Published papers

Background: Thirty percent of patients with schizophrenia do not respond to non-clozapine antipsychotics and are termed treatment-resistant schizophrenia (TRS). The 40-Hz auditory steady-state response (ASSR) is a well-known to be reduced in patients with schizophrenia compared to healthy controls (HCs), suggesting impaired gamma oscillation in schizophrenia. Given no ASSR study on TRS, we aimed to examine the neurophysiological basis of TRS employing 40-Hz ASSR paradigm. Method: We compared ASSR measures among HCs, patients with non-TRS, and patients with TRS. TRS criteria were defined by a score of 4 or higher on two items of the Positive and Negative Syndrome Scale (PANSS) positive symptoms despite standard antipsychotic treatment. Participants were examined for ASSR with 40-Hz click-train stimulus, and then time-frequency analysis was performed to calculate evoked power and phase-locking factor (PLF) of 40-Hz ASSR. Results: A total of 79 participants were included: 27 patients with TRS (PANSS = 92.6 ± 15.8); 27 patients with non-TRS (PANSS = 63.3 ± 14.7); and 25 HCs. Evoked power in 40-Hz ASSR was lower in the TRS group than in the HC group (F2,79 = 8.37, p = 0.015; TRS vs. HCs: p = 0.012, d = 1.1) while no differences in PLF were found between the groups. Conclusion: These results suggest that glutamatergic and GABAergic neurophysiological dysfunctions are involved in the pathophysiology of TRS. Our findings warrant more comprehensive and longitudinal studies for deep phenotyping of TRS.

Background: One-third of patients with schizophrenia are treatment-resistant to non-clozapine antipsychotics (TRS), while the rest respond (NTRS). Examining whether TRS and NTRS represent different pathophysiologies is an important step toward precision medicine. Methods: Focusing on cortical thickness (CT), we analyzed international multi-site cross-sectional datasets of magnetic resonance imaging comprising 110 patients with schizophrenia (NTRS = 46, TRS = 64) and 52 healthy controls (HCs). We utilized a logistic regression with L1-norm regularization to find brain regions related to either NTRS or TRS. We conducted nested 10-fold cross-validation and computed the accuracy and area under the curve (AUC). Then, we applied the NTRS classifier to patients with TRS, and vice versa. Results: Patients with NTRS and TRS were classified from HCs with 65% and 78% accuracies and with the AUC of 0.69 and 0.85 (p = 0.014 and < 0.001, corrected), respectively. The left planum temporale (PT) and left anterior insula/inferior frontal gyrus (IFG) contributed to both NTRS and TRS classifiers. The left supramarginal gyrus only contributed to NTRS and right superior temporal sulcus and right lateral orbitofrontal cortex only to the TRS. The NTRS classifiers successfully distinguished those with TRS from HCs with the AUC of 0.78 (p < 0.001), while the TRS classifiers classified those with NTRS from HCs with the AUC of 0.69 (p = 0.015). Conclusion: Both NTRS and TRS could be distinguished from HCs on the basis of CT. The CT pathological basis of NTRS and TRS has commonalities, and TRS presents unique CT features.

Antipsychotic drugs are the mainstay in the treatment of schizophrenia. However, one-third of patients do not show adequate improvement in positive symptoms with non-clozapine antipsychotics. Additionally, approximately half of them show poor response to clozapine, electroconvulsive therapy, or other augmentation strategies. However, the development of novel treatment for these conditions is difficult due to the complex and heterogenous pathophysiology of treatment-resistant schizophrenia (TRS). Therefore, this review provides key findings, potential treatments, and a roadmap for future research in this area. First, we review the neurobiological pathophysiology of TRS, particularly the dopaminergic, glutamatergic, and GABAergic pathways. Next, the limitations of existing and promising treatments are presented. Specifically, this article focuses on the therapeutic potential of neuromodulation, including electroconvulsive therapy, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation. Finally, we propose multivariate analyses that integrate various perspectives of the pathogenesis, such as dopaminergic dysfunction and excitatory/inhibitory imbalance, thereby elucidating the heterogeneity of TRS that could not be obtained by conventional statistics. These analyses can in turn lead to a precision medicine approach with closed-loop neuromodulation targeting the detected pathophysiology of TRS.

