human psychopharmacology Hum. Psychopharmacol Clin Exp 2014; 29: 199–202. Published online 8 January 2014 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/hup.2386
SHORT COMMUNICATION
Switching antipsychotics to aripiprazole or blonanserin and plasma monoamine metabolites levels in patients with schizophrenia Itaru Miura1,2*, Tetsuya Shiga1, Akihiko Katsumi1, Keiko Kanno-Nozaki1, Hirobumi Mashiko1, Shin-Ichi Niwa1 and Hirooki Yabe1 1 2
Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, Fukushima, Japan Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY, USA
Objective Blonanserin is a novel atypical antipsychotic drug that has efficacy equal to risperidone. We investigated the effects of aripiprazole and blonanserin on clinical symptoms and plasma levels of homovanillic acid (pHVA) and 3-methoxy-4hydroxyphenylglycol in the switching strategy of schizophrenia. Methods Twenty two Japanese patients with schizophrenia were enrolled into this open study. The antipsychotics of all patients were switched to aripiprazole or blonanserin for the improvement of clinical symptoms or side effects. Plasma monoamine metabolites levels were analyzed with high-performance liquid chromatography. Results There were no significant effects for time (p = 0.346) or time × group interaction (p = 0.27) on the changes of positive and negative syndrome scale (PANSS) total score, although blonanserin decreased PANSS scores. We observed negative correlation between pHVA at baseline and the change in PANSS total score (rs = 0.450, p = 0.046). We also found positive correlation between the changes in pHVA and the changes in PANSS total (rs = 0.536, p = 0.015) and positive (rs = 0.572, p = 0.008) scores. Conclusions There were no differences between blonanserin and aripiprazole in the improvement of clinical symptoms. Our results suggest that pHVA may be useful indicator for the switching strategy to aripiprazole or blonanserin in schizophrenia. Copyright © 2014 John Wiley & Sons, Ltd. key words—schizophrenia; aripiprazole; blonanserin; switching strategy; homovanillic acid
INTRODUCTION In the treatment of schizophrenia, switching antipsychotics is a common strategy to improve clinical symptoms or decrease drug side effects. However, care must be taken because switching sometimes leads to worsening of psychotic symptoms. Aripiprazole is a partial agonist for dopamine D2 receptors (Burris et al., 2002), which is widely used for schizophrenia. Blonanserin is a novel atypical antipsychotic drug that has efficacy similar to risperidone, and also favorable profiles for side effects such as weight gain or hyperprolactinemia (Kishi et al., 2013). Homovanillic acid (HVA) and 3-methoxy-4hydroxyphenylglycol (MHPG) are the major metabolites of dopamine and noradrenaline, respectively. Although it is difficult to *Correspondence to: I. Miura MD, PhD, Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan. Tel: +81-24-547-1331; Fax: +81-24-5486735 E-mail: [email protected]
Copyright © 2014 John Wiley & Sons, Ltd.
regard plasma monoamine metabolites as direct reflections of central activity, it is estimated that 30–50% of plasma HVA (pHVA) (Maas et al., 1980) and one-third of plasma MHPG (pMHPG) (Kopin et al., 1983) are derived from the brain, respectively. In this study, we investigated the effects of aripiprazole and blonanserin on clinical symptoms and plasma monoamine metabolites in the switching strategy of schizophrenia.
