t 1.63, P0.13 t 0.61, P0.55
Paired t-tests: *P B0.01; **PB0.001. WMS, Wechsler Memory Scale; WCST, Wisconsin Card Sorting Test; CPT, Continuous Performance Test.
Statistic
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the acute exacerbation stage while our study enrolled patient whose clinical conditions were relatively stable. Just as reported by Peuskens et al. [27], our results also showed significant improvement of negative symptom subscores. In previous studies, amisulpride and risperidone were both generally well tolerated [27]. Our results also indicated the patients treated with amisulpride had not significant change in ESRS score and other safety assessments. The improvement in the MADRS score in this study suggests that amisulpride may be effective in the management of affective symptoms of schizophrenia. This result supports that of Peuskens et al.’s study [27]. In this study, the change in MADRS did not correlate with the reduction in EPS. Although it has been reported that amisulpride-treated group may show greater improvements in their quality of life than both the haloperidol-treated group and the placebo group [2931], the quality of life of patients treated by amisulpride did not change significantly after switching from risperidone to amisulpride in our study. After switching the treatment from risperidone to amisulpride, there was no change in any of the metabolic factors or the body weight, except for the prolactin level. This is consistent that reported by many previous studies [5]. Compton et al. [32] reviewed the literature and found little direct support for a correlation between plasma prolactin levels and the emergence of sexual side effects. Our CSFQ showed no significant change compared with pre-switching level even in the presence of increasing serum prolactin level. This finding deserves further exploration. Our study is the first study to compare the effects of risperidone and amisulpride on cognitive functions in a switching study. An improvement in memory test was found. The main pharmacological difference between amisulpride and risperidone may be that amisulpride has no 5HT-2A affinity, while risperidone is a 5HT-2A antagonist. Many studies have demonstrated that 5HT-2A antagonism enhances cognitive function [3335]. Tyson et al. [36] reported that antagonizing 5HT-2A results in an increase in prefrontal dopamine turnover and a consequent improvement of the cognitive function. These changes are likely mediated by the prefrontal cortex. In this study, we obtained a puzzling result. That is, if 5HT-2A antagonism enhanced cognitive function, why does a medication without 5HT affinity, such as amisulpride, resulted in a significant memory improvement after switching from a medication with 5HT-2A antagonism? In previous study, Tyson et al. [36] divided patients into two groups according to the 5HT-2A affinity of the individual medication and found that the high 5HT-2A affinity group showed a decrement in performance on tests of visual recognition memory and planning ability. While the low 5HT-2A affinity group showed
improvements on these measures. In another study, Tyson et al. also reported patients on low 5HT-2A affinity antipsychotics exhibited a better performance on a measure of selective attention and adjustment to living. Our result partially supported Tyson et al.’s results. In addition, Wagner et al. [37] also reported that the atypical antipsychotic amisulpride (devoid of 5HT-2A affinity) was as effective at alleviating cognitive deficits as olanzapine (high 5HT-2A affinity) and that amisulpride also has a strong effect on attention an executive function. The assertion that serotonin antagonizing effect enhances learning and memory needs to reexamined [38,39]. Regarding memory tests, Wagner et al. [37] reported that amisulpride was not inferior to olanzapine with regards to working memory and declarative memory. Our study showed that, after switching to amisulpride, the patients showed a significant improvement in relation to memory. This finding implied that amisulpride may influence the memory in a different way compared to other atypical antipsychotics, resulting in a clinical result comparable to that of a serotonin-dopamine antagonist [40]. Regarding the attention tests, some attention tests such as the CPT and the WCST did not improve significantly after switching in our study. Vaiva et al. [41] reported that low-dose amisulpride may be particularly useful for attention phenomena in the deficit forms of schizophrenia. In Vaiva’s study, the daily dose of amisulpride (100 mg or lower) was much lower than that in our study (304.2 mg/day). The amisulpride preferentially blocks presynaptic dopamine autoreceptors at low doses and therefore enhancing dopaminergic transmission [13] which is cardinal to attention tests, whereas higher doses block postsynaptic receptors, thus inhibiting dopaminergic hyperactivity. As for the CPT, our result was comparable with those of some previous studies. Liu et al. [40,42] found that CPT deficits are stable vulnerability indicators rather than state markers. Previous studies also showed that schizophrenic patients have deficits on the WCST. This impairment is a potential marker of genetic predisposition for schizophrenia [43]. Therefore, the performance of the CPT and the WCST in patients with schizophrenia may be less changeable. The results of the present study need be interpreted with caution due to the following limitations. Firstly, this study only recruited a small number of patients. Secondly, this was a relatively short-term (13-week) study. There are few study results available on switching to amisulpride. Longer term data are needed to confirm the findings from this study. Thirdly, the high drop-out rate (4/23) weakens the results. Fourthly, this was a single arm open-label study that used one switching strategy. Switching antipsychotic agents is common in clinical practice; therefore, it would be beneficial to incorporate a
The effect of amisulpride: A switch study number of switching strategies in a parallel design. Finally, this was a non-randomized study which only included clinically stable patients. To validate the results, randomized, double-blinded studies with longer follow-up durations need to be conducted in the future.
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Conclusion Thirteen weeks after the patients switched from risperidone to amisulpride, their efficacy scores improve significantly, and their safety profiles showed no significant change. The laboratory data, with the exception of the serum prolactin level, also showed no significant change. Improvement in the memory was noted. These results supported that amisulpride is an effective medication for clinically stable patients with schizophrenia with the potential added benefit of improving some cognitive functions. Key points . Amisulpride is not inferior to risperidone on efficacy and safety profile . Amisulpride may be effective in the management of affective symptoms of schizophrenia . After switching the treatment from risperidone to amisulpride, there was no change in any of the metabolic factors or the body weight, except for the prolactin levels . After switching to amisulpride, the results of the memory subtests of WMS-III improved significantly Acknowledgements This work was partially support by a grant from Sanofi-Synthelabo Taiwan Limited. The authors are grateful to Ms Tsai-Hua Chang, Ms Ching Lin Chu, Ms Shu Chuan Lin and Ms Linda J. Chang for their invaluable assistance in the preparation of the manuscript. Statement of interest This work was partially support by a grant from Sanofi-Synthelabo Taiwan Limited.
