Search

Electroconvulsive therapy (ECT) is an effective treatment of major depressive disorder (MDD). However, high relapse rates after ECT represent clinical problems. To date, influence of number of ECT sessions on relapse rate remains to be elucidated. We evaluated associations between number of ECT sessions and relapse rate.This retrospective review collected clinical data of 53 patients with MDD who received ECT. They underwent a 1-year follow-up after their last ECT session. We performed survival analysis to evaluate associations between number of ECT sessions and time until rehospitalisation or suicide.The patients were divided into a higher number of ECT group (≧8 sessions) and lower number of ECT group (8 sessions). No significant difference was found regarding the patients' clinical and demographic data. Survival analysis using log-rank test revealed that the cumulative survival rate in the higher number of ECT group (79%) was higher compared with the lower number of ECT group (49%) (Patients who underwent a higher number of ECT had improved survival rate compared with those who received a lower number. Therefore, additional sessions might be necessary, even in patients who achieved remission within seven ECT sessions, to prevent relapse.Key pointsHigh rate of relapse after ECT is a key problem.Impact of the Number of ECT sessions on relapse remains to be elucidated.In the present study, the patients with MDD who underwent eight or more sessions of ECT showed significant lower relapse rate compared with those who received less than eight sessions.

Background Cocaine (benzoylmethylecgonine) is one of the most widely used illegal psychostimulant drugs worldwide, and mortality from acute intoxication is increasing. Suppressing hyperthermia is effective in reducing cocaine-related mortality, but a definitive therapy has not yet been found. In this study, we assessed the ability of risperidone to attenuate acute cocaine-induced hyperthermia and delineated the mechanism of its action. Methods Rats were injected i.p. with saline, risperidone, ketanserin, ritanserin, haloperidol, or SCH 23 390 before and after injection of cocaine (30 mg/kg) or with WAY-00 635, SB 206 553, or sulpiride before cocaine injection; thereafter, the rectal temperature was measured every 30 minutes for up to 4 hours. In vivo microdialysis was used to reveal the effect of risperidone on cocaine-induced elevation of dopamine (DA), serotonin (5-HT), and noradrenaline concentrations in the anterior hypothalamus. For post-administration experiments, saline or risperidone (0.5 mg/kg) were injected into rats, and cocaine (30 mg/kg) was injected 15 minutes later. For every 30 minutes thereafter, DA, 5-HT, and noradrenaline levels were measured for up to 240 minutes after cocaine administration. Results Risperidone, 5-HT2A receptor antagonists, and D1 receptor antagonistic drugs prevented and reversed cocaine-induced hyperthermia. In contrast, receptor antagonists for 5-HT1A, 5-HT2B/2C, and D2 did not alter cocaine-induced hyperthermia. Risperidone treatment further attenuated cocaine-induced elevation of DA. Conclusions Our results indicate that risperidone attenuates cocaine-induced hyperthermia primarily by blocking the activities of the 5-HT2A and D1 receptors and may be potentially useful for treating cocaine-induced acute hyperthermia in humans.

Isaku Kurotori,1 Katsutoshi Shioda,1 Takaaki Abe,1 Rika Kato,1 Shizukiyo Ishikawa,2 Shiro Suda1 1Department of Psychiatry; 2Department of Medical Education Center, Jichi Medical University, Tochigi, JapanCorrespondence: Katsutoshi ShiodaDepartment of Psychiatry, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanTel +81-285-58-7364Fax +81-285-44-6198Email kazs@jichi.ac.jpPurpose: To determine the clinical characteristics and course of severe avoidant/restrictive food intake disorder (ARFID) in hospitalized children and adolescents and compare them with those of patients with restricting-type anorexia nervosa (R-AN).Patients and methods: We conducted a retrospective chart review of inpatients diagnosed with ARFID or R-AN based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, at Jichi Children’s Medical Center Tochigi between April 1, 2007 and March 31, 2017. We compared the characteristics of the ARFID and R-AN patients at admission, during hospitalization, and after discharge.Results: Both the ARFID (n=13) and R-AN (n=79) patients required hospitalization for their medically unstable state. The features of ARFID group included concern about the aversive consequences of eating and avoidance of eating due to sensory concerns. Significant differences were found at admission between ARFID and R-AN groups in age (10.7 vs 12.7 years), family history of mental disorders (46.2% vs 17.7%), comorbid developmental disorders (6 vs 3 cases), and the time from onset to admission (3.9 vs 6.3 months). The body weight status, % ideal body weight (%IBW), % expected body weight (%EBW)