METHODS Subjects comprised 22 Japanese patients (11 men and 11 women; mean age ± SD, 44.1 ± 14.9 years) who were diagnosed with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. The duration of illness was 154.0 ± 148.5 months, and all patients had been treated with antipsychotics (14 patients received one antipsychotic and eight received two or more antipsychotics) before the study. The antipsychotics of all patients Received 1 October 2013 Accepted 3 December 2013
200
i. miura
were switched to aripiprazole or blonanserin based on the physician’s decision for the purpose of the improvement of clinical symptoms or side effects. The physicians selected aripiprazole or blonanserin based on the clinical judgment from symptoms and side effects of each patient. The switching methods, duration, and the dose of aripiprazole and blonanserin were not fixed, and the endpoint was defined as follows: (i) 8 weeks after completion of the switching or (ii) when switching was discontinued for any reason. Positive and negative syndrome scale (PANSS), Clinical Global Impression (CGI), and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) (Inada et al., 2003) were evaluated at baseline and endpoint. Patients with a CGI-I score of 6 or 7 or a ≥30% increase from baseline in the PANSS total score were defined as worsened patients. Antipsychotic doses were converted to chlorpromazine equivalents (CPZE) based on a previous report (Inagaki and Inada, 2008). Blood samples were collected at baseline and endpoint before breakfast, and pHVA and pMHPG were analyzed with high-performance liquid chromatography with electrochemical detection by using modified methods of Gerhardt et al. (1986). The intra-assay coefficients of variation for pHVA and pMHPG in our laboratory were 3.9% and 3.6%, respectively. The inter-assay coefficients of variation for pHVA and pMHPG were 7.2% and 5.7%, respectively. This protocol was approved by the ethics committee of Fukushima Medical University, and the patients consented to participate after having been informed of the purpose of the study. Student’s t test (paired) was used for comparisons before and after the switch with respect to the changes in PANSS scores in each group. Wilcoxon’s signed rank test was used for other comparisons before and after the switch. The differences in PANSS scores between the bronanserin group and the aripiprazole group were compared by repeatedmeasures analysis of variance. The Mann–Whitney U test was used for other comparisons between the two groups. Spearman’s rank correlation coefficient was used for the associations between monoamine metabolites levels and clinical symptoms. The significance level was defined as p < 0.05. RESULTS At baseline, except for age (blonanserin group: 50.8 ± 12.8 years; aripiprazole group: 39.5 ± 15.7 years, p = 0.043), no differences were observed between the two groups, including duration of illness (p = 0.92), PANSS total (p = 0.68), and DIEPSS (p = 0.53) scores, CGI-S (p = 0.68), CPZE (p = 0.68), pHVA (p = 0.32), Copyright © 2014 John Wiley & Sons, Ltd.
ET AL.
or pMHPG (p = 0.35). Duration from baseline to endpoint was 15.8 ± 6.4 weeks. In the aripiprazole group (n = 12), two patients dropped out and two patients had switching stopped due to exacerbation of psychotic symptoms. In the blonanserin group (n = 10), switching was completed in all patients. At endpoint, dose of aripiprazole and blonanserin was 21.8 ± 8.3 mg/day and 17.0 ± 9.1 mg/day, respectively. Repeated-measures analysis of variance revealed no significant effects for time (total: p = 0.346; positive: p = 0.592; negative: p = 0.23) or time × group interactions (total: p = 0.27; positive: p = 0.233; negative: p = 0.357) on the changes of PANSS scores (Table 1). There were no significant differences between the two groups in the changes in DIEPSS score (p = 0.579), pHVA (p = 0.315), and pMHPG (p = 0.912), whereas there was a trend level difference in the changes in CPZE (p = 0.052) (Table 1). Figure 1 shows the changes in pHVA and pMHPG in two groups. In the whole sample, we observed negative correlation between pHVA at baseline and the change in PANSS total score (rs = 0.450, p = 0.046). A trend for negative correlation was found between pHVA at baseline and the change in PANSS positive (rs = 0.411, p = 0.072) and negative (rs = 0.381, p = 0.097) scores. We also found positive correlation between the changes in pHVA and the changes in PANSS total (rs = 0.536, p = 0.015) and positive (rs = 0.572, p = 0.008) scores. A trend for positive correlation was found between the changes in pHVA and PANSS negative (rs = 0.433, p = 0.056) score. DISCUSSION To the best of our knowledge, this is the first report showing the effects of aripiprazole and blonanserin on plasma monoamine metabolites levels in the switching strategy. There were no differences between blonanserin and aripiprazole in the improvement of clinical symptoms, although only blonanserin decreased PANSS scores significantly. A possible reason for the absence of differences between the two groups was that our sample size was very small. Furthermore, our subjects including chronic schizophrenia patients were heterogeneous. Particularly, there were great differences in the changes in PANSS scores between worsened patients and non-worsened patients in aripiprazole group. On the other hand, there was a trend level difference in the change of CPZE between the two groups. Aripiprazole is a partial agonist for dopamine D2 receptors, whereas blonanserin is a potent D2 antagonist, which has a high brain/pituitary ratio (Tateno et al., 2013). The differences between the two drugs in pharmacological profiles may contribute Hum. Psychopharmacol Clin Exp 2014; 29: 199–202. DOI: 10.1002/hup
201
switching to aripiprazole or blonanserin Table 1.
