Effect of lemborexant on pharmacokinetics of clozapine: A potential drug-drug interaction mediated by time-dependent inhibition of CYP3A4.

Clozapine (CLZ) is extensively used for treatment-resistant schizophrenia (TRS) with caution to avoid serious adverse events such as agranulocytosis and drug-drug interactions (DDIs). In the current report, we present a case of a 35-year-old male non-smoking TRS patient whose steady-state plasma trough concentrations (Ctrough ) of CLZ and its active metabolite, N-desmethylclozapine (NDMC), were significantly increased after initiating oral administration of lemborexant (LEM), a dual orexin receptor antagonist, for the treatment of insomnia. The patient experienced oversedation with sleepiness and fatigue while maintaining high levels of Ctrough of CLZ. The increased concentrations of CLZ returned to normal ranges after the discontinuation of LEM dosing, implying a pharmacokinetic DDI between CLZ and LEM. To gain insight into possible mechanisms, we performed in vitro assays of CYP1A2- and CYP3A4-mediated CLZ metabolism by measuring the formations of NDMC and clozapine N-oxide (CNO). In accordance with previous studies, the incubation of CLZ with each enzyme resulted in the production of both metabolites. LEM had only a weak inhibitory effect on CYP1A2- and CYP3A4-mediated CLZ metabolism. However, the preincubation of LEM with CYP3A4 in the presence of NADPH showed a significant enhancement of inhibitory effects on CLZ metabolism with IC50 values for the formations of CNO and NDMC of 2.8 µM and 4.1 µM, respectively, suggesting that LEM exerts as a potent time-dependent inhibitor for CYP3A4. Taken together, the results of the current study indicate that co-medication of CLZ with LEM may lead to increase in exposure to CLZ and risks of CLZ-related adverse events.

Achievements and Current Status of the Fukushima Health Management Survey.

The Fukushima Health Management Survey (FHMS) was established in response to the Fukushima Daiichi Nuclear Power Plant accident on March 11, 2011. The primary objectives of the study are to monitor residents' long-term health and promote their future well-being, and to determine the health effects of long-term low-dose radiation exposure. This special issue summarizes the results and current status of the FHMS and discusses the challenges and future directions of the FHMS. The FHMS, a cohort study of all people who were residents in Fukushima Prefecture at the time of the accident, consists of a Basic Survey, Thyroid Ultrasound Examination, Comprehensive Health Check, Mental Health and Lifestyle Survey, and Pregnancy and Birth Survey. The radiation exposure was estimated based on the behavioral records examined using the Basic Survey. Although the response rate was low in the Basic Survey, the representativeness of the radiation exposure data was confirmed using additional surveys. There appears to be no relationship between the radiation exposure and risk of thyroid cancer, although more thyroid cancer cases were detected than initially expected. The ongoing Comprehensive Health Check and Mental Health and Lifestyle Survey have provided evidence of worsening physical and mental health status. The Pregnancy and Birth Survey showed rates of preterm delivery, low birth weight, and congenital abnormalities similar to the national average. Considering the above evidence, the Fukushima Prefectural Government decided to end the Pregnancy and Birth Survey at the end of March 2021, as recommended by the Prefectural Oversight Committee. The framework of the FHMS has not changed, but the FHMS needs to adapt according to the survey results and the changing needs of the eligible residents and municipalities.

Associations Between External Radiation Doses and the Risk of Psychological Distress or Post-traumatic Stress After the Fukushima Daiichi Nuclear Power Plant Accident: the Fukushima Health Management Survey.

BACKGROUND: The relationship between radiation levels and mental health status after a nuclear disaster is unknown. We examined the association between individual external radiation doses and psychological distress or post-traumatic stress after the Fukushima Daiichi nuclear power plant accident in March 2011 in Japan. METHODS: The Mental Health and Lifestyle Survey was conducted from January 2012. Based on the estimated external radiation doses for the first 4 months, a total of 64,184 subjects were classified into <1 mSv, 1 to <2 mSv, and ≥2 mSv groups. Odds ratios (ORs) and 95% confidence intervals (CIs) of psychological distress and post-traumatic stress, with the <1 mSv group as the reference, were calculated using logistic regression analysis adjusted for age, sex, evacuation, perception of radiation risk, and subjective health status. RESULTS: The prevalence of psychological distress/post-traumatic stress in the <1 mSv, 1 to <2 mSv, and ≥2 mSv groups was 15.1%/22.1%, 14.0%/20.1%, and 15.0%/21.7%, respectively. In women, although the ≥2 mSv group tended to have a higher risk of psychological distress with the age-adjusted OR of 1.13 (95% CI, 0.99-1.30), the adjusted OR decreased to 1.00 (95% CI, 0.86-1.16) after controlling for all variables. On the other hand, there were no dose-dependent associations between radiation dose and post-traumatic stress. CONCLUSION: Although external radiation doses were not associated with psychological distress, evacuation and perception of radiation risk may increase the risk of psychological distress in women in the higher dose group.

