Innovations In Clinical Neuroscience

MAR-APR 2018

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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12 ICNS INNOVATIONS IN CLINICAL NEUROSCIENCE March-April 2018 • Volume 15 • Number 3–4 of diabetes associated with olanzapine might be diabetic ketoacidosis (DKA), requiring admission to an intensive care unit. Patients exposed to antipsychotics have approximately 10 times increased risk of DKA compared to the general population, and the majority of patients who developed DKA following antipsychotics were treated with olanzapine and clozapine in the first six months of treatment. 3 The mechanisms underlying the onset of diabetes by olanzapine are reported to be increased peripheral and hepatic insulin resistance that is mainly due to a weight gain effect. 4 These mechanisms might provide olanzapine-induced, slowly progressive glucose intolerance, such as the onset of Type 2 diabetes, but do not explain olanzapine- related acute-onset DKA. The mechanism of rapid-onset diabetes by olanzapine is poorly understood. In clinical research, olanzapine- treated patients with schizophrenia displayed biphasic changes in insulin secretion in a hyperglycemic challenge. Insulin secretion decreased at Week 2 and increased at Week 8 as the body weight increased. 5 Olanzapine might reduce insulin secretion at an early stage of the treatment. Research has shown that olanzapine evoked endoplasmic reticulum (ER) stress, as evidenced by mild activation of the ER stress sensor molecule PKR-like ER kinase (PERK). However, phosphorylation of the alpha subunit of eukaryotic initiation Factor 2, an event immediately downstream of PERK activation, was not observed, resulting in sustained ER stress and beta-cell apoptosis. 6 Olanzapine is thought to directly influence pancreatic beta-cells and impair insulin secretion at an early stage of treatment, which is a mechanism of acute-onset glucose intolerance. Clinicians should consider the risk of DKA when starting treatment with olanzapine. Further research regarding the direct effect of olanzapine on the pancreatic beta-cell is needed. References 1. Iwaku K, Otuka F, Taniyama M. Acute-onset type 1 diabetes that developed during the administration of olanzapine. Intern Med. 2017;56(3):335–339. 2. Nakamura M, Nagamine T. Severe hyperglycemia induced by olanzapine was improved with a recovery of insulin secretion after switching to risperidone and introducing insulin therapy. Intern Med. 2010;49(23):2635–2637. 3. Polcwiartek C, Vang T, Bruhn CH, et al. Diabetic ketoacidosis in patients exposed to antipsychotics: a systematic literature review and analysis of Danish adverse drug event reports. Psychopharmacology (Berl). 2016;233(21– 22):3663–3672. 4. Newcomer JW. Antipsychotic medications: metabolic and cardiovascular risk. J Clin Psychiatry. 2007;68 Suppl 4:8–13. 5. Chiu CC, Chen CH, Chen BY, et al. The time- dependent change of insulin secretion in schizophrenic patients treated with olanzapine. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34: 866–870. 6. Ozasa R, Okada T, Nadanaka S, et al. The antipsychotic olanzapine induces apoptosis in insulin-secreting pancreatic B cells by blocking PERK-mediated translational attenuation. Cell Struct Funct. 2013;38(2):183–195. With regard, Takahiko Nagamine, MD, PhD Dr. Nagamine is with the Department of Psychiatric Internal Medicine, Sunlight Brain Research Center, Yamaguchi, Japan. Correspondence: Takahiko Nagamine, MD, PhD; Email: tnagamine@outlook.com. Funding/financial disclosures: No funding was provided for the preparation of this letter. The author has conflicts of interest related to the content of this letter. PROLAC TIN LEVELS IN PATIENTS WITH SCHIZOPHRENIA WHO WERE SWITCHED FROM DAILY TO ONCE- MONTHLY ARIPIPRA ZOLE TREATMENT Dear Editor: Schizophrenia is a chronic and progressive psychiatric disorder requiring long-term treatment with antipsychotics. The use of long-acting injectable antipsychotics (LAI) has been shown to increase adherence, reduce risk of relapse, and support recovery for patients with schizophrenia by achieving an optimal dopamine (D) 2 receptor occupancy. 1 Among several oral antipsychotics, a significant association between D 2 receptor occupancy levels and serum prolactin levels has been demonstrated. 2 We reported that a fluctuation range of prolactin levels after switching to paliperidone palmitate (PP) might be useful to confirm optimal D 2 receptor occupancy in maintenance treatment with LAI. 3 In our subsequent report, safety switching to PP was supported by sequential changes of prolactin levels matched to time profiles of serum concentrations of active moiety in a pharmacokinetic analysis study. 4 Aripiprazole once-monthly (AOM) is also an atypical LAI. Though the pharmacological mechanisms of PP and AOM are different, they are both active at D 2 receptors. Here, we investigate the efficacy and tolerability of AOM in patients who were switched from oral aripiprazole, as well as examine its relationship to prolactin levels based on a 12-month prospective-designed method. The ethics committee of Kusatsu Hospital, Hiroshima, approved this study. Research outline . Patients with schizophrenia who were switched to AOM 400mg were enrolled under the following inclusion criteria: treated with aripiprazole daily for at least the previous two months, ongoing AOM treatment for more than 12 months, not having changed antipsychotic treatment, and fulfilled recommended dose switching method. A total of 10 male patients and 15 female patients, with a mean age of 43.5 and 39.5 years, respectively, entered the study after providing written informed consent. The 18-item Brief Psychiatric Rating Scale (BPRS) total scores, 9-item Drug-induced Extrapyramidal Symptoms Scale (DIEPSS) total scores, and the fasting serum prolactin levels divided by sex and daily oral aripiprazole dosage (switched from 24mg [n=8] or 30mg [n=2] in male subjects and from18 mg [n=2], 24mg [n=9] or 30mg [n=4] in female subjects) were assessed at baseline and at one, three, six, and 12 months. Multiple comparisons were performed with repeated measured analysis of variance (ANOVA), followed by post-hoc analysis. The BPRS scores were significantly decreased at six and 12 months in female L E T T E R S T O T H E E D I T O R

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