Publisher：診断と治療社  

DOI： 10.34433/dt.0000000704

CiNii Research

Language：English   Publisher：Neuropsychopharmacology Reports  

Aim: Depressive disorder is often evaluated using established rating scales. However, consistent data collection with these scales requires trained professionals. In the present study, the “rater & estimation-system” reliability was assessed between consensus evaluation by trained psychiatrists and the estimation by 2 models of the AI-MADRS (Montgomery-Asberg Depression Rating Scale) estimation system, a machine learning algorithm-based model developed to assess the severity of depression. Methods: During interviews with trained psychiatrists and the AI-MADRS estimation system, patients responded orally to machine-generated voice prompts from the AI-MADRS structured interview questions. The severity scores estimated from two models of the AI-MADRS estimation system, the max estimation model and the average estimation model, were compared with those by trained psychiatrists. Results: A total of 51 evaluation interviews conducted on 30 patients were analyzed. Pearson's correlation coefficient with the scores evaluated by trained psychiatrists was 0.76 (95% confidence interval 0.62–0.86) for the max estimation model, and 0.86 (0.76–0.92) for the average estimation model. The ANOVA ICC rater & estimation-system reliability with the evaluation scores by trained psychiatrists was 0.51 (−0.09 to 0.79) for the max estimation model, and 0.75 (0.55–0.86) for the average estimation model. Conclusion: The average estimation model of AI-MADRS demonstrated substantially acceptable rater & estimation-system reliability with trained psychiatrists. Accumulating a broader training dataset and the refinement of AI-MADRS interviews are expected to improve the performance of AI-MADRS. Our findings suggest that AI technologies can significantly modernize and potentially revolutionize the realm of depression assessments.

DOI： 10.1002/npr2.12404

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PubMed

Language：English   Publisher：Neuropsychopharmacology Reports  

Aim: The present study aimed to examine the association between copy number variations (CNVs) in parkin (PRKN) and schizophrenia (SCZ) and autism spectrum disorder (ASD) in a large case–control sample. Method: Array comparative genomic hybridization was performed on 3111 cases with SCZ, 1236 cases with ASD, and 2713 controls. We systematically prioritized likely pathogenic CNVs (LP-CNVs) in PRKN and examined their association with SCZ and ASD. Results: In total, 3014 SCZ cases (96.9%), 1205 ASD cases (97.5%), and 2671 controls (98.5%) passed quality control. We found that monoallelic carriers of LP-CNVs in PRKN were common (70/6890, 1.02%) and were not at higher risk of SCZ (p = 0.29) or ASD (p = 0.72). We observed that the distribution pattern of LP-CNVs in the Japanese population was consistent with those in other populations. We also identified a patient diagnosed with SCZ and early-onset Parkinson's disease carrying biallelic pathogenic CNVs in PRKN. The absence of Parkinson's symptoms in 10 other monoallelic carriers of the same pathogenic CNV further reflects the lack of effect of monoallelic pathogenic variants in PRKN in the absence of a second hit. Conclusion: The present findings suggest that monoallelic CNVs in PRKN do not confer a significant risk for SCZ or ASD. However, further studies to investigate the association between biallelic CNVs in PRKN and SCZ and ASD are warranted.