References [1] Coulouvrat C, Dondey-Nouvel L, Coulouvrat C, DondeyNouvel L. Safety of amisulpride (Solian): a review of 11 clinical studies. Int Clin Psychopharmacol 1999;14(4): 20918. [2] Perrault G, Depoortere R, Morel E, et al. Psychopharmacological profile of amisulpride: an antipsychotic drug with presynaptic D2/D3 dopamine receptor antagonist activity and limbic selectivity. J Pharmacol Exp Ther 1997;280(1): 7382.
185
[3] Schoemaker H, Claustre Y, Fage D, et al. Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity. J Pharmacol Exp Ther 1997;280(1):8397. [4] Moller HJ. Amisulpride: a review of its efficacy in schizophrenia. Acta Psychiatr Scand Suppl 2000;400:1722. [5] Rein W, Coulouvrat C, Dondey-Nouvel L, Rein W, Coulouvrat C, Dondey-Nouvel L. Safety profile of amisulpride in short- and long-term use. Acta Psychiatri Scand Suppl 2000;400:237. [6] Green MF, Marshall BD Jr, Wirshing WC, et al. Does risperidone improve verbal working memory in treatmentresistant schizophrenia? Am J Psychiatry 1997;154 (6): 799804. [7] Liddle PF, Liddle PF. Cognitive impairment in schizophrenia: its impact on social functioning. Acta Psychiatr Scand Suppl 2000;400:1116. [8] Remington G, Kapur S. Atypical antipsychotics: are some more atypical than others? Psychopharmacology (Berlin) 2000;148(1):315. [9] Serretti A, De Ronchi D, Lorenzi C, Berardi D. New antipsychotics and schizophrenia: a review on efficacy and side effects. Curr Med Chem 2004;11(3):34358. [10] Tollefson GD, Sanger TM, Tollefson GD, Sanger TM. Anxious-depressive symptoms in schizophrenia: a new treatment target for pharmacotherapy? Schizophr Res 1999;35(Suppl):S1321. [11] Tollefson GD, Andersen SW, Tollefson GD, Andersen SW. Should we consider mood disturbance in schizophrenia as an important determinant of quality of life? J Clin Psychiatry 1999;60(Suppl 5):2329; discussion 30. [12] Haddad PM, Wieck A, Haddad PM, Wieck A. Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management. Drugs 2004;64(20):2291314. [13] Markianos M, Hatzimanolis J, Lykouras L, Markianos M, Hatzimanolis J, Lykouras L. Gonadal axis hormones in male schizophrenic patients during treatment with haloperidol and after switch to risperidone. Psychopharmacology 1999;143(3):2702. [14] Markianos M, Hatzimanolis J, Lykouras L, Markianos M, Hatzimanolis J, Lykouras L. Switch from neuroleptics to clozapine does not influence pituitary-gonadal axis hormone levels in male schizophrenic patients. Eur Neuropsychopharmacol 1999;9(6):5336. [15] Kern RS, Green MF, Marshall BD Jr, et al. Risperidone versus haloperidol on secondary memory: can newer medications aid learning? Schizophr Bull 1999;25(2):22332. [16] Matsui M, Sumiyoshi T, Abe R, Kato K, Yuuki H, Kurachi M. Impairment of story memory organization in patients with schizophrenia. Psychiatry Clin Neurosci 2007;61(4): 43740. [17] Bruder GE, Wexler BE, Sage MM, Gil RB, Gorman JM. Verbal memory in schizophrenia: additional evidence of subtypes having different cognitive deficits. Schizophr Res 2004;68(23):13747. [18] Guy W. Clinical global impression. ECDEU Assessment Manual for Psychopharmacology (revised). Rockville, MD: National Institute of Mental Health; 1976. p 21721. [19] Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987;13(2):26176. [20] Barnes TR, Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry 1989;154:6726. [21] Anonymous. Abnormal Involuntary Movement Scale (AIMS). Psychopharmacol Bull 1988;24(4):7813. [22] Chouinard G, Margolese HC. Manual for the Extrapyramidal Symptom Rating Scale (ESRS). Schizophr Res 2005;76(23):24765. [23] Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 1970;212:1119. [24] Chen KC, Yang YK, Lee IH, Yeh TL, Lu R-B, Chen PS. Sexual dysfunction and physicians’ perception in medicated
186
[25]
[26]
[27]
Int J Psych Clin Pract Downloaded from informahealthcare.com by Universite De Sherbrooke on 11/06/14 For personal use only.
