Differential genetic associations and expression of PAPST1/SLC35B2 in bipolar disorder and schizophrenia.

Lithium's inhibitory effect on enzymes involved in sulfation process, such as inhibition of 3'(2')-phosphoadenosine 5'-phosphate (PAP) phosphatase, is a possible mechanism of its therapeutic effect for bipolar disorder (BD). 3'-Phosphoadenosine 5'-phosphosulfate (PAPS) is translocated from cytosol to Golgi lumen by PAPS transporter 1 (PAPST1/SLC35B2), where it acts as a sulfa donor. Since SLC35B2 was previously recognized as a molecule that facilitates the release of D-serine, a co-agonist of N-methyl-D-aspartate type glutamate receptor, altered function of SLC35B2 might be associated with the pathophysiology of BD and schizophrenia (SCZ). We performed genetic association analyses of the SLC35B2 gene using Japanese cohorts with 366 BD cases and 370 controls and 2012 SCZ cases and 2170 controls. We then investigated expression of SLC35B2 mRNA in postmortem brains by QPCR using a Caucasian cohort with 33 BD and 34 SCZ cases and 34 controls and by in situ hybridization using a Caucasian cohort with 37 SCZ and 29 controls. We found significant associations between three SNPs (rs575034, rs1875324, and rs3832441) and BD, and significantly reduced SLC35B2 mRNA expression in postmortem dorsolateral prefrontal cortex (DLPFC) of BD. Moreover, we observed normalized SLC35B2 mRNA expression in BD subgroups who were medicated with lithium. While there was a significant association of SLC35B2 with SCZ (SNP rs2233437), its expression was not changed in SCZ. These findings indicate that SLC35B2 might be differentially involved in the pathophysiology of BD and SCZ by influencing the sulfation process and/or glutamate system in the central nervous system.

Association studies of WD repeat domain 3 and chitobiosyldiphosphodolichol beta-mannosyltransferase genes with schizophrenia in a Japanese population.

Schizophrenia and schizophrenia-like symptoms induced by the dopamine agonists and N-methyl-D aspartate type glutamate receptor antagonists occur only after the adolescent period. Similarly, animal models of schizophrenia by these drugs are also induced after the critical period around postnatal week three. Based upon the development-dependent onsets of these psychotomimetic effects, by using a DNA microarray technique, we identified the WD repeat domain 3 (WDR3) and chitobiosyldiphosphodolichol beta-mannosyltransferase (ALG1) genes as novel candidates for schizophrenia-related molecules, whose mRNAs were up-regulated in the adult (postnatal week seven), but not in the infant (postnatal week one) rats by an indirect dopamine agonist, and phencyclidine, an antagonist of the NMDA receptor. WDR3 and other related proteins are the nuclear proteins presumably involved in various cellular activities, such as cell cycle progression, signal transduction, apoptosis, and gene regulation. ALG1 is presumed to be involved in the regulation of the protein N-glycosylation. To further elucidate the molecular pathophysiology of schizophrenia, we have evaluated the genetic association of WDR3 and ALG1 in schizophrenia. We examined 21 single nucleotide polymorphisms [SNPs; W1 (rs1812607)-W16 (rs6656360), A1 (rs8053916)-A10 (rs9673733)] from these genes using the Japanese case-control sample (1,808 schizophrenics and 2,170 matched controls). No significant genetic associations of these SNPs were identified. However, we detected a significant association of W4 (rs319471) in the female schizophrenics (allelic P = 0.003, genotypic P = 0.008). Based on a haplotype analysis, the observed haplotypes consisting of W4 (rs319471)-W5 (rs379058) also displayed a significant association in the female schizophrenics (P = 0.016). Even after correction for multiple testing, these associations remained significant. Our findings suggest that the WDR3 gene may likely be a sensitive factor in female patients with schizophrenia, and that modification of the WDR3 signaling pathway warrants further investigation as to the pathophysiology of schizophrenia.

Genetic and molecular risk factors within the newly identified primate-specific exon of the SAP97/DLG1 gene in the 3q29 schizophrenia-associated locus.