Introduction This study investigated combined prescriptions of drugs for mood disorders and physical comorbidities that need special attention in the light of frequent physical comorbidities in patients with mood disorders. Methods We used the claims sampling data of 581,990 outpatients in January 2015 from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. Fisher's exact test was performed to compare the prescription rates of non-steroidal anti-inflammatory drugs (NSAIDs), loop/thiazide diuretics, angiotensin-converting enzyme inhibitors, and/or angiotensin II receptor blockers between lithium users and age- and sex-matched non-lithium users; NSAIDs, antiplatelet drugs, and/or anticoagulants between selective serotonin reuptake inhibitor (SSRI)/serotonin-noradrenaline reuptake inhibitor (SNRI) users and non-users; warfarin between mirtazapine users and non-users; and the proportions of patients in the two groups with a diagnosis of somatic conditions for which these medications were indicated and actually received them. A Bonferroni corrected p-value of<0.05/3 was considered statistically significant. Results Prescriptions of the above-mentioned medications were less frequent in lithium and mirtazapine users and comparable in SSRI/SNRI users, compared to non-users (18.3 vs. 31.9%, p=7.6×10 -10; 0.78 vs. 1.65%, p=0.01; 23.1 vs. 24.1%, p=0.044). In a subgroup of patients with somatic diseases for which these medications were indicated, the prescription rates were comparable in lithium and mirtazapine users and higher in SSRI/SNRI users compared to non-users (28.0 vs. 29.4%, p=0.73; 4.7 vs. 7.4%, p=0.28; 35.6 vs. 33.4%, p=0.0026). Discussion Pharmacotherapy with drugs for mood disorders and physical comorbidities that require attention was commonly observed in clinical practice.

The excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) contribute to epileptogenesis. Thirty patients with epilepsy and 31 healthy controls are scanned using positron emission tomography with our recently developed radiotracer for AMPARs, [11C]K-2, which measures the density of cell-surface AMPARs. In patients with focal-onset seizures, an increase in AMPAR trafficking augments the amplitude of abnormal gamma activity detected by electroencephalography. In contrast, patients with generalized-onset seizures exhibit a decrease in AMPARs coupled with increased amplitude of abnormal gamma activity. Patients with epilepsy had reduced AMPAR levels compared with healthy controls, and AMPARs are reduced in larger areas of the cortex in patients with generalized-onset seizures compared with those with focal-onset seizures. Thus, epileptic brain function can be regulated by the enhanced trafficking of AMPAR due to Hebbian plasticity with increased simultaneous neuronal firing and compensational downregulation of cell-surface AMPARs by the synaptic scaling.