[28]
[29]
[30]
[31]
[32]
[33]
[34]
Y.-T. Wang et al. patients with major depression in Taiwan. Depression Anxiety 2007;in press. Yao G, Chung CW, Yu CF, et al. Development and verification of validity and reliability of the WHOQOLBREF Taiwan version. J Formosan Med Assoc 2002;101(5): 34251. Montgomery SA, Smeyatsky N, de Ruiter M, et al. Profiles of antidepressant activity with the Montgomery-Asberg Depression Rating Scale. Acta Psychiatr Scand Suppl 1985;320:3842. Peuskens J, Bech P, Moller HJ, Bale R, Fleurot O, Rein W. Amisulpride vs. risperidone in the treatment of acute exacerbations of schizophrenia. Amisulpride study group. Psychiatry Res 1999;88(2):10717. Sechter D, Peuskens J, Fleurot O, et al. Amisulpride vs. risperidone in chronic schizophrenia: results of a 6-month double-blind study. Neuropsychopharmacology 2002;27(6): 107181. Colonna L, Saleem P, Dondey-Nouvel L, et al. Long-term safety and efficacy of amisulpride in subchronic or chronic schizophrenia. Amisulpride Study Group. Int Clin Psychopharmacology 2000;15(1):1322. Hwang TJ, Lee SM, Sun HJ, et al. Amisulpride versus risperidone in the treatment of schizophrenic patients: a double-blind pilot study in Taiwan. J Formosan Med Assoc 2003;102(1):306. Loo H, Poirier-Littre MF, Theron M, et al. Amisulpride versus placebo in the medium-term treatment of the negative symptoms of schizophrenia. Br J Psychiatry 1997;170: 1822. Compton MT, Miller AH. Antipsychotic-induced hyperprolactinemia and sexual dysfunction. Psychopharmacol Bull 2002;36(1):14364. Potkin SG, Fleming K, Jin Y, Gulasekaram B. Clozapine enhances neurocognition and clinical symptomatology more than standard neuroleptics. J Clin Psychopharmacol 2001;21(5):47983. Poyurovsky M, Koren D, Gonopolsky I, et al. Effect of the 5-HT2 antagonist mianserin on cognitive dysfunction in
[35]
[36]
[37]
[38] [39]
[40]
[41]
[42]
[43]
chronic schizophrenia patients: an add-on, double-blind placebo-controlled study. Eur Neuropsychopharmacol 2003; 13(2):1238. Umbricht D, Vollenweider FX, Schmid L, et al. Effects of the 5-HT2A agonist psilocybin on mismatch negativity generation and AX-continuous performance task: implications for the neuropharmacology of cognitive deficits in schizophrenia. Neuropsychopharmacology 2003;28(1): 17081. Tyson PJ, Roberts KH, Mortimer AM. Are the cognitive effects of atypical antipsychotics influenced by their affinity to 5HT-2A receptors? Int J Neurosci 2004;114(6):593611. Wagner M, Quednow BB, Westheide J, et al. Cognitive improvement in schizophrenic patients does not require a serotonergic mechanism: randomized controlled trial of olanzapine vs amisulpride. Neuropsychopharmacology 2005;30(2):38190. Meneses A. 5-HT system and cognition. Neurosci Biobehav Rev 1999;23(8):111125. Tyson PJ, Laws KR, Flowers KA, Tyson A, Mortimer AM. Cognitive function and social abilities in patients with schizophrenia: relationship with atypical antipsychotics. Psychiatry Clin Neurosci 2006;60(4):4739. Liu SK, Hwu HG, Chen WJ, Liu SK, Hwu HG, Chen WJ. Clinical symptom dimensions and deficits on the Continuous Performance Test in schizophrenia. Schizophr Res 1997;25(3):21119. Vaiva G, Thomas P, Llorca PM, et al. SPECT imaging, clinical features, and cognition before and after low doses of amisulpride in schizophrenic patients with the deficit syndrome. Psychiatry Res 2002;115(12):3748. Liu SK, Chiu CH, Chang CJ, et al. Deficits in sustained attention in schizophrenia and affective disorders: stable versus state-dependent markers. Am J Psychiatry 2002; 159(6):97582. Zalla T, Joyce C, Szoke A, et al. Executive dysfunctions as potential markers of familial vulnerability to bipolar disorder and schizophrenia. Psychiatry Res 2004;121(3):20717.
ORIGINAL ARTICLE
Effects of amisulpride on the cognitive function of patients with schizophrenia who switched from risperidone
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YU-TING WANG1,4, NAN-YING CHIU3, SHAW-HWA JOU3, YEN KUANG YANG1,2, I HUI LEE1,2, CHING-CHENG WANG3, KAO CHING CHEN1,2 & YI-CHENG LIAO3 1
Department of Psychiatry, National Cheng Kung University Hospital, Tainan, Taiwan, 2Department of Psychiatry, College of Medicine, National Cheng Kung University, Tainan, Taiwan, 3Department of Psychiatry, Changhua Christian Hospital, Changhua, Taiwan, and 4Department of Psychiatry, St. Martin De Porres Hospital, Chiayi, Taiwan
Abstract Objectives. The aims of this 13-week study were to examine the efficacy and safety of amisulpride, and effects on cognitive function in patients with schizophrenia after they switched from risperidone. Methods. Twenty-three patients with schizophrenia whose antipsychotic was switched from risperidone to amisulpride were recruited. The efficacy, safety, and cognitive function were assessed. Results. Significant improvements were noted in the PANSS, CGI-S, and MADRS. The prolactin level, but not any of the remaining laboratory variables, increased significantly. The cognitive function improved significantly, particularly in memory subtests. Conclusions. Switching antipsychotic from risperidone to amisulpride in schizophrenia might have significantly improved not only the efficacy, but also various domains of cognitive function. However, hyperprolactinemia existed and was sometimes even worse.