Clinical results before and after the switch Total (n = 20)
PANSS total PANSS positive PANSS negative CGI-S CGI-I DIEPSS pHVA (ng/ml) pMHPG (ng/ml) CPZE (mg/day)
Aripiprazole group (n = 10)
Blonanserin group (n = 10)
baseline
endpoint
baseline
endpoint
baseline
endpoint
79.7 ± 13.3 17.9 ± 4.4 20.3 ± 4.9 4.2 ± 1.0
75.2 ± 21.1 16.9 ± 8.0 19.1 ± 4.8** 3.8 ± 1.2 3.7 ± 1.4 4.0 ± 3.2 13.9 ± 6.4 8.8 ± 2.6 482.9 ± 222.6***
77.8 ± 9.3 17.6 ± 3.7 19.5 ± 5.5 4.0 ± 0.5
78.6 ± 26.6 18.8 ± 10.5 19.2 ± 5.5 3.9 ± 1.5 4.0 ± 1.6 2.7 ± 2.9 15.2 ± 8.0 7.7 ± 2.3 540.8 ± 212.9
81.6 ± 16.6 18.1 ± 5.3 21.1 ± 4.4 4.4 ± 1.3
71.8 ± 14.3* 15.0 ± 4.0* 18.9 ± 4.3** 3.6 ± 0.7 3.3 ± 1.3 5.2 ± 3.0 12.5 ± 4.5 9.9 ± 2.6 425.0 ± 227.6***
4.9 ± 4.4 15.1 ± 10.9 9.8 ± 5.0 619.8 ± 230.3
4.6 ± 4.9 12.7 ± 5.4 8.1 ± 2.9 596.6 ± 243.6
5.1 ± 4.0 17.4 ± 14.4 11.4 ± 6.3 643.0 ± 226.8
Difference between the two groups, p value 0.270a 0.233a 0.357a 0.353b 0.579c 0.315c 0.912c 0.052c
PANSS, Positive and Negative Syndrome Scale; CGI, Clinical Global Impression; DIEPSS, Drug-Induced Extrapyramidal Symptoms Scale; pHVA, plasma homovanillic acid level; pMHPG, plasma 3-methoxy-4hydroxyphenylglycol level; CPZE, chlorpromazine equivalents. a time × group interaction (repeated-measures analysis of variance); bMann-Whitney U test; cdifference between two groups in the changes after the switch (Mann-Whitney U test). *p < 0.05; **p < 0.01 (paired t test, compared with baseline); ***p < 0.01 (Wilcoxon’s signed rank test, compared with baseline).
Aripiprazole group
Blonanserin group 60
Plasma HVA level (ng/ml)
Plasma HVA level (ng/ml)
40 35 30 25 20 15 10 5 0
50 40 30 20 10 0
baseline
endpoint
baseline
endpoint
worsened patients Figure 1.