Background: The glutamate (Glu) and gamma aminobutyric acid (GABA) hypotheses of schizophrenia were proposed in the 1980s. However, current findings on those metabolite levels in schizophrenia have been inconsistent, and the relationship between their abnormalities and the pathophysiology of schizophrenia remains unclear. To summarize the nature of the alterations of glutamatergic and GABAergic systems in schizophrenia, we conducted meta-analyses of proton magnetic resonance spectroscopy (1H-MRS) studies examining these metabolite levels. Methods: A systematic literature search was conducted using Embase, Medline, PsycINFO, and PubMed. Original studies that compared four metabolite levels (Glu, glutamine [Gln], Glx [Glu+Gln], and GABA), as measured by 1H-MRS, between individuals at high risk for psychosis, patients with first-episode psychosis, or patients with schizophrenia and healthy controls (HC) were included. A random-effects model was used to calculate the effect sizes for group differences in these metabolite levels of 18 regions of interest between the whole group or schizophrenia group and HC. Subgroup analysis and meta-regression were performed based on the status of antipsychotic treatment, illness stage, treatment resistance, and magnetic field strength. Results: One-hundred-thirty-four studies met the eligibility criteria, totaling 7993 participants with SZ-spectrum disorders and 8744 HC. 14 out of 18 ROIs had enough numbers of studies to examine the group difference in the metabolite levels. In the whole group, Glx levels in the basal ganglia (g = 0.32; 95% CIs: 0.18–0.45) were elevated. Subgroup analyses showed elevated Glx levels in the hippocampus (g = 0.47; 95% CIs: 0.21–0.73) and dorsolateral prefrontal cortex (g = 0.25; 95% CIs: 0.05–0.44) in unmedicated patients than HC. GABA levels in the MCC were decreased in the first-episode psychosis group compared with HC (g = −0.40; 95% CIs: −0.62 to −0.17). Treatment-resistant schizophrenia (TRS) group had elevated Glx and Glu levels in the MCC (Glx: g = 0.7; 95% CIs: 0.38–1.01; Glu: g = 0.63; 95% CIs: 0.31–0.94) while MCC Glu levels were decreased in the patient group except TRS (g = −0.17; 95% CIs: −0.33 to −0.01). Conclusions: Increased glutamatergic metabolite levels and reduced GABA levels indicate that the disruption of excitatory/inhibitory balance may be related to the pathophysiology of schizophrenia-spectrum disorders.

Although several randomized controlled trials (RCTs) have compared the effectiveness, efficacy, and safety of antipsychotic monotherapy (APM) versus placebo in patients with major depressive disorder (MDD), no meta-analysis has examined this topic. We conducted a systematic literature search using MEDLINE and Embase to identify relevant RCTs and performed a meta-analysis to compare the following outcomes between APM and placebo: response and remission rates, study discontinuation due to all causes, lack of efficacy, and adverse events, changes in total scores on depression severity scales, and individual adverse event rates. A total of 13 studies were identified, with 14 comparisons involving 3,197 participants that met the eligibility criteria. There were significant differences between APM and placebo in response and remission rates and changes in the primary depression severity scale in favor of APM, and study discontinuation due to adverse events and several individual adverse events in favor of placebo. No significant difference was observed in discontinuation due to all causes. APM could have antidepressant effects in the acute phase of MDD, although clinicians should be aware of an increased risk of some adverse events.

Background: To summarize the current state of knowledge on antipsychotic treatment strategies for the acute phase and treatment resistance in schizophrenia, we conducted a systematic review of guidelines and algorithms. Methods: We conducted a systematic literature search to identify clinical guidelines and algorithms on this topic using MEDLINE and Embase. We extracted information on recommendations for antipsychotic treatment strategies, including those for non-response (i.e., increasing antipsychotic dose and switching to another antipsychotic) and treatment resistance. Results: We identified a total of 17 guidelines/algorithms in various countries that were published after 2011. With respect to antipsychotic dose, most of the guidelines (N = 10/11) agreed starting with a low dose or the lowest licensed/effective dose and then titrating the dose upwards. Regarding antipsychotic treatment strategies for non-response, all of the guidelines (N = 9/9) recommended increasing antipsychotic dose towards the upper end of its approved dose range. Five guidelines suggested for increasing beyond the therapeutic dose range in exceptional cases, while overall 10 guidelines including them were negative about such strategy. The vast majority of guidelines (N = 16/17) recommended switching to another antipsychotic for non-response; however, some guidelines mentioned the lack of evidence for these strategies other than the use of clozapine. All the guidelines (N = 17/17) endorsed initiating clozapine after failure to respond to 2 different antipsychotics. Four guidelines endorsed an early use of clozapine, yet as the third antipsychotic. Conclusion: The currently available guidelines and algorithms recommended increasing antipsychotic dose and switching to another antipsychotic, particularly clozapine for treatment-resistant schizophrenia, during the acute phase of schizophrenia for non-response.

