論文 - 内田　裕之

Glutamatergic and GABAergic metabolite levels in schizophrenia-spectrum disorders: a meta-analysis of ¹H-magnetic resonance spectroscopy studies

Nakahara T., Tsugawa S., Noda Y., Ueno F., Honda S., Kinjo M., Segawa H., Hondo N., Mori Y., Watanabe H., Nakahara K., Yoshida K., Wada M., Tarumi R., Iwata Y., Plitman E., Moriguchi S., de la Fuente-Sandoval C., Uchida H., Mimura M., Graff-Guerrero A., Nakajima S.

Molecular Psychiatry （Molecular Psychiatry）  27 （ 1 ） 744 - 757 2022年01月

ISSN  13594184

　概要を見る

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.

• Access to Document (DOI)

Clozapine Once-Daily Versus Divided Dosing Regimen: A Cross-sectional Study in Japan

Kitagawa K., So R., Nomura N., Tsukahara M., Misawa F., Kodama M., Uchida H., Bies R., Straubinger T., Banker C., Mizuno Y., Mimura M., Takeuchi H.

Journal of Clinical Psychopharmacology （Journal of Clinical Psychopharmacology）  42 （ 2 ） 163 - 168 2022年

ISSN  02710749

　概要を見る

Objective Clozapine is generally recommended to be prescribed in a divided dosing regimen based on its relatively short plasma half-life. However, there has been little evidence to support the superiority of divided dosing of clozapine over once-daily dosing. To our knowledge, there have been no studies examining differences in actual plasma concentrations or adverse effects between the 2 dosing strategies of clozapine. We aimed to compare actual plasma concentrations of clozapine between once-daily and divided dosing regimens, and to examine the relationships of these regimens with psychiatric symptoms and adverse effects of clozapine. Methods We analyzed data from 108 participants of a previous study conducted in 2 hospitals in Japan. A population pharmacokinetic model was used to estimate the peak and trough plasma concentrations of clozapine based on actual plasma concentrations. We evaluated psychiatric symptoms with the Brief Evaluation of Psychosis Symptom Domains and adverse effects of clozapine with the Glasgow Antipsychotic Side-effects Scale for Clozapine. Results The estimated peak and trough plasma concentrations of clozapine did not differ significantly between once-daily and divided dosing regimens. There were no significant differences in psychiatric symptoms except for depression/anxiety or subjective adverse effects of clozapine between the 2 dosing strategies. Conclusions Our findings tentatively support the feasibility and clinical utility of once-daily dosing of clozapine in clinical practice. Further studies are needed to replicate these findings and determine causality between dosing strategies and clinical outcomes.

• Access to Document (DOI)

Clinical features of catatonic non-convulsive status epilepticus: A systematic review of cases

Ogyu K., Kurose S., Uchida H., Kanemoto K., Mimura M., Takeuchi H.

Journal of Psychosomatic Research （Journal of Psychosomatic Research）  151   110660 2021年12月

ISSN  00223999

　概要を見る

Objective: Non-convulsive status epilepticus (NCSE) can manifest as catatonia, although it is unclear how frequently such cases have been reported. The common clinical features of these two conditions are also unclear. Methods: Using the MEDLINE and Embase databases, we performed a systematic literature search to identify cases diagnosed with both catatonia, according to the Bush-Francis Catatonia Rating Scale, and NCSE, according to the Salzburg Consensus Criteria (last search: March 29, 2021). We extracted data on demographics, clinical features of catatonia, EEG findings, and treatments. Results: A total of 66 patients with catatonic NSCE (men, 49%; mean age, 42.0 years) were identified from our search. Of the 66 cases described: 30 (46%) showed motor symptoms; 35 (38%) occurred in patients with preceding episodes of epileptic seizures; 19 (29%) showed subtle ictal clinical phenomena, such as minor twitching of the mouth, periorbital region, and extremities; 22 (33%) presented with psychiatric symptoms prior to the onset of catatonia; 17 (26%) had a history of psychiatric diseases; and in 10 cases (15%), NSCE was confirmed by intentional or non-intentional long-term EEG monitoring. Benzodiazepines were used as the initial treatment for NCSE in 30 cases (49%), of which 20 cases (73%) improved with monotherapy. Discussion: A substantial number of cases included in the present review involved catatonia without any symptoms indicative of epilepsy, suggesting that NCSE may be misdiagnosed as a psychiatric disease, and highlighting the importance of the accurate diagnosis and treatment of NCSE in patients presenting with catatonia.