Syndrome of inappropriate antidiuretic hormone release (SIADH) can sometimes be caused by an adverse effect of certain psychotropic drugs. However, suvorexant has never been reported to cause SIADH. A 77-year-old man with type 2 diabetes was admitted to the Jichi Medical University Hospital for the treatment of major depression. During the treatment, he was prescribed suvorexant for insomnia. Twelve days after the initiation of suvorexant, he developed hyponatremia, which met the diagnostic criteria of SIADH. We suspected the hyponatremia to be an adverse drug effect of suvorexant because no other cause for SIADH was detected. Accordingly, suvorexant was discontinued 15 days after the onset of SIADH, and hyponatremia improved in 6 days. Although suvorexant has fewer adverse drug reactions and is considered relatively safe, clinicians should be aware of the possibility of SIADH induced by suvorexant. CITATION: Takano M, Okada T, Kobayashi T, Suda S. Syndrome of inappropriate antidiuretic hormone secretion induced by suvorexant: a case report. J Clin Sleep Med. 2021;17(3):593–594.

Background Recent studies have indicated the potential clinical use of near-infrared spectroscopy (NIRS) as a tool for assisting in the diagnosis of major depressive disorder (MDD). Although sleep complaints are often manifested in MDD, no study has elucidated the possible association between the objective evaluation of sleep and NIRS signals in MDD. Methods Fourteen patients with MDD and 15 healthy controls wore waist actigraphy equipment before the NIRS scan to investigate sleep parameters. We performed a 52-channel NIRS scan and measured changes in oxygenated hemoglobin ([oxy-Hb]) during a verbal fluency task. Results In patients with MDD, a significant negative correlation was observed between the 17-item Hamilton Depressive Rating Scale score and cerebral reactivity of the right temporal region (p s :=−0.804 to −0.762; FDR-corrected; p =0.008–0.012). The Pittsburgh Sleep Questionnaire Index, which enables assessment of continuous sleep quality and disturbances, was negatively correlated with [oxy-Hb] changes in the left prefrontal cortex (p s =−0.630 to −0.551; FDR-corrected; p =0.043–0.048). Actigraphic sleep variables prior to the NIRS measurement showed no significant correlation with [oxy-Hb] changes. Limitations The limitations were small sample size with the low severity of depression and the use of actigraphy for only one night. Conclusion Self-rated sleep disturbance were associated with decreased left prefrontal reactivity during a verbal fluency task in patients with MDD. Our result indicates that the reactivity of the prefrontal region is susceptible to sleep complaints, providing further evidence to support potential clinical application of NIRS.

(Introduction) Pneumonia is a well-known major physical complication that can occur in the course of treatment for severe psychiatric disorders and antipsychotic treatment. However, there are few reports indicating the differences between pneumonia in the field of psychiatric medicine and the more commonly encountered type of pneumonia. In the present study, we examined the specific characteristics of in-hospital pneumonia in psychiatric wards and factors influencing the aggravation of this infection. (Methods) We retrospectively analyzed 22 patients in the psychiatric ward of Jichi Medi- cal University Hospital, which also has general wards, in whom pneumonia developed during hospitalization. We extracted occurrence, outcome, and sputum culture test results as charac- teristics. Severity of pneumonia was classified using the Pneumonia Severity Index (PSI) as follows : classes I -III, minor group (MG : 15 patients) and classes IV-V, moderate to severe group (MSG: seven patients). We examined the following factors related to the aggravation of pneumonia: body mass index (BMI), length of psychiatric treatment, number of hospital admis- sions, Global Assessment of Functioning (GAF) score, dose of antipsychotics, dose of benzodi- azepines (chlorpromazine and diazepam equivalent doses), and dose of antiparkinsonian agents (biperiden equivalent dose). (Results) Aspiration occurred prior to the onset of pneumonia in one patient, and one patient required ventilator management. There were no patient deaths. Streptococcus pneu- moniae and Staphylococcus aureus were detected in five and four patients, respectively. Nei- ther methicillin-resistant Staphylococcus aureus nor Pseudomonas aeruginosa was detected. In comparison with MG patients, MSG patients had significantly lower BMI (18.3 ?2.6 vs. 21.2? 3.5), significantly higher numbers of hospital admissions (3.4?i3.3 times vs. 1.1+?L1.4 times), and a significantly higher ratio of GAF scores of 30 or less (85.7% VS 33.3%). The doses of benzo- diazepines and antiparkinsonian agents were significantly higher for MSG patients in comparison with MG patients (benzodiazepines : 2.3?2.4 mg vs. 0.4?i1.1 mg; antiparkinsonian agents: 2.3?2.4 mg vs. 0.4? 1.1 mg). No significant differences were observed in the doses of antipsy- chotics. Sputum culture tests were performed in 18 patients. (Conclusion) Outcomes were comparatively favorable and the results of bacterial culture tests tended to show no antibiotic-resistant bacteria, differing in that regard from hospital- acquired pneumonia. In fact, the characteristics of cases of pneumonia in hospitalized psychiatric patients were similar to those of community-acquired pneumonia. Low BMI, multiple psychiatric ward admissions, and GAF scores of 30 or less all reflect poor mental control. The results of the present study suggest a relationship between the severity of pneumonia and both insufficient psychiatric treatment and the use of benzodiazepines and antiparkinsonian agents.