DOI： 10.1002/npr2.12370

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Publisher：医歯薬出版  

DOI： 10.32118/ayu28807568

CiNii Research

Publisher：医歯薬出版  

DOI： 10.32118/ayu28807549

CiNii Research

Publisher：医歯薬出版  

DOI： 10.32118/ayu28807590

CiNii Research

Publisher：医歯薬出版  

DOI： 10.32118/ayu28807563

CiNii Research

Language：English   Publisher：BMC Psychiatry  

Background: Asenapine has unique orally-related side effects, such as a bitter taste induced by sublingual administration, which often results in discontinuation of the medication. While the FDA has approved black-cherry-flavored asenapine, several countries have prescribed only unflavored versions. Specifically, Asians commonly report experiencing the bitterness of asenapine because they are more sensitive to bitter tastes than other ethnic groups. In this study, with the aim of improving adherence by reducing the bitterness of asenapine, we investigated the effects of d-sorbitol, which reduced the bitterness parameters of taste sensors in our previous basic study on the bitterness and continuity of asenapine among patients with schizophrenia. Methods: Twenty adult patients with schizophrenia were included in this single-blind, placebo-controlled, crossover trial. Participants rinsed their mouths with single-administration of d-sorbitol or a placebo prior to each administration of asenapine. We then conducted the questionnaires and assessed changes in the bitterness of asenapine (primary end point) and willingness to continue its use (secondary end point). Results: d-sorbitol significantly improved the bitterness of asenapine (p = 0.038). Although it did not significantly increase the willingness to continue asenapine (p = 0.180), it did show improvement over the placebo in enhancing willingness to continue, especially in patients who were not accustomed to its taste. Conclusion: Our findings indicate that single-administration of d-sorbitol significantly reduces the bitterness of asenapine. In countries where flavored asenapine is not available, this finding could benefit patients who were not accustomed to its bitter taste. Trial registration: This study was registered in the Japan Registry of Clinical Trials (jRCTs041210019) on May 14, 2021.

DOI： 10.1186/s12888-024-05549-x

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PubMed

Language：English   Publisher：Psychiatry and Clinical Neurosciences  

Aim: Clinical studies reported that patients with schizophrenia are at a higher risk of developing dementia than people without schizophrenia. However, early neuropathological studies have shown that the incidence of Alzheimer's disease (AD) in schizophrenia patients does not differ from that in controls. These inconsistent results may be attributable to the inclusion of non-AD dementia, but there have been few clinicopathological studies in older patients with schizophrenia based on the current neuropathological classification. This study aimed to investigate the neuropathological basis of incident dementia in older patients with schizophrenia. Methods: We systematically examined 32 brains of old patients with schizophrenia using standardized pathological methods. The severity of dementia-related neuropathologies was analyzed using standardized semiquantitative assessments. After excluding patients who fulfilled the neuropathological criteria, clinicopathological variables were compared between patients with and without incident dementia to identify potential differences. Results: Seven patients fulfilled the pathological criteria for AD (n = 3), argyrophilic grain disease (AGD) (n = 2), dementia with Lewy bodies (n = 1), and AGD/progressive supranuclear palsy (n = 1). Among 25 patients for whom a neuropathological diagnosis was not obtained, 10 had dementia, but the clinicopathological findings did not differ from the remaining 15 patients without dementia. Conclusion: Two types of older schizophrenia patient present dementia: patients with co-existing neurodegenerative disease and patients who do not meet pathological criteria based on the current classification. To understand the neurobiological aspects of incident dementia in older patients with schizophrenia, further clinicopathological studies are needed that do not simply analyze incident dementia as a comorbidity of conventional dementia-related neuropathologies.

DOI： 10.1111/pcn.13597

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Publisher：Psychiatry and Clinical Neurosciences  

DOI： 10.1111/pcn.13498

Scopus

Language：Japanese   Publisher：一般社団法人 日本移植学会  

<p>"【目的】</p><p>世界の中でアジア地区は生体肝移植ドナーの併存精神疾患が多いとされる。今回、生体肝移植ドナーの併存精神疾患の多施設調査について報告する。</p><p>【方法】</p><p>肝臓移植8施設において、生体移植ドナーの併存精神疾患を後方視的に抽出し、１）ドナー評価時に精神疾患併存の生体肝移植ドナーが移植したレシピエントの予後、２）ドナー評価時/移植後に精神疾患併存の生体肝移植ドナーとその移植レシピエントの特性、を検討した。</p><p>【結果】</p><p>精神疾患併存は、546例のうち46例(ドナー評価時の併存16例を含む8.4%）だった。１）ドナー評価時に精神疾患が併存したドナー16例から移植されたレシピエントの生存率は、併存しないドナーと比して有意差はなかった（Log-rank test: p=0.738, HR: 0.788[95%CI: 0.194-3.198], 最終生存率(%): 62.5 vs 73.8）。２）ドナーに精神疾患（ドナー評価時の併存精神疾患を含）が併存した場合、移植レシピエントにも精神疾患が併存しやすかった（χ2=11.28,自由度＝1,p＜.001）。</p><p>【結論】</p><p>今回の結果では、生体肝移植ドナーに精神疾患が併存すると肝移植レシピエントにも精神疾患が併存しやすく、精神科的問題が重なる可能性がある。生体肝移植ドナーの精神科サポートは肝移植レシピエントと比べて整備されておらず、円滑な連携の標準化が求められる。当日は具体的な併存精神疾患や連携医療を明示する。</p>