• Access to Document (DOI)

Cancellation of outpatient appointments in patients with attention-deficit/hyperactivity disorder

Nomura K., Tarumi R., Yoshida K., Sado M., Suzuki T., Mimura M., Uchida H.

PLoS ONE （PLoS ONE）  16 （ 11 November ） e0260431 2021年11月

　概要を見る

Background Regular visit to psychiatric clinic is essential for successful treatment of any psychiatric condition including attention-deficit/hyperactivity disorder (AD/HD). However, cancellation of outpatient appointments in patients with AD/HD, which represents a significant medical loss, has not been systematically investigated to our knowledge. Methods A systematic chart review was conducted for patients visiting the Shimada Ryoiku medical Center for Challenged Children in Japan at the age of 15 years from January to December 2013. The primary outcome measure was the cancellation rate, defined as the number of missed visits divided by the number of scheduled visits. The cancellation rates during 24 months after the first visit were compared between outpatients with AD/HD and other psychiatric disorders, including pervasive developmental disorders (PDD), and developmental coordination disorders and/or communication disorders (DCD-CD). A generalized linear model with binomial distribution was used to examine factors associated with cancellation rates exclusively in the AD/HD group. Results We included 589 patients (mean ± SD age, 5.6 ± 3.4 years; 432 males) in the analysis. The cancellation rate in patients with AD/HD was 12.3% (95% confidence interval [CI]: 10.0–15.1), which was significantly higher than in those with PDD (5.6%, 95% CI: 3.8–8.3) and DCD-CD (5.3%, 95% CI: 3.6–7.8). Prescriptions of osmotic-release oral system-methylphenidate (OROS-MPH) and antipsychotics were associated with fewer cancellations in AD/HD patients (odds ratios: 0.61, 95% CI: 0.39–0.95 and 0.49, 95% CI: 0.25–0.95, respectively), although these significances did not find in the subgroup analysis including only patients with 6 years old. Conclusions Patients with AD/HD were more likely to miss appointments compared to those with other psychiatric disorders. The impact of AD/HD medications as well as potential psychiatric symptoms of their parents or caregivers on appointment cancellations needs to be evaluated in more detail in future investigations.

• Access to Document (DOI)

Clinical characteristics of patients with schizophrenia maintained without antipsychotics: A cross-sectional survey of a case series

Tani H., Tomita M., Suzuki T., Mimura M., Uchida H.

Clinical Psychopharmacology and Neuroscience （Clinical Psychopharmacology and Neuroscience）  19 （ 4 ） 773 - 779 2021年11月