Objective Catatonia is a motor dysregulation syndrome often accompanied by deep vein thrombosis (DVT) and pulmonary embolism (PE). Although electroconvulsive therapy (ECT) is effective for catatonia, it is unknown whether ECT contributes to the onset of a PE from a residual DVT. The objective of this case series is to examine and propose safety methods for ECT in catatonia patients with a DVT. Methods Data were obtained retrospectively via chart review for 5 psychiatric inpatients diagnosed with catatonia based on DSM-IV-TR or DSM-5 criteria from April 2010 to March 2017 who underwent ECT after developing a DVT. Results All 5 patients received anticoagulation therapy after the onset of DVT and underwent subsequent ECT. Three patients had distal DVT (thromboses located below the knee in the calf veins) before ECT, which did not result in an onset of PE in the course of ECT. One had a proximal DVT (thromboses in the popliteal vein and above), and the ECT session was completed without the occurrence of PE. In the fifth patient, a proximal DVT developed into a PE after an ECT session. Conclusions These results suggest that it is important to determine the location of a DVT and to continue anticoagulation therapy until a proximal DVT disappears before ECT is performed.

The effects of repetitive transcranial magnetic stimulation (rTMS) on physical activity and sleep patterns in individuals with major depressive disorder (MDD) remain unclear.We examined the effects of rTMS treatment on the rest-activity cycle and sleep disturbances in MDD. In this open-label pilot study, 14 patients with medication-resistant MDD underwent 10 rTMS sessions over the bilateral dorsolateral prefrontal cortex. In addition to Hamilton Depression Rating Scale and Pittsburgh Sleep Quality Index scores, waist actigraphy was used to evaluate alterations in the rest-activity cycle over the course of rTMS treatments. Actigraphic data were evaluated at baseline and in the first (rTMS sessions 1-3), second (rTMS sessions 4-7), and third (rTMS sessions 8-10) sections.Although Hamilton Depression Rating Scale and Pittsburgh Sleep Quality Index scores were significantly improved by rTMS, sleep variables assessed by actigraphy did not show significant changes. However, post hoc tests indicated a significant increase in mean steps per day between the baseline and first section time points (P = 0.014; t13 = -2.316).Our data indicated that a daytime physical activity response to rTMS occurred in early sessions, whereas subjective symptom improvements were consistent across all sessions. Future double-blind placebo-controlled studies assessing the effects of rTMS on the rest-activity cycle and sleep disturbances in MDD are warranted.

Background Profound changes in gene expression can result from abnormalities in the concentrations of sequence-specific transcription factors like specificity protein 1 ( Sp1 ). Specificity protein 1 binding sites have been reported in the promoter regions of several genes implicated in autism. We hypothesize that dysfunction of Sp1 could affect the expression of multiple autism candidate genes, contributing to the heterogeneity of autism. Methods We assessed any alterations in the expression of Sp1 and that of autism candidate genes in the postmortem brain (anterior cingulate gyrus [ACG], motor cortex, and thalamus) of autism patients ( n = 8) compared with healthy control subjects ( n = 13). Alterations in the expression of candidate genes upon Sp1 /DNA binding inhibition with mithramycin and Sp1 silencing by RNAi were studied in SK-N-SH neuronal cells. Results We observed elevated expression of Sp1 in ACG of autism patients ( p = .010). We also observed altered expression of several autism candidate genes. GABRB3 , RELN , and HTR2A showed reduced expression, whereas CD38 , ITGB3 , MAOA , MECP2 , OXTR, and PTEN showed elevated expression in autism. In SK-N-SH cells, OXTR , PTEN , and RELN showed reduced expression upon Sp1 /DNA binding inhibition and Sp1 silencing. The RNA integrity number was not available for any of the samples. Conclusions Transcription factor Sp1 is dysfunctional in the ACG of autistic brain. Consequently, the expression of potential autism candidate genes regulated by Sp1 , especially OXTR and PTEN , could be affected. The diverse downstream pathways mediated by the Sp1 -regulated genes, along with the environmental and intracellular signal-related regulation of Sp1 , could explain the complex phenotypes associated with autism.