The changes in plasma homovanillic acid levels in two groups
to our results of the changes in CPZE. It should be noted that there are some difficulties to compare the two groups directly. This is a non-randomized open study, and pHVA of blonanserin group was higher than that of aripiprazole group at baseline, although the difference was not significant. Because pHVA is possible indicator of response to antipsychotics (Kelley et al., 1999), there is possibility that blonanserin group had more responders to antipsychotics than aripiprazole group. We found that pHVA at baseline correlated the improvement of PANSS scores, which is consistent with the previous study (Miura et al., 2012b). Furthermore, the change in pHVA correlated the changes in PANSS total and positive scores. However, previous studies reported that pHVA was related to the response to aripiprazole (Miura et al., 2012a; Yoshimura et al., 2012), these were the results in drug-naïve or drug-free schizophrenic patients. Our results suggest that pHVA Copyright © 2014 John Wiley & Sons, Ltd.
may be useful indicator for switching to aripiprazole or blonanserin. Actually, pHVA of all three worsened patients increased at endpoint. Because both aripiprazole and blonanserin have relatively weak sedative effects, care must be taken for the prevention of worsening symptoms. Our study has some limitations. This is a nonrandomized open study, and the physician’s decision on the selection of antipsychotics might have affected on our results. Furthermore, our sample size was very small and subjects were heterogeneous. Therefore, our results were preliminary. In conclusion, there were no differences between blonanserin and aripiprazole in the improvement of clinical symptoms in the switching strategy of schizophrenia. Our results suggest that pHVA may be useful indicator for switching to aripiprazole or blonanserin. Further studies with a larger number of patients are needed to confirm our preliminary results. Hum. Psychopharmacol Clin Exp 2014; 29: 199–202. DOI: 10.1002/hup
202
i. miura
CONFLICT OF INTEREST Dr. Miura has received speaker’s honoraria from Dainippon Sumitomo, Janssen, Meiji Seika, Otsuka, and Yoshitomi. He has received grant support from the Eli Lilly Fellowship for Clinical Psychopharmacology. Dr. Niwa receives grant support from Janssen, GlaxoSmithKline, Astellas, Meiji Seika, Yoshitomi, Eli Lillly, Otsuka, Asahi Kasei, Eisai, Kyowa Hakko Kirin, Pfizer, Shionogi, and Dainippon Sumitomo. He has received consulting fees/honorarium in the past from Janssen, Astellas, Eli Lilly, and Otsuka. Drs. Shiga, Katsumi, Kanno-Nozaki, Mashiko, and Yabe have no disclosures to declare. REFERENCES Burris KD, Molski TF, Xu C, et al. 2002. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 302: 381–389. Gerhardt GA, Drebing CJ, Freedman R. 1986. Simultaneous determination of free homovanillic acid, (3-methoxy-4hydroxyphenyl)ethylene glycol, and vanilmandelic acid in human plasma by high-performance liquid chromatography coupled with dual-electrode coulometric electrochemical detection. Anal Chem 58: 2879–2883. Inada T, Beasley CM, Jr, Tanaka Y, Walker DJ. 2003. Extrapyramidal symptom profiles assessed with the Drug-Induced Extrapyramidal Symptoms Scale: comparison with Western scale in the clinical double-blind
Copyright © 2014 John Wiley & Sons, Ltd.
