Takamitsu Shimada

Structural alterations of the superior temporal gyrus in schizophrenia: Detailed subregional differences

BACKGROUND Reduced gray matter volumes in the superior temporal gyrus (STG) have been reported in patients with schizophrenia. Such volumetric abnormalities might denote alterations in cortical thickness, surface area, local gyrification or all of these factors. The STG can be anatomically divided into five subregions using automatic parcellation in FreeSurfer: lateral aspect of the STG, anterior transverse temporal gyrus of Heschl gyrus (HG), planum polare (PP) of the STG, planum temporale (PT) of the STG and transverse temporal sulcus. METHODS We acquired magnetic resonance imaging (MRI) 3T scans from 40 age- and sex-matched patients with schizophrenia and 40 healthy subjects, and the scans were automatically processed using FreeSurfer. General linear models were used to assess group differences in regional volumes and detailed thickness, surface area and local gyrification. RESULTS As expected, patients with schizophrenia had significantly smaller bilateral STG volumes than healthy subjects. Of the five subregions in the STG, patients with schizophrenia showed significantly and marginally reduced volumes in the lateral aspect of the STG and PT of the STG bilaterally compared with healthy subjects. The volumetric alteration in bilateral lateral STG was derived from both the cortical thickness and surface area but not local gyrification. There was no significant laterality of the alteration in the lateral STG between patients and controls and no correlation among the structures and clinical characteristics. CONCLUSIONS These findings suggest that of five anatomical subregions in the STG, the lateral STG is one of the most meaningful regions for brain pathophysiology in schizophrenia.

Specific gene expression patterns of 108 schizophrenia-associated loci in cortex

The latest genome-wide association study of schizophrenia identified 108 distinct genomic loci that contribute to schizophrenia. Brain development and function depend on the precise regulation of gene expression. The expression of many genes is differentially regulated across brain regions and developmental time points. We investigated the specific gene expression patterns arising from the 108 schizophrenia-associated loci using multiple publicly available databases and multiple regional brain datasets from developing and adult post-mortem human brains. The temporal-spatial expression analysis revealed that the genes in these loci were intensively enriched in the cortex during several developmental stages. These cortex-specific genes were particularly expressed in the fetal brain and adult neocortex.

Impact of Familial Loading on Prefrontal Activation in Major Psychiatric Disorders: A Near-Infrared Spectroscopy (NIRS) Study

Family history (FH) is predictive of the development of major psychiatric disorders (PSY). Familial psychiatric disorders are largely a consequence of genetic factors and typically exhibit more severe impairments. Decreased prefrontal activity during verbal fluency testing (VFT) may constitute an intermediate phenotype for PSY. We investigated whether familial PSY were associated with a greater severity of prefrontal dysfunction in accordance with genetic loading. We measured prefrontal activity during VFT using near-infrared spectroscopy (NIRS) in patients with schizophrenia (SCZ, n = 45), major depressive disorder (MDD, n = 26) or bipolar disorder (BIP, n = 22) and healthy controls (HC, n = 51). We compared prefrontal activity among patients with or without FH and HC. Patients in the SCZ, MDD and BIP patient groups had lower prefrontal activity than HC subjects. Patients with and without FH in all diagnostic groups had lower prefrontal activity than HC subjects. Moreover, SCZ patients with FH had lower prefrontal activity than SCZ patients without FH. When we included patients with SCZ, MDD or BIP in the group of patients with PSY, the effects of psychiatric FH on prefrontal activity were enhanced. These findings demonstrate the association of substantially more severe prefrontal dysfunction with higher genetic loading in major psychiatric disorders.