The synapse-associated protein 97/discs, large homolog 1 of Drosophila (DLG1) gene encodes synaptic scaffold PDZ proteins interacting with ionotropic glutamate receptors including the N-methyl-D-aspartate type glutamate receptor (NMDAR) that is presumed to be hypoactive in brains of patients with schizophrenia. The DLG1 gene resides in the chromosomal position 3q29, the microdeletion of which confers a 40-fold increase in the risk for schizophrenia. In the present study, we performed genetic association analyses for DLG1 gene using a Japanese cohort with 1808 schizophrenia patients and 2170 controls. We detected an association which remained significant after multiple comparison testing between schizophrenia and the single nucleotide polymorphism (SNP) rs3915512 that is located within the newly identified primate-specific exon (exon 3b) of the DLG1 gene and constitutes the exonic splicing enhancer sequence. When stratified by onset age, although it did not survive multiple comparisons, the association was observed in non-early onset schizophrenia, whose onset-age selectivity is consistent with our recent postmortem study demonstrating a decrease in the expression of the DLG1 variant in early-onset schizophrenia. Although the present study did not demonstrate the previously reported association of the SNP rs9843659 by itself, a meta-analysis revealed a significant association between DLG1 gene and schizophrenia. These findings provide a valuable clue for molecular mechanisms on how genetic variations in the primate-specific exon of the gene in the schizophrenia-associated 3q29 locus affect its regulation in the glutamate system and lead to the disease onset around a specific stage of brain development.

Association of schizophrenia onset age and white matter integrity with treatment effect of D-cycloserine: a randomized placebo-controlled double-blind crossover study.

BACKGROUND: It has been reported that drugs which promote the N-Methyl-D-aspartate-type glutamate receptor function by stimulating the glycine modulatory site in the receptor improve negative symptoms and cognitive dysfunction in schizophrenia patients being treated with antipsychotic drugs. METHODS: We performed a placebo-controlled double-blind crossover study involving 41 schizophrenia patients in which D-cycloserine 50 mg/day was added-on, and the influence of the onset age and association with white matter integrity on MR diffusion tensor imaging were investigated for the first time. The patients were evaluated using the Positive and Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS), Brief Assessment of Cognition in Schizophrenia (BACS), and other scales. RESULTS: D-cycloserine did not improve positive or negative symptoms or cognitive dysfunction in schizophrenia. The investigation in consideration of the onset age suggests that D-cycloserine may aggravate negative symptoms of early-onset schizophrenia. The better treatment effect of D-cycloserine on BACS was observed when the white matter integrity of the sagittal stratum/ cingulum/fornix stria terminalis/genu of corpus callosum/external capsule was higher, and the better treatment effect on PANSS general psychopathology (PANSS-G) was observed when the white matter integrity of the splenium of corpus callosum was higher. In contrast, the better treatment effect of D-cycloserine on PANSS-G and SANS-IV were observed when the white matter integrity of the posterior thalamic radiation (left) was lower. CONCLUSION: It was suggested that response to D-cycloserine is influenced by the onset age and white matter integrity. TRIAL REGISTRATION: UMIN Clinical Trials Registry (number UMIN000000468 ). Registered 18 August 2006.

A distinctive abnormality of diffusion tensor imaging parameters in the fornix of patients with bipolar II disorder.

Diffusion tensor imaging (DTI) studies have revealed a changed integrity in the white matter of bipolar disorder. However, only a few investigations have examined bipolar II disorder (BP-II). A cross-sectional study was conducted to compare thirty-eight patients with BP-II (mean age = 38.26 years, F/M = 19/19) with thirty-eight age- and gender-matched healthy controls (mean age = 34.45 years, F/M = 18/20). Tract Based Spatial Statistics (TBSS) analysis of the fractional anisotropy (FA) was done with age, gender and education years as covariates, then a complementary atlas-based region-of-interest (ROI) analysis including the axial diffusivity (AD) and radial diffusivity (RD) was conducted to obtain further information. The patients with BP-II showed a significant decrease in FA in the corpus callosum (commissure fibers), fornix (association fibers) and right anterior corona radiata (projection fibers) compared to the controls. Moreover, a significant increase in the RD was observed in all of the fibers of the BP-II patients, while the AD significantly increased only in the fornix of the patients. Thus, in addition to the abnormal integrity of the commissure and projection fibers, the present study suggested an involvement of the limbic association fibers in the pathophysiology of BP-II induced by a distinctive neuropathology.