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studies of schizophrenic patients treated with either olanzapine or haloperidol. Int Clin Psychopharmacol 18: 39–48. Inagaki A, Inada T. 2008. Dose equivalence of psychotropic drugs. Part XXI: dose equivalence of novel antipsychotics: Blonanserin. Jpn J Clin Psychopharmacol 11: 887–890. Kelley ME, Yao JK, van Kammen DP. 1999. Plasma Catecholamine metabolites as markers for psychosis and antipsychotic response in schizophrenia. Neuropsychopharmacol 20(6): 603–611. Kishi T, Matsuda Y, Nakamura H, Iwata N. 2013. Blonanserin for schizophrenia: Systematic review and meta-analysis of double-blind, randomized, control trials. J Psychiatr Res 47: 149–154. Kopin IJ, Gordon EK, Jimerson DC, Polinsky RJ. 1983. Relation between plasma and cerebrospinal fluid levels of 3-methoxy-4-hydroxyphenylglycol. Science 219: 73–75. Maas JW, Hattox SE, Greene NM, Landis DH. 1980. Estimates of dopamine and serotonin synthesis by the awake human brain. J Neurochem 34: 1547. Miura I, Takeuchi S, Katsumi A, et al. 2012a. Effects of aripiprazole and the Taq1A polymorphism in the dopamine D2 receptor gene on the clinical response and plasma monoamine metabolites level during the acute phase of schizophrenia. J Clin Psychopharmacol 32: 106–109. Miura I, Takeuchi S, Katsumi A, et al. 2012b. Effect of switching to risperidone after unsuccessful treatment with aripiprazole on plasma monoamine metabolites level in the treatment of acute schizophrenia. Hum Psychopharmacol 27: 517–520. Tateno A, Arakawa R, Okumura M, et al. 2013. Striatal and extrastriatal dopamine D2 receptor occupancy by a novel antipsychotic, blonanserin: a PET study with [11C]raclopride and [11C] FLB 457 in schizophrenia. J Clin Psychopharmacol 33: 162–169. Yoshimura R, Hori H, Ikenouchi-Sugita A, et al. 2012. Aripiprazole altered plasma levels of brain-derived neurotrophic factor and catecholamine metabolites in first-episode untreated Japanese schizophrenia patients. Hum Psychopharmacol 27: 33–38.
Hum. Psychopharmacol Clin Exp 2014; 29: 199–202. DOI: 10.1002/hup
SHORT COMMUNICATION
Switching antipsychotics to aripiprazole or blonanserin and plasma monoamine metabolites levels in patients with schizophrenia Itaru Miura1,2*, Tetsuya Shiga1, Akihiko Katsumi1, Keiko Kanno-Nozaki1, Hirobumi Mashiko1, Shin-Ichi Niwa1 and Hirooki Yabe1 1 2
Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, Fukushima, Japan Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY, USA
Objective Blonanserin is a novel atypical antipsychotic drug that has efficacy equal to risperidone. We investigated the effects of aripiprazole and blonanserin on clinical symptoms and plasma levels of homovanillic acid (pHVA) and 3-methoxy-4hydroxyphenylglycol in the switching strategy of schizophrenia. Methods Twenty two Japanese patients with schizophrenia were enrolled into this open study. The antipsychotics of all patients were switched to aripiprazole or blonanserin for the improvement of clinical symptoms or side effects. Plasma monoamine metabolites levels were analyzed with high-performance liquid chromatography. Results There were no significant effects for time (p = 0.346) or time × group interaction (p = 0.27) on the changes of positive and negative syndrome scale (PANSS) total score, although blonanserin decreased PANSS scores. We observed negative correlation between pHVA at baseline and the change in PANSS total score (rs = 0.450, p = 0.046). We also found positive correlation between the changes in pHVA and the changes in PANSS total (rs = 0.536, p = 0.015) and positive (rs = 0.572, p = 0.008) scores. Conclusions There were no differences between blonanserin and aripiprazole in the improvement of clinical symptoms. Our results suggest that pHVA may be useful indicator for the switching strategy to aripiprazole or blonanserin in schizophrenia. Copyright © 2014 John Wiley & Sons, Ltd. key words—schizophrenia; aripiprazole; blonanserin; switching strategy; homovanillic acid
INTRODUCTION In the treatment of schizophrenia, switching antipsychotics is a common strategy to improve clinical symptoms or decrease drug side effects. However, care must be taken because switching sometimes leads to worsening of psychotic symptoms. Aripiprazole is a partial agonist for dopamine D2 receptors (Burris et al., 2002), which is widely used for schizophrenia. Blonanserin is a novel atypical antipsychotic drug that has efficacy similar to risperidone, and also favorable profiles for side effects such as weight gain or hyperprolactinemia (Kishi et al., 2013). Homovanillic acid (HVA) and 3-methoxy-4hydroxyphenylglycol (MHPG) are the major metabolites of dopamine and noradrenaline, respectively. Although it is difficult to *Correspondence to: I. Miura MD, PhD, Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan. Tel: +81-24-547-1331; Fax: +81-24-5486735 E-mail: [email protected]
Copyright © 2014 John Wiley & Sons, Ltd.
regard plasma monoamine metabolites as direct reflections of central activity, it is estimated that 30–50% of plasma HVA (pHVA) (Maas et al., 1980) and one-third of plasma MHPG (pMHPG) (Kopin et al., 1983) are derived from the brain, respectively. In this study, we investigated the effects of aripiprazole and blonanserin on clinical symptoms and plasma monoamine metabolites in the switching strategy of schizophrenia.
