Search

Endoplasmic reticulum-mitochondrial contact sites (ERMCS) play an important role in mitochondrial dynamics, calcium signaling, and autophagy. Disruption of the ERMCS has been linked to several neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). However, the etiological role of ERMCS in these diseases remains unclear. We previously established tyrosine hydroxylase reporter (TH-GFP) iPSC lines from a PD patient with a PRKN mutation to perform correlative light-electron microscopy (CLEM) analysis and live cell imaging in GFP-expressing dopaminergic neurons. Here, we analyzed ERMCS in GFP-expressing PRKN-mutant dopaminergic neurons from patients using CLEM and a proximity ligation assay (PLA). The PLA showed that the ERMCS were significantly reduced in PRKN-mutant patient dopaminergic neurons compared to the control under normal conditions. The reduction of the ERMCS in PRKN-mutant patient dopaminergic neurons was further enhanced by treatment with a mitochondrial uncoupler. In addition, mitochondrial calcium imaging showed that mitochondrial Ca2+ flux was significantly reduced in PRKN-mutant patient dopaminergic neurons compared to the control. These results suggest a defect in calcium flux from ER to mitochondria is due to the decreased ERMCS in PRKN-mutant patient dopaminergic neurons. Our study of ERMCS using TH-GFP iPSC lines would contribute to further understanding of the mechanisms of dopaminergic neuron degeneration in patients with PRKN mutations.

Various eye movement abnormalities and impairments in visual information processing have been reported in patients with schizophrenia. Therefore, dysfunction of saccadic eye movements is a potential biological marker for schizophrenia. In the present study, we used a pharmacological model of schizophrenia symptoms in marmosets and compared the eye movement characteristics of marmosets during free-viewing, using an image set identical to those used for human studies. It contains natural and complex images that were randomly presented for 8 s. As a pharmacological model of schizophrenia symptoms, a subanesthetic dose of ketamine was injected intramuscularly for transient and reversible manipulation. Eye movements were recorded and compared under a ketamine condition and a saline condition as a control. The results showed that ketamine affected eye movement characteristics during free-viewing. Saccades amplitude and scanpath length were significantly reduced in the ketamine condition. In addition, the duration of saccades was longer under the ketamine condition than under the saline condition. A similar tendency was observed for the duration of fixations. The number of saccades and fixations tended to decrease in the ketamine condition. The peak saccades velocity also decreased after ketamine injection whereas there was no difference in the main sequence relationship between saccades amplitude and peak velocity. These results suggest that ketamine affected visual exploration but did not affect the oculomotor aspect of saccades in marmosets, consistent with studies in patients with schizophrenia. Therefore, we conclude that the subanesthetic dose of ketamine is a promising pharmacological model of schizophrenia symptoms in common marmosets and can be used in combination with free-viewing paradigms to establish “translatable markers” for schizophrenia in primates.

In several clinical guidelines for schizophrenia, long-term use of anticholinergic drugs is not recommended. We investigated the characteristics of the use of anticholinergics in patients with schizophrenia by considering psychotropic prescription patterns and differences among hospitals. A cross-sectional, retrospective prescription survey at the time of discharge was conducted on 2027 patients with schizophrenia from 69 Japanese hospitals. We examined the relations among psychotropic drug prescriptions regarding anticholinergic prescription. We divided the hospitals into three groups—low rate group (LG), medium rate group (MG), and high rate group (HG)—according to their anticholinergic prescription rates, and analyzed the relationship between anticholinergic prescription rates and antipsychotic prescription. Anticholinergic drugs were prescribed to 618 patients (30.5%), and the prescription rates were significantly higher for high antipsychotic doses, antipsychotic polypharmacy, and first-generation antipsychotics (FGAs) use. The anticholinergic prescription rate varied considerably among hospitals, ranging from 0 to 66.7%, and it was significantly higher in patients with antipsychotic monotherapy, antipsychotic polypharmacy, and normal and high doses of antipsychotics in HG than in those LG and MG. The anticholinergics prescription rate in patients with second-generation antipsychotic monotherapy in HG was also significantly higher than in those LG and MG; however, the difference was no longer significant in patients with FGA monotherapy. Conclusively, in addition to high antipsychotic doses, antipsychotic polypharmacy, and FGA use, hospital characteristics influence the prescribing of anticholinergic drugs.