Differences in social functioning among patients with major psychiatric disorders: Interpersonal communication is impaired in patients with schizophrenia and correlates with an increase in schizotypal traits

Impaired social functioning is a hallmark of major psychiatric disorders. The purpose of this study was to detect a disorder-specific factor of social dysfunction among patients with major psychiatric disorders (PSY), including schizophrenia (SCZ), bipolar disorder (BIP) and major depressive disorder (MDD). Social functioning was assessed in patients with SCZ (n=80), BIP (n=27) or MDD (n=29) and healthy controls (HC, n=68) using the Social Functioning Scale (SFS). Compared to HC, the SCZ, BIP and MDD patient groups showed lower total SFS scores. No differences in the total scores for social functioning were observed between patient groups. We next investigated seven subscales of the SFS among PSY and observed significant diagnostic effects on all subscales of the SFS. Notably, patients with SCZ have poorer interpersonal communication than patients with MDD. Furthermore, the poorer interpersonal communication score was significantly correlated with an increase in schizotypal personality traits, as assessed by the Schizotypal Personality Questionnaire (SPQ) in HC. Although there were no differences in overall social functioning among PSY, disorder-specific factors, such as interpersonal communication, were evident in SCZ. The correlation between poor interpersonal communication and the increase in schizotypal traits suggests that poor interpersonal communication may be an intermediate phenotype of SCZ.

Schizophrenia risk variants in ITIH4 and CALN1 regulate gene expression in the dorsolateral prefrontal cortex.

On the basis of the findings from European GenomeWide Association Studies (GWAS) in the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC1) [9394 cases and 12 462 controls for GWAS and 8442 cases and 21 397 for replication (Ripke et al., 2011)] and the subsequent study (CLOZUK) [2640 cases and 2878 controls (Hamshere et al., 2013)], Li et al. (2015) have tried to replicate the associations of genetic variants including genome-wide significant variants and variants located in the predicted MIR137 target genes in the Han Chinese population (Li et al., 2015). They have found that two single-nucleotide polymorphisms (SNPs) in the interalpha-trypsin inhibitor heavy chain family, member 4 (ITIH4) (rs2239547) and the calneuron 1 (CALN1) (rs2944829) genes, were associated with risk for schizophrenia at genome-wide significant threshold in Chinese GWAS (3750 cases and 6468 controls) and/or the replication (3585 cases and 5496 controls) cohorts. They compared these SNP findings between PGC1/ PGC1+CLOZUK and their studies; however, they used rs12699131 (35.4 kb upstream from rs2944829, r= 0.79 in CEU 1000 Genomes Pilot 1) but not rs2944829 in only PGC1 GWAS sample for the comparison. Recently, the latest and largest GWAS, which combined all available schizophrenia samples in the PGC2 (34 241 cases, 45 604 controls and 1235 trios for GWAS and 1513 cases and 66 236 controls for replication), has been published (Ripke et al., 2014), and these two SNPs (rs2239547 and rs2944829) in the GWAS were available directly in the public database (https://www.med.unc.edu/pgc/downloads). Therefore, we combined the Chinese GWAS and the replication data with those of PGC2 using their odds ratios (OR) and SE derived from 95% confidence interval of OR. The meta-analysis still supported their findings at genome-wide significant level [rs2239547 (minor C-allele) OR= 0.93, P= 1.98× 10, rs2944829 (minor A-allele) OR= 0.94, P= 1.97× 10]. These findings suggest that these SNPs could contribute to risk for schizophrenia in both European and Asian populations.

Cognitive clustering in schizophrenia patients, their first-degree relatives and healthy subjects is associated with anterior cingulate cortex volume

Cognitive impairments are a core feature in schizophrenia patients (SCZ) and are also observed in first-degree relatives (FR) of SCZ. However, substantial variability in the impairments exists within and among SCZ, FR and healthy controls (HC). A cluster-analytic approach can group individuals based on profiles of traits and create more homogeneous groupings than predefined categories. Here, we investigated differences in the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery (six subscales) among SCZ, unaffected FR and HC. To identify three homogeneous and meaningful cognitive groups regardless of categorical diagnoses (SCZ, FR and HC), cognitive clustering was performed, and differences in the BACS subscales among the cognitive cluster groups were investigated. Finally, the effects of diagnosis and cognition on brain volumes were examined. As expected, there were significant differences in the five BACS subscales among the diagnostic groups. The cluster-analytic approach generated three meaningful subgroups: (i) neuropsychologically normal, (ii) intermediate impaired and (iii) widespread impaired. The cognitive subgroups were mainly affected by the clinical diagnosis, and significant differences in all BACS subscales among clusters were found. The effects of the diagnosis and cognitive clusters on brain volumes overlapped in the frontal, temporal and limbic regions. Frontal and temporal volumes were mainly affected by the diagnosis, whereas the anterior cingulate cortex (ACC) volumes were affected by the additive effects of diagnosis and cognition. Our findings demonstrate a cognitive continuum among SCZ, FR and HC and support the concept of cognitive impairment and the related ACC volumes as intermediate phenotypes in SCZ.