METHODS Subjects comprised 22 Japanese patients (11 men and 11 women; mean age ± SD, 44.1 ± 14.9 years) who were diagnosed with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. The duration of illness was 154.0 ± 148.5 months, and all patients had been treated with antipsychotics (14 patients received one antipsychotic and eight received two or more antipsychotics) before the study. The antipsychotics of all patients Received 1 October 2013 Accepted 3 December 2013
200
i. miura
were switched to aripiprazole or blonanserin based on the physician’s decision for the purpose of the improvement of clinical symptoms or side effects. The physicians selected aripiprazole or blonanserin based on the clinical judgment from symptoms and side effects of each patient. The switching methods, duration, and the dose of aripiprazole and blonanserin were not fixed, and the endpoint was defined as follows: (i) 8 weeks after completion of the switching or (ii) when switching was discontinued for any reason. Positive and negative syndrome scale (PANSS), Clinical Global Impression (CGI), and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) (Inada et al., 2003) were evaluated at baseline and endpoint. Patients with a CGI-I score of 6 or 7 or a ≥30% increase from baseline in the PANSS total score were defined as worsened patients. Antipsychotic doses were converted to chlorpromazine equivalents (CPZE) based on a previous report (Inagaki and Inada, 2008). Blood samples were collected at baseline and endpoint before breakfast, and pHVA and pMHPG were analyzed with high-performance liquid chromatography with electrochemical detection by using modified methods of Gerhardt et al. (1986). The intra-assay coefficients of variation for pHVA and pMHPG in our laboratory were 3.9% and 3.6%, respectively. The inter-assay coefficients of variation for pHVA and pMHPG were 7.2% and 5.7%, respectively. This protocol was approved by the ethics committee of Fukushima Medical University, and the patients consented to participate after having been informed of the purpose of the study. Student’s t test (paired) was used for comparisons before and after the switch with respect to the changes in PANSS scores in each group. Wilcoxon’s signed rank test was used for other comparisons before and after the switch. The differences in PANSS scores between the bronanserin group and the aripiprazole group were compared by repeatedmeasures analysis of variance. The Mann–Whitney U test was used for other comparisons between the two groups. Spearman’s rank correlation coefficient was used for the associations between monoamine metabolites levels and clinical symptoms. The significance level was defined as p < 0.05. RESULTS At baseline, except for age (blonanserin group: 50.8 ± 12.8 years; aripiprazole group: 39.5 ± 15.7 years, p = 0.043), no differences were observed between the two groups, including duration of illness (p = 0.92), PANSS total (p = 0.68), and DIEPSS (p = 0.53) scores, CGI-S (p = 0.68), CPZE (p = 0.68), pHVA (p = 0.32), Copyright © 2014 John Wiley & Sons, Ltd.
ET AL.