DOI： 10.11386/jst.58.supplement_s116_2

CiNii Research

Language：English   Publisher：Psychiatry and Clinical Neurosciences  

Aim: The aims of the present study were: (i) to examine the association between schizophrenia (SCZ) and 47, XXY or 47, XXX in a large case–control sample; and (ii) to characterize the clinical features of patients with SCZ with these X chromosome aneuploidies. Methods: To identify 47, XXY and 47, XXX, array comparative genomic hybridization (aCGH) was performed in 3188 patients with SCZ and 3586 controls. We examined the association between 47, XXY and 47, XXX and SCZ in males and females separately using exact conditional tests to control for platform effects. Clinical data were retrospectively examined for patients with SCZ with X chromosome aneuploidies. Results: Of the analyzed samples, 3117 patients (97.8%) and 3519 controls (98.1%) passed our quality control. X chromosome aneuploidies were exclusively identified in patients: 47, XXY in seven patients (0.56%), 47, XXX in six patients (0.42%). Statistical analysis revealed a significant association between SCZ and 47, XXY (P = 0.028) and 47, XXX (P = 0.011). Phenotypic data were available from 12 patients. Treatment-resistance to antipsychotics and manic symptoms were observed in six patients each (four with 47, XXY and two with 47, XXX for both), respectively. Statistical analysis revealed that treatment-resistance to antipsychotics, mood stabilizer use, and manic symptoms were significantly more common in patients with 47, XXY than in male patients without pathogenic copy number variations. Conclusion: These findings indicate that both 47, XXY and 47, XXX are significantly associated with risk for SCZ. Patients with SCZ with 47, XXY may be characterized by treatment-resistance and manic symptoms.

DOI： 10.1111/pcn.13474

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PubMed

Language：English   Publisher：Biological Psychiatry  

Background: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). Methods: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. Results: In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25–0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. Conclusions: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.

DOI： 10.1016/j.biopsych.2022.04.003

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Language：English   Publisher：Brain  