Key Words: Amisulpride, cognitive function, hyperprolactinemia
Introduction Amisulpride, a substituted benzamide derivative, is an atypical antipsychotic with selective high affinity for the dopamine D2 and D3 receptor subtypes [13]. Since amisulpride is essentially devoid of 5HT2 antagonism, its moderate affinity for striatal D2 receptors and preferential occupancy of limbic cortical D2/ D3 receptors may acccount for its therapeutic efficacy and low liability to induce EPS [4,5]. In contrast to amisulpride, risperidone is a central 5HT2 and dopamine D2 receptor antagonist with relatively higher affinity for 5 HT2 receptors. A review of previous literature revealed that the efficacy of one atypical antipsychotic over another often depends on the primary measure. Atypical antipyschotics have demonstrated equivalence on positive and negative symptoms [69]. Clinically, side-effects are a critical factor in choosing medication. Among the treatment of atypical antipsychotic agents, these following side effects are very common: affect symptoms, hyperprolactinemia, sexual dysfunction, and changes in cognitive function. In addition to positive and negative symptoms, affective impairments are another major feature of
schizophrenia [10]. These affective impairments may be detrimental to the quality of life for patients with schizophrenia [11]. However, few studies have been performed in this regard. Antipsychotic-induced hyperprolactinemia has been reported as the major cause of sexual dysfunction in patients with schizophrenia [12]. However, few studies have examined the effects of hyperprolactinemia associated with amisulpride for treating patient with schizophrenia [13,14]. Cognitive impairment is a cardinal feature in patient with schizophrenia. Their verbal memory, vigilance, and executive function were identified by a recent review to be associated with functional outcome [15]. Matsui et al. [16] reported that compared to healthy population, schizophrenia patients have deficits in organization of story memory, which are related to symptoms such as disorganized thoughts and behavior. Bruder et al. [17] also reported that a subgroup of schizophrenia patients had a specific verbal memory deficit that is not limited to working memory, but extends to learning and recall of verbal material [6]. Compared with typical antipsychotics, atypical antipsychotic like risperidone was demonstrated to be better in
Correspondence: Dr Nan-Ying Chiu, Department of Psychiatry, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua, Taiwan 500. Tel: 886 4 7238595, ext 7170, 1032. Fax: 886 4 7299371. E-mail: [email protected]
(Received 28 June 2007; accepted 12 November 2007) ISSN 1365-1501 print/ISSN 1471-1788 online # 2008 Informa UK Ltd. DOI: 10.1080/13651500701805727
The effect of amisulpride: A switch study improving cognitive functions such as verbal working memory [6] and verbal declarative memory [15]. However, few studies have shown any difference in cognitive improvement between different kinds of atypical antipsychotics, for example, risperidone and amisulpride. The aims of this study were to examine: (1) the clinical efficacy and adverse effects; (2) the affective symptoms; (3) the plasma prolactin level changes and sexual dysfunction; (4) the cognitive changes; in patients with schizophrenia after they switched from risperidone to amisulpride.
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Subjects and methods Subjects Prior to the study, the protocol was approved by the local Institutional Review Board and informed consent was obtained from the participants. Twenty-three subjects who met the criteria of DSM-IV-TR for schizophrenia were recruited from the outpatient psychiatric clinics at the Changhua Christian Hospital and the National Cheng Kung University Hospital in Taiwan. Four subjects dropped out because of the following reasons, respectively: (1) the subject titrated drug dose by herself due to weight gain; (2) exacerbation of
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psychotic symptoms; (3) agitation; and (4) agitation along with schizophrenia exacerbation. The subjects’ demographic data are shown in Table I. All participants had initially received risperidone within the 16 mg/day range for at least 3 months before the study. The patients with partial improvement were considered eligible cases for our study. ‘‘Partial improvement’’ was defined as having a Clinical Global Impression-Severity Score (CGI-S) of 14. If the patients’ CGI-S scores were 12, they may also experience troublesome side effects attributable to the current treatment regimen. The exclusion criteria included: (1) pregnant or lactating women; (2) patients treated with anticonvulsants, antidepressant, or mood stabilizing agents; (3) patients with specific systemic disease or other medical conditions that may interfere with the evaluation of the therapeutic response or the safety of amisulpride; (4) patients with high suicidal risk; (5) patients with any substance abuse or dependence; (6) patients who had been previous treated with amisulpride; and (7) patients with drug treatment resistance. This was a 13-week, open label, non-randomized, single-treatment, flexible-dose study of oral amisulpride (1001200 mg/day). Patients’ antipsychotic was switched from risperidone to amisulpride by a fixed strategy. That is, the institution of amisulpride
Table I. Demographic data and daily doses of antipsychotics.
No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Mean9SD 1
Sex F M F F F M F M F F F F M M F F M F M M M M M
Duration of Duration of Age illness antipsychotics (years old) (years) therapy (years) 32.3 44 22.8 20.8 27.8 36.3 24.3 30 22.1 28.9 47.2 21 29.8 19.8 40.7 42.7 47 35 22.4 34 46.9 42.7 23.9 3299.4
7 14 4 3 10 2 4 14 8 13 18 1.5 14 3 25 13 21 10 7 10 20 25 2 10.497.6
6 14 0.5 3 10 2 4 14 8 12 11 0.5 10 3 16 13 21 10 25 2 6.796.2
Pre-switching Daily dose of daily dose of risperidone amisulpride at the end of study Completed study Yes Yes Yes No1 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No2 Yes Yes Yes No3 No4 Yes Yes Yes
mg/day
frequency
3 4 3 2 1 3 1 2 2 2 2 3 4 2 5 2 2 5 4 2 6 4 4 2.991.3
HS BID HS HS QD HS QD HS QD QD HS HS HS HS BID QD HS HS HS HS HS HS HS
The subject titrated drug dose by herself due to the adverse event of weight gain. Exacerbation of psychotic symptoms. 3 Agitation. 4 Agitation. Schizophrenia exacerbation. 2
mg/day 400 200 400 400 400 600 200 100 200 200 200 200 600 100 400 200 200 400 400 400 400 300 200 304.29141.4
frequency BID QD HS HS HS HS HS QD HS QD QD HS BID QD HS QD QD QD QD BID HS HS HS
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treatment was gradually achieved and risperidone was discontinued within 1 week (from Day 0 to Day 7). After the 7-day switching period, the patients received amisulpride alone for the next 12 weeks (Day 8 to Day 91). Measurements Most of the tests described below were performed twice, namely before and after switching, while the efficacy and safety measures were checked four times, (on Day 0, Day 7, Day 35, and Day 91).