Autism is a pervasive developmental disorder diagnosed in early childhood. Abnormalities of serotonergic neurotransmission have been reported in autism. Serotonin transporter (5-HTT), which modulates serotonin levels, is a major therapeutic target in autism. Therefore, factors that regulate 5-HTT expression might be implicated in autism. One candidate 5-HTT-regulatory protein is the presynaptic protein, syntaxin 1A (STX1A). We examined the association of STX1A with autism in a trio association study using DNA samples from Japanese trios with autistic probands. In TDT analysis, rs69510130 ( p = 0.027) showed nominal associations with autism; modest haplotype association was also observed. We further compared STX1A mRNA expression between the autistic and control groups in the postmortem brain. In the anterior cingulate gyrus region, STX1A expression in the autism group was found to be significantly lower than that of the control group. Thus, we suggest a possible role of STX1A in the pathogenesis of autism.

Autism is a pervasive neurodevelopmental disorder diagnosed in early childhood. Growth factors have been found to play a key role in the cellular differentiation and proliferation of the central and peripheral nervous systems. Epidermal growth factor (EGF) is detected in several regions of the developing and adult brain, where, it enhances the differentiation, maturation, and survival of a variety of neurons. Transforming growth factor-beta (TGFbeta) isoforms play an important role in neuronal survival, and the hepatocyte growth factor (HGF) has been shown to exhibit neurotrophic activity. We examined the association of EGF, TGFbeta1, and HGF genes with autism, in a trio association study, using DNA samples from families recruited to the Autism Genetic Resource Exchange; 252 trios with a male offspring scored for autism were selected for the study. Transmission disequilibrium test revealed significant haplotypic association of EGF with autism. No significant SNP or haplotypic associations were observed for TGFbeta1 or HGF. Given the role of EGF in brain and neuronal development, we suggest a possible role of EGF in the pathogenesis of autism.

To clarify whether reelin signaling is involved in dopaminergic neurotransmission in the adult mouse brain, we investigated dopamine function in mice lacking reelin (reeler). We found that methamphetamine-induced locomotor activity is significantly attenuated in reeler mice. To elucidate the mechanism of this phenomenon, we first investigated presynaptic dopamine release; however, there were no significant differences in wildtype, heterozygous reeler and homozygous reeler mice. Next, we examined the locomotor response to intra-accumbens injection of dopamine D1 and D2 receptor agonists, and found that lack of reelin signaling results in decreases in both D1 and D2 receptor-mediated dopaminergic functions. In addition, we measured dopamine receptor binding in the striatum, and found that both D1 and D2 classes of dopamine receptors are reduced in reeler mice. Furthermore, we found that the phosphorylation levels of DARPP-32 are also changed by lack of reelin signaling. Finally, to distinguish between a developmental role of reelin or an acute role of reelin in adult mouse, we intraventricularly infused CR-50, a monoclonal antibody against reelin. Interestingly, infusion of CR-50 also significantly reduced methamphetamine-induced hyperlocomotion in wildtype mice, showing that reelin has an acute role in the dopaminergic system. These results indicate that reelin signaling plays a pivotal role in the dopaminergic system in adult mice, especially in postsynaptic levels.

Several previous studies have reported a significant linkage between markers in the alpha 7 nicotinic cholinergic receptor subunit ( CHRNA7 ) gene and either schizophrenia or the P50 sensory gating deficit, a schizophrenia endophenotype. However, CHRFAM7A , a partially duplicated gene 1.6 Mb upstream of the CHRNA7 gene, has complicated further genetic analysis. We genotyped 14 polymorphic markers throughout the full-length CHRNA7 gene and the duplicated region in 188 unrelated Han Chinese patients with schizophrenia and 188 controls. The duplicated regions were assessed by genotyping up- and down-stream polymorphic markers in the vicinity of each region and analyzing the linkage disequilibrium (LD) between each pair of markers. No evidence of risk variants for schizophrenia in either the CHRNA7 gene or the partially duplicated region was found in the LD analysis. A significant deviation from the Hardy–Weinberg equilibrium (HWE) was found only in the genotypic distribution of SNP9 (IVS4-1912) in patients ( p = 0.00829), but not in controls. In conclusion, our LD analysis did not reveal any association between schizophrenia in our Han Chinese population and the CHRNA7 gene or its partially duplicated region. However, we could not exclude the possibility of a weak genetic effect due to the small sample size. Analyses of larger samples and higher-density markers, particularly around SNP9 (IVS4-1912), are still needed.

