Introduction
Atypical antipsychotics are characterised by a potent serotonin (5-HT)-2 receptor-blocking action in addition to D2 antagonism. Atypical antipsychotics have the same efficacy as typical antipsychotics but a lower risk of extrapyramidal symptoms (EPS) and impaired cognition (Reference Lieberman, Stroup and Mcevoy1). However, they have potentially serious side effects, including weight gain, sedation, akathisia and hyperprolactinaemia (Reference Lieberman, Stroup and Mcevoy1). Therefore, new atypical antipsychotics with a better safety profile suitable for long-term management of patients with schizophrenia have long been sought.
Blonanserin (2-(4-ethyl-l- piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta [b]pyridine) has a D2 receptor-blocking activity comparable to that of haloperidol, as well as potent 5-HT-2 receptor-blocking activity and weak 5TH-2C, D1 and α 1 receptor-blocking activities while being almost devoid of histamine H1 and muscarinic M1 antagonist activity (Reference Deeks and Keating2,Reference Noda, Kurumiy, Miura and Oka3). Blonanserin displays a positive atypical index equal to that of sulpiride (Reference Oka, Hamamura and Lee4).
Clinical trials have shown that blonanserin is effective in the treatment of both positive and negative symptoms of schizophrenia in Japan and Korea (Reference Murasaki5–Reference Yang, Bahk and Cho7). In a Japanese study, blonanserin improved memory 1 and 2 scores on the Wechsler memory scale-revised (WMS-R) and attention scores on the Wechsler adult intelligence scale-revised (WAIS-R) (Reference Miura8). In this study, we administered blonanserin to 48 Japanese patients with schizophrenia for whom other atypical antipsychotics were not sufficiently effective or tolerated. The objective was to evaluate the effectiveness and tolerability of blonanserin and its ability to induce social functions in the treatment of Japanese patients with intractable schizophrenia.
Cases and methods
Blonanserin was administered to 48 patients [14 male and 34 female, aged 21–68 years, mean 42.31 years (±12.24)] with 45 schizophrenia and 3 schizoaffective disorder as diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-4). The diagnosis was performed with the clinical features by the attending psychiatrist and the other two investigators. The subtypes of schizophrenia were 34 paranoid, 10 hebephrenic and 1 catatonic. Fourteen patients had the hereditary form of schizophrenia. Other atypical antipsychotics were not effective or well tolerated. The average duration of illness was 16.81 years. Thirty-seven patients had a history of hospitalisation, and 25 patients were in-patients before the switch to blonanserin. According to the clozapine treatment and monitoring guidelines in Japan, 24 patients had treatment-resistant schizophrenia and 9 patients had treatment-intolerant schizophrenia (Reference Oshimo9). Clozapine had not been administered to these patients because clozapine was not available in Japan until April 2010. Fifteen psychiatrists diagnosed and participated in their treatment. This is a retrospective study based on medical records by psychiatrists who were not the attending psychiatrists. The Clinical Global Impression of Severity (CGI-S) score, Global Assessment of Functioning (GAF) score and social role of the patients were assessed before the switch to blonanserin and at the cutoff point or 1 year after switching to blonanserin. No other antipsychotic was administered at the same time as blonanserin. We investigated the reasons for the discontinuation of previous antipsychotics and initiation of blonanserin, the efficacy of blonanserin and the improvement in social function 1 year after blonanserin therapy.
Results
They had been administered an average of 1.98 (±1.08) classes of atypical antipsychotics. An adjunct anticholinergic, biperiden, was administered to 12 patients (25%) at an average dose of 2.08 mg/day. An adjunctive mood stabiliser was given to 15 patients (31.3%): valproic acid to 12, lithium to 2 and carbamazepine to 1. Before switching to blonanserin, the 48 Japanese intractable schizophrenia patients were treated with risperidone (13), olanzapine (13), aripiprazole (11), quetiapine (5), perospirone (2) and typical antipsychotics (4). They were switched to blonanserin for its effectiveness (54.2%; 26/48) or tolerability (45.8%; 22/48). The average maximum dose of blonanserin was 13.89 mg/day (±18.5). Blonanserin improved the effectiveness of 65.4% (17/26) of cases and the tolerability in 95.5% (21/22) of cases. Twenty-two cases were switched to blonanserin because of intolerance to other antipsychotics, including six cases of sedation, six cases of amenorrhoea, three cases of akathisia, two cases of dystonia, two cases of extrapyramidal signs, one cases of high serum creatine phosphokinase, one case of obesity and one case of headache. The six cases of amenorrhoea included three cases of hyperprolactinaemia. One patient who switched because of sedation still felt sedated after switching to blonanserin and dropped out. Of 48 patients, 33 patients continued blonanserin for 1 year. The mean CGI-S scores improved from 4.60 (±1.31) to 3.19 (±1.58). The CGI-S scores of the 33 patients who continued blonanserin for 1 year were improved to 2.48 (±1.12). The mean GAF score improved from 29.8 (±10.9) to 51.7 (±16.8). The maintenance dose of blonanserin was 11.52 mg/day (±7.94). Twenty-two cases were maintained at the maximum dose, and it was decreased in 11 cases. Among the 33 patients who continued blonanserin, 19 patients (39.6%; 19/48) were able to function socially, 11 as full-time housewives, 4 as full-time workers and 4 as part-time workers. Before blonanserin administration, only the patient having akathisia was able to work, and the other 18 were not able to function socially. Blonanserin was discontinued because it was ineffective against psychosis (27.1%; 13/48) or not well tolerated (4.2%; 2/48). Blonanserin was also discontinued because it caused akathisia and sedation. The ratio of discontinuation for intolerance versus ineffectiveness was 0.15, which was the lowest among all atypical psychotics (Table 1).