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Efficacy measures The measures included the Clinical Global Impression-Severity and Improvement (CGI-S and CGI-I) [18], and the Positive and Negative Syndrome Scale (PANSS) [19]. Safety measures The measures included the Barnes Akathisia Scale (BAS) [20], the Abnormal Involuntary Movement Scale (AIMS) [21], the EPS Rating Scale (ESRS) [22], the Simpson-Angus Scale (SAS) [23], the Changes in Sexual Function Questionnaire (CSFQ) [24], and the Quality of Life (QOL28) [25]. In addition, the usage of anticholingeric agent and beta blocker was also recorded during the study period. Affective symptoms assessment The assessment was Montgomery-Asberg Depression Rating Scale. (MADRS) [26]. Laboratory assessments The laboratory assessments included hemoglobin (Hb), hematocrit (HcT), platelets (Pl), red blood cell count (RBC), white blood cell count (WBC), asparatate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), creatine (Cr), alkaline phosphatase (Alk-P), sodium (Na), potassium (K), fasting glucose, fasting lipid profile; prolactin, luteinizing hormone (LH), thyroid stimulating hormone (TSH), and body weight. Cognitive function assessments The assessments included the Wisconsin Card Sorting Test (WCST), the Continuous Performance Test (CPT), and the Wechsler Memory Scale, revised version (WMS-III). Statistics The results are presented as means with standard deviations and/or 95% confidence intervals. All
patients were included in the analysis of the efficacy and the safety measurements using last-observationcarried forward data (LOCF) technique, which helped us to obtain the complete data needed for analysis and decrease the bias resulting from the dropped-out participant. Either repeated-measure ANOVA or paired t tests were performed to analyze the laboratory assessments and the cognitive measures data. The post hoc multiple comparison tests were performed using the levels of the first visit as the reference. Multiple comparisons would decrease the P values. In our study, P values equal to or less than 0.01 were considered significant in order to avoid spuriously significant findings. For the efficacy assessments, we chose to present only PANSS, CGIS and QOL28. For the safety assessments, we presented ESRS only. But ESRS is regarded as insignificant. For the lab data, only prolactin level is presented. Changes in the categorical variables were analyzed using either chi-square or Fisher’s exact test. Sign tests were used to analyze the concomitant medication usage. In the categorical analysis of the laboratory variable, the subset of patients with normal laboratory values for a given variable at the baseline was analyzed according to whether the patients were above or below the normal range at endpoint. The SPSS software (SPSS Inc., Chicago, IL) was used for the statistical analyses. Results The mean dose of risperidone was 2.9 (SD 1.3) mg/day and the mean dose of amisulpride was 304.2 (SD 141.4) mg/day. The doses of trihexyphenidyl and propranolol before switching were 2.70 (SD 1.75, N10) and 20 (SD 11.55, N7) mg/day, respectively, the doses after switching were 1.45 (SD 1.72) and 20 (SD 17.32) mg/day, respectively. The dose of propranolol did not change significantly after switching, either. Significant improvements in the PANSS, the CGI-S, and the MADRS were noted. Some efficacy and safety results are shown in Table II. No significant changes were found in laboratory assessment categories except prolactin increase. Neither did the body weight, the CSFQ, or the QOL 28 show any significant change. The results of the cognitive tests are shown in Table III. Some significant changes were found in the following subtests: logical memory, visual reproduction, logical memory delay, visual reproduction delay recall. Discussion Compared with a previous study, the doses of amisulpride we used were lower, while our amisulpride/risperidone ratio was similar [27]. The low doses of amisulpride in our study maybe attributed
The effect of amisulpride: A switch study
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Table II. Main change in the efficacy/safety assessments and laboratory data during the 13-week amisulpride treatment.
N
Visit 1 Day 0 M9SD
N
Visit 2 Day 7 M9SD
N
Visit 3 Day 35 M9SD
N
Visit 4 Day 91 M9SD
51.81915.33*** 11.1494.88** 12.4393.86** 24.3097.47*** 3.9191.53 4.1794.46*** 3.0090.85** 4.3591.27
Statistics
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$
Efficacy assessments PANSS 23 PANSS P 23 PANSS N 23 PANSS G 23 PANSS S 23 MADRS 23 CGI-S 23 QOL28 23 Safety assessments Rating scales$ ESRS 23 Laboratory assessments% Prolactin (ng/ml) 21
65.30919.56 14.2295.68 16.3596.07 30.2698.78 4.4891.86 10.7499.53 3.4890.73 4.3091.36
23 23 23 23 23 23 23
60.91918.89* 12.8795.18* 15.6596.03* 28.4398.95* 3.9691.58 7.4898.55** 3.3590.83
23 23 23 23 23 23 23 22
53.30913.25* 11.3094.09* 13.1794.30* 24.9696.72* 3.8791.46 5.6196.75** 2.9190.60* 4.2291.13
23 23 23 23 23 23 23 21
5.0496.09
23
4.3595.36
22
3.2695.02
22
105.27971.5
23
2.1793.33
21 132.77965.92**
F(3,20)8.78, F(3,20)7.02, F(3,20)4.96, F(3,20)8.25, F(3,20)1.75, F(3,20)9.90, F(3,20)7.11, F(3,20)0.16,
PB0.01 PB0.01 PB0.01 PB0.01 P0.19 PB0.001 PB0.01 P0.85
F(3,20)3.80, PB0.05 t 3.86, PB0.001
$
Last-observation-carried forward data (LOCF) technique was used. The post hoc multiple comparison tests were performed and the data of the first visit were as the reference. *P B0.01, **PB0.001 (two-tailed). % Paired t-tests: *PB0.01, **P B0.001 (two-tailed). PANSS, Positive and Negative Syndrome Scale; MADRS, MontgomeryAsberg Depression Rating Scale; CGI, Clinical Global Impression; QOL28, the Quality of Life; ESRS, the EPS Rating Scale.