Background: While altered expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type receptor has been reported in postmortem studies of schizophrenia, these findings are inconsistent. Therefore, we aimed to systematically review postmortem studies that investigated AMPA receptor expressions in schizophrenia. Methods: A systematic literature search was conducted for postmortem studies that measured AMPA receptor subunit expressions or receptor bindings in schizophrenia compared to healthy individuals on February 3, 2021, using Medline and Embase. Results: A total of 39 relevant articles were identified from 1360 initial reports. The dorsolateral prefrontal cortex (DLPFC) was the most investigated region (15 studies), followed by the medial temporal lobe (8 studies). For the DLPFC, 4/15 studies (26.7%) showed increased AMPA receptor binding or subunit expression in patients with schizophrenia compared to that in controls, especially in GRIA1 and GRIA4, 2/15 studies (13.3%) reported a decrease, particularly in GRIA2, and 8/15 studies (56.7%) found no significant differences. A decreased expression or receptor binding was observed in 6/8 studies (75.0%) in the subregions of the hippocampus in patients with schizophrenia compared to that in controls, whereas the other two studies found no significant differences. Conclusion: Published data have reported decreased subunit expression or receptor binding in the hippocampus in schizophrenia. These findings were inconsistent in other brain regions, which might be due to the heterogeneity of this population, various study design, physiological changes after death, and limited number of studies. Future in vivo studies are warranted to examine AMPA receptor expressions in human brains, together with their comprehensive clinical characterization.

Background: Predicting relapse during maintenance treatment for depression is challenging. The objective of this analysis was to investigate the association between the time taken to achieve remission in the acute phase, and the subsequent relapse rate or time to relapse using the Sequenced Treatment Alternatives to Relieve Depression dataset. Method: Data of 1296 outpatients with nonpsychotic depression who entered a 12-month naturalistic follow-up period after achieving remission with citalopram for up to 14 weeks were analyzed. One-way analysis of variance and the Jonckheere-Terpstra trend test were performed to compare the relapse rates and days to relapse during the follow-up period among those who achieved remission at weeks 2, 4, 6, 9, 12, and 14. Remission and relapse were defined as scores of ≤5 and ≥11, respectively, on the 16-Item Quick Inventory of Depressive Symptomatology and Self-Report. Results: The relapse rates were significantly different among those who achieved remission each week (F(5, 1087) = 4.995, p < 0.001). The lowest and highest relapse rates were observed in those who achieved remission at weeks 4 (25.7 %) and 12 (42.4 %), respectively, with a significant difference (p = 0.006). There was also a significant negative trend between the weeks taken to achieve remission and the days to relapse (z = −6.13, p < 0.001). Conclusions: Patients with depression who show a faster response to antidepressant treatment are more likely to maintain remission in the long term. This finding suggests that, to prevent relapse, close attention should be paid to patients who require a relatively long time to achieve remission.

Objective: The prediction of response to pharmacotherapy has not been sufficiently explored in children and adolescents with psychiatric disorders, which was addressed in this study. Methods: Data from four double-blind, placebo-controlled studies (sertraline and fluvoxamine for anxiety disorders, risperidone for autistic disorder, and fluoxetine for major depressive disorder) in children and adolescents funded by the National Institute of Mental Health were used. The response was defined as a score of 1 or 2 on the Clinical Global Impression-Global Improvement (CGI-I) at the endpoint. Logistic regression analysis was performed to evaluate associations between response status and the following variables: sex, diagnosis, treatment allocation, and CGI-Severity of Illness (CGI-S) score at baseline. Moreover, the presence of early improvement (a score of ≤3 in the CGI-I) at Week 1 was added to the independent variables in an additional binary logistic regression analysis, using the data from two studies. Results: A total of 599 patients were included in the analysis. In the binary logistic regression analysis, active drug use (odds ratio [OR] = 8.64, P < 0.001) and female sex (OR = 1.89, P = 0.002) were significantly associated with treatment response. In the second binary logistic regression, the presence of early improvement in the CGI-I (OR = 3.47, P = 0.009), as well as active drug use (OR = 15.05, P < 0.001) and female sex (OR = 2.87, P = 0.016), were associated with subsequent responses. Conclusion: Allocation to active drugs, female sex, and early improvement may predict treatment response to pharmacotherapy among children and adolescents with psychiatric disorders.

