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Clozapine is an atypical antipsychotic used for treatment-resistant schizophrenia. In Japan, its use requires management by a blood monitoring system called the Clozaril Patient Monitoring Service (CPMS) for the early detection of serious side effects such as agranulocytosis, which is extremely rare. Monitoring services vary among the clozapine suppliers in different countries. Additionally, Japanese patients can be started on clozapine treatment exclusively through an 18-week inpatient admission at a psychiatric hospital capable of coordinating with a hematologist. One reported reason for the lack of widespread clozapine use in Japan is the difficulty in establishing collaboration with hematologists when agranulocytosis/leukopenia occurs. Hence, we conducted a nationwide web-based survey of CPMS-registered psychiatric facilities in Japan to determine the status of collaboration with hematology departments. Valid responses were received from the psychiatrists responsible for prescribing clozapine at 203 of the 547 facilities (response rate: 37.1 %). The largest number of psychiatric facilities (61 %) collaborated with hematologists at another facility with a psychiatry department, while psychiatrists in 32 % of the facilities worked with hematologists at their own facilities. Most patients with clozapine-induced agranulocytosis/leukopenia could be treated with clozapine discontinuation and follow-up in psychiatric inpatient units with the assistance of a hematologist. The actual workload of hematologists was limited, and the patients might experience the burden of repeated blood sampling. This study suggests that disseminating information regarding the status of collaborations with hematologists may promote the widespread use of clozapine in Japan. SHORT COMMENT FOR TWITTER: This study suggests that most patients with clozapine-induced agranulocytosis/leukopenia could be treated with clozapine discontinuation and follow-up in psychiatric inpatient units with the assistance of a hematologist., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier B.V.)

Using natural language processing (NLP) technology to analyze and organize textual information in psychiatric electronic medical records can identify undiscovered factors associated with treatment discontinuation. This study aimed to evaluate brexpiprazole treatment continuation rate and factors affecting brexpiprazole discontinuation using a database that employs the MENTAT® system with NLP technology. This retrospective observational study evaluated patients with schizophrenia who were newly initiated on brexpiprazole (April 18, 2018-May 15, 2020). The first prescriptions of brexpiprazole were followed up for 180 days. Factors associated with brexpiprazole discontinuation were assessed using structured and unstructured patient data (April 18, 2017-December 31, 2020). The analysis population comprised 515 patients; mean (standard deviation) age of patients was 48.0 (15.3) years, and 47.8 % were male. Using Kaplan-Meier analysis, the cumulative brexpiprazole continuation rate at 180 days was 29 % (estimate: 0.29; 95 % confidence interval, 0.25-0.33). Univariate Cox proportional hazards analysis identified 16 variables independently associated with brexpiprazole discontinuation. Multivariate analysis identified eight variables associated with treatment discontinuation: variables with hazard ratio <1 were the presence of physical complications, longer hospitalization duration, and maximum chlorpromazine-equivalent dose of antipsychotics of >200 to ≤400 mg/day vs ≤200 mg/day in the past year; variables with hazard ratio >1 were previous electroconvulsive therapy, availability of key contact person information, a history of crime committed/reported, increase in brexpiprazole dose to 2 mg in >28 days, and appearance/worsening of symptoms other than positive symptoms. In conclusion, we identified potential new factors that may be associated with brexpiprazole discontinuation, which may improve the treatment strategy and continuation rate in patients with schizophrenia., Competing Interests: Declaration of competing interest MI reports consulting fees from Eli Lilly Japan K.K., Sumitomo Dainippon Pharma Co., Ltd., Pfizer Japan Inc., Abbott Japan Co., Ltd., Janssen Pharmaceutical K.K., and Otsuka Pharmaceutical Co., Ltd.; and honoraria from Janssen Pharmaceutical K.K., Eli Lilly Japan K.K., Otsuka Pharmaceutical Co., Ltd., Meiji Seika Pharma Co., Ltd., Astellas Pharma Inc., Sumitomo Dainippon Pharma Co., Ltd., Ono Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., Takeda Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., MSD K.K., Eisai Co. Ltd., Daiichi-Sankyo Co. Ltd., Novartis Pharma K.K., Teijin Ltd., Shionogi & Co., Ltd., Hisamitsu Pharmaceutical Co., Inc., and Asahi Kasei Corporation. HA and DS are full-time employees of Otsuka Pharmaceutical Co., Ltd. and report profit of stock or stock options from Otsuka Pharmaceutical Co., Ltd. YS is a full-time employee of Otsuka Pharmaceutical Co., Ltd. NM is a contracted advisor for the Medical Affairs group, working once a week at Otsuka Pharmaceutical Co., Ltd., and reports consulting fees from Otsuka Pharmaceutical Co., Ltd., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