ISSN  17381088

　概要を見る

Objective: While antipsychotics are necessary for relapse prevention in the treatment of schizophrenia in general, some minority of patients may be maintained without continuous antipsychotic treatment. However, the characteristics of such patients are not well known and previous reports have not evaluated key elements such as physical comorbidities and functioning. Methods: Among 635 patients with schizophrenia who participated in a 12-year follow-up, those who were maintained without antipsychotic treatment for at least one year after the study were investigated. The patients underwent comprehensive assessments, including Positive and Negative Syndrome Scale (PANSS) for psychopathology, Cumulative Illness Rating Scale for Geriatrics (CIRS-G) for physical comorbidities, and Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz), Barthel Index, and EuroQoL five dimensions (EQ5D) for function. Results: Six patients were included (mean ± standard deviation age, 66.8 ± 17.4 years; 4 inpatients). The four inpatients were old (77.8 ± 4.8 years) and chronically ill (duration of illness, 49.3 ± 12.5 years) with a high PANSS score (total score, 118.0 ± 9.8; negative syndrome subscale, 41.3 ± 6.9), low functioning (FACT-Sz, 9.8 ± 3.6; Barthel Index, 8.8 ± 9.6), and serious physical comorbidities (CIRS-G, 15.5 ± 1.1). By contrast, the two outpatients were relatively young (45.0 ± 12.0 years) and clinically in good condition (PANSS total score, 44.5 ± 0.5; Barthel Index, 100 for both; EQ5D, 0.85 ± 0.04). Conclusion: Although the number is limited, two types of patients with schizophrenia were identified who were free from ongoing antipsychotic treatment; 1) older chronic inpatients with serious physical comorbidities, and 2) younger outpatients with milder impairments. Future explorations are needed to identify those who will be successfully withdrawn from continuous antipsychotic treatment.

• Access to Document (DOI)

Antipsychotic treatment strategies for acute phase and treatment resistance in schizophrenia: A systematic review of the guidelines and algorithms

Shimomura Y., Kikuchi Y., Suzuki T., Uchida H., Mimura M., Takeuchi H.

Schizophrenia Research （Schizophrenia Research）  236   142 - 155 2021年10月

ISSN  09209964

　概要を見る

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.

• Access to Document (DOI)

Development of a risk stratification scoring system for deep vein thrombosis upon psychiatric admission

Ishida T., Shibahashi K., Sugai S., Abe D., Hamabe Y., Kashiyama T., Mimura M., Suzuki T., Uchida H.

Journal of Psychosomatic Research （Journal of Psychosomatic Research）  147   110540 2021年08月

ISSN  00223999

　概要を見る

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.

• Access to Document (DOI)

Pre-existing psychiatric disorder is related to lower mortality from road traffic accident: A Japanese nationwide retrospective cohort study

Ishida T., Kuwahara Y., Shibahashi K., Okura Y., Sugiyama K., Yoshimura K., Hamabe Y., Mimura M., Suzuki T., Uchida H.

Injury （Injury）  52 （ 6 ） 1390 - 1395 2021年06月

ISSN  00201383

　概要を見る

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.

• Access to Document (DOI)

Effects of Discontinuation of Drugs Used for Augmentation Therapy on Treatment Outcomes in Depression: A Systematic Review and Meta-analysis

Kato H., Koizumi T., Takeuchi H., Tani H., Mimura M., Uchida H.

Pharmacopsychiatry （Pharmacopsychiatry）  54 （ 3 ） 106 - 116 2021年05月

ISSN  01763679

　概要を見る

Introduction There has been no consensus on whether and how long add-on drugs for augmentation therapy should be continued in the treatment of depression. Methods Double-blind randomized controlled trials that examined the effects of discontinuation of drugs used for augmentation on treatment outcomes in patients with depression were identified. Meta-analyses were performed to compare rates of study withdrawal due to any reason, study-defined relapse, and adverse events between patients who continued augmentation therapy and those who discontinued it. Results Seven studies were included (n=841 for continuing augmentation therapy; n=831 for discontinuing augmentation therapy). The rate of study withdrawal due to any reason was not significantly different between the 2 groups (risk ratio [RR]=0.86, 95% confidence interval [CI]=0.69-1.08, p=0.20). Study withdrawal due to relapse was less frequent in the continuation group than in the discontinuation group (RR=0.61, 95% CI=0.40-0.92, p=0.02); however, this statistical significance disappeared when one study using esketamine as augmentation was excluded. Analysis of the data from 5 studies that included a stabilization period before randomization found less frequent relapse in the continuation group than in the discontinuation group (RR=0.47, 95% CI=0.36-0.60, p<0.01). This finding was repeated when the esketamine study was excluded. Discussion No firm conclusions could be drawn in light of the small number of studies included. Currently available evidence suggests that add-on drugs, other than esketamine, used for augmentation therapy for depression may be discontinued. This may not be the case for patients who are maintained with augmentation therapy after remission.