to the following reasons: (1) the cases we enrolled were relatively clinically stable; and (2) the pre-switch dose of risperidone was also low. Moreover, all of the subjects in our study had received risperidone for at least 3 months before the study and the dose of concomitant anticholinergic drug was not significantly increased during the amisulpride treatment compared to the dose during the risperidone treatment. Thus, the change in efficacy scores, the safety profiles and the cognitive functions after switching may be attributed to the difference between these two medications themselves. Previous head-to-head comparison studies [27,28] showed no significant difference between the improvements in the amisulpride and risperidone
treatment groups, as assessed by reductions from baseline in the PANSS total scores, the PANSS positive and negative subscores, and the CGI severity scores. In our study, the efficacy scores showed significant improvements after switching. The result of our study partially supported the result of previous head-to-head study; we also found that the clinical effect of amisulpride is not inferior to risperidone. Two reasonable explanations for the discrepancy in the results may be: (1) the study design, since our study is a single-arm study, any treatment effect may have been confounded by the possible improvement in the patient by merely participating in the study; and (2) the differences in the clinical conditions of the participants. Peuskens et al. [27] chose the patients in
Table III. The pre- and post- (after a 3-month) amisulpride treatment cognitive measurements.
Psychological tests WMS-III Logical memory Visual reproduction Working memory Delay recall: logical memory Delay recall: visual reproduction WCST Perseverative errors Completed categories CPT Unmask task d? B Mask task D? B
N
Visit 1 Day 0 M9SD
Visit 4 Day 91 M9SD
19 19 19 19 19
6.7993.26 8.9593.15 95.42914.78 7.1693.18 8.9593.17
9.0593.69** 10.5893.31* 97.47912.62 9.2193.81** 11.4293.63**
t 3.29, PB0.001 t 2.9, P 0.01 t 0.9, P 0.38 t 3.32, PB0.001 t 3.86, PB0.001
20 20
14.499.17 2.0591.39
12.4599.06 2.5591.73
t 1.42, P0.17 t 1.45, P0.16
14 14
3.9091.06 2.0090.78
4.0290.98 1.9390.72
t 0.75, P0.46 t 0.25, P0.81
14 14
3.5091.27 1.9290.59
3.7991.15 2.0790.75
t 1.63, P0.13 t 0.61, P0.55
Paired t-tests: *P B0.01; **PB0.001. WMS, Wechsler Memory Scale; WCST, Wisconsin Card Sorting Test; CPT, Continuous Performance Test.
Statistic
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the acute exacerbation stage while our study enrolled patient whose clinical conditions were relatively stable. Just as reported by Peuskens et al. [27], our results also showed significant improvement of negative symptom subscores. In previous studies, amisulpride and risperidone were both generally well tolerated [27]. Our results also indicated the patients treated with amisulpride had not significant change in ESRS score and other safety assessments. The improvement in the MADRS score in this study suggests that amisulpride may be effective in the management of affective symptoms of schizophrenia. This result supports that of Peuskens et al.’s study [27]. In this study, the change in MADRS did not correlate with the reduction in EPS. Although it has been reported that amisulpride-treated group may show greater improvements in their quality of life than both the haloperidol-treated group and the placebo group [2931], the quality of life of patients treated by amisulpride did not change significantly after switching from risperidone to amisulpride in our study. After switching the treatment from risperidone to amisulpride, there was no change in any of the metabolic factors or the body weight, except for the prolactin level. This is consistent that reported by many previous studies [5]. Compton et al. [32] reviewed the literature and found little direct support for a correlation between plasma prolactin levels and the emergence of sexual side effects. Our CSFQ showed no significant change compared with pre-switching level even in the presence of increasing serum prolactin level. This finding deserves further exploration. Our study is the first study to compare the effects of risperidone and amisulpride on cognitive functions in a switching study. An improvement in memory test was found. The main pharmacological difference between amisulpride and risperidone may be that amisulpride has no 5HT-2A affinity, while risperidone is a 5HT-2A antagonist. Many studies have demonstrated that 5HT-2A antagonism enhances cognitive function [3335]. Tyson et al. [36] reported that antagonizing 5HT-2A results in an increase in prefrontal dopamine turnover and a consequent improvement of the cognitive function. These changes are likely mediated by the prefrontal cortex. In this study, we obtained a puzzling result. That is, if 5HT-2A antagonism enhanced cognitive function, why does a medication without 5HT affinity, such as amisulpride, resulted in a significant memory improvement after switching from a medication with 5HT-2A antagonism? In previous study, Tyson et al. [36] divided patients into two groups according to the 5HT-2A affinity of the individual medication and found that the high 5HT-2A affinity group showed a decrement in performance on tests of visual recognition memory and planning ability. While the low 5HT-2A affinity group showed
improvements on these measures. In another study, Tyson et al. also reported patients on low 5HT-2A affinity antipsychotics exhibited a better performance on a measure of selective attention and adjustment to living. Our result partially supported Tyson et al.’s results. In addition, Wagner et al. [37] also reported that the atypical antipsychotic amisulpride (devoid of 5HT-2A affinity) was as effective at alleviating cognitive deficits as olanzapine (high 5HT-2A affinity) and that amisulpride also has a strong effect on attention an executive function. The assertion that serotonin antagonizing effect enhances learning and memory needs to reexamined [38,39]. Regarding memory tests, Wagner et al. [37] reported that amisulpride was not inferior to olanzapine with regards to working memory and declarative memory. Our study showed that, after switching to amisulpride, the patients showed a significant improvement in relation to memory. This finding implied that amisulpride may influence the memory in a different way compared to other atypical antipsychotics, resulting in a clinical result comparable to that of a serotonin-dopamine antagonist [40]. Regarding the attention tests, some attention tests such as the CPT and the WCST did not improve significantly after switching in our study. Vaiva et al. [41] reported that low-dose amisulpride may be particularly useful for attention phenomena in the deficit forms of schizophrenia. In Vaiva’s study, the daily dose of amisulpride (100 mg or lower) was much lower than that in our study (304.2 mg/day). The amisulpride preferentially blocks presynaptic dopamine autoreceptors at low doses and therefore enhancing dopaminergic transmission [13] which is cardinal to attention tests, whereas higher doses block postsynaptic receptors, thus inhibiting dopaminergic hyperactivity. As for the CPT, our result was comparable with those of some previous studies. Liu et al. [40,42] found that CPT deficits are stable vulnerability indicators rather than state markers. Previous studies also showed that schizophrenic patients have deficits on the WCST. This impairment is a potential marker of genetic predisposition for schizophrenia [43]. Therefore, the performance of the CPT and the WCST in patients with schizophrenia may be less changeable. The results of the present study need be interpreted with caution due to the following limitations. Firstly, this study only recruited a small number of patients. Secondly, this was a relatively short-term (13-week) study. There are few study results available on switching to amisulpride. Longer term data are needed to confirm the findings from this study. Thirdly, the high drop-out rate (4/23) weakens the results. Fourthly, this was a single arm open-label study that used one switching strategy. Switching antipsychotic agents is common in clinical practice; therefore, it would be beneficial to incorporate a
The effect of amisulpride: A switch study number of switching strategies in a parallel design. Finally, this was a non-randomized study which only included clinically stable patients. To validate the results, randomized, double-blinded studies with longer follow-up durations need to be conducted in the future.
