Published papers

Background: Ketamine is effective for treatment-resistant depression (TRD), where its mechanism remains unclear. Though the amygdala plays an important role in emotional processing and mood state, no study has explored the relationship between amygdalar subfield volumes and ketamine's effect in patients with TRD. We hypothesized that amygdalar subfield volume changes would correlate with clinical response to ketamine in patients with TRD. Methods: We used data from a double-blind, randomized, placebo-controlled trial (jRCTs031210124). Among 31 completers, 11 (35.5 %) participants in the ketamine group and 15 (48.4 %) participants in the placebo group underwent 0.8 mm-isotropic T1-and T2-weighted multimodal magnetic resonance imaging scans before and after the interventions. Depressive symptoms were assessed with the Montgomery Åsberg Depression Rating Scale (MADRS). We focused on the three amygdalar subfields: laterobasal (LB), centromedial, and superficial nuclei. Multivariable and post-hoc univariate regression analyses were conducted to explore the factors associated with the change in the MADRS total and subdomain scores. Results: There was a significant interaction between the volume changes in the right LB and group for the MADRS dysphoria score changes (F (3, 22) = 3.63, p = 0.029, R2 = 0.24, treatment by volume change interaction: β = 0.61, p = 0.028). Post-hoc analyses found that changes in MADRS dysphoria scores related to volume changes in the right LB in the ketamine group (β = 0.65, p = 0.028), but not in the placebo group. Conclusions: The reductions in right LB volumes correlate with better clinical responses to ketamine in patients with TRD, suggesting ketamine may exert its effect by attenuating amygdalar overactivity in this population.

Introduction: The therapeutic potential of psychedelics for various mental disorders has gained significant interest. Previous studies have highlighted that psychedelics induce psychoactive effects, including challenging aspects of experiences. These experiences are assessed using the Challenging Experience Questionnaire (CEQ), yet its Japanese version has been unavailable. This study aimed to create a Japanese version of the CEQ. Methods: We followed the “Principles of Good Practice for the Translation and Cultural Adaptation Process for Patient-Reported Outcomes (PRO) Measures: Report of the ISPOR Task Force for Translation and Cultural Adaptation.” Initially, two Japanese psychiatrists independently conducted the forward translations. These were then reconciled into a single version, which was back-translated into English. The original authors reviewed this back-translation for accuracy, leading to revisions through continuous dialogue until the original authors approved the final version. Results: The final, approved back-translated version of the CEQ is presented in the figure. Conclusions: This study developed a Japanese version of the CEQ, enabling the assessment of challenging experiences during psychedelic-assisted therapy for Japanese speakers. Further studies are needed to assess the reliability and validity of this newly translated version.

Background: Tau accumulation in the nucleus basalis of Meynert (nbM) has been documented in Alzheimer's disease (AD), but its relationship to neuropathological changes in other brain regions and cognitive deficits remains unclear, particularly between early-onset AD (EOAD) and late-onset AD (LOAD). Objective: To evaluate tau accumulation patterns in the nbM and other brain regions in EOAD and LOAD using 18F-florzolotau PET and examine correlations with cognitive function. Methods: Thirty-eight amyloid-positive AD patients (15 EOAD, 23 LOAD) and 46 healthy controls underwent 18F-florzolotau PET. Tau levels were quantified in the nbM and Braak-staging regions. Postmortem brain samples were examined to assess 18F-florzolotau binding to tau deposits. Results: EOAD showed a higher overall tau burden, including in the nbM, compared with LOAD. However, nbM tau levels correlated more strongly with cognitive decline in LOAD than EOAD. The relationship between nbM tau and neocortical tau differed between EOAD and LOAD. Histopathology revealed abundant 18F-florzolotau labeling of neurofibrillary tangles (NFTs) and ghost tangles in AD nbM samples. Conclusions: This study provides the first in vivo PET evidence of differential nbM tau pathology between EOAD and LOAD, with higher accumulation but weaker correlation to cognition in EOAD. The distinct relationships between nbM and cortical tau in EOAD and LOAD suggest divergent pathological trajectories. 18F-florzolotau PET successfully visualized NFTs and extracellular ghost tangles in the nbM across AD stages. These findings highlight the importance of considering age of onset when evaluating tau pathology and its clinical correlates in AD.