Aim: Psychiatric patients have increased risk of deep vein thrombosis (DVT). However, there is no systematic data on risk assessment of DVT among psychiatric inpatients. The aim of this study was to develop a risk stratification scoring system for DVT among psychiatic patients on admission. Methods: A systematic review of psychiatric patient's charts, who were admitted to the Tokyo Metropolitan Matsuzawa Hospital from June 2012 to February 2016 and underwent screening for DVT, was conducted. Patients were randomly divided into development (n = 2634) and validation (n = 2634) groups. Estimated risk values in the multiple logistic regression model for the development sample were rounded to the nearest integer, and used as points of associated factors in the risk stratification scoring system; the total scores were tested in the validation sample. The score's discriminatory ability was assessed with the area under the receiver operating characteristic curve (AUC). Results: Among the 5268 patients, 258 (4.9%) had DVT. Advancing age, female sex, active cancer, previous venous thromboembolism, transfer from a general hospital, catatonia, and major depressive episode were all significantly associated with the presence of DVT in the development sample. The total score showed good discriminatory ability in the validation sample (AUC: 0.816, 95% confidence interval: 0.781–0.851); scores of 0–1, 2–3, 4–5, and ≥ 6 were associated with very low risk (0.7%), low risk (4.6%), moderate risk (14.9%), and high risk (35%) for DVT, respectively. Conclusion: Our risk stratification scoring system showed good performance for detection of DVT among psychiatric patients on admission.

Despite the clinical importance of polydipsia, no diagnostic criteria or severity scales that comprehensively assess this condition are available. Thus, we aimed to develop diagnostic criteria and a severity scale for polydipsia based on a systematic review and well-experienced clinicians’ consensus. We performed a systematic review, identified 27 studies related to diagnostic criteria or severity classification for polydipsia, and extracted items used to assess polydipsia in these studies. Ten well-experienced clinicians—5 psychiatrists and 5 nurses—participated in the Delphi method. They evaluated 39 items extracted based on the results of the systematic review regarding (1) their necessity in diagnosing and assessing the severity of polydipsia, and (2) their relative importance rated on 7-point scale among the items included in the severity scale. The Polydipsia Diagnostic Criteria (PDC) included 4 essential items—excessive drinking, low serum sodium level or low serum osmolality, abnormal normalized diurnal weight gain, and low urine specific gravity—based on consensus reached using the Delphi method. The Polydipsia Severity Scale (PSS) included 13 items with a maximum score of 59. The first diagnostic criteria and symptom scale for polydipsia were developed based on the findings of a systematic review and well-experienced clinicians’ consensus.

Introduction Conventional treatment guidelines of schizophrenia do not necessarily provide solutions on clinically important issues. Methods A total of 141 certified psychiatrists of the Japanese Society of Clinical Neuropsychopharmacology evaluated treatment options regarding 19 clinically relevant situations in the treatment of schizophrenia with a 9-point scale (1=disagree and 9=agree). Results First-line antipsychotics varied depending on predominant symptoms: risperidone (mean±standard deviation score, 7.9±1.4), olanzapine (7.5±1.6), and aripiprazole (6.9±1.9) were more likely selected for positive symptoms; aripiprazole (7.6±1.6) for negative symptoms; aripiprazole (7.3±1.9), olanzapine (7.2±1.9), and quetiapine (6.9±1.9) for depression and anxiety; and olanzapine (7.9±1.5) and risperidone (7.5±1.5) for excitement and aggression. While only aripiprazole was categorized as a first-line treatment for relapse prevention (7.6±1.0) in patients without noticeable symptoms, aripiprazole (8.0±1.6) and brexpiprazole (6.9±2.3) were categorized as such for social integration. First-line treatments in patients who are vulnerable to extrapyramidal symptoms include quetiapine (7.5±2.0) and aripiprazole (6.9±2.1). Discussion These clinical recommendations represent the expert consensus on the use of a particular antipsychotic medication for a particular situation, filling a current gap in the literature.