Aims The aim of this study was to evaluate differences in vulnerability to traumatic stress and the 1-year course of post-traumatic stress symptoms among patients with pre-existing psychiatric disorders after the Great East Japan Earthquake. Methods The Impact of Event Scale-Revised (IES-R) was used to assess post-traumatic stress symptoms in 612 patients with schizophrenic (ICD-10 F2; n = 163), mood (F3; n = 299), or neurotic disorders (F4; n = 150) at 1-4 months and again at 13-16 months after the disaster (retention rate: 68%). Results The mean IES-R total score for all diagnostic groups was 18.6 at index and 13.4 at follow up. The mean IES-R total score for patients with neurotic disorders (22.5) was significantly higher than that of patients with mood disorders (18.1) and schizophrenic disorders (15.9). At follow up, these scores decreased for all groups and inter-group differences were not observed. Conclusions Vulnerability to traumatic stress after a disaster was most severe in patients with neurotic disorders, followed by mood disorders, and, lastly, schizophrenic disorders. This difference among the three diagnostic groups was not found 1 year after the disaster.

We examined the influence of electroconvulsive seizure (ECS) and imipramine (IMI) treatment on the transcription and translation of cyclic nucleotide phosphodiesterase type IV (PDE IV) isozymes in the rat brain. Our in situ hybridization studies revealed an increase of PDE IV-B mRNA level in various brain regions after acute ECS. However, the increase of PDE IV activity was produced not by acute but by chronic ECS treatment in the frontal cortex. Increased PDE IV-B mRNA expression in frontal but not in hippocampal subfields was induced also after chronic ECS treatment. Although an increase in PDE IV-A mRNA expression of the dentate gyrus in the hippocampus was observed, no change of PDE IV activity was produced in the hippocampus by acute or chronic ECS treatment. These results suggest that the repeated increases of PDE IV-B mRNA expression are attributable to the increase of PDE IV translation. Increased PDE IV-B transcription and PDE IV translation in the frontal cortex were also produced after chronic IMI treatment. This is the first report demonstrating an expressional regulation of Drosophila melanogaster dunce (dnc) gene homologue PDE IV isozymes in the brain. Although no pathophysiological conditions with reduced PDE IV activity in the nervous system are known except for a learning deficit in the mutant fly dnc−, our results suggest possible treatments to cope with reduced PDE IV activity.

GIRK2 (G protein-gated inwardly rectifying K + channel 2) located on the Down syndrome region 21q22.2 in humans has been reported to have several alternative transcripts and transcripts longer than 4 kb that do not have the poly-A tail. We sequenced GIRK2 transcripts with a long 3′-untranslated region (3′-UTR) containing multiple adenylate uridylate-rich elements (AREs) with the poly-A tail. In a 16-kb transcript, 28 AUUUA pentanucleotides, 9 AUUUUA hexanucleotides, 5 AUUUUUA heptanucleotides, and 3 UUAUUUA[U/A][U/A] nonanucleotides were found. Northern blot and in situ hybridization revealed abundant expression of the 16-kb transcripts in the rat brain despite no detectable signals in other tissues examined. The AREs have been reported to mediate the turnover of mRNAs encoding proteins regulating cellular proliferation/differentiation and body response to inflammatory and environmental stimuli. This is the first study indicating that ion channel transcripts have multiple AREs.

Autism spectrum disorders (ASD) are life-long neurodevelopmental conditions. The pathophysiology is poorly understood, and the clinical diagnosis can only be made through behavioural assessments. The prevalence of ASD has increased eight-fold over the last three decades. Paralleling this rise, research interest in the disorder has been accumulating, centering on two aspects: risk factors that would explain the increase in prevalence, and precursors that could predict an emergence of ASD prior to 2 years of age. As regard factors responsible for the increased prevalence, an increasing trend of low birthweight (4.2% in 1980 v. 9.6% in 2006 at Japan) and advanced paternal age at birth are potentially implicated. To explore these issues, and to yield an early diagnostic algorithm for ASD, the authors initiated the ongoing Hamamatsu Birth Cohort for Mothers and Children (HBC) in 2007. The strengths of the HBC include frequent, direct face-to-face assessments of all the participating mothers and children during the first 4 years of life (12 assessments); this depth of assessments will disclose subtle changes in the developmental domains of individuals with ASD, which might otherwise be overlooked. A total of 1200 pregnant women are to be recruited by the end of 2010. Assembled information comprises a range of variables related to the mother’s characteristics and child development. The comprehensiveness of the HBC will provide an informative data source that will elucidate early trajectories of children with ASD in addition to revealing detailed, developmental properties of typically developing children.