Electroconvulsive Therapy for Parkinson's Disease with Depression and Neuroleptic Malignant Syndrome: A Case Report.

Parkinson's disease is often complicated by psychiatric symptoms. Psychiatrists are caught in a dilemma between such symptoms and physical treatment since Parkinson's disease sometimes shows treatment resistance based on pharmacological treatment-induced dopamine dysfunction. Here, we report on a 64-year-old woman with a 15-year history of Parkinson's disease with stage IV severity based on the Hoehn and Yahr scale. She was admitted to our hospital with a diagnosis of major depressive disorder with psychotic features. Unfortunately, her treatment course for depression was complicated by neuroleptic malignant syndrome. Because we were concerned about the persistence of her depressive symptoms, the risk of psychotropic drugs causing adverse effects, and progressive disuse syndrome, we administered modified electroconvulsive therapy. Her symptoms of neuroleptic malignant syndrome and depression sufficiently improved after five sessions of modified electroconvulsive therapy. Additionally, the primary motor symptoms of her Parkinson's disease also markedly improved. The improvement of neuroleptic malignant syndrome and her motor symptoms based on dopamine dysfunction can be explained by electroconvulsive therapy's effectiveness in activating dopamine neurotransmission. Besides, the marked improvement of her depressive episode with psychotic features was presumed to involve dopamine receptor activation and regulation. Because advanced Parkinson's disease can sometimes be refractory to treatment based on pharmacological treatment-induced dopamine dysfunction, psychiatrists often have difficulty treating psychiatric symptoms; electroconvulsive therapy may stabilize the dopaminergic system in such cases, presenting a possible non-pharmacologic treatment option for Parkinson's disease.

Effects of the -141C insertion/deletion polymorphism in the dopamine D2 receptor gene on the dopamine system in the striatum in patients with schizophrenia.

The relationships between -141C insertion/deletion (Ins/Del) polymorphisms in the dopamine D2 receptor gene and the two dopamine system integrators, i.e., dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) and calcineurin (CaN), are still unclear. In this study, we assessed the effect of this polymorphism on DARPP-32 and CaN protein expression in the postmortem striatum of patients with schizophrenia and control individuals. The expression levels of truncated DARPP and CaN were lower in Del allele carriers. These findings provide important insights into the mechanism by which this genotype could result in a poor response to antipsychotic drugs.

Role of (-)-epigallocatechin gallate in the pharmacokinetic interaction between nadolol and green tea in healthy volunteers.

PURPOSE: The aim of the present study is to investigate a possible role of a single dose of (-)-epigallocatechin gallate (EGCG), the major catechin in green tea, for the pharmacokinetic interaction between green tea and nadolol in humans. METHODS: In a randomized three-phase crossover study, 13 healthy volunteers received single doses of 30 mg nadolol orally with water (control), or an aqueous solution of EGCG-concentrated green tea extract (GTE) at low or high dose. Plasma concentrations and urinary excretion of nadolol were determined up to 48 h. In addition, blood pressure and pulse rate were monitored. In vitro transport kinetic experiments were performed using human embryonic kidney 293 cells stably expressing organic anion transporting polypeptide (OATP)1A2 to evaluate the inhibitory effect of EGCG on OATP1A2-mediated substrate transport. RESULTS: Single coadministration of low and high dose GTE significantly reduced the plasma concentrations of nadolol. The geometric mean ratios with 90% CI for area under the plasma concentration-time curves from 0 to infinity of nadolol were 0.72 (0.56-0.87) for the low and 0.60 (0.51-0.69) for the high dose. There were no significant differences in Tmax, elimination half-life, and renal clearance between GTE and water phases. No significant changes were observed for blood pressure and pulse rate between phases. EGCG competitively inhibited OATP1A2-mediated uptake of sulphobromophthalein and nadolol with Ki values of 21.6 and 19.4 µM, respectively. CONCLUSIONS: EGCG is suggested to be a key contributor to the interaction of green tea with nadolol. Moreover, even a single coadministration of green tea may significantly affect nadolol pharmacokinetics.

