Genetic correlations between subcortical brain volumes and psychiatric disorders.

Psychiatric disorders as well as subcortical brain volumes are highly heritable. Large-scale genome-wide association studies (GWASs) for these traits have been performed. We investigated the genetic correlations between five psychiatric disorders and the seven subcortical brain volumes and the intracranial volume from large-scale GWASs by linkage disequilibrium score regression. We revealed weak overlaps between the genetic variants associated with psychiatric disorders and subcortical brain and intracranial volumes, such as in schizophrenia and the hippocampus and bipolar disorder and the accumbens. We confirmed shared aetiology and polygenic architecture across the psychiatric disorders and the specific subcortical brain and intracranial volume.

Intelligence decline between present and premorbid IQ in schizophrenia: Schizophrenia Non-Affected Relative Project (SNARP).

Schizophrenia patients (SCZ) display widespread cognitive deficits that are strongly associated with functional outcomes. Cognitive impairments occur along a genetic continuum among SCZ, their unaffected first-degree relatives (FRs) and healthy controls (HCs). Although SCZ impairs the premorbid intelligence quotient (IQ) and causes a subsequent intelligence decline (ID), a decrease in present IQ from the premorbid level, it remains unclear when during the illness course these impairments develop. Differences in premorbid and present IQ and ID were investigated among 125 SCZ, 61 FRs and 107 HCs, using analysis of covariance and a paired t-test. Furthermore, these subjects were classified into preserved and deteriorated IQ groups based on the degree of ID, and we investigated which factors contribute to this classification. We found significant differences in premorbid and present IQ among the diagnostic groups. Compared with HCs, SCZ and FRs displayed lower premorbid and present IQ. There was no significant difference in premorbid IQ between SCZ and FRs, but SCZ had a significantly lower present IQ than FRs. Only SCZ showed a significant ID. As most FRs and HCs did not display an ID, there were fewer subjects with deteriorated IQ among FRs and HCs than among SCZ. Subjects with preserved IQ showed higher educational attainment than those with deteriorated IQ among SCZ and FRs. These findings suggest that the impairment of premorbid IQ and the ID in SCZ become evident before and around the time of onset, respectively, and different pathophysiological mechanisms might be related to these impairments.

Meta-analysis of physical activity and effects of social function and quality of life on the physical activity in patients with schizophrenia.

Schizophrenia patients have increased mortality and morbidity, mainly due to premature cardiovascular disease resulting from decreased physical activity (PA). However, which PA intensity is impaired in the patients and how factors such as social function and quality of life (QoL) are related to decreased PA is unknown. To assess PA, social function and QoL, the International Physical Activity Questionnaire (IPAQ), Social Functioning Scale (SFS) and Schizophrenia Quality of Life Scale (SQLS), respectively, were used in 109 schizophrenia patients and 69 healthy subjects. A meta-analysis comparing PA intensities (vigorous, moderate and light) assessed by the single PA measurement between schizophrenia patients and healthy subjects after including our case-control sample was performed. Furthermore, the effects of social function and QoL on each level of PA intensity were investigated in patients and controls. The meta-analysis in 212 schizophrenia patients and 132 healthy subjects revealed that patients showed lower total PA, particularly vigorous PA, than controls (I2 = 0, Hedges' g = - 0.41, P = 2.80 × 10-4). The decreased total PA was correlated with impaired total SFS scores (ß = 0.24, P = 2.86 × 10-3), withdrawal (ß = 0.23, P = 3.74 × 10-3) and recreation (ß = 0.23, P = 3.49 × 10-3) without significant heterogeneity between patients and controls. In contrast, the decreased total PA was affected by low independence-performance (ß = 0.22, P = 0.034), employment/occupation (ß = 0.27, P = 8.74 × 10-3), psychosocial (ß = - 0.24, P = 0.021) and motivation/energy (ß = - 0.26, P = 0.013), but only in patients. Similar findings were obtained for vigorous PA but not moderate or light PA. Our findings suggest that the impaired vigorous PA in schizophrenia patients may be mediated by schizophrenia-specific factors of social functioning and QoL. Understanding these factors has important implications for increasing PA participation in schizophrenia patients.

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

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.

Genome-Wide Variants Shared Between Smoking Quantity and Schizophrenia on 15q25 Are Associated With CHRNA5 Expression in the Brain.

Cigarette smokers with schizophrenia consume more cigarettes than smokers in the general population. Schizophrenia and smoking quantity may have shared genetic liability. Genome-wide association studies (GWASs) of schizophrenia and smoking quantity have highlighted a biological pleiotropy in which a robust 15q25 locus affects both traits. To identify the genetic variants shared between these traits on 15q25, we used summary statistics from large-scale GWAS meta-analyses of schizophrenia in the Psychiatric Genomics Consortium 2 and smoking quantity assessed by cigarettes smoked per day in the Tobacco and Genetics Consortium. To evaluate the regulatory potential of the shared genetic variants, expression quantitative trait loci analysis in 10 postmortem brain regions was performed using the BRAINEAC dataset in 134 neuropathologically normal individuals. Twenty-two genetic variants on 15q25 were associated with both smoking quantity and schizophrenia at the genome-wide significance level (P < 5.00 × 10-8). Major alleles of all variants were associated with higher smoking quantity and risk of schizophrenia. These genetic variants were associated with PSMA4, CHRNA3, and CHRNB4 expression in specific brain regions (lowest P = 4.81 × 10-4) and with CHRNA5 expression in multiple brain regions (lowest P = 8.70 × 10-6). Risk-associated major alleles of these variants were commonly associated with higher expression in several brain regions, excluding the medulla, at the transcript level. In addition, the risk-associated major allele at rs637137 was associated with higher CHRNA5 expression at the specific exon level in multiple brain regions (lowest P = 2.37 × 10-5). Our findings suggest that genome-wide variants shared between smoking quantity and schizophrenia contribute to a common pathophysiology underlying these traits involving altered CHRNA5 expression in the brain.

Cerebellar activation during a motor task in conversion disorder with motor paralysis: A case report and fMRI study.

BACKGROUND: Motor conversion disorders are characterized by movement symptoms without a neurological cause. A psychogenic etiology is presumed for these disorders, but little is known about their underlying neural mechanisms. Functional magnetic resonance imaging (fMRI) has been utilized to understand the mechanisms associated with unexplained motor symptoms. Here, we used fMRI to investigate the cerebral response to motor stimulation in a patient with conversion disorder with motor paralysis to determine the underlying neural mechanisms of this disorder. METHODS: Brain activation induced by movements of the bilateral ankle joints (repeated plantar flexion and dorsiflexion) was recorded using fMRI in a patient with conversion disorder with unexplained motor paralysis. We acquired 2 types of imaging data: (i) data obtained while motor paralysis remained present and (ii) data obtained after motor paralysis had completely improved. We used a within-subject fMRI block design to compare the patient's brain activities during the motor task and at rest. RESULTS: Cerebral motor areas were significantly activated during the motor task relative to at rest, both when motor paralysis remained present and when paralysis had improved (FWE-corrected P < .05), although there was greater activation in motor areas when motor paralysis had improved than when motor paralysis remained. Notably, activation in the cerebellum posterior lobe during the motor task when motor paralysis remained (FWE-corrected P < .05) disappeared after motor paralysis had completely improved. CONCLUSIONS: The cerebellum is a region that is closely associated with voluntary motion. We suggest that complementary abnormal function in the cerebellum might be associated with the neural basis of conversion disorder with motor paralysis.

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.

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.

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 member's 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 patient's 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 patient's 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.

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.