The neurobiological basis for autism remains poorly understood. Given the role of growth factors in brain development, we hypothesized that epidermal growth factor (EGF) may play a role in the pathophysiology of autism. In this study, we examined whether serum levels of EGF are altered in adult subjects with high-functioning autism.We measured serum levels of EGF in the 17 male subjects with high-functioning autism and 18 age-matched healthy male subjects.The serum levels of EGF in the subjects with high-functioning autism (72.4 +/- 102.8 pg/mL [mean +/- SD]) were significantly lower (Mann-Whitney U = 22.0, p.001) than those of normal control subjects (322.3 +/- 122.0 pg/mL [mean +/- SD]). However, there were no correlations between serum EGF levels and clinical variables in the subjects with autism.This study suggests that decreased levels of EGF might be implicated in the pathophysiology of high-functioning autism.

The Great East Japan Earthquake and subsequent tsunami of March 11, 2011 severely damaged a widespread region of northeastern Japan. Consequently, the Fukushima Nuclear Power Plant experienced a level seven 3 reactors melted down, which released a large amount of radioactive materials into the air. Due to the structural damage and radiation leaks, the victims are facing prolonged psychological distress.Eighty-two subjects with mental disorders who made their initial visit during the first 4 months after the earthquake and one hundred and ninety-four subjects with mental disorders who had been admitted during the first one year after the earthquake to the Jichi Medical University Hospital, which is located at the edge of the disaster-stricken region, were recruited for this study. Enrolled participants were assessed according to ICD-10. A questionnaire survey was employed to evaluate the severity of psychological distress and total amount of damage.The conditions of 22% of the outpatients had been worsened by the psychological distress related to the earthquake. Seven percent of the patients who had been hospitalized showed marked exacerbations due to the psychological distress associated with the disaster.It is of note that the exacerbation of psychiatric symptoms due to the disaster was evident among patients with mental disorders who lived even at the edge of the disaster area (i. e., subject to an earthquake intensity of 5 upper and 150 km from the Fukushima Nuclear Power Plant). The results suggest that the close follow-up of disaster victims with mental disorders is of critical importance.

Accumulating evidence from neurobiological and epidemiological studies indicates that altered development caused by environmental factors in early life, especially the gestational period, may lead to the development of physical illnesses in adulthood such as type II diabetes and cardiovascular diseases. However, recent studies have suggested that altered growth associated with adverse events around the time of birth is a factor that contributes to cognitive dysfunction as well as psychiatric disorders in adulthood, including autism spectrum disorders (ASDs), mood disorders, schizophrenia, and Alzheimer’s disease (AD). Environmental factors in early life, including placental dysfunction, maternal malnutrition during pregnancy, psychological distress in pregnant mothers, and infections during both the gestational and postnatal period, have been associated with alterations in gene expression regulated by epigenetic factors. These alterations have been proposed to trigger permanent changes in the programming of neural cells, whereby the processes of cell proliferation and migration, neuronal growth, synaptogenesis, and myelination would be grossly affected; as a result, individuals may be predisposed to various neurocognitive impairments that in turn can lead to specific neuropsychiatric disorders. In this chapter, we describe the association between growth disturbances in early life and subsequent neurocognitive development, and will focus in particular on early detrimental events, especially those involving nutritional factors, that can affect the development of the central nervous system (CNS) and be associated with the sequelae (i.e., psychiatric disorders) of such damage. Continued examination of the mechanisms underlying the associations between disturbed growth in early life and subsequent consequences in adulthood is expected to yield a better understanding of the pathophysiology of many neuropsychiatric disorders.