Spatial and temporal expression patterns of genes around nine neuroticism-associated loci

ABSTRACT Neuroticism is a high‐order personality trait. Individuals with higher neuroticism have increased risks of various psychiatric disorders and physical health outcomes. Neuroticism is related to physiological differences in the brain. A recent genome‐wide association study identified nine distinct genomic loci that contribute to neuroticism. Brain development and function depend on the precise regulation of gene expression, which is differentially regulated across brain regions and developmental stages. Using multiple publicly available human post‐mortem databases, we investigated, in brain and non‐brain tissues and across several developmental life stages, the spatial and temporal expression patterns of genes arising from nine neuroticism‐associated loci. Functional gene‐network analysis for neuroticism‐associated genes was performed. The spatial expression analysis revealed that the nearest genes (GRIK3, SRP9, KLHL2, PTPRD, ELAVL2, CRHR1 and CELF4) from index single‐nucleotide polymorphisms (SNPs) at the nine loci were intensively enriched in the brain compared with their representation in non‐brain tissues (p < 1.56 × 10− 3). The nearest genes associated with the glutamate receptor activity network consisted mainly of GRIK3 (FDR q = 4.25 × 10− 2). The temporal expression analysis revealed that the neuroticism‐associated genes were divided into three expression patterns: KLHL2, CELF4 and CRHR1 were preferentially expressed during postnatal stages; PTPRD, ELAVL2 and MFHAS1 were expressed during prenatal stages; and the other three genes were not expressed during specific life stages. These findings suggest that the glutamate network might be a target for investigating the neurobiological mechanisms underlying susceptibilities to higher neuroticism and several psychiatric disorders and that neuroticism is mediated by genes specifically expressed in the brain during several developmental stages. HIGHLIGHTSThe spatial and temporal expression patterns of genes around nine neuroticism‐associated loci were investigated.The nearest genes at the nine loci preferentially expressed in brain tissues rather than non‐brain tissues.The nearest genes were associated with the glutamate receptor activity network.Neuroticism is mediated by genes specifically expressed in the brain during several developmental stages.

Olfactory function in neuropsychiatric disorders.

Recent clinical studies have identified olfactory dysfunction in patients with neuropsychiatric disorders. Although these studies showed differences in olfactory function between healthy individuals and neuropsychiatric patients, no studies have compared the differences in olfactory function among neuropsychiatric disorders. The aim of the present study was to investigate olfactory function among various neuropsychiatric disorders. Three-hundred and eighteen outpatients diagnosed according to the ICD-10 code participated in the study. Olfactory function was assessed using the Open Essence test. The differences in olfactory function among disorders were compared by analyses of (co-)variance. As expected, olfactory function was significantly affected by the age and marginally affected by the gender. We investigated the differences in olfactory function among patients with different neuropsychiatric disorders (F0-F9). Olfactory function significantly differed among the diagnostic groups. Post hoc analysis showed that patients with F0 had decreased olfactory function compared to patients from the other diagnostic groups. In particular, patients with Alzheimers disease (AD) had significantly poorer olfactory function compared to patients with other neuropsychiatric disorders. There were no differences among the other groups. These findings suggest that patients with AD had poorer olfactory function compared not only to healthy subjects but also to patients with several other neuropsychiatric disorders.