INTRODUCTION: Late-life mood disorders (LLMDs) may represent prodromal manifestations of neurodegenerative dementia; however, the neuropathological basis of LLMDs, including depression and bipolar disorder, remains unclear. We aimed to investigate the involvement of Alzheimer's disease (AD) and non-AD tau pathologies in LLMD participants. METHODS: Fifty-two LLMD participants and 47 age- and sex-matched healthy controls (HCs) underwent tau and amyloid beta (Aβ) positron emission tomography (PET) imaging using 18F-florzolotau and 11C-Pittsburgh compound B. Additionally, we conducted a clinicopathological correlation analysis in 208 autopsy cases, including various neurodegenerative diseases. RESULTS: LLMD participants were more likely to be tau PET and Aβ PET positive than HCs. The PET results were supported by the post mortem results that showed a higher likelihood of diverse tauopathies in patients with late-life mania or depression than those without. DISCUSSION: Our PET and autopsy assays suggest that AD and diverse non-AD tau pathologies might underlie the neuropathological basis of some LLMD cases. Highlights: Late-life mood disorders (LLMDs) may represent prodromal states of dementia. The neuropathological basis of LLMDs remains unclear. LLMD subjects were highly likely to be tau positron emission tomography (PET) positive. Brain bank data supported our PET results. Alzheimer's disease (AD) and diverse non-AD tau pathologies can contribute to LLMDs.

Background: Bilateral repetitive transcranial magnetic stimulation (BL-rTMS) over the dorsolateral prefrontal cortex is effective for treatment-resistant depression (TRD). Owing to a shorter treatment time, bilateral theta burst stimulation (BL-TBS) can be more efficient protocol. The non-inferiority of BL-TBS to BL-rTMS was established in late-life TRD; however, this has not been determined in adults of other age groups. Therefore, we investigated the non-inferiority in efficacy of BL-TBS versus BL-rTMS for TRD across a wide range of ages in a randomized, single-blind, multicenter trial. Methods: The study included 180 participants with major depressive disorder (moderate or greater severity) who were unresponsive to at least one antidepressant treatment between September 2018 and July 2022. Following venlafaxine treatment, patients were randomly assigned to BL-rTMS or BL-TBS (1:1 ratio). The primary outcome was baseline-adjusted Montgomery-Åsberg Depression Rating Scale scores at 6 weeks. The non-inferiority margin of −3.86 was compared against the baseline-adjusted difference. Secondary outcomes included other depression rating scales. Results: Seventy-seven patients were randomly assigned to BL-rTMS and 81 to BL-TBS, of whom 73 and 76 were assessed for the primary outcome, respectively. There was a −2.44 point difference, favoring BL-rTMS (one-tailed lower 95 % CI = −4.19, p = 0.091 for non-inferiority), and non-inferiority of BL-TBS was not established. However, non-inferiority was observed for secondary outcomes. The all-cause dropout rates and number of adverse effects were similar between them. Conclusion: Our study could not establish the non-inferiority of BL-TBS compared to BL-rTMS in terms of efficacy for patients with TRD across the adult lifespan.

Background: Mental health problems, particularly depression, significantly impact the working-age population and incur substantial socioeconomic costs. Electrodermal activity (EDA) and skin temperature, measurable through wearable devices, have emerged as potential biomarkers of depression. However, there is a lack of long-term observational studies in real-world settings. Methods: This 4-week observational study analyzed data from 147 office workers across 11 Japanese companies. Participants wore wearable devices during working hours for four weeks to collect EDA and skin temperature data. Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9), and stress was assessed using the 10-item version of the Perceived Stress Scale (PSS-10). The associations between electrodermal activity, skin temperature, and depressive/stress states were analyzed using the Mann–Whitney U test and logistic regression analysis. Results: Participants with PHQ-9 scores ≥5 showed higher median skin conductance and median tonic signal, although these differences lost statistical significance after Bonferroni correction. Logistic regression analysis revealed a negative correlation between age and both PHQ-9 and PSS-10 scores (OR=0.525, 0.646). The mean and standard deviation of skin temperature showed a positive association with depressive symptoms (OR=1.687, 1.733), while normalized EDASymp showed a negative association (OR=0.564). Conclusions: This study suggests that EDA and skin temperature, measured by wearable devices, may be associated with depressive symptoms among office workers. These physiological indicators could be utilized for mental health monitoring and early intervention in the workplace. Further validation with larger samples, and long-term follow-up studies, are warranted.