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Conclusion Thirteen weeks after the patients switched from risperidone to amisulpride, their efficacy scores improve significantly, and their safety profiles showed no significant change. The laboratory data, with the exception of the serum prolactin level, also showed no significant change. Improvement in the memory was noted. These results supported that amisulpride is an effective medication for clinically stable patients with schizophrenia with the potential added benefit of improving some cognitive functions. Key points . Amisulpride is not inferior to risperidone on efficacy and safety profile . Amisulpride may be effective in the management of affective symptoms of schizophrenia . After switching the treatment from risperidone to amisulpride, there was no change in any of the metabolic factors or the body weight, except for the prolactin levels . After switching to amisulpride, the results of the memory subtests of WMS-III improved significantly Acknowledgements This work was partially support by a grant from Sanofi-Synthelabo Taiwan Limited. The authors are grateful to Ms Tsai-Hua Chang, Ms Ching Lin Chu, Ms Shu Chuan Lin and Ms Linda J. Chang for their invaluable assistance in the preparation of the manuscript. Statement of interest This work was partially support by a grant from Sanofi-Synthelabo Taiwan Limited.
References [1] Coulouvrat C, Dondey-Nouvel L, Coulouvrat C, DondeyNouvel L. Safety of amisulpride (Solian): a review of 11 clinical studies. Int Clin Psychopharmacol 1999;14(4): 20918. [2] Perrault G, Depoortere R, Morel E, et al. Psychopharmacological profile of amisulpride: an antipsychotic drug with presynaptic D2/D3 dopamine receptor antagonist activity and limbic selectivity. J Pharmacol Exp Ther 1997;280(1): 7382.
185
[3] Schoemaker H, Claustre Y, Fage D, et al. Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity. J Pharmacol Exp Ther 1997;280(1):8397. [4] Moller HJ. Amisulpride: a review of its efficacy in schizophrenia. Acta Psychiatr Scand Suppl 2000;400:1722. [5] Rein W, Coulouvrat C, Dondey-Nouvel L, Rein W, Coulouvrat C, Dondey-Nouvel L. Safety profile of amisulpride in short- and long-term use. Acta Psychiatri Scand Suppl 2000;400:237. [6] Green MF, Marshall BD Jr, Wirshing WC, et al. Does risperidone improve verbal working memory in treatmentresistant schizophrenia? Am J Psychiatry 1997;154 (6): 799804. [7] Liddle PF, Liddle PF. Cognitive impairment in schizophrenia: its impact on social functioning. Acta Psychiatr Scand Suppl 2000;400:1116. [8] Remington G, Kapur S. Atypical antipsychotics: are some more atypical than others? Psychopharmacology (Berlin) 2000;148(1):315. [9] Serretti A, De Ronchi D, Lorenzi C, Berardi D. New antipsychotics and schizophrenia: a review on efficacy and side effects. Curr Med Chem 2004;11(3):34358. [10] Tollefson GD, Sanger TM, Tollefson GD, Sanger TM. Anxious-depressive symptoms in schizophrenia: a new treatment target for pharmacotherapy? Schizophr Res 1999;35(Suppl):S1321. [11] Tollefson GD, Andersen SW, Tollefson GD, Andersen SW. Should we consider mood disturbance in schizophrenia as an important determinant of quality of life? J Clin Psychiatry 1999;60(Suppl 5):2329; discussion 30. [12] Haddad PM, Wieck A, Haddad PM, Wieck A. Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management. Drugs 2004;64(20):2291314. [13] Markianos M, Hatzimanolis J, Lykouras L, Markianos M, Hatzimanolis J, Lykouras L. Gonadal axis hormones in male schizophrenic patients during treatment with haloperidol and after switch to risperidone. Psychopharmacology 1999;143(3):2702. [14] Markianos M, Hatzimanolis J, Lykouras L, Markianos M, Hatzimanolis J, Lykouras L. Switch from neuroleptics to clozapine does not influence pituitary-gonadal axis hormone levels in male schizophrenic patients. Eur Neuropsychopharmacol 1999;9(6):5336. [15] Kern RS, Green MF, Marshall BD Jr, et al. Risperidone versus haloperidol on secondary memory: can newer medications aid learning? Schizophr Bull 1999;25(2):22332. [16] Matsui M, Sumiyoshi T, Abe R, Kato K, Yuuki H, Kurachi M. Impairment of story memory organization in patients with schizophrenia. Psychiatry Clin Neurosci 2007;61(4): 43740. [17] Bruder GE, Wexler BE, Sage MM, Gil RB, Gorman JM. Verbal memory in schizophrenia: additional evidence of subtypes having different cognitive deficits. Schizophr Res 2004;68(23):13747. [18] Guy W. Clinical global impression. ECDEU Assessment Manual for Psychopharmacology (revised). Rockville, MD: National Institute of Mental Health; 1976. p 21721. [19] Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987;13(2):26176. [20] Barnes TR, Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry 1989;154:6726. [21] Anonymous. Abnormal Involuntary Movement Scale (AIMS). Psychopharmacol Bull 1988;24(4):7813. [22] Chouinard G, Margolese HC. Manual for the Extrapyramidal Symptom Rating Scale (ESRS). Schizophr Res 2005;76(23):24765. [23] Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 1970;212:1119. [24] Chen KC, Yang YK, Lee IH, Yeh TL, Lu R-B, Chen PS. Sexual dysfunction and physicians’ perception in medicated
186
[25]
[26]
[27]
Int J Psych Clin Pract Downloaded from informahealthcare.com by Universite De Sherbrooke on 11/06/14 For personal use only.