Response to benzodiazepines and the clinical course in malignant catatonia associated with schizophrenia: A case report

Background: Malignant catatonia (MC) is a disorder consisting of catatonic symptoms, hyperthermia, autonomic instability, and altered mental status. Neuroleptic malignant syndrome (NMS) caused by antipsychotics is considered a variant of MC. Benzodiazepine (BZD) medications are safe and effective treatments providing rapid relief from MC. This case study reports a detailed clinical course of a case of MC associated with schizophrenia initially diagnosed as NMS that responded successfully to BZDs but not to dantrolene. Case presentation: A 53-year-old man with schizophrenia was admitted to the psychiatric hospital because of excitement, monologue, muscle rigidity, and insomnia. In the 3 days before admission, the patient had discontinued his medications after his family members death. He presented with hyperthermia, tachycardia, hypertension, excessive sweating, and an elevated serum creatine phosphokinase (CPK) level. On the basis of these features, he was suspected to have NMS. The patient was treated with dantrolene for 7 days without improvement despite having a normalized serum CPK level. The patient was transferred to our university hospital for an in-depth examination and treatment of his physical status. Infection and pulmonary embolism were excluded as possible causes. To treat his excitement and auditory hallucination, an intravenous drip (IVD) of haloperidol was initiated, but this treatment increased the patients catatonic and psychotic symptoms, although his serum CPK level had remained within a normal range. As a result, the treatment was changed to diazepam. After an IVD of diazepam, the patients symptoms rapidly improved, and the IVD was subsequently replaced with oral administration of lorazepam. Eventually, the patient was diagnosed with MC associated with schizophrenia. BZD therapy was dramatically effective. Conclusion: Catatonia, MNS, and MC may be due to a common brain pathophysiology and these conditions may be in a spectrum, although uncertainty in the boundaries among conditions, and the BZD treatment may be useful. Most importantly, catatonia has not been described as a subtype of schizophrenia on the basis of the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria, and the medications for catatonia and schizophrenia are different. Antipsychotics are not effective in relieving catatonia, or they may induce NMS, whereas BZDs are effective for treating both MC and NMS.

Smoking Rates and Number of Cigarettes Smoked per Day in Schizophrenia: A Large Cohort Meta-Analysis in a Japanese Population

Abstract Background Cigarette smoking is consistently more common among schizophrenia patients than the general population worldwide; however, the findings of studies in Japan are inconsistent. Recently, the smoking rate has gradually decreased among the general population. Methods We performed a meta-analysis of smoking status in a large Japanese cohort of (1) 1845 schizophrenia patients and 196845 general population and (2) 842 schizophrenia patients and 766 psychiatrically healthy controls from 12 studies over a 25-year period, including 301 patients and 131 controls from our study. Results In our case-control sample, schizophrenia patients had a significantly higher smoking rate than healthy controls (P=.031). The proportion of heavy smokers (P=.027) and the number of cigarettes smoked per day (P=8.20×10–3) were significantly higher among schizophrenia patients than healthy controls. For the smokers in the schizophrenia group, atypical antipsychotics dosage was positively correlated with cigarettes per day (P=1.00×10–3). A meta-analysis found that schizophrenia patients had a higher smoking rate than the general population for both men (OR=1.53, P=.035; schizophrenia patients, 52.9%; general population, 40.1%) and women (OR=2.40, P=1.08×10–5; schizophrenia patients, 24.4%; general population, 11.8%). In addition, male schizophrenia patients had a higher smoking rate than male healthy controls (OR=2.84, P=9.48×10–3; schizophrenia patients, 53.6%; healthy controls, 32.9%), but the difference was not significant for women (OR=1.36, P=.53; schizophrenia patients, 17.0%; healthy controls,14.1%). Among both males and females, schizophrenia patients had a higher smoking rate than both the general population (OR=1.88, P=2.60×10–5) and healthy controls (OR=2.05, P=.018). These rates were not affected by the patients’ recruitment year (P>.05). The cigarettes per day values of schizophrenia patients and the general population were 22.0 and 18.8, respectively. Conclusions Schizophrenia patients are approximately 2 times more likely to smoke than the general population and healthy controls based on data collected over a decade in Japan.