• Access to Document (DOI)

Continuous versus extended antipsychotic dosing in schizophrenia: Less is more

Servonnet A., Uchida H., Samaha A.N.

Behavioural Brain Research （Behavioural Brain Research）  401   113076 2021年03月

ISSN  01664328

　概要を見る

Antipsychotic drugs temper psychotic symptoms by interacting with dopamine D2 receptors to reduce dopamine neurotransmission. Currently, the standard of care involves antipsychotic treatment protocols that achieve steady-state levels of medication. Maintaining patients on continuous treatment is thought to be necessary to keep them stabilised. However, continuous antipsychotic exposure increases the risk of adverse effects over time. These effects include metabolic and cardiovascular disorders, extrapyramidal complications, and dopamine receptor supersensitivity, the latter of which could potentially promote both treatment tolerance and psychosis relapse. In the present review, we describe evidence showing that continuous exposure to antipsychotic drugs can not only worsen long-term outcome, but—past acute phase treatment—it is also unnecessary to effectively manage schizophrenia symptoms. We also describe evidence that regular but extended dosing, allowing predictable periods of lower antipsychotic levels/D2 occupancy, is both safe and effective in patients, and it greatly reduces drug exposure overall. Studies in laboratory animals show that compared to continuous antipsychotic exposure, regular but extended dosing actually has superior antipsychotic-like efficacy, and it also substantially reduces the likelihood of both motor side effects and dopamine receptor supersensitivity. We propose that regular, but extended dosing should be considered in the long-term treatment of people with schizophrenia, because the available evidence suggests it can be just as effective as continuous treatment, while decreasing overall drug exposure and potentially reducing harmful side effects.

• Access to Document (DOI)

Pharmacological Treatment of Schizophrenia: Japanese Expert Consensus

Sakurai H., Yasui-Furukori N., Suzuki T., Uchida H., Baba H., Watanabe K., Inada K., Kikuchi Y.S., Kikuchi T., Katsuki A., Kishida I., Kato M.

Pharmacopsychiatry （Pharmacopsychiatry）  54 （ 2 ） 60 - 67 2021年03月

ISSN  01763679

　概要を見る

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.

• Access to Document (DOI)

Development of diagnostic criteria and severity scale for polydipsia: A systematic literature review and well-experienced clinicians’ consensus

Sakuma M., Misawa F., Maeda M., Fujii Y., Uchida H., Mimura M., Takeuchi H.

Psychiatry Research （Psychiatry Research）  297   113708 2021年03月

ISSN  01651781

　概要を見る

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.

• Access to Document (DOI)

Single Versus Multiple Daily Dosing Regimens of Psychotropic Drugs for Psychiatric Disorders: A Systematic Review and Meta-Analysis.

Kikuchi Y, Shimomura Y, Suzuki T, Uchida H, Mimura M, Takeuchi H

The Journal of clinical psychiatry 82 （ 2 ）  2021年02月

ISSN  0160-6689

• Access to Document (DOI)

Effects of Long-Acting Injectable Paliperidone Palmitate on Clinical and Functional Outcomes in Patients With Schizophrenia Based on Illness Duration.

Kim S, Kim S, Koh M, Choi G, Kim JJ, Paik IH, Kim SH, Choi YS, Lee Y, Suh J, Takeuchi H, Uchida H, Kim E

The Journal of clinical psychiatry 82 （ 1 ）  2021年01月

ISSN  0160-6689

• Access to Document (DOI)

Dimensional distribution of cortical abnormality across antipsychotics treatment-resistant and responsive schizophrenia

Itahashi T., Noda Y., Iwata Y., Tarumi R., Tsugawa S., Plitman E., Honda S., Caravaggio F., Kim J., Matsushita K., Gerretsen P., Uchida H., Remington G., Mimura M., Aoki Y.Y., Graff-Guerrero A., Nakajima S.