BackgroundBoth impairment and sex differences in social cognition and neurocognition have been documented in schizophrenia. However, whether sex differences exist in the association between social cognition and neurocognition are not known. We aimed to investigate the contribution of areas of neurocognition to theory of mind (ToM) and hostility bias, representing social cognition, according to sex in early course schizophrenia.MethodsIn this cross-sectional study, we assessed neurocognition using the Japanese version of the Brief Assessment of Cognition in Schizophrenia (BACS) and assessed the ToM and hostility bias subdomains of social cognition using the Social Cognition Screening Questionnaire (SCSQ) in 131 participants (65 female, 66 male) diagnosed with schizophrenia within 5 years of onset. Sex differences were analyzed using t-tests. The associations of neurocognitive subdomains with ToM and hostility bias according to sex were analyzed using multiple regression analysis. Results were adjusted by age, estimated premorbid intelligence quotient, and symptomatology.ResultsNo sex differences were found in ToM (p = 0.071) or hostility bias (p = 0.057). Higher verbal fluency was significantly associated with higher ToM in females (p < 0.01), whereas higher executive function was significantly associated with higher ToM in males (p < 0.05). Higher verbal fluency was significantly associated with lower hostility bias in females (p < 0.05), whereas neurocognition and hostility bias were not significantly associated in males.ConclusionThe results suggest that neurocognition associated with social cognition differ according to sex. These differences should be considered for more effective treatment of social cognition.

Individuals with autism spectrum disorder (ASD) have an increased risk of adverse childhood experiences (ACEs) than typically developed (TD) children. Since multiple lines of studies have suggested that ACEs are related to myelination in the frontal lobe, an exposure to ACEs can be associated with white matter microstructural disruption in the frontal lobe, which may be implicated in subsequential psychological deficits after the adulthood. In this study, we investigated the relationship between ACEs and microstructural integrity on frontal lobe-related white matter tracts using diffusion tensor imaging in 63 individuals with ASD and 38 TD participants. Using a tractography-based analysis, we delineated the uncinate fasciculus (UF), dorsal cingulum (Ci), and anterior thalamic radiation (ATR), which are involved in the neural pathology of ASD, and estimated each diffusion parameter. Compared to the TD participants, individuals with ASD displayed significantly lower fractional anisotropy (FA) and higher radial diffusivity (RD) in the left ATR. Then, ASD individuals exposed to severe ACEs displayed higher RD than those exposed to mild ACEs and TD participants in the left ATR. Moreover, the severity of ACEs, particularly neglect, correlated with lower FA and higher RD in the left UF and ATR in individuals with ASD, which was not observed in TD participants. These results suggest that an exposure to ACEs is associated with abnormality in the frontal lobe-related white matter in ASD.