or pMHPG (p = 0.35). Duration from baseline to endpoint was 15.8 ± 6.4 weeks. In the aripiprazole group (n = 12), two patients dropped out and two patients had switching stopped due to exacerbation of psychotic symptoms. In the blonanserin group (n = 10), switching was completed in all patients. At endpoint, dose of aripiprazole and blonanserin was 21.8 ± 8.3 mg/day and 17.0 ± 9.1 mg/day, respectively. Repeated-measures analysis of variance revealed no significant effects for time (total: p = 0.346; positive: p = 0.592; negative: p = 0.23) or time × group interactions (total: p = 0.27; positive: p = 0.233; negative: p = 0.357) on the changes of PANSS scores (Table 1). There were no significant differences between the two groups in the changes in DIEPSS score (p = 0.579), pHVA (p = 0.315), and pMHPG (p = 0.912), whereas there was a trend level difference in the changes in CPZE (p = 0.052) (Table 1). Figure 1 shows the changes in pHVA and pMHPG in two groups. In the whole sample, we observed negative correlation between pHVA at baseline and the change in PANSS total score (rs = 0.450, p = 0.046). A trend for negative correlation was found between pHVA at baseline and the change in PANSS positive (rs = 0.411, p = 0.072) and negative (rs = 0.381, p = 0.097) scores. We also found positive correlation between the changes in pHVA and the changes in PANSS total (rs = 0.536, p = 0.015) and positive (rs = 0.572, p = 0.008) scores. A trend for positive correlation was found between the changes in pHVA and PANSS negative (rs = 0.433, p = 0.056) score. DISCUSSION To the best of our knowledge, this is the first report showing the effects of aripiprazole and blonanserin on plasma monoamine metabolites levels in the switching strategy. There were no differences between blonanserin and aripiprazole in the improvement of clinical symptoms, although only blonanserin decreased PANSS scores significantly. A possible reason for the absence of differences between the two groups was that our sample size was very small. Furthermore, our subjects including chronic schizophrenia patients were heterogeneous. Particularly, there were great differences in the changes in PANSS scores between worsened patients and non-worsened patients in aripiprazole group. On the other hand, there was a trend level difference in the change of CPZE between the two groups. Aripiprazole is a partial agonist for dopamine D2 receptors, whereas blonanserin is a potent D2 antagonist, which has a high brain/pituitary ratio (Tateno et al., 2013). The differences between the two drugs in pharmacological profiles may contribute Hum. Psychopharmacol Clin Exp 2014; 29: 199–202. DOI: 10.1002/hup
201
switching to aripiprazole or blonanserin Table 1.
Clinical results before and after the switch Total (n = 20)
PANSS total PANSS positive PANSS negative CGI-S CGI-I DIEPSS pHVA (ng/ml) pMHPG (ng/ml) CPZE (mg/day)
Aripiprazole group (n = 10)
Blonanserin group (n = 10)
baseline
endpoint
baseline
endpoint
baseline
endpoint
79.7 ± 13.3 17.9 ± 4.4 20.3 ± 4.9 4.2 ± 1.0
75.2 ± 21.1 16.9 ± 8.0 19.1 ± 4.8** 3.8 ± 1.2 3.7 ± 1.4 4.0 ± 3.2 13.9 ± 6.4 8.8 ± 2.6 482.9 ± 222.6***
77.8 ± 9.3 17.6 ± 3.7 19.5 ± 5.5 4.0 ± 0.5
78.6 ± 26.6 18.8 ± 10.5 19.2 ± 5.5 3.9 ± 1.5 4.0 ± 1.6 2.7 ± 2.9 15.2 ± 8.0 7.7 ± 2.3 540.8 ± 212.9
81.6 ± 16.6 18.1 ± 5.3 21.1 ± 4.4 4.4 ± 1.3
71.8 ± 14.3* 15.0 ± 4.0* 18.9 ± 4.3** 3.6 ± 0.7 3.3 ± 1.3 5.2 ± 3.0 12.5 ± 4.5 9.9 ± 2.6 425.0 ± 227.6***
4.9 ± 4.4 15.1 ± 10.9 9.8 ± 5.0 619.8 ± 230.3
4.6 ± 4.9 12.7 ± 5.4 8.1 ± 2.9 596.6 ± 243.6
5.1 ± 4.0 17.4 ± 14.4 11.4 ± 6.3 643.0 ± 226.8
Difference between the two groups, p value 0.270a 0.233a 0.357a 0.353b 0.579c 0.315c 0.912c 0.052c
PANSS, Positive and Negative Syndrome Scale; CGI, Clinical Global Impression; DIEPSS, Drug-Induced Extrapyramidal Symptoms Scale; pHVA, plasma homovanillic acid level; pMHPG, plasma 3-methoxy-4hydroxyphenylglycol level; CPZE, chlorpromazine equivalents. a time × group interaction (repeated-measures analysis of variance); bMann-Whitney U test; cdifference between two groups in the changes after the switch (Mann-Whitney U test). *p < 0.05; **p < 0.01 (paired t test, compared with baseline); ***p < 0.01 (Wilcoxon’s signed rank test, compared with baseline).