While the long-term administration of antipsychotics is known to cause dopamine supersensitivity psychosis (DSP), recent studies revealed that DSP helps form the foundation of treatment resistance. Electroconvulsive shock (ES) is one of the more effective treatments for treatment-resistant schizophrenia. The objective of this study was to examine whether repeated ES can release rats from dopamine supersensitivity states such as striatal dopamine D2 receptor (DRD2) up-regulation and voluntary hyperlocomotion following chronic administration of haloperidol (HAL). HAL (0.75 mg/kg/day) was administered for 14 days via mini-pumps implanted in rats, and DRD2 density and voluntary locomotion were measured one day after drug cessation to confirm the development of dopamine supersensitivity. The rats with or without dopamine supersensitivity received repeated ES or sham treatments, and then DRD2 density was assessed and a voluntary locomotion test was performed. Chronic treatment with HAL led to the up-regulation of striatal DRD2 and hyperlocomotion in the rats one day after drug cessation. We thus confirmed that these rats experienced a dopamine supersensitivity state. Moreover, after repeated ES, locomotor activity and DRD2 density in the DSP model rats fell to the control level, while an ES sham operation had no effect on the dopamine supersensitivity state. The present study suggests that repeated ES could release DSP model rats from dopamine supersensitivity states. ES may be helpful for patients with DSP., Competing Interests: Declaration of competing interest Dr. Oda received grant funding from the SENSHIN Medical Research Foundation. Dr. Kanahara received grant funding from the Ministry of Health, Labour and Welfare of Japan and the SENSHIN Medical Research Foundation and reports honoraria from Otsuka, Eli Lilly, Meiji Seika, Sumitomo Dainippon, and Janssen. Dr. Shirayama received research support from Eisai, Eli Lilly Japan, Otsuka Pharmaceutical, MSD K.K., Taisho Toyama Pharmaceutical Company, Pfizer Japan, Takeda, and Mitsubishi-Tanabe. Dr. Hashimoto has served as a scientific consultant to Astellas, Dainippon-Sumitomo, and Taisho, and received research support from Abbvie, Dainippon-Sumitomo, Mochida Pharmaceutical Company, Otsuka, and Taisho. Dr. Iyo received consultant fees from Eli Lilly, Sumitomo Dainippon, Pfizer, and Abbott and reports honoraria from Janssen, Eli Lilly, Otsuka, Meiji Seika, Astellas, Sumitomo Dainippon, Ono, GlaxoSmithKline, Takeda, Mochida, Kyowa Hakko, MSD, Eisai, Daiichi-Sankyo, Novartis, Teijin, Shionogi, Hisamitsu, and Asahi Kasei. Dr. Oishi and Dr. Nakata have no potential conflicts of interest to report. Dr. M. Kimura, Dr. Oishi, Dr. H. Kimura, Dr. Yoshino, and Dr. Niitsu have no potential conflicts of interest to report., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Although a variety of factors are known to be significantly related to poor prognosis in schizophrenia, their interactions remain unclear. Dopamine supersensitivity psychosis (DSP) is a clinical concept related to long-term pharmacotherapy and could be one of the key factors contributing to the development of treatment-resistant schizophrenia (TRS). The present study aims to explore the effect of DSP on progression to TRS., Methods: Two-hundreds and sixty-five patients were classified into either a TRS or Non-TRS group based on retrospective survey and direct interview. The key factors related to prognosis, including the presence or absence of DSP episodes, were extracted, and each factor was compared between the two groups., Results: All parameters except for the duration of untreated psychosis (DUP) were significantly worse in the TRS group compared to the Non-TRS group. In particular, the TRS group presented with a significantly higher rate of DSP episodes than the Non-TRS group. Regression analysis supported the notion that DSP plays a pivotal role in the development of TRS. In addition, deficit syndrome was suggested to be a diagnostic subcategory of TRS., Conclusions: Our data confirmed that the key predicting factors of poor prognosis which have been established would actually affect somehow the development of TRS. In addition, the occurrence of a DSP episode during pharmacotherapy was shown to promote treatment refractoriness., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: This study was designed to evaluate efficacy and safety of aripiprazole once-monthly (AOM) by verifying non-inferiority of AOM to oral aripiprazole in Asian patients with schizophrenia., Method: The study consisted of a screening phase and three phases: an oral conversion phase (≤12weeks), an oral stabilization phase (≤12weeks) and a 52-week double-blind phase. Patients meeting stabilization criteria for 4weeks during the oral stabilization phase were randomly assigned (1:1) to AOM (400mg) or oral aripiprazole (6-24mg/day). The primary endpoint was Kaplan-Meier estimated rate of non-exacerbation of psychotic symptoms/non-relapse at Week 26., Results: A total of 724 patients were screened, and 502 patients entered the oral stabilization phase. Of 455 patients randomized in the double-blind phase, 228 received AOM and 227 received oral aripiprazole. The non-exacerbation of psychotic symptoms/non-relapse rates at Week 26 were 95.0% (AOM) and 94.7% (oral aripiprazole) and the difference was 0.3% (95% CI: -3.9,4.5), thus non-inferiority of AOM compared to oral aripiprazole with respect to non-exacerbation of psychotic symptoms/non-relapse rate was shown with a margin of -3.9% which is well above the pre-defined non-inferiority limit (-15%). The proportions of patients meeting exacerbation of psychotic symptoms/relapse criteria and stabilization of psychotic