Schizophrenia is a heterogeneous psychiatric disorder characterized by positive symptoms such as hallucinations and delusions, negative symptoms such as anhedonia and flat affect, and cognitive impairment. Recently, glucuronate (GlucA) levels were reported to be significantly higher in serum of patients with schizophrenia than those in healthy controls. The accumulation of GlucA is known to be related to treatment-resistant schizophrenia, since GlucA is known to promote drug excretion by forming conjugates with drugs. However, the cause of GlucA accumulation remains unclear. Aldo-keto reductase family one member A1 (AKR1A1) is an oxidoreductase that catalyzes the reduction of GlucA. Genetic loss of AKR1A1 function is known to result in the accumulation of GlucA in rodents. Here, we aimed to explore genetic defects in AKR1A1 in patients with schizophrenia, which may result in the accumulation of GlucA. We identified 28 variants of AKR1A1 in patients with schizophrenia and control subjects. In particular, we identified a silent c.753G > A (rs745484618, p. Arg251Arg) variant located at the first position of exon 8 to be associated with schizophrenia. Using a minigene assay, we found that the c.753G > A variant induced exon 8 skipping in AKR1A1, resulting in a frameshift mutation, which in turn led to truncation of the AKR1A1 protein. Using the recombinant protein, we demonstrated that the truncated AKR1A1 completely lost its activity. Furthermore, we showed that AKR1A1 mRNA expression in the whole blood cells of individuals with the c.753G > A variant tended to be lower than that in those without the variants, leading to lower AKR activity. Our findings suggest that AKR1A1 carrying the c.753G > A variant induces exon skipping, leading to a loss of gene expression and enzymatic activity. Thus, GlucA patients with schizophrenia with the c.753G > A variant may show higher GlucA levels, leading to drug-resistant schizophrenia, since drug excretion by GlucA is enhanced.

Schizophrenia is a mental illness that involves both genetic and environmental factors. Clozapine, an atypical antipsychotic, is a well-established therapy for treatment-resistant schizophrenia. In this study, we focused on a set of monozygotic twins with treatment-resistant schizophrenia in which one twin effectively responded to clozapine treatment and the other did not. Our previous study generated neurons from induced pluripotent stem (iPS) cells derived from these patients and compared the transcriptome profiles between mock- and clozapine-treated neurons. In this study, we performed genome-wide DNA methylation profiling to investigate the mechanisms underlying gene expression changes. First, we extracted the differentially methylated sites from each twin based on statistical analysis. Then, we combined the DNA methylation profiling with transcriptome profiling from our previous RNA-seq data. Among the genes with altered methylation and expression, we found the different proportions of the genes related to neuronal and synaptic functions between the clozapine responder and non-responder (35.7 and 6.7%, respectively). This trend was observed even when the basal differences between the responder and non-responder was excluded. These results suggest that effective clozapine action may correct the abnormalities of neuronal and synapse functions in schizophrenia via changes in methylation.

Background: Despite their high lifetime prevalence, major depressive disorder (MDD) is often difficult to diagnose, and there is a need for useful biomarkers for the diagnosis of MDD. Eye movements are considered a non-invasive potential biomarker for the diagnosis of psychiatric disorders such as schizophrenia. However, eye movement deficits in MDD remain unclear. Thus, we evaluated detailed eye movement measurements to validate its usefulness as a biomarker in MDD.Methods: Eye movements were recorded from 37 patients with MDD and 400 healthy controls (HCs) using the same system at five University hospitals. We administered free-viewing, fixation stability, and smooth pursuit tests, and obtained 35 eye movement measurements. We performed analyses of covariance with group as an independent variable and age as a covariate. In 4 out of 35 measurements with significant group-by-age interactions, we evaluated aging effects. Discriminant analysis and receiver operating characteristic (ROC) analysis were conducted.Results: In the free-viewing test, scanpath length was significantly shorter in MDD (p = 4.2 × 10−3). In the smooth pursuit test, duration of saccades was significantly shorter and peak saccade velocity was significantly lower in MDD (p = 3.7 × 10−3, p = 3.9 × 10−3, respectively). In the fixation stability test, there were no significant group differences. There were significant group differences in the older cohort, but not in the younger cohort, for the number of fixations, duration of fixation, number of saccades, and fixation density in the free-viewing test. A discriminant analysis using scanpath length in the free-viewing test and peak saccade velocity in the smooth pursuit showed MDD could be distinguished from HCs with 72.1% accuracy. In the ROC analysis, the area under the curve was 0.76 (standard error = 0.05, p = 1.2 × 10−7, 95% confidence interval = 0.67–0.85).Conclusion: These results suggest that detailed eye movement tests can assist in differentiating MDD from HCs, especially in older subjects.