A Decrease in the Volume of Gray Matter as a Risk Factor for Postoperative Delirium Revealed by an Atlas-based Method.

OBJECTIVE: Delirium is a common syndrome in older patients after surgery. Although an atrophic change in the whole brain may be a potential risk factor for postoperative delirium, the anatomically specific change related to the vulnerability still remains a significant issue. DESIGN: Prospective study. SETTING: University hospital. PARTICIPANTS: 116 consecutive patients who underwent elective cardiac operations. MEASUREMENTS: Before the surgery, magnetic resonance imaging (MRI) was evaluated. The MRI data were processed to calculate the absolute volumes of the predefined region of interest using Statistical Parametrical Mapping 8 with an atlas-based method. The evaluated volume was expressed as the fraction (%) of the total intracranial volume. Postoperative delirium was diagnosed according to the DSM-IV criteria for delirium. RESULTS: Delirium developed in 19 of 116 patients (16.4%) with an age range from 58 to 84 years. Based on a comparison with the age-controlled non-delirium patients (over 57 years; n = 65), a statistically significant reduction in the gray matter volume of the delirium patients was observed in the defined gyri of the temporal and limbic lobes. Moreover, a moderate value (>0.8) of area under the curve to predict postoperative delirium was revealed by receiver operating characteristic curve analysis of the gyri of temporal lobe. CONCLUSIONS: The decreased volume of gray matter could be associated with the vulnerability to delirium after surgery. The atlas-based method would be a potential tool to pre-screen the brain structure of individual patients for the prediction of postoperative delirium.

Erratum to: Association study of H2AFZ with schizophrenia in a Japanese case-control sample.

Table 1 contains several errors as originally published. Table 1 should read as follows; the corrected values are shown in italics.

Association study of H2AFZ with schizophrenia in a Japanese case-control sample.

It is widely accepted that malfunction of the N-methyl-D-aspartate (NMDA)-type glutamate receptor may be involved in the pathophysiology of schizophrenia. Several recent microRNA (miRNA) studies have demonstrated that the expression of the glutamate system-related miR-132 and miR-212 is changed in postmortem schizophrenic brains. Here we attempted to obtain further insight into the relationships among schizophrenia, the NMDA receptor, the molecular cascades controlled by these miRNAs and commonly predicted target genes of the two miRNAs. We focused on the H2AFZ (encoding H2A histone family, member Z) gene, whose expression was shown in our screening study to be modified by a schizophrenomimetic NMDA antagonist, phencyclidine. By performing polymerase chain reaction with fluorescent signal detention using the TaqMan system, we examined four tag single nucleotide polymorphisms (SNPs; SNP01-04) located around and within the H2AFZ gene for their genetic association with schizophrenia. The subjects were a Japanese cohort (2,012 patients with schizophrenia and 2,170 control subjects). We did not detect any significant genetic association of these SNPs with schizophrenia in this cohort. However, we observed a significant association of SNP02 (rs2276939) in the male patients with schizophrenia (allelic P = 0.003, genotypic P = 0.008). A haplotype analysis revealed that haplotypes consisting of SNP02-SNP03 (rs10014424)-SNP04 (rs6854536) also showed a significant association in the male patients with schizophrenia (P = 0.018). These associations remained significant even after correction for multiple testing. The present findings suggest that the H2AFZ gene may be a susceptibility factor in male subjects with schizophrenia, and that modification of the H2AFZ signaling pathway warrants further study in terms of the pathophysiology of schizophrenia.

Oral Dysesthesia Rating Scale: a tool for assessing psychosomatic symptoms in oral regions.