[28]
[29]
[30]
[31]
[32]
[33]
[34]
Y.-T. Wang et al. patients with major depression in Taiwan. Depression Anxiety 2007;in press. Yao G, Chung CW, Yu CF, et al. Development and verification of validity and reliability of the WHOQOLBREF Taiwan version. J Formosan Med Assoc 2002;101(5): 34251. Montgomery SA, Smeyatsky N, de Ruiter M, et al. Profiles of antidepressant activity with the Montgomery-Asberg Depression Rating Scale. Acta Psychiatr Scand Suppl 1985;320:3842. Peuskens J, Bech P, Moller HJ, Bale R, Fleurot O, Rein W. Amisulpride vs. risperidone in the treatment of acute exacerbations of schizophrenia. Amisulpride study group. Psychiatry Res 1999;88(2):10717. Sechter D, Peuskens J, Fleurot O, et al. Amisulpride vs. risperidone in chronic schizophrenia: results of a 6-month double-blind study. Neuropsychopharmacology 2002;27(6): 107181. Colonna L, Saleem P, Dondey-Nouvel L, et al. Long-term safety and efficacy of amisulpride in subchronic or chronic schizophrenia. Amisulpride Study Group. Int Clin Psychopharmacology 2000;15(1):1322. Hwang TJ, Lee SM, Sun HJ, et al. Amisulpride versus risperidone in the treatment of schizophrenic patients: a double-blind pilot study in Taiwan. J Formosan Med Assoc 2003;102(1):306. Loo H, Poirier-Littre MF, Theron M, et al. Amisulpride versus placebo in the medium-term treatment of the negative symptoms of schizophrenia. Br J Psychiatry 1997;170: 1822. Compton MT, Miller AH. Antipsychotic-induced hyperprolactinemia and sexual dysfunction. Psychopharmacol Bull 2002;36(1):14364. Potkin SG, Fleming K, Jin Y, Gulasekaram B. Clozapine enhances neurocognition and clinical symptomatology more than standard neuroleptics. J Clin Psychopharmacol 2001;21(5):47983. Poyurovsky M, Koren D, Gonopolsky I, et al. Effect of the 5-HT2 antagonist mianserin on cognitive dysfunction in
[35]
[36]
[37]
[38] [39]
[40]
[41]
[42]
[43]
chronic schizophrenia patients: an add-on, double-blind placebo-controlled study. Eur Neuropsychopharmacol 2003; 13(2):1238. Umbricht D, Vollenweider FX, Schmid L, et al. Effects of the 5-HT2A agonist psilocybin on mismatch negativity generation and AX-continuous performance task: implications for the neuropharmacology of cognitive deficits in schizophrenia. Neuropsychopharmacology 2003;28(1): 17081. Tyson PJ, Roberts KH, Mortimer AM. Are the cognitive effects of atypical antipsychotics influenced by their affinity to 5HT-2A receptors? Int J Neurosci 2004;114(6):593611. Wagner M, Quednow BB, Westheide J, et al. Cognitive improvement in schizophrenic patients does not require a serotonergic mechanism: randomized controlled trial of olanzapine vs amisulpride. Neuropsychopharmacology 2005;30(2):38190. Meneses A. 5-HT system and cognition. Neurosci Biobehav Rev 1999;23(8):111125. Tyson PJ, Laws KR, Flowers KA, Tyson A, Mortimer AM. Cognitive function and social abilities in patients with schizophrenia: relationship with atypical antipsychotics. Psychiatry Clin Neurosci 2006;60(4):4739. Liu SK, Hwu HG, Chen WJ, Liu SK, Hwu HG, Chen WJ. Clinical symptom dimensions and deficits on the Continuous Performance Test in schizophrenia. Schizophr Res 1997;25(3):21119. Vaiva G, Thomas P, Llorca PM, et al. SPECT imaging, clinical features, and cognition before and after low doses of amisulpride in schizophrenic patients with the deficit syndrome. Psychiatry Res 2002;115(12):3748. Liu SK, Chiu CH, Chang CJ, et al. Deficits in sustained attention in schizophrenia and affective disorders: stable versus state-dependent markers. Am J Psychiatry 2002; 159(6):97582. Zalla T, Joyce C, Szoke A, et al. Executive dysfunctions as potential markers of familial vulnerability to bipolar disorder and schizophrenia. Psychiatry Res 2004;121(3):20717.