Objectives: Treatment decisions for severe aortic stenosis (AS) are complex, since there are two active and comparable options: transcatheter aortic valve implantation and surgical aortic valve replacement. The disease predominantly affects older individuals, who are frequently comorbid with from cognitive impairment. This study aimed to establish a screening-triggered system to assess the decision-making capacity of patients with AS, support their decision-making, and facilitate referrals to specialists when necessary. Methods: This is a retrospective pre-post observational study. Relevant healthcare professionals were trained to assess and support patients' decision-making capacities. Results: Subtotals of 203 and 244 patients were enrolled before and after the implementation of the system, respectively. The requests for decision-making support significantly increased (from 1.5 % to 14.8 % of the patients). 11.5 % of the patients were identified as with declined decision-making capacity. The proportion of patients who received active treatments for AS significantly decreased from 95.0 % to 83.0 %. The nurses' documentation of patients' decision-making capacities significantly increased. Conclusion: This screening-triggered system identified a substantial proportion of patients with declined decision-making capacity. A significant decrease in patients receiving active treatments for AS and increased documentation of patients' decision-making capacities in nursing records were observed. A future randomized controlled is warranted.

Background: Approximately 30 % of patients with treatment-resistant depression (TRD) respond to ketamine; however, no replicable predictors of response have been reported. The imbalance between excitatory and inhibitory neurotransmissions may be implicated in the mechanism of action of ketamine. This study aimed to evaluate whether the ratio of glutamate and glutamine (Glx) to GABA levels at baseline in the dorsal anterior cingulate cortex (dACC) could predict ketamine response in patients with TRD. Method: This exploratory study analyzed data from a double-blind randomized clinical trial with an open-label extension study (jRCTs031210124). Fifteen participants in the ketamine group and 15 of 16 participants in the placebo group received repeated intravenous ketamine during the double-blind and open-label extension periods, respectively. We measured Glx and GABA levels in the dACC before and after treatment during the double-blind period using proton magnetic resonance spectroscopy. The 17-item Hamilton Depression Rating Scale (HDRS-17) was measured for depressive symptomatology. General linear models were used to examine the relationship between baseline Glx/GABA ratio and HDRS-17 score changes. Result: Changes in HDRS-17 scores (mean (±SD)) following ketamine treatment were −4.9 (6.5) and −4.9 (5.2) in the double-blind and open-label periods, respectively. A higher baseline dACC Glx/GABA ratio was correlated with greater improvement in HDRS-17 (β = −0.42, p = 0.040). In the ketamine group, a reduction in the dACC Glx/GABA ratio was correlated with greater HDRS-17 improvement (β = 0.74, p = 0.009) with no such association in the placebo group. Conclusion: These results suggest that excitatory-inhibitory imbalance in the dACC may predict the efficacy of ketamine in TRD.

Background: This investigation probed the neurophysiological disparities between patients with bipolar disorder (BD) and healthy controls (HC) utilizing resting-state electroencephalography (rs-EEG) microstate (MS) analysis. The study, conducted at Keio University Hospital from 2017 to 2023, sought to differentiate BD from HC for early detection. Methods: The study included 36 BD (average age: 48.3 years) and 36 age- and sex-matched HC (average age: 47.8 years). Participants underwent a 5-min rs-EEG recording with eyes closed. MS analysis focused on the duration, occurrence, and coverage of MS (A − E) transitions. Comparisons were executed using Mann-Whitney U tests, and a logistic regression model distinguished the groups based on these MS indices. Results: Patients with BD exhibited a shorter MS-D duration (p < 0.001) and longer MS-C (p = 0.027) and MS-E (p = 0.020) durations compared to HC. The occurrence and coverage of MS-D were significantly lower in BD (p < 0.001 for both). The logistic regression model accurately classified 84.7% of cases (χ2(3)=42.03, p < 0.001). Limitations: Limitations include the potential influence of medication on MS dynamics and the cross-sectional design, which prevents causal conclusions. Longitudinal studies are required to comprehend the relationship between MS alterations and BD symptoms. Conclusion: Decreased MS-D indices, along with increased MS-C and MS-E indices in BD, imply dysfunction in the frontoparietal network and impairments in the default mode and salience networks. The altered temporal dynamics of rs-EEG MSs provide a unique neurophysiological profile of BD, suggesting that MS indices could potentially serve as neurophysiological markers for BD diagnosis.

