rTMS Therapy Reduces Hypofrontality in Patients With Depression as Measured by fNIRS.

Multichannel functional near-infrared spectroscopy (fNIRS) is a tool used to capture changes in cerebral blood flow. A consistent result for depression is a decrease in blood flow in the frontal cortex leading to hypofrontality, which indicates multidomain functional impairment. Repetitive transcranial magnetic stimulation (rTMS) and elective convulsive therapy (ECT) are alternatives to antidepressant drugs for the treatment of depression but the underlying mechanism is yet to be elucidated. The aim of the current study was to evaluate cerebral blood flow using fNIRS following rTMS treatment in patients with depression. The cerebral blood flow of 15 patients with moderate depression after rTMS treatment was measured using fNIRS. While there was clear hypofrontality during pre-treatment (5 ± 2.5), a notable increase in oxygenated hemoglobin was observed after 30 sessions with rTMS (50 ± 15). This increased blood flow was observed in a wide range of channels in the frontal cortex; however, the centroid values were similar between the treatments. Increased blood flow leads to the activation of neuronal synapses, as noted with other neuromodulation treatments such as electroconvulsive therapy. This study describes the rTMS-induced modulation of blood oxygenation response over the prefrontal cortex in patients with depression, as captured by fNIRS. Future longitudinal studies are needed to assess cerebral blood flow dynamics during rTMS treatment for depression.

Safety profile of clozapine: Analysis using national registry data in Japan.

Clozapine is the only effective antipsychotic drug used for the treatment of treatment-resistant schizophrenia. Although it has been shown that the frequency of clozapine use is very low in Japan, our previous study revealed that the number of clozapine prescriptions has been increasing in recent years, and that risk factors leading to discontinuation of clozapine were also identified as age ≥40 years, poor tolerability to olanzapine, previous treatment with clozapine, and white blood cell count <6000/mm3. The main cause for discontinuation of clozapine is the occurrence of a wide range of adverse events, including neutropenia/leukopenia and fatal cardiac disorders. In this study, we analyzed the physical details and backgrounds of patients with adverse events that led to clozapine discontinuation using a national registry database of more than 8000 Japanese patients. The physical adverse events that led to discontinuation of clozapine were neutropenia/leukopenia, glucose intolerance, cardiac disorders, gastrointestinal disorders, neuroleptic malignant syndrome, pleurisy, pulmonary embolism, sedation/somnolence, and seizures. Neutropenia/leukopenia had the highest incidence (5.0%). Neutropenia/leukopenia and cardiac disorders tended to occur early in the treatment period, indicating the need for careful monitoring for these adverse events in the early stages of clozapine treatment. Gastrointestinal disorders occurred over a long period of time, suggesting the need for careful observation during the maintenance period. The data obtained in our study will lead to the optimal and safe use of clozapine treatment.

A descriptive study of 10-year clozapine use from the nationwide database in Japan.

This survey was conducted to identify the actual usage of clozapine and changes required to increase the number of patients with schizophrenia who would benefit from clozapine. We obtained Clozaril® Patient Monitoring Service (CPMS) data for 8,263 patients that received clozapine between July 2009 and January 2020. Patients were divided into the early (n=3,696 cases, which have been analyzed previously) and late groups (n=4,567 cases) according to the date of the treatment initiation. In total, 417 facilities offered the drug, with a surge in cases in the late group (40.0 hospitals/year, 568.6 cases/year vs. 39.3 hospitals/year, 1,141.8 cases/year). We found a significant between-group difference in the mean dosage during treatment (early group: 309.1 mg/day; late group: 247.9 mg/day). The treatment continuation rates at 1 and 4 years in all study participants were 77.2% and 65.1%, respectively. The incidences of granulocytopenia and agranulocytosis were 5.5% and 1.0%, respectively. The discontinuation rate because of granulocytopenia was significantly lower in the late group. There were no differences in the discontinuation rate because of glucose intolerance between the groups. An assessment of the current CPMS regulations may be required to further examine the clozapine use effectiveness.

Clozapine Is Better Tolerated in Younger Patients: Risk Factors for Discontinuation from a Nationwide Database in Japan.

OBJECTIVE: The effectiveness of clozapine is clearly superior to other antipsychotics in the treatment of refractory schizophrenia. Clozapine leads to various side effects, and therefore many patients are forced to discontinue. In this study, we analyzed the registry database of all cases in Japan to identify risk factors for discontinuation of clozapine. METHODS: The Clozaril patient monitoring service® (CPMS) database from July 31, 2009 to January 26, 2020 was acquired. We defined the following exclusion criteria: patients who had ever taken clozapine by a non-CPMS method, such as an individual import or clinical trial, patients who did not receive clozapine after being enrolled in CPMS, and patients with initial doses other than 12.5 mg (outside the current protocol). Therefore, all patients in this study are new users. Multivariate Cox regression analysis was used to investigate independent risk factors associated with time to discontinuation of clozapine. RESULTS: We identified 8,263 patients as the study population. Clozapine discontinuation was significantly associated with age 40 and older [hazard ratio (HR)=1.66, p<0.001], intolerance to olanzapine (HR=1.31, p=0.018), previous treatment with clozapine (HR=1.30, p=0.001), and leukocyte counts <6,000/mm3 (HR=1.24, p<0.001). The Kaplan-Meier curves for clozapine discontinuation by age group revealed that older age at the time of clozapine introduction tended to have lower continuation rates. CONCLUSION: Careful administration is important because patients with these factors have a high risk of discontinuation. In addition, the initiation of clozapine during the younger period was more effective and more tolerated.

fNIRS Assessment during an Emotional Stroop Task among Patients with Depression: Replication and Extension.