Although intranasal oxytocin is expected to be a novel therapy for the core symptoms of autism spectrum disorder, which has currently no approved medication, the efficacy of repeated administrations was inconsistent, suggesting that the optimal dose for a single administration of oxytocin is not optimal for repeated administration. The current double-blind, placebo-controlled, multicentre, crossover trial (ClinicalTrials.gov Identifier: NCT03466671) was aimed to test the effect of TTA-121, a new formulation of intranasal oxytocin spray with an enhanced bioavailability (3.6 times higher than Syntocinon® spray, as assessed by area under the concentration-time curve in rabbit brains), which enabled us to test a wide range of multiple doses, on autism spectrum disorder core symptoms and to determine the dose-response relationship. Four-week administrations of TTA-121, at low dose once per day (3 U/day), low dose twice per day (6 U/day), high dose once per day (10 U/day), or high dose twice per day (20 U/day), and 4-week placebo were administered in a crossover manner. The primary outcome was the mean difference in the reciprocity score (range: 0-14, higher values represent worse outcomes) on the Autism Diagnostic Observation Schedule between the baseline and end point of each administration period. This trial with two administration periods and eight groups was conducted at seven university hospitals in Japan, enrolling adult males with high-functioning autism spectrum disorder. Enrolment began from June 2018 and ended December 2019. Follow-up ended March 2020. Of 109 males with high-functioning autism spectrum disorder who were randomized, 103 completed the trial. The smallest P-value, judged as the dose-response relationship, was the contrast with the peak at TTA-121 6 U/day, with inverted U-shape for both the full analysis set (P = 0.182) and per protocol set (P = 0.073). The Autism Diagnostic Observation Schedule reciprocity score, the primary outcome, was reduced in the TTA-121 6 U/day administration period compared with the placebo (full analysis set: P = 0.118, mean difference = -0.5; 95% CI: -1.1 to 0.1; per protocol set: P = 0.012, mean difference = -0.8; 95% CI: -1.3 to -0.2). The per protocol set was the analysis target population, consisting of all full analysis set participants except those who deviated from the protocol. Most dropouts from the full analysis set to the per protocol set occurred because of poor adherence to the test drug (9 of 12 in the first period and 8 of 15 in the second period). None of the secondary clinical and behavioural outcomes were significantly improved with the TTA-121 compared with the placebo in the full analysis set. A novel intranasal spray of oxytocin with enhanced bioavailability enabled us to test a wide range of multiple doses, revealing an inverted U-shape dose-response curve, with the peak at a dose that was lower than expected from previous studies. The efficacy of TTA-121 shown in the current exploratory study should be verified in a future large-scale, parallel-group trial.

DOI： 10.1093/brain/awab291

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PubMed

Language：English   Publisher：Translational Psychiatry  

Several large-scale whole-exome sequencing studies in patients with schizophrenia (SCZ) and autism spectrum disorder (ASD) have identified rare variants with modest or strong effect size as genetic risk factors. Dysregulation of cellular calcium homeostasis might be involved in SCZ/ASD pathogenesis, and genes encoding L-type voltage-gated calcium channel (VGCC) subunits Cav1.1 (CACNA1S), Cav1.2 (CACNA1C), Cav1.3 (CACNA1D), and T-type VGCC subunit Cav3.3 (CACNA1I) recently were identified as risk loci for psychiatric disorders. We performed a screening study, using the Ion Torrent Personal Genome Machine (PGM), of exon regions of these four candidate genes (CACNA1C, CACNA1D, CACNA1S, CACNA1I) in 370 Japanese patients with SCZ and 192 with ASD. Variant filtering was applied to identify biologically relevant mutations that were not registered in the dbSNP database or that have a minor allele frequency of less than 1% in East-Asian samples from databases; and are potentially disruptive, including nonsense, frameshift, canonical splicing site single nucleotide variants (SNVs), and non-synonymous SNVs predicted as damaging by five different in silico analyses. Each of these filtered mutations were confirmed by Sanger sequencing. If parental samples were available, segregation analysis was employed for measuring the inheritance pattern. Using our filter, we discovered one nonsense SNV (p.C1451* in CACNA1D), one de novo SNV (p.A36V in CACNA1C), one rare short deletion (p.E1675del in CACNA1D), and 14 NSstrict SNVs (non-synonymous SNV predicted as damaging by all of five in silico analyses). Neither p.A36V in CACNA1C nor p.C1451* in CACNA1D were found in 1871 SCZ cases, 380 ASD cases, or 1916 healthy controls in the independent sample set, suggesting that these SNVs might be ultra-rare SNVs in the Japanese population. The neuronal splicing isoform of Cav1.2 with the p.A36V mutation, discovered in the present study, showed reduced Ca2+-dependent inhibition, resulting in excessive Ca2+ entry through the mutant channel. These results suggested that this de novo SNV in CACNA1C might predispose to SCZ by affecting Ca2+ homeostasis. Thus, our analysis successfully identified several ultra-rare and potentially disruptive gene variants, lending partial support to the hypothesis that VGCC-encoding genes may contribute to the risk of SCZ/ASD.

DOI： 10.1038/s41398-022-01851-y

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