Aripiprazole group
Blonanserin group 60
Plasma HVA level (ng/ml)
Plasma HVA level (ng/ml)
40 35 30 25 20 15 10 5 0
50 40 30 20 10 0
baseline
endpoint
baseline
endpoint
worsened patients Figure 1.
The changes in plasma homovanillic acid levels in two groups
to our results of the changes in CPZE. It should be noted that there are some difficulties to compare the two groups directly. This is a non-randomized open study, and pHVA of blonanserin group was higher than that of aripiprazole group at baseline, although the difference was not significant. Because pHVA is possible indicator of response to antipsychotics (Kelley et al., 1999), there is possibility that blonanserin group had more responders to antipsychotics than aripiprazole group. We found that pHVA at baseline correlated the improvement of PANSS scores, which is consistent with the previous study (Miura et al., 2012b). Furthermore, the change in pHVA correlated the changes in PANSS total and positive scores. However, previous studies reported that pHVA was related to the response to aripiprazole (Miura et al., 2012a; Yoshimura et al., 2012), these were the results in drug-naïve or drug-free schizophrenic patients. Our results suggest that pHVA Copyright © 2014 John Wiley & Sons, Ltd.
may be useful indicator for switching to aripiprazole or blonanserin. Actually, pHVA of all three worsened patients increased at endpoint. Because both aripiprazole and blonanserin have relatively weak sedative effects, care must be taken for the prevention of worsening symptoms. Our study has some limitations. This is a nonrandomized open study, and the physician’s decision on the selection of antipsychotics might have affected on our results. Furthermore, our sample size was very small and subjects were heterogeneous. Therefore, our results were preliminary. In conclusion, there were no differences between blonanserin and aripiprazole in the improvement of clinical symptoms in the switching strategy of schizophrenia. Our results suggest that pHVA may be useful indicator for switching to aripiprazole or blonanserin. Further studies with a larger number of patients are needed to confirm our preliminary results. Hum. Psychopharmacol Clin Exp 2014; 29: 199–202. DOI: 10.1002/hup
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CONFLICT OF INTEREST Dr. Miura has received speaker’s honoraria from Dainippon Sumitomo, Janssen, Meiji Seika, Otsuka, and Yoshitomi. He has received grant support from the Eli Lilly Fellowship for Clinical Psychopharmacology. Dr. Niwa receives grant support from Janssen, GlaxoSmithKline, Astellas, Meiji Seika, Yoshitomi, Eli Lillly, Otsuka, Asahi Kasei, Eisai, Kyowa Hakko Kirin, Pfizer, Shionogi, and Dainippon Sumitomo. He has received consulting fees/honorarium in the past from Janssen, Astellas, Eli Lilly, and Otsuka. Drs. Shiga, Katsumi, Kanno-Nozaki, Mashiko, and Yabe have no disclosures to declare. REFERENCES Burris KD, Molski TF, Xu C, et al. 2002. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 302: 381–389. Gerhardt GA, Drebing CJ, Freedman R. 1986. Simultaneous determination of free homovanillic acid, (3-methoxy-4hydroxyphenyl)ethylene glycol, and vanilmandelic acid in human plasma by high-performance liquid chromatography coupled with dual-electrode coulometric electrochemical detection. Anal Chem 58: 2879–2883. Inada T, Beasley CM, Jr, Tanaka Y, Walker DJ. 2003. Extrapyramidal symptom profiles assessed with the Drug-Induced Extrapyramidal Symptoms Scale: comparison with Western scale in the clinical double-blind
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Hum. Psychopharmacol Clin Exp 2014; 29: 199–202. DOI: 10.1002/hup