Multiple lines of evidence suggest a serotoninergic dysfunction in autism. The role of LMX1B in the development and maintenance of serotoninergic neurons is well known. In order to examine the role, if any, of LMX1B with autism pathophysiology, a trio-based SNP association study using 252 family samples from the AGRE was performed. Using pair-wise tagging method, 24 SNPs were selected from the HapMap data, based on their location and minor allele frequency. Two SNPs (rs10732392 and rs12336217) showed moderate association with autism with p values 0.018 and 0.022 respectively in transmission disequilibrium test. The haplotype AGCGTG also showed significant association (p = 0.008). Further, LMX1B mRNA expressions were studied in the postmortem brain tissues of autism subjects and healthy controls samples. LMX1B transcripts was found to be significantly lower in the anterior cingulate gyrus region of autism patients compared with controls (p = 0.049). Our study suggests a possible role of LMX1B in the pathophysiology of autism. Based on previous reports, it is likely to be mediated through a seretoninergic mechanism. This is the first report on the association of LMX1B with autism, though it should be viewed with some caution considering the modest associations we report.

Background It has recently been hypothesized that hyperglutamatergia in the brain is involved in the pathophysiology of autism. However, there is no conclusive evidence of the validity of this hypothesis. As peripheral glutamate/glutamine levels have been reported to be correlated with those of the central nervous system, the authors examined whether the levels of 25 amino acids, including glutamate and glutamine, in the platelet-poor plasma of drug-naive, male children with high-functioning autism (HFA) would be altered compared with those of normal controls. Methodology/Principal Findings Plasma levels of 25 amino acids in male children (N = 23) with HFA and normally developed healthy male controls (N = 22) were determined using high-performance liquid chromatography. Multiple testing was allowed for in the analyses. Compared with the normal control group, the HFA group had higher levels of plasma glutamate and lower levels of plasma glutamine. No significant group difference was found in the remaining 23 amino acids. The effect size (Cohen's d) for glutamate and glutamine was large: 1.13 and 1.36, respectively. Using discriminant analysis with logistic regression, the two values of plasma glutamate and glutamine were shown to well-differentiate the HFA group from the control group; the rate of correct classification was 91%. Conclusions/Significance The present study suggests that plasma glutamate and glutamine levels can serve as a diagnostic tool for the early detection of autism, especially normal IQ autism. These findings indicate that glutamatergic abnormalities in the brain may be associated with the pathobiology of autism.

We measured the mRNA levels of apolipoprotein E receptor type 2 (ApoER2) and very low-density lipoprotein receptor (VLDLR) in peripheral blood lymphocytes from 43 patients with major depressive disorder (27 drug-free patients and 16 medicated patients) and 43 age-matched healthy controls using a quantitative real-time RT-PCR method. The correlations between mRNA levels of both receptors and clinical variables in patients were also examined. The expression of ApoER2 mRNA, but not VLDLR, was significantly lower in patients as compared to controls, irrespective of the medication status. There was no statistically significant correlation between the reduction of ApoER2 mRNA levels and any of the clinical variables measured in patients. Results from this preliminary study suggest that the expression of ApoER2 may serve as a trait marker for major depressive disorder.

The prevalence of postpartum depression (PPD) in the general population has been reported to be 10% to 15% worldwide. However, the relevance of age of the parturients to the emergence of PPD has not been well documented. To address this, we estimated the age-specific 3-month cumulative incidence of PPD using the Hamamatsu Birth Cohort for Mothers and Children (HBC).Women with PPD were defined as those scoring 9 points or higher using the Edinburgh Postnatal Depression Scale 3 months after childbirth.Among 675 participating parturients, 100 women were found to have PPD; the cumulative incidence of PPD over the 3 months after childbirth was 14.8%. The age-specific estimates were 20.8% for25 years, 14.2% for 25 to 29 years, 11.5% for 30 to 34 years, and 17.9% for ≥ 35 years. In the logistic regression analysis, the increased OR for having PPD among parturients aged ≥ 35 years was 1.7, which remained significant after controlling for age of partner, parity, and household income.Although the sample was representative, the sample size was modest.The cumulative incidence of PPD was significantly different across age groups, with the highest estimates in the advanced age band. The heightened estimate was not accounted for by the age of the partner, parity, or annual household income.