NeuroImage: Clinical （NeuroImage: Clinical）  32   102852 2021年01月

　概要を見る

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.

• Access to Document (DOI)

Translational medicine of the glutamate AMPA receptor

MIYAZAKI B.T., ABE H., UCHIDA H., TAKAHASHI T.

Proceedings of the Japan Academy Series B: Physical and Biological Sciences （Proceedings of the Japan Academy Series B: Physical and Biological Sciences）  97 （ 1 ） 1 - 21 2021年

ISSN  03862208

　概要を見る

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.

• Access to Document (DOI)

Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants

Eap C.B., Gründer G., Baumann P., Ansermot N., Conca A., Corruble E., Crettol S., Dahl M.L., de Leon J., Greiner C., Howes O., Kim E., Lanzenberger R., Meyer J.H., Moessner R., Mulder H., Müller D.J., Reis M., Riederer P., Ruhe H.G., Spigset O., Spina E., Stegman B., Steimer W., Stingl J., Suzen S., Uchida H., Unterecker S., Vandenberghe F., Hiemke C.

World Journal of Biological Psychiatry （World Journal of Biological Psychiatry）  2021年

ISSN  15622975

　概要を見る

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.

• Access to Document (DOI)

Comprehensive assessment of exposure to clozapine in association with side effects among patients with treatment-resistant schizophrenia: a population pharmacokinetic study.

Nomura N, Kitagawa K, So R, Misawa F, Kodama M, Takeuchi H, Bies R, Straubinger T, Banker C, Mizuno Y, Mimura M, Uchida H

Therapeutic advances in psychopharmacology 11   20451253211016189 2021年

ISSN  2045-1253

• Access to Document (DOI)

Neural correlates of mild behavioral impairment: A functional brain connectivity study using resting-state functional magnetic resonance imaging

Matsuoka T., Ueno D., Ismail Z., Rubinstein E., Uchida H., Mimura M., Narumoto J.

Journal of Alzheimer's Disease （Journal of Alzheimer's Disease）  83 （ 3 ） 1221 - 1231 2021年

ISSN  13872877

　概要を見る

Background: Mild behavioral impairment (MBI) is associated with accelerated cognitive decline and greater risk of dementia. However, the neural correlates of MBI have not been completely elucidated. Objective: The study aimed to investigate the correlation between cognitively normal participants and participants with amnestic mild cognitive impairment (aMCI) using resting-state functional magnetic resonance imaging. Methods: The study included 30 cognitively normal participants and 13 participants with aMCI (20 men and 23 women; mean age, 76.9 years). The MBI was assessed using the MBI checklist (MBI-C). Region of interest (ROI)-to-ROI analysis was performed to examine the correlation between MBI-C scores and functional connectivity (FC) of the default mode network, salience network, and frontoparietal control network (FPCN). Age, Mini-Mental State Examination score, sex, and education were used as covariates. A p-value of 0.05, with false discovery rate correction, was considered significant. Results: A negative correlation was observed between the MBI-C total score and FC of the left posterior parietal cortex with the right middle frontal gyrus. A similar result was obtained for the MBI-C affective dysregulation domain score. Conclusion: FPCN dysfunction was detected as a neural correlate of MBI, especially in the affective dysregulation domain. This dysfunction may be associated with cognitive impairment in MBI and conversion of MBI to dementia; however, further longitudinal data are needed to examine this relationship.

• Access to Document (DOI)

Effects of 30-minute single sessions of yoga and Pilates on frailty in patients with psychiatric disorders: A pilot randomized controlled trial.

Ikai-Tani S, Tani H, Kamiyama S, Mimura M, Uchida H

International journal of geriatric psychiatry 2020年12月

ISSN  0885-6230

• Access to Document (DOI)