symptoms/maintenance criteria were 6.6% and 92.5% in both groups. Discontinuation rates due to all reasons were 25.9% (AOM) and 33.5% (oral aripiprazole). AOM was well tolerated as well as oral aripiprazole., Conclusions: Non-inferiority of AOM to oral aripiprazole was established. AOM is efficacious in maintenance treatment of stabilized schizophrenia, with comparable efficacy and tolerability to oral aripiprazole., Clinical Trials Registration: JapicCTI-101175., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Accumulating evidence suggests that patients with schizophrenia are exposed to a high risk of osteoporosis/osteopenia caused by long-term antipsychotic treatment. The degree of bone mineral density (BMD) loss that a given antipsychotic may cause is not known. Examinations using a bone turnover marker may more accurately predict the ongoing bone states in psychiatric patients. We measured prolactin, estradiol, testosterone, and bone resorption marker (TRACP-5b) levels in 167 patients with schizophrenia and 60 normal controls. The patients showed significantly higher levels of prolactin and lower levels of TRACP-5b compared to the controls. Moreover, prolactin was negatively correlated with estradiol and testosterone in the group of all male subjects and the male patients. TRACP-5b was positively correlated with prolactin in the female patients and negatively correlated with estradiol in the group of all female subjects. The results show that the bone resorption rate was rather attenuated in the patients compared to the normal controls, suggesting a complicated etiology of BMD loss in schizophrenia patients. Several meaningful correlations between key factors in this study confirmed that hyperprolactinemia induced the suppression of sex hormones, and possibly led to the higher bone turnover. These results indicate that measurement of the resorption marker TRACP-5b might be useful to clarify the pathology of BMD loss., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: Dopamine supersensitivity psychosis (DSP) is considered to be one cause of treatment-resistant schizophrenia (TRS). The authors investigated the efficacy of risperidone long-acting injections (RLAI) in patients with TRS and DSP., Method: This is a multicenter, prospective, 12-month follow-up, observational study that included unstable and severe TRS patients with and without DSP. 115 patients with TRS were recruited and divided into two groups according to the presence or absence of DSP which was judged on the basis of the clinical courses and neurological examinations. RLAI was administered adjunctively once every 2weeks along with oral antipsychotics. We observed changes in scores for the Brief Psychiatric Rating Scales (BPRS), Clinical Global Impression-Severity of Illness (CGI-S), Global Assessment of Functioning Scale (GAF), and Extrapyramidal Symptom Rating Scale (ESRS) during the study. Of the assessed 94 patients, 61 and 33 were categorized into the DSP and NonDSP groups, respectively., Results: While baseline BPRS total scores, CGI-S scores and GAF scores did not differ, the ESRS score was significantly higher in the DSP group compared with the NonDSP group. Treatment significantly reduced BPRS total scores and CGI-S scores, and increased GAF scores in both groups, but the magnitudes of change were significantly greater in the DSP group relative to the NonDSP group. ESRS scores were also reduced in the DSP group. Responder rates (≥20% reduction in BPRS total score) were 62.3% in the DSP group and 21.2% in the NonDSP group., Conclusions: It is suggested that DSP contributes to the etiology of TRS. Atypical antipsychotic drugs in long-acting forms, such as RLAI, can provide beneficial effects for patients with DSP., Clinical Trials Registration: UMIN (UMIN000008487)., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: A relapse prevention program called the Information Technology Aided Relapse Prevention Programme in Schizophrenia (ITAREPS) has been developed and is reported to be highly effective. However the effectiveness was influenced by user adherence to the protocol of the program, the exact effectiveness and the role of the ITAREPS have been partially uncertain., Objective: The purpose of this study is to evaluate the effectiveness of the ITAREPS excluding the effect of user adherence to the protocol of the program., Method: We attempted to perform a randomized controlled trial by the devised method with visiting nurse service. Outpatients with schizophrenia were randomized to the ITAREPS (n=22) or control group (n=23) and were observed for 12 months., Results: The risk of rehospitalization was reduced in the ITAREPS group (2 [9.1%]) compared with the control group (8 [34.8%]) (hazard ratio=0.21, 95% CI 0.04-0.99, p=0.049; number needed to treat (NNT)=4, 95% CI 2.1-35.5). The mean number of inpatient days was significantly lower in the ITAREPS group (18.5 days) compared with the control group (88.8 days) (p=0.036). The ratio of the number of rehospitalizations to that of relapses was significantly lower (p=0.035) and the mean change in total BPRS scores at relapse from baseline was significantly less in the ITAREPS group (p=0.019)., Conclusions: The relapse prevention effectiveness of the ITAREPS was high, and we confirmed that the ITAREPS, i.e., detecting signs of relapse and increasing medication during the warning state, is an effective intervention during the early stages of relapse., (© 2013. Published by Elsevier B.V. All rights reserved.)