Amyloid β protein (Aβ) is known as a pathological substance in Alzheimer's disease (AD) and is assumed to coexist with a degree of activated microglia in the brain. However, it remains unclear whether these two events occur in parallel with characteristic hypometabolism in AD in vivo. The purpose of the present study was to clarify the in vivo relationship between Aβ accumulation and neuroinflammation in those specific brain regions in early AD.Eleven nootropic drug-naïve AD patients underwent a series of positron emission tomography (PET) measurements with [(11)C](R)PK11195, [(11)C]PIB and [(18)F]FDG and a battery of cognitive tests within the same day. The binding potentials (BPs) of [(11)C](R)PK11195 were directly compared with those of [(11)C]PIB in the brain regions with reduced glucose metabolism.BPs of [(11)C](R)PK11195 and [(11)C]PIB were significantly higher in the parietotemporal regions of AD patients than in ten healthy controls. In AD patients, there was a negative correlation between dementia score and [(11)C](R)PK11195 BPs, but not [(11)C]PIB, in the limbic, precuneus and prefrontal regions. Direct comparisons showed a significant negative correlation between [(11)C](R)PK11195 and [(11)C]PIB BPs in the posterior cingulate cortex (PCC) (p 0.05, corrected) that manifested the most severe reduction in [(18)F]FDG uptake.A lack of coupling between microglial activation and amyloid deposits may indicate that Aβ accumulation shown by [(11)C]PIB is not always the primary cause of microglial activation, but rather the negative correlation present in the PCC suggests that microglia can show higher activation during the production of Aβ in early AD.

The FXYD domain-containing ion transport regulator 6 (FXYD6) gene encodes phosphohippolin that regulates cellular ion transport by altering the kinetic properties of Na,K-ATPase. Phosphohippolin is highly expressed in brain regions that are relevant to schizophrenia. The FXYD6 gene is located at chromosome 11q22–24, one of the most established linkage regions for schizophrenia. Therefore, it may be possible that genetic variants in FXYD6, including the regulatory genomic elements could cause abnormal function or expression of phosphohippolin and increase the genetic risk for schizophrenia. A previous study suggested that polymorphisms in FXYD6 are associated with schizophrenia in UK samples. However, conflicting results have been reported in the Japanese population. In this study, we aimed to test the prior genetic association findings using different samples from the ethnically homogeneous Japanese population (1,060 schizophrenic patients and 1,060 age- and sex-matched controls). From the FXYD6 gene, we examined six single nucleotide polymorphisms (rs11216573, rs555577, rs1815774, rs4938445, rs4938446, and rs497768), all of which were previously analyzed for association. We did not detect any significant allelic, genotypic or haplotypic association in our Japanese samples. Meta-analysis incorporating previous and the present studies also showed that the FXYD6 gene is not associated with schizophrenia. We conclude that the FXYD6 gene does not have a major influence on susceptibility to schizophrenia across populations. © 2010 Wiley-Liss, Inc.

金沢大学医薬保健研究域医学系, The neurobiological basis of autism spectrum disorder (ASD) remains poorly understood. Given the role of CD38 in social recognition through oxytocin (OT) release, we hypothesized that CD38 may play a role in the etiology of ASD. Here, we first examined the immunohistochemical expression of CD38 in the hypothalamus of post-mortem brains of non-ASD subjects and found that CD38 was colocalized with OT in secretory neurons. In studies of the association between CD38 and autism, we analyzed 10 single nucleotide polymorphisms (SNPs) and mutations of CD38 by re-sequencing DNAs mainly from a case-control study in Japan, and Caucasian cases mainly recruited to the Autism Genetic Resource Exchange (AGRE). The SNPs of CD38, rs6449197 (p< 0.040) and rs3796863 (p< 0.005) showed significant associations with a subset of ASD (IQ > 70; designated as high-functioning autism (HFA)) in the U.S. 104 AGRE family trios, but not with Japanese 188 HFA subjects. A mutation that caused tryptophan to replace arginine at amino acid residue 140 (R140W; (rs1800561, 4693C>T)) was found in 0.6-4.6% of the Japanese population and was associated with ASD in the smaller case-control study. The SNP was clustered in pedigrees in which the fathers and brothers of T-allele-carrier probands had ASD or ASD traits. In this cohort OT plasma levels were lower in subjects with the T allele than in those without. One proband with the T allele who was taking nasal OT spray showed relief of symptoms. The two variant CD38 poloymorphysms tested may be of interest with regard of the pathophysiology of ASD. © 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society.

The neurobiological basis for autism remains poorly understood. We hypothesized that adipokines, such as adiponectin, may play a role in the pathophysiology of autism. In this study, we examined whether serum levels of adiponectin are altered in subjects with autism. We measured serum levels of adiponectin in male subjects with autism (n=31) and age-matched healthy male subjects (n=31). The serum levels of adiponectin in the subjects with autism were significantly lower than that of normal control subjects. The serum adiponectin levels in the subjects with autism were negatively correlated with their domain A scores in the Autism Diagnostic Interview-Revised, which reflects their impairments in social interaction. This study suggests that decreased levels of serum adiponectin might be implicated in the pathophysiology of autism.