BACKGROUND: The concept of cenesthopathy was first introduced by Dupré and Camus in 1907 to describe clinically unexplainable bodily sensations mainly attributed to psychiatric pathology. If it occurs in oral regions, it is termed oral cenesthopathy and it has been of special interest to psychiatrists and dentists. While there is no independently defined criteria for this condition, which is classified as either a delusional or a somatoform disorder, clinical practice and research require a standard scale to measure and rate its symptoms. In this study, we included any types of psychosomatic symptoms in oral regions as oral dysesthesia, and developed an Oral Dysesthesia Rating Scale (Oral DRS) and evaluated its validity and reliability as an assessment tool. METHODS: The scale was developed based on literature review and extensive clinical experience. Twelve reviewers assessed relevancy of each item to oral dysesthesia symptoms by 1-4 scoring scale and item content validity index was computed. To evaluate the inter-rater reliability of Oral DRS, pairs of raters administered the scale to 40 randomly selected patients with complaints of oral dysesthesia symptoms and Cohen's weighted kappa coefficient was determined for each item. RESULTS: The scale assesses the severity of feelings of foreign body [A1], exudation [A2], squeezing-pulling [A3], movement [A4], misalignment [A5], pain [A6], and spontaneous thermal sensation or tastes [A7], and the degree of impairment in eating [B1], articulation [B2], work [B3], and social activities [B4] on a scale of 0-5. Items A1, A2, A3, A4, B3, and B4 demonstrated acceptable content validity. Inter-rater reliabilities were good or excellent for all items evaluated. CONCLUSION: The Oral DRS can help define the nosography of clinically unexplainable oral dysesthesia through further case evaluation and clinical research and facilitate devising of treatment modalities.

Clinical course of the bipolar II disorder in a Japanese sample.

BACKGROUND: The bipolar II disorder has been recognized a mental disorder distinctive from the bipolar I disorder, showing the stability of diagnosis in prospective studies. However, the characterization of the bipolar II disorder still remains under investigation. METHODS: The present study was conducted on consecutively admitted bipolar II inpatients diagnosed by DSM-IV-TR to delineate the clinical features. RESULTS: The types of initial mood disorders of the bipolar II inpatients were divided into four groups, i.e., major depressive episode (MDE), hypomanic episode (HME), and dysthymic and cyclothymic disorders. Seventy-one percent of all the patients belonged to the MDE group, a half of which underwent the first HME following the first MDE. The number of patients that exhibited the HME within one year after the first MDE was the highest in a widely distributed interval of years between the first MDE and the first HME. The cyclothymic disorder group was relatively young at the onset and was more prone to attempt suicide. Moreover, there might be a complex connection with other psychiatric disorders, such as anxiety disorders, in the longitudinal course of the bipolar disorder. LIMITATION: The present study was carried out on a limited number of patients admitted to one hospital. The data are partly based on the retrospective information from the patients and their relatives. The generalization of the results requires further studies. CONCLUSION: The bipolar II disorder could be divided into heterogeneous groups in the longitudinal course. Hence, paying attention to the heterogeneity in clinical practice and a study of the disorder are required.

[The trends of mood disorders in ICD-11: bipolar and depressive disorders].

The international classification of diseases 11th (ICD-11) revision is due by 2015. The ICD-11 beta draft has recently been released, which includes a prospective change in the content of mood disorders. The ICD-11 may separate the disorders into bipolar and depressive disorders as a consequence of an evaluation for the feasibility of a meta-structure for mental and behavioral disorders. In addition, the bipolar disorders may be divided into type I and II disorders. The depressive disorders may include new diseases, i. e., disruptive mood dysregulation disorder, mixed depressive anxiety, and premenstrual dysphoric disorder. Our epidemiological data from patients with mood disorders diagnosed using the ICD-10 or DSM-IV have proven their utility in clinical use, and suggested a required revision for the criteria of the diagnosis. A part of persistent mood disorders, such as cyclothymia and dysthymia, seem to be the prodromal state of bipolar disorders. For an accurate assessment of manic and hypomanic episodes, a precise estimation of the physiological effects of antidepressants as well as a sufficient review of clinical information from family members of patients are mandatory. The mixed affective episode may be deleted in the new version, because our data also indicate that this episode is a very rare clinical state. Moreover, it appears that inpatients with bipolar II disorder diagnosed by the DSM-IV in our hospital showed heterogeneous clinical properties, such as the onset age and interval between the first depressive and first hypomanic episode. After a worldwide and intensive discussion, it appears that the newly revised ICD-11 will be an advanced scientific tool for psychiatry.

An anxiogenic drug, FG 7142, induced an increase in mRNA of Btg2 and Adamts1 in the hippocampus of adult mice.