Background: Beneficial effects of transcranial direct current stimulation (tDCS) are relevant to cognition and functional capacity, in addition to psychiatric symptoms in patients with schizophrenia. However, whether tDCS would improve higher-order cognition, e.g., semantic memory organization, has remained unclear. Recently, text-mining analyses have been shown to reveal semantic memory. The purpose of the current study was to determine whether tDCS would improve semantic memory, as evaluated by text-mining analyses of category fluency data, in patients with schizophrenia.Methods: Twenty-eight patients entered the study. Cognitive assessment including the category fluency task was conducted at baseline (before tDCS treatment) and 1 month after t administration of tDCS (2 mA × 20 min, twice per day) for 5 days, according to our previous study. The category fluency data were also obtained from 335 healthy control subjects. The verbal outputs (i.e., animal names) from the category fluency task were submitted to singular valued decomposition (SVD) analysis. Semantic memory structures were estimated by calculating inter-item cosines (i.e., similarities) among animal names frequently produced in the category fluency task. Data were analyzed longitudinally and cross-sectionally to compare the semantic structure within the patient group (i.e., baseline vs. follow-up) and between groups (patients vs. healthy controls). In the former, semantic associations for frequent items were compared in the form of cosine profiles, while in the latter, the difference in the magnitude of the correlations for inter-item cosines between healthy controls and patients (baseline, follow-up) was examined.Results: Cosine profiles in the patient group became more cluster-based (i.e., pet, carnivores, and herbivores) at follow-up compared to those at baseline, yielding higher cosines within subcategories. The correlational coefficient of inter-item cosines between healthy controls and patients was significantly greater at follow-up compared to baseline; semantic associations in patients approached the normality status after multi-session tDCS.Conclusions: To our knowledge, this is the first study to demonstrate the facilitative effect of tDCS on semantic memory organization in patients with schizophrenia. Text-mining analysis was indicated to effectively evaluate semantic memory structures in patients with psychiatric disorders.

Patients with schizophrenia exhibit impairments in their social activity, intelligence quotient (IQ), daily living skills, and social function. Social activity is a high-order outcome measure of their lives. Here we attempted to longitudinally evaluate the effects of IQ, daily living skills, social function, psychiatric symptoms, and medications on social activity in patients with schizophrenia. The purpose of the current study is to identify the specific factor that affects longitudinal changes in social activity. Sixty-five patients with schizophrenia were assessed at two time points [time 2 (T2, follow-up) − time 1 (T1, baseline) = 1.71 ± 0.79 years]. Social activity, IQ, daily living skills, and social function were assessed using the Social Activity Assessment (SAA; h/week), short form of the Wechsler Adult Intelligence Scale (WAIS)-III (WAIS-SF), University of California San Diego (UCSD) Performance-Based Skills Assessment (UPSA), and Social Functioning Scale (SFS), respectively. IQ, daily living skills, social function, and social activity were significantly improved between T1 and T2 (t = 2.0–4.4, p = 0.048–3.60 × 10−5). IQ, daily living skills, and social function positively correlated with social activity (lowest p = 1.27 × 10−5), and psychiatric symptoms negatively correlated with social activity over time (lowest p = 3.26 × 10−9). The longitudinal change in social activity was independently and positively correlated with a change in social function (beta = 0.35, p = 4.63 × 10−3), particularly interpersonal communication (beta = 0.35, p = 4.32 × 10−3). The longitudinal changes in other factors did not directly affect the change in social activity (p > 0.05). Based on these findings, social activity is more affected by social function than by other factors.