Deficit syndrome, which is characterized by primary and enduring negative symptoms, is a homogeneous subtype within schizophrenia. Negative symptoms in schizophrenia are currently considered to be closely linked with frontal lobe impairment. However, the etiology in the frontal lobe of people with deficit syndrome is not fully understood. We measured regional cerebral blood flow (rCBF) with single photon emission computed tomography (SPECT) in 33 patients with deficit syndrome, 40 patients with nondeficit syndrome, and 45 healthy controls, and we compared groups using the voxel-wise method. Schizophrenia combined group, the deficit syndrome and the nondeficit syndrome presented hypoperfusion in mainly the medial and lateral prefrontal cortices. The deficit syndrome group showed a significant decrease in rCBF in the right orbitofrontal cortex (OFC) compared to the nondeficit group. These results demonstrated that at-rest hypofrontality was a common feature within the disease group and suggested that the OFC might play an important role in the development of severe negative symptoms in people with deficit syndrome., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Aberrant neuronal development is one of the integrative theories for the etiology of schizophrenia. The plexin A2 (PLXNA2) gene is one of the receptor genes for axonal guidance factors. Recently, four single nucleotide polymorphisms (SNPs), rs841865, rs752016, rs1327175 and rs2498028, from the PLXNA2 genomic interval have been reported to be associated with schizophrenia in samples from European Americans, Latin Americans and Asian Americans. We tested these four SNPs for association with disease in two Asian populations: 1140 case-control Japanese samples and 293 Chinese pedigrees (1163 samples). In the Japanese samples, significant differences in the allelic frequency and genotypic distribution of rs841865 (p=0.019 and 0.020, respectively) were observed between cases and controls. Haplotype analysis also revealed a significant association of the gene with the disease (global p=0.028). In contrast, there was no genetic contribution of PLXNA2 to Chinese schizophrenia, either by linkage analysis or association tests (allelic and haplotypic transmission disequilibrium tests). These findings suggest that PLXNA2 confers a varying genetic risk for schizophrenia among different populations.

Physiological deficits in inhibition of the P50 auditory evoked potential in schizophrenia have been related to diminished expression of alpha7 nicotinic acetylcholine receptors. Diminished P50 inhibition is correlated with neuropsychological deficits in attention, one of the principal neurocognitive disturbances in schizophrenia. Nicotine administration improves P50 inhibition, presumably by achieving additional activation of these diminished receptors, but its toxicity and marked tachyphylaxis make it an ineffective therapeutic. Nicotine also has weak positive effects on several neurocognitive deficits in schizophrenia, which raises the possibility that the alpha7 nicotinic receptor is a clinically relevant therapeutic target that should be addressed by less toxic agents. Tropisetron, a drug already approved for clinical use outside the United States as an anti-emetic, is a partial agonist at alpha7 nicotinic receptors and an antagonist at 5-HT(3) receptors. As an initial proof-of-principle study, we determined that a single administration of tropisetron significantly improves P50 inhibition in schizophrenia. These data are consistent with biological activity at a pathophysiological mechanism in schizophrenia and support further trials of this drug as a possible therapeutic for neurocognitive deficits in schizophrenia.

We investigated, using proton magnetic resonance spectroscopy (1H-MRS), whether the tardive dyskinesia (TD) often seen in schizophrenic patients is associated with cellular abnormalities in the basal ganglia system. The subjects in this study included schizophrenic patients with TD (TD group, n=7), schizophrenic patients without TD (non-TD group, n=7), and healthy volunteers (N group, n=7). We examined the 1H-MRS peaks of N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) in the regions of the left and right lenticular nucleus. In the left lenticular nucleus, the Cho/Cr ratio was significantly greater in the TD and non-TD groups than in the N group (Mann-Whitney U test; p<0.007 and p<0.006, respectively). Further, a significant linear trend was observed in the means of the ratio across the three groups (p<0.005); the TD group was the highest, the N group the lowest, and the non-TD group intermediate. No significant difference in the NAA/Cr ratio was found among groups. These results indicate that neural abnormalities in the basal ganglia may be linked with the neuroleptic medications and the process of the fundamental illness per se, and that more excessive damage to this neural substrate may lead to development of TD. However, as this is a preliminary study, further studies with a large number of subjects are required to verify our findings.