Background: Previous studies have reported inconsistent results on the mortality from trauma among psychiatric patients comparing to non-psychiatric population, which may be partly explained by the inclusion of both suicidal and accidental trauma. This study aimed to investigate the association of psychiatric diagnoses on admission with the outcomes of hospitalized patients for accidental trauma, namely road traffic injury. Methods: Detailed information of patients aged 15 years or older who were hospitalized for road traffic injury between 2004 and 2017 was extracted from the Japan Trauma Data Bank. The primary outcome was to compare in-hospital mortality between patients with and without a psychiatric disorder. We also conducted a subgroup analysis among patients with and without a serious head injury. Results: Altogether, 85,069 patients were included. Of these, 3,895 patients (4.6%) had a psychiatric diagnosis. The in-hospital mortality rate was significantly lower among patients with a psychiatric diagnosis than those without (5.4% vs. 8.3%; adjusted odds ratio [OR] 0.57, 95% confidence interval [CI] 0.47-0.70, p<0.001). In a subgroup analysis of patients with a serious head injury, in-hospital mortality was significantly lower in patients with a psychiatric diagnosis than in those without (10.5% vs. 17.3%; adjusted OR 0.48, 95% CI 0.37-0.62, p<0.001); in-hospital mortality of patients without a serious head injury showed no differences between patients with or without a psychiatric diagnosis (2.8% vs. 3.5%; adjusted OR 0.84, 95% CI 0.61-1.16, p=0.295). Conclusions: In-hospital mortality from road traffic injury was significantly lower among patients with a psychiatric diagnosis than those without, which was primarily evident in a subgroup of patients with a serious head injury. While further replication is necessary, results might be indicative of the neuroprotective effect of psychotropic medications.

Objectives: More than 40 drugs are available to treat affective disorders. Individual selection of the optimal drug and dose is required to attain the highest possible efficacy and acceptable tolerability for every patient. Methods: This review, which includes more than 500 articles selected by 30 experts, combines relevant knowledge on studies investigating the pharmacokinetics, pharmacodynamics and pharmacogenetics of 33 antidepressant drugs and of 4 drugs approved for augmentation in cases of insufficient response to antidepressant monotherapy. Such studies typically measure drug concentrations in blood (i.e. therapeutic drug monitoring) and genotype relevant genetic polymorphisms of enzymes, transporters or receptors involved in drug metabolism or mechanism of action. Imaging studies, primarily positron emission tomography that relates drug concentrations in blood and radioligand binding, are considered to quantify target structure occupancy by the antidepressant drugs in vivo. Results: Evidence is given that in vivo imaging, therapeutic drug monitoring and genotyping and/or phenotyping of drug metabolising enzymes should be an integral part in the development of any new antidepressant drug. Conclusions: To guide antidepressant drug therapy in everyday practice, there are multiple indications such as uncertain adherence, polypharmacy, nonresponse and/or adverse reactions under therapeutically recommended doses, where therapeutic drug monitoring and cytochrome P450 genotyping and/or phenotyping should be applied as valid tools of precision medicine.

Psychiatric and neurological disorders severely hamper patient’s quality of life. Despite their high unmet needs, the development of diagnostics and therapeutics has only made slow progress. This is due to limited evidence on the biological basis of these disorders in humans. Synapses are essential structural units of neurotransmission, and neuropsychiatric disorders are considered as “synapse diseases”. Thus, a translational approach with synaptic physiology is crucial to tackle these disorders. Among a variety of synapses, excitatory glutamatergic synapses play central roles in neuronal functions. The glutamate,-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) is a principal component of glutamatergic neurotransmission; therefore, it is considered to be a promising translational target. Here, we review the limitations of current diagnostics and therapeutics of neuropsychiatric disorders and advocate the urgent need for the promotion of translational medicine based on the synaptic physiology of AMPAR. Furthermore, we introduce our recent translational approach to these disorders by targeting at AMPARs.