Table 1 Reason for discontinuation of atypical psychotics in 48 Japanese patients with intractable schizophrenia
CPK, elevated creatine phosphokinase; EPS, extrapyramidal symptoms. Ratio: ratio of discontinuation for intolerance versus ineffectiveness.
Discussion
The ratio of discontinuation for intolerance versus effectiveness of blonanserin was the lowest among the atypical psychotics (Table 1). On the other hand, the discontinuation ratios of risperidone and olanzapine were high (Table 1). In this study, blonanserin was effective in 65% of Japanese patients with intractable schizophrenia. Other open label studies have indicated that blonanserin was as effective as risperidone or haloperidol (Reference Murasaki5–Reference Yang, Bahk and Cho7). In addition, blonanserin was well tolerated and had a better safety profile. Risperidone induced amenorrhoea, hyperprolactinaemia, EPS and dystonia. These adverse events were related to D2 receptor-blocking activity (Reference Lieberman, Stroup and Mcevoy1). Blonanserin blocked D2 receptor activity more strongly than risperidone or haloperidol,but blonanserin induced these side effects at a lower rate in our study. Blonanserin more strongly blocks 5HT2A activity than risperidone (Reference Deeks and Keating2) and therefore might induce lower rates of EPS and dystonia. Recently, atypical psychotics were reported to have different risks of hyperprolactinaemia, and this is related to the drug concentrations in the brain and plasma (Reference Arakawa, Okumura and Ito10). Blonanserin crosses the blood–brain barrier at higher levels than risperidone or haloperidol (Reference Arakawa, Okumura and Ito10). Blonanserin was reported to induce akathisia more frequently than risperidone or haloperidol (Reference Murasaki5–Reference Yang, Bahk and Cho7). In our study, blonanserin induced five cases of akathisia, but four patients continued blonanserin after the dose was reduced or biperiden was added. Five patients who had reported akathisia while taking aripiprazole or risperidone were able to continue blonanserin. For management of akathisia, the dose of blonanserin might be important. Blonanserin improved obesity and sedation. Blonanserin has weak 5TH2C and α 1 receptor-blocking activities while being almost devoid of histamine H1 activity (Reference Deeks and Keating2,Reference Noda, Kurumiy, Miura and Oka3). In our study, 57.6% of the patients who continued blonanserin functioned socially. Blonanserin has D3 receptor-binding affinity (Reference Deeks and Keating2). Because a selective blockade of D3 receptors enhances frontocortical cholinergic transmission, D3-receptor function is related to social recognition in humans and rodents (Reference Millan, Di Cara and Dekeyne11,Reference Bombin, Arango and Mayoral12).
There are some limitations in this study. The diagnosis was performed considering clinical features alone. Three patients with schizoaffective disorder were included. It was difficult to evaluate CGI-S, GAF and social functioning retrospectively. Therefore, the validity and bias might be included.
Fifteen percent of the patients with chronic schizophrenia were reported to discontinue risperidone (RIS), olanzapine (OLZ) or quetiapine (QTP) owing to intolerance within 18 months (Reference Lieberman, Stroup and Mcevoy1). The intolerance of the antipsychotics is one of the important factors to continue the treatment of schizophrenia. Blonanserin may be suitable for the long-term management of patients with intractable schizophrenia.
Acknowledgements
This study was partly supported by a grant from the Zikei Institute of Psychiatry. The authors declare no conflict of interest.