Clozapine is an efficacious atypical antipsychotic for treatment-refractory schizophrenia. Clinical response and appearance of adverse events vary among individual patients receiving clozapine, with genetic and non-genetic factors potentially contributing to individual variabilities. Pharmacogenetic studies investigate associations between genetic variants and drug efficacy and toxicity. To date, most pharmacogenetic studies of clozapine have been conducted through candidate gene approaches. A recent advance in technology made it possible to perform comprehensive genetic mapping underlying clinical phenotypes and outcomes, which allow novel findings beyond biological hypotheses based on current knowledge. In this paper, we will summarize the studies on clozapine pharmacogenetics that have extensively examined clinical response and agranulocytosis. While there is still limited evidence on clozapine efficacy, recent genome-wide studies provide further evidence of the involvement of the human leukocyte antigen (HLA) region in clozapine-induced agranulocytosis.

Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.

BackgroundDisorganization of semantic memory in patients with schizophrenia has been studied by referring to their category fluency performance. Recently, data-mining techniques such as singular value decomposition (SVD) analysis have been reported to be effective in elucidating the latent semantic memory structure in patients with schizophrenia. The aim of this study is to investigate semantic memory organization in patients with schizophrenia using a novel method based on data-mining approach.MethodCategory fluency data were collected from 181 patients with schizophrenia and 335 healthy controls at the Department of Psychiatry, Osaka University. The 20 most frequently reported animals were chosen for SVD analysis. In the two-dimensional (2D) solution, item vectors (i.e., animal names) were plotted in the 2D space of each group. In the six-dimensional (6D) solution, inter-item similarities (i.e., cosines) were calculated among items. Cosine charts were also created for the six most frequent items to show the similarities to other animal items.ResultsIn the 2D spatial representation, the six most frequent items were grouped in the same clusters (i.e., dog, cat as pet cluster, lion, tiger as wild/carnivorous cluster, and elephant, giraffe as wild/herbivorous cluster) for patients and healthy adults. As for 6D spatial cosines, the correlations (Pearson’s r) between 17 items commonly generated in the two groups were moderately high. However, cosine charts created for the three pairs from the six most frequent animals (dog–cat, lion–tiger, elephant–giraffe) showed that pair-wise similarities between other animals were less salient in patients with schizophrenia.DiscussionSemantic memory organization in patients with schizophrenia, revealed by SVD analysis, did not appear to be seriously impaired in the 2D space representation, maintaining a clustering structure similar to that in healthy controls for common animals. However, the coherence of those animals was less salient in 6D space, lacking pair-wise similarities to other members of the animal category. These results suggests subtle but structural differences between the two groups. A data-mining approach by means of SVD analysis seems to be effective in evaluating semantic memory in patients with schizophrenia, providing both a visual representation and an objective measure of the structural alterations.

Patients with schizophrenia elicit several clinical features, such as psychotic symptoms, cognitive impairment, and subtle decline of intelligence. The latter two features become evident around the onset of the illness, although they may exist even before the disease onset in a substantial proportion of cases. Here, we review the literature concerning intelligence decline (ID) during the progression of schizophrenia. ID can be estimated by comparing premorbid and current intellectual quotient (IQ) by means of the Adult Reading Test and Wechsler Adult Intelligence Scale (WAIS), respectively. For the purpose of brief assessment, we have recently developed the WAIS-Short Form, which consists of Similarities and Symbol Search and well reflects functional outcomes. According to the degree of ID, patients were classified into three distinct subgroups; deteriorated, preserved, and compromised groups. Patients who show deteriorated IQ (deteriorated group) elicit ID from a premorbid level (≥10-point difference between current and premorbid IQ), while patients who show preserved or compromised IQ do not show such decline (90 or below 90, respectively. We have recently shown the distribution of ID in a large cohort of schizophrenia patients. Consistent with previous studies, approximately 30% of schizophrenia patients had a decline of less than 10 points, i.e., normal intellectual performance. In contrast, approximately 70% of patients showed deterioration of IQ. These results indicate that there is a subgroup of schizophrenia patients who have mild or minimal intellectual deficits, following the onset of the disorder. Therefore, a careful assessment of ID is important in identifying appropriate interventions, including medications, cognitive remediation, and social/community services.