Aim: This study aimed to determine the effects of damage to various brain regions on moral judgment using a novel third-party punishment task with fully manipulated conditions. Methods: We assessed 35 individuals with brain damage (26 with frontal lobe and nine with non-frontal lobe damage) and 30 healthy controls (HCs) using a moral judgment task consisting of 40 vignettes across five conditions, with varying degrees of intentionality and consequences. Participants rated the protagonist's “badness” and their aroused feelings. Cognitive impairments and empathetic traits were also assessed. Results: Compared to HCs, individuals with brain damage judged protagonists to be more blameworthy than did HCs in vignettes where harmful intentions were absent (No Negligence, p = 0.02; No Harm, p = 0.02). The order of moral judgment ratings across conditions was consistent between groups, indicating preserved knowledge of social/moral norms in brain-damaged individuals. Although these are preliminary results, there are no significant differences in moral judgment ratings between individuals with frontal and non-frontal lobe damage. Conclusion: This study revealed that individuals with damage to diverse brain regions show excessive punitive tendencies toward the actions of others without malicious intention. These effects cannot be fully explained by changes in empathy or emotional responses. Moral judgment ratings did not significantly differ between individuals with frontal and non-frontal lobe damage. However, given the small sample size of the non-frontal lesion group, these findings should be interpreted with caution, and further research is necessary to confirm this conclusion.

Background: Because of the increasing prevalence of dementia in Japan, the government introduced financial incentives for specialized care for dementia at acute care hospitals in 2016. Our hospital then introduced a multidisciplinary collaborative specialized team, referred to as dementia-specialized care team. The aim of this study is to examine the influence of dementia-specialized care team on clinical outcomes for elderly inpatients. Methods: In this retrospective observational study at a general hospital with 650 beds in Japan, we compared clinical outcomes such as incidence of falls, prescription of hypnotics, length of hospital stay, in-hospital mortality, and discharge destinations in inpatients aged 65 years and older between a two-year pre-intervention period (2014–2015) and a two-year post-intervention period (2017–2018). Results: During the observation period, a total of 34,097 patients were admitted, with 16,237 patients in the pre-intervention period and 17,860 patients in the post-intervention period. The proportion of patients receiving any hypnotics decreased from 21.2 % to 19.2 %, notably with benzodiazepine from 19.8 % to 13.2 %. The incidence of falls from a seated or lying position, particularly at night, was significantly lower (from 0.5 % to 0.2 %) as was the length of hospital stay (from 13.7 days to 13.2 days) during the post-intervention period. Conclusion: After the implementation of dementia-specialized care team, favorable outcomes such as a reduction in the use of hypnotics, the incidence of falls, and the length of hospitalization were observed. Introduction of the team and associated incentives may be effective in improving clinical outcomes in elderly inpatients.

Objective: Corticosteroids can cause psychiatric symptoms known as corticosteroid-induced psychiatric disorders (CIPDs). Little is known regarding the relationship between intravenous pulse methylprednisolone (IVMP) and CIPDs. Therefore, we aimed to examine the relationship between corticosteroid use and CIPDs in this retrospective study. Methods: Patients who were prescribed corticosteroids during their hospitalization at a university hospital and referred to our consultation-liaison service were selected. Patients diagnosed with CIPDs according to the ICD-10 codes were included. The incidence rates were compared between patients receiving IVMP and those receiving any other corticosteroid treatment. The association between IVMP and CIPDs was examined by classifying patients with CIPD into three groups according to the use of IVMP and timing of CIPD onset. Results: Of the 14,585 patients who received corticosteroids, 85 were diagnosed with CIPDs, with an incidence rate of 0.6%. Among the 523 patients who received IVMP, the incidence rate of CIPDs was 6.1% (n = 32), which was significantly higher than that in patients receiving any other corticosteroid treatment. Among the patients with CIPDs, 12 (14.1%) developed CIPDs during IVMP, 19 (22.4%) developed CIPDs after IVMP, and 49 (57.6%) developed CIPDs without IVMP. There was no significant difference in the doses at the time of CIPD improvement among the three groups when we excluded one patient whose CIPD improved during IVMP. Conclusion: Patients receiving IVMP were more likely to develop CIPDs than those who did not receive IVMP. Furthermore, corticosteroid doses at the time of improvement of CIPDs were constant, regardless of IVMP use.

Objective: This study aimed to evaluate Long-interval Intracortical Inhibition (LICI) in the Dorsolateral Prefrontal Cortex (DLPFC) of individuals with Autism Spectrum Disorder (ASD) using transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) with source-based estimation analyses. Methods: We applied the LICI paradigm to the left DLPFC of 32 individuals with ASD and 34 healthy controls. First, sensor-level Local Mean Field Power (LMFP) was calculated from TMS-evoked potentials for all participants to detect the LICI effect. Subsequently, source-based analyses were performed using dynamic statistical parametric mapping to minimize the influence of volume conduction. Finally, time–frequency (TF) analyses at the source level were conducted to further characterize the LICI effects. Results: LMFP analysis revealed that cortical activity in the interval of 165–234 ms post-stimulation was suppressed by LICI (p = 0.024). Source-based analyses confirmed inhibitory effects within the same time range. Additionally, TF analyses indicated suppressive effects within 30–300 ms in the theta to alpha bands. However, no significant group differences in the LICI effects were detected. Conclusions: TMS-EEG combined with LICI alone may be insufficient to detect GABA(B) receptor dysfunction in ASD. Significance: This is the first TMS-EEG study to elucidate the LICI effect by applying source-estimation methods in ASD.