Evaluation of Brain Activity Using Near-infrared Spectroscopy in Inflammatory Bowel Disease Patients.

Depression is implicated as a risk factor for the recurrence of inflammatory bowel disease (IBD). Near-infrared spectroscopy (NIRS) and brain-derived neurotrophic factor (BDNF) are useful tools for evaluation of brain activity and a depressive state, respectively. The aim of this study was to clarify the association between brain activity or depressive symptoms and IBD using NIRS and BDNF. This study included 36 ulcerative colitis (UC) patients, 32 Crohn's disease (CD) patients, and 17 healthy controls (HC). Center for Epidemiologic Studies Depression Scale (CES-D) scores were determined, NIRS was performed, and serum BDNF levels were measured in all subjects. NIRS showed that the mean oxygenated hemoglobin concentration was significantly lower in the frontal lobe in the UC group than in the HC group (HC 167 ± 106 vs. UC 83.1 ± 85.3, p < 0.05). No significant difference was seen between the HC and CD groups. There were also no significant differences in CED-D scores and BDNF levels among the groups. Changes in the NIRS values of the UC group may indicate decreased brain activity and a fundamental difference between UC and CD, which are often lumped together as two types of IBD.

Perception of Radiation Risk as a Predictor of Mid-Term Mental Health after a Nuclear Disaster: The Fukushima Health Management Survey.

Predictive factors including risk perception for mid-term mental health after a nuclear disaster remain unknown. The purpose of this study was to examine the association between perceived radiation risk and other factors at baseline and mid-term mental health after the Fukushima Daiichi nuclear disaster of 2011 in Japan. A mail-based questionnaire survey was conducted in January 2012 and January 2013. Mental health status was assessed using the K6 scale. Psychological distress over the 2-year period was categorized into the following four groups: chronic, recovered, resistant, or worsened. Most participants (80.3%) were resistant to the disaster. A positive association was found between the radiation risk perception regarding immediate effects and the worsened group in women. Baseline post-traumatic stress disorder (PTSD) or a history of psychiatric disease predicted being in the chronic or worsened group in mid-term course. These results suggest that evacuees who believed that their health was substantially affected by the nuclear disaster were at an increased risk of having poor mid-term mental health in women. Careful assessment of risk perception after a nuclear disaster, including the presence of PTSD or a history of psychiatric disease, is needed for appropriate interventions.

Elevated postmortem striatal t-DARPP expression in schizophrenia and associations with DRD2/ANKK1 polymorphism.

BACKGROUND: Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) and calcineurin (CaN) have been implicated in the pathogenesis of schizophrenia because they function as molecular integrators of dopamine and glutamate signaling. DARPP-32 and CaN are mainly expressed in the caudate nucleus and putamen; however, a few postmortem brain studies have focused on DARPP-32 expression in striatum from patients with schizophrenia. METHODS: We used immunoblotting techniques and postmortem tissue samples from patients with schizophrenia and from normal control individuals to examine the expression of two major DARPP-32 isoforms, full-length (FL-DARPP) and truncated (t-DARPP), and of CaN in the striatum. We also assessed whether there was any significant correlation between the expression levels of either protein and the A1 allele of Taq1A genotype in the dopamine D2 receptor (DRD2) gene/ankyrin-repeat containing kinase 1 (ANKK1) gene. RESULTS: We found that the mean t-DARPP expression level in the caudate was higher in patients with schizophrenia than in control individuals (P<0.05) and the A1 allele of Taq1A genotype in DRD2/ANKK1 was significantly associated with elevated expression of t-DARPP in the caudate. Also, the A1 allele was significantly correlated with the total score of antemortem psychiatric symptoms. CONCLUSION: These results may reflect potential molecular mechanisms important to the pathogenesis of schizophrenia.