BACKGROUND: Anxiety and stress-related disorders are among the most common psychiatric disorders. The hippocampus is a crucial brain area involved in the neural circuits of the pathophysiology of anxiety and stress-related disorders, and GABA is one of most important neurotransmitters related to these disorders. An anxiogenic drug and a pharmacological stressor, FG7142 (N-methyl-ß-carboline-3-carboxamide), produces anxiety in humans and experimental animals, acting at the benzodiazepine sites of the GABAA receptors as a partial inverse agonist. This drug as well as immobilization stress produced an increased mRNA in a number of genes, e.g., Btg2 and Adamsts1, in the cortex of rodents. The present study was carried out to clarify the effect of the anxiogenic drug on the gene expressions in the hippocampus and to obtain a new insight into the GABAergic system involved in the pathophysiology of the disorders. METHOD: We examined the effects of FG7142 on the gene expression of Btg2 and Adamts1 in the hippocampus of mice using a quantitative RT-PCR method as well as an in situ hybridization method. RESULTS: The intraperitoneal administration of FG7142 at a dose of 20 mg/kg, but not 10 mg/kg, induced a statistically significant increase in the hippocampal mRNA of both genes in adult mice (postnatal days 56), being blocked by co-administrations of flumazenil (twice of 10 mg/kg, i.p.), an antagonist at the benzodiazepine binding site, while FG7142 failed to produce any change in the gene expressions in infant mice (postnatal days 8). In addition, the in situ hybridization experiment demonstrated an upregulation of the gene expressions restricted to the dentate gyrus of the hippocampus in adult mice. CONCLUSIONS: The present study suggests a functional coupling between the GABAergic system and the transcriptional regulation of the two genes (Btg2 and Adamsts1) in the hippocampus of adult mice, which may play a role in the brain function related to anxiety and stress such as memory of fear.

Improvement of asymmetrical temporal blood flow in refractory oral somatic delusion after successful electroconvulsive therapy.

Oral cenesthopathy is a somatic delusion in the oral area and categorized as delusional disorder, somatic type. Patients experience unusual and annoying sensations in the mouth such as pulling on the teeth, moving teeth, overly secreting mucus, tingling and pain, and so on, without a somatic base. The condition is usually treatment-resistant and impairs patients' quality of life. We report a case of oral cenesthopathy successfully treated with the modified electroconvulsive therapy, who demonstrated altered regional cerebral blood flow before and after the treatment detected by single-photon emission computed tomography.

Effects of novelty stress on hippocampal gene expression, corticosterone and motor activity in mice.

Exposure to novelty, a mild psychological stressor, induces neuronal activations in the hippocampus of rodents, which may play an important role in the adaptation to stress. We examined the changes in three parameters, i.e., gene expression in the hippocampus using a RT-PCR method, corticosterone and motor activity, in mice exposed to a new environment for 120min. A sharp and short-lasting increase in the gene expression of a set of stress-related genes previously reported, e.g., Fos and Nr4a1, was observed during the stress, with a similar pattern of changes in corticosterone. The motor activity gradually decreased during the novelty stress, indicating a process of adaptation to the new environment. In addition, in order to minimize the effects of elevated adrenal hormones by the stress, we carried out experiments on adrenalectomized (ADX) mice. However, the adrenalectomy produced minimal changes in the pattern and the magnitude of the gene response after the stress, while the motor activity showed a relatively slower pattern of adaptation in the ADX mice. Hence, the present study suggests that there was a coordinated adaptation process to the new environment in mice, and that the transcriptional response was mediated by neuronal networks rather than by adrenal hormones.

[A case of thiamine deficiency with psychotic symptoms--blood concentration of thiamine and response to therapy].

We report the case of a 63-year-old woman with thiamine deficiency who showed auditory hallucinations, a delusion of persecution, catatonic stupor, and catalepsy but no neurological symptoms including oculomotor or gait disturbance. Brain MRI did not show high-intensity T2 signals in regions including the thalami, mamillary bodies, or periaqueductal area. Her thiamine concentration was 19 ng/mL, only slightly less than the reference range of 20-50 ng/mL. Her psychosis was unresponsive to antipsychotics or electroconvulsive therapy, but was ameliorated by repetitive intravenous thiamine administrations at 100-200 mg per day. However, one month after completing intravenous treatment, her psychosis recurred, even though she was given 150 mg of thiamine per day orally and her blood concentration of thiamine was maintained at far higher than the reference range. Again, intravenous thiamine administration was necessary to ameliorate her symptoms. The present patient indicates that the possibility of thiamine deficiency should be considered in cases of psychosis without neurological disturbance and high-intensity T2 MRI lesions. Also, this case suggests that a high blood thiamine concentration does not necessarily correspond to sufficient thiamine levels in the brain. Based on this, we must reconsider the importance of a high dose of thiamine administration as a therapy for thiamine deficiency. The validity of the reference range of the thiamine concentration, 20-50 ng/mL, is critically reviewed.