Objective: This study aimed to optimally evaluate the effect of the long-interval intracortical inhibition (LICI) in the dorsolateral prefrontal cortex (DLPFC) through transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) by eliminating the volume conductance with signal source estimation and using a realistic sham coil as a control. Methods: We compared the LICI effects from the DLPFC between the active and sham stimulation conditions in 27 healthy participants. Evoked responses between the two conditions were evaluated at the sensor and source levels. Results: At the sensor level, a significant LICI effect was confirmed in the active condition in the global mean field power analysis; however, in the local mean field power analysis focused on the DLPFC, no LICI effect was observed in the active condition. However, in the signal source estimation analysis for the DLPFC, we could reconfirm a significant LICI effect (p = 0.023) in the interval 30–250 ms post-stimulus, compared to the sham condition. Conclusions: Our results demonstrate that application of realistic sham stimulation condition and source estimation method allows for a robust and optimal identification of the LICI effect in the DLPFC. Significance: The optimal DLPFC-LICI effect was identified by the use of the sophisticated sham coil.

Despite its superior effectiveness for treatment-resistant schizophrenia, clozapine has a high burden of adverse drug reactions (ADRs), which require monitoring and treatment. This global Delphi study has established consensus guidelines for absolute neutrophil count (ANC) thresholds for consideration of clozapine cessation and provided monitoring protocols for ADR management. Recommendations include lowering ANC cessation thresholds to 1·0 × 109 cells per L (0·5 × 109 cells per L for Duffy antigen receptor for chemokines-null individuals) and discontinuing routine ANC monitoring after 2 years. Comprehensive ADR monitoring every 3 months should address the metabolic syndrome, constipation, gastro-oesophageal reflux, sialorrhea, nocturnal enuresis, tachycardia, sleep apnoea, sedation, and other ADRs. Consumer representatives underscored the need for shared decision-making, streamlined monitoring, and accessible patient education. Although barriers persist, these findings support updating global policies to reduce burden on patients, enhance adherence, and optimise clinical outcomes. Incorporating evidence-based guidelines into practice could transform clozapine care, balancing safety with practicality to improve the lives of those with treatment-resistant schizophrenia.

Aim: This study aims to investigate the acute and sustained antidepressant effects of repeated ketamine infusions in patients with treatment-resistant depression (TRD), and to identify early metabolomic changes predictive of treatment outcomes using metabolome analyses. Methods: This open-label study investigated the effects of four intravenous ketamine infusions (0.5 mg/kg) administered over 2 weeks in 30 patients with TRD. Clinical outcomes, including the Montgomery-Åsberg Depression Rating Scale (MADRS), were evaluated at baseline, 1–2 h after each infusion, and monthly during a 12-month follow-up. Plasma levels of 11 depression-associated metabolites were measured at baseline and 1.5–2 h after the first infusion. A general linear model was employed to analyze the association between metabolite changes after the first infusion and the MADRS score percent improvements after the fourth infusion and at 12 months. Remission was defined as a MADRS score of ≤10. Results: All participants completed the four infusions. The MADRS score decreased from 30.6 ± 6.1 at baseline to 20.3 ± 11.5 after the fourth infusion, with a remission rate of 26.7%. At 12 months, 13.3% of participants remained in remission. Changes in 3-hydroxybutyrate levels after the first infusion predicted the MADRS score percent improvements after the fourth infusion (β = 1.35, 95% CI: 0.41–2.30, P = 0.005) and at 12 months (β = 1.38, 95% CI: 0.37–2.39, P = 0.007). Conclusion: While repeated ketamine infusions demonstrated rapid antidepressant effects, sustained remission was achieved in a minority of patients with TRD. 3-Hydroxybutyrate may serve as a biomarker for predicting treatment response. These findings underscore the potential for individualized strategies using ketamine infusions. Clinical Trial Registration: jRCTs031210648 (Japan Registry of Clinical Trials).