OBJECTIVE: Accumulated evidence collected via functional near-infrared spectroscopy (fNIRS) has been reported with regard to mental disorders. A previous finding revealed that emotional words evoke left frontal cortex activity in patients with depression. The primary aim of the current study was to replicate this finding using an independent dataset and evaluate the brain region associated with the severity of depression using an emotional Stroop task. METHODS: Oxygenized and deoxygenized hemoglobin recording in the brain by fNIRS on 14 MDD patients and 20 normal controls. RESULTS: Hyperactivated oxygenized hemoglobin was observed in the left frontal cortex on exposure to unfavorable stimuli, but no significant difference was found among patients with depression compared with healthy controls on exposure to favorable stimuli. This result is consistent with previous findings. Moreover, an evoked wave associated with the left upper frontal cortex on favorable stimuli was inversely correlated with the severity of depression. CONCLUSION: Our current work using fNIRS provides a potential clue regarding the location of depression symptom severity in the left upper frontal cortex. Future studies should verify our findings and expand them into a precise etiology of depression.

Clinical application of DEX/CRH test and multi-channel NIRS in patients with depression.

BACKGROUND: To reduce the number of patients with depression, biomarkers for clarifying psychiatric disorders are warranted. Numerous candidates have been proposed; however, near-infrared spectroscopy (NIRS) with multi-channel probes and a dexamethasone/corticotropin-releasing hormone (DEX/CRH) test are still surviving for practical demand. Thirty-one outpatients with depressed moods were analyzed using both biological tests. RESULTS: The non-suppressors, as indicated by the DEX/CRH test, exhibited a high severity on the Hamilton Depression Scale and severe anxiety on the State Trait Anxiety Scale. In addition, a unique response was identified via NIRS in the same group suggested by the DEX/CRH assessment. CONCLUSIONS: The results obtained from these biological tests did not fit well with the category defined by operative diagnostic criteria, such as the Diagnostic and Statistical Manual of Mental Disorders or The International Classification of Diseases. Thus, it is critical that the utility evaluations of candidate biomarkers not be assessed by comparisons with the categorized criteria for a specific psychiatric disorder. Trial registration UMIN000013214, Registered 21 February 2014.

Correlation between frontal lobe oxy-hemoglobin and severity of depression assessed using near-infrared spectroscopy.

INTRODUCTION: The search for objective biomarkers of psychiatric disorders has a long history. Despite this, no universally accepted instruments or methods to detect biomarkers have been developed. One potential exception is near-infrared spectroscopy, although interpreting the measures of blood flow recorded with this technique remains controversial. In this study, we aimed to investigate the relationship between recorded blood flow and depression severity assessed using the Hamilton depression scale in patients with various psychiatric disorders. METHODS: Enrolled patients (n=43) had DSM-IV diagnoses of major depressive disorder (n=25), bipolar disorder I (n=5), schizophrenia (n=3), dysthymic disorder (n=3), psychotic disorder (n=3), panic disorder (n=2), and Obsessive Compulsive Disorder (n=2). The verbal fluency task was administered during blood flow recording from the frontal and temporal lobes. RESULTS: We found that severity of depression was negatively correlated with the integral value of blood flow in the frontal lobe, irrespective of psychiatric diagnosis (F=5.94, p=0.02). DISCUSSION: Our results support blood flow in the frontal lobe as a potential biomarker of depression severity across various psychiatric disorders. LIMITATION: Limited sample size, no replication in the second set.

[The Current Status of the Department of Neuropsychiatry at Osaka Medical College].

Since there is a growing need for psychiatric treatment in general hospitals, the decreas- ing number of treatment beds has become a marked problem in Japan. One of the financial reasons is a difference in the reimbursement of medical fees between medical treatments in physical departments of the same hospital. Our neuropsychiatry department has accepted patients with psychiatric disorders suffering from various physical complications in order to meet local or hospital demand ; however, it is the case that the psychiatric ward has been required to decrease the number of beds from the aspect of management rationalization. According to the comparative analysis of four practical cases treated on our ward, the reim- bursement of medical fees was much lower than medical fees for the same treatment if patients had been treated on general physical wards. This result is considered to show one of the difficulties of maintaining psychiatric wards in general hospitals. It is essential to improve the reimbursement of medical fees for psychiatric wards. Moreover, we propose introducing the DPC (Diagnostic Procedure Combination) into treatment, especially on psychiatric wards. The demand for psychiatric treatment at general hospitals will increase in the future due to Japan having the world's most rapidly aging society. Maintaining a clinical budget equal to the available resources will help avoid a decreasing number of beds.

Phosphorylation of c-Cbl protooncogene product following ethanol administration in rat cerebellum: possible involvement of Fyn kinase.

We have previously shown that ethanol administration results in tyrosine phosphorylation of the 130 kDa protein in rat brain, and identified the protein as Cas, the crk-associated src substrate. In the present study, we demonstrate that Cbl of a 120 kDa protein is also tyrosine-phosphorylated in the cerebellum in response to ethanol administration. We also investigated whether Fyn kinase was involved in ethanol-induced Cbl phosphorylation. Immunoprecipitation experiments showed that the amount of coimmunoprecipitated Fyn kinase with an anti-Cbl antibody increased in extracts from ethanol-administered rats compared to those from saline-administered rats. Exogenous Fyn kinase was shown to phosphorylate on tyrosine residue(s) of Cbl from the cerebellum in vitro. Furthermore, Fyn kinase and Cbl were demonstrated immunohistochemically to be coexpressed in white matter in the cerebellum. These findings indicate that Cbl is tyrosine-phosphorylated in rat cerebellum in response to ethanol administration, and also raise the possibility that Fyn kinase may be involved in the process.