White matter abnormalities as a risk factor for postoperative delirium revealed by diffusion tensor imaging.

OBJECTIVE: Delirium is a common and critical clinical syndrome in older persons. The authors examined whether any abnormalities in the white matter (WM) assessed by diffusion tensor imaging (DTI) predisposes patients to develop delirium after cardiac surgery and also analyzed other risk factors for delirium. METHOD: In 116 consecutive patients who underwent scheduled cardiac operations, fractional anisotropy (FA) values obtained by DTI before the surgery and pre-, peri-, and postoperative factors were evaluated. The postoperative delirium was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for delirium. RESULTS: Delirium developed in 19 of 116 patients (16.4%). Eighteen of the patients with delirium (94.7%) were older than 60 years. A multivariate logistic regression analysis showed that advanced age and poor performance on a semantic fluency task (the Word Fluency test animal) were important predictive indicators of the delirium. In addition, a voxel-by-voxel analysis using the Statistical Parametrical Mapping 2 revealed that the FA values of the patients with postoperative delirium were significantly lower than those of the nondelirium patients in the bilaterally widespread deep WMs and bilateral thalamus, whereas the analysis treating age as a nuisance variable indicated a significant change in only four clusters of the brain areas, e.g., the left frontal lobe WM, and left thalamus, when compared with the nondelirium group. CONCLUSION: The abnormalities in the deep WMs and thalamus that were mainly accelerated by aging may account for the vulnerability to postoperative delirium, and the semantic word fluency could be a useful predictive indicator of delirium.

Increased binding of inhibitory neuronal receptors in the hippocampus in kainate-treated rats with spontaneous limbic seizures.

To gain a better understanding of the relationship between epileptogenicity and inhibitory neuronal mechanisms, we examined variations in A1 adenosine (A1A) receptor binding in the hippocampi of rats with spontaneous limbic seizures in the chronic phase after systemic kainic acid treatment. Six weeks after kainate treatment, rats with spontaneous limbic seizures were killed for histological and in vitro autoradiographic analyses of the brain. The analyses were performed using [(3)H] 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an A1A receptor antagonist. Relative to controls, DPCPX binding was increased in the CA3 region and in the molecular layer of the dentate gyrus in the kainate-treated rats. This is the first evidence of upregulation of the A1A receptor in a model of chronic temporal lobe epilepsy. Increased binding of the A1A receptor may contribute to epileptogenesis in the epileptic focus.

Effects of FG7142 and immobilization stress on the gene expression in the neocortex of mice.

Several psychiatric disorders are often precipitated or exacerbated by exposure to stressors. FG7142 (N-methyl-beta-carboline-3-carboxamide), a partial inverse agonist of benzodiazepine receptors, mimics the physiological (an increased release in the adrenal steroid hormone) and neurochemical (an enhanced neurotransmission of monoamines) changes induced by stressful stimuli. We examined the effects of FG7142 and immobilization stress on the gene expression of the mouse neocortex in order to obtain a new insight into the molecular stress-responsive system. The effect of FG7142 (20 mg/kg, i.p.) on the gene expression of the brain area was examined using a DNA microarray method. The genes showing a significant change in expression were investigated in further experiments using the quantitative RT-PCR method. There was an increase in the mRNA of seven genes in the neocortex of mice 1h after treatment with FG7142. In addition, there was an increase in the mRNAs of five of the seven genes (Fos, Cyr61, Btg2, Adamts1, and Gem) in the neocortex of mice exposed to the stress for 1h. The up-regulation of these five genes by both FG7142 and immobilization stress indicates that these genes may be involved in the stress-responsive system. Dysfunctions of the system may be associated with the pathophysiology of psychiatric disorders.