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Previous cross-sectional studies have reported that adolescent patients with anorexia nervosa (AN) showed global gray matter volume (GMV) reductions at the acute phase which were restored at the weight-recovered phase, compared with healthy controls (HC). However, few studies have investigated white matter volume (WMV) or cortical thickness in the context of AN, and results have been inconsistent. Voxel-based morphometry analyses for GM and WM, and cortical thickness analyses for GM were conducted in 31 adolescent patients with AN (vs. 18 HC) in the acute phase, and 16 patients with AN (vs. 13 HC) in the follow-up weight-recovered phase, over an approximately 1-year follow-up interval. At the acute phase, the AN patients showed significant reductions of GMVs and cortical thickness in widespread brain regions, compared with HC. Significant WMV reductions were identified in the bilateral superior longitudinal fascicle, superior thalamic radiation, corona radiata, and fornix, pons, and medulla in the patients. At the weight-recovered phase, the AN patients showed a significant GMV reduction in the left hippocampus, and a WMV reduction in the pons, compared with the HC. There was no difference in cortical thickness between two groups at the weight-recovered phase. In conclusion, the widespread volumetric reductions in GM and WM, and reduced cortical thickness observed in AN patients in the acute phase were not evident in the follow-up weight-recovered phase. The volume reductions observed in the hippocampus and pons in the weight-recovered phase could potentially reflect delayed neurogenesis or recovery from starvation in the AN patients.

Significance There are no biomarkers for schizophrenia (SCZ), a disorder of dysfunctional neural networks. We demonstrate that a master regulator of cytoskeleton (“CRMP2”) and, hence, neural circuitry, may form the basis for such a biomarker because its activity is uniquely imbalanced in SCZ patients. We show that SCZ patients are characterized by an excess of active CRMP2 not only in their brains (where it is correlated with dendritic abnormalities) but also in their peripheral blood lymphocytes. The abundance of active CRMP2 and insufficiency of opposing inactive p-CRMP2 likely disrupts neuronal function. Because peripheral blood CRMP2 appears to reflect intracerebral processes, it could form the basis of a rapid, minimally invasive, sensitive, and specific clinical diagnostic aid for SCZ in young patients., There are no validated biomarkers for schizophrenia (SCZ), a disorder linked to neural network dysfunction. We demonstrate that collapsin response mediator protein-2 (CRMP2), a master regulator of cytoskeleton and, hence, neural circuitry, may form the basis for a biomarker because its activity is uniquely imbalanced in SCZ patients. CRMP2’s activity depends upon its phosphorylation state. While an equilibrium between inactive (phosphorylated) and active (nonphosphorylated) CRMP2 is present in unaffected individuals, we show that SCZ patients are characterized by excess active CRMP2. We examined CRMP2 levels first in postmortem brains (correlated with neuronal morphometrics) and then, because CRMP2 is expressed in lymphocytes as well, in the peripheral blood of SCZ patients versus age-matched unaffected controls. In the brains and, more starkly, in the lymphocytes of SCZ patients

Background: Self-poisoning is commonly observed in individuals as a component of suicide attempts and self-harm. The effectiveness of interventions for self-poisoning is unclear. The objective of this study was to examine the effectiveness of assertive case management intervention in preventing suicidal behaviour in self-poisoning patients.Methods: We conducted a secondary analysis of data from the ACTION-J study. Participants were self-poisoning patients with clear suicidal intent who were admitted to emergency departments and who had a primary psychiatric diagnosis (as per DSM-IV-TR axis 1). Patients were randomly assigned either to assertive case management (intervention group) or enhanced usual care (control group). The primary outcome measure was the incidence of a first recurrent suicidal attempt within 6 months after group assignment.Results: There were 297 self-poisoning patients in the intervention group and 295 in the control group. The primary outcome was significantly lower in the intervention group than in the control group (risk ratio [RR]: 0.473, 95% confidence interval [CI]: 0.284 to 0.788). The incidence of a first recurrent suicidal attempt within 1 and 3 months after group assignment was also significantly lower in the intervention group, as was the number of overall self-harm episodes over the entire study period (incidence rate ratio [IRR]: 0.711, 95% CI: 0.582 to 0.866). Furthermore, the number of non-suicidal self-harm episodes and suicide attempts was significantly lower in the intervention group than in the control group.Conclusion: Assertive case management is effective when promptly introduced in a hospital setting as an intervention following a suicide attempt, particularly for self-poisoning patients.Trial Registration: This study is registered at ClinicalTrials.gov (NCT00736918) and UMIN-CTR (C000000444).

The hippocampus is thought to play an important role in conveying contextual information to the amygdala as the neural basis of panic disorder (PD). Previous studies have revealed functional abnormalities in the hippocampus in patients with PD compared with healthy control subjects (HC), but no study has reported volume abnormalities in the hippocampus or evaluated minute structural changes in the hippocampus in such patients. We thus investigated volume abnormalities in the subfields of the hippocampus to better understand the neurobiological basis of PD. The hippocampus was extracted from structural brain magnetic resonance images obtained from 38 patients with PD and 38 HC and then segmented into six subfields. The relative volume of each subfield was compared between the two groups. The severity of symptoms was assessed using the Panic Disorder Severity Scale (PDSS) and social functioning was assessed using the Global Assessment of Functioning (GAF) scale. Our results revealed that patients with PD had a significantly smaller volume of the right cornu ammonis (CA) 2/3 hippocampal subfield compared with HC. No significant associations were found between the volumes of the right CA 2/3 and the PDSS or GAF scores in correlation analyses. In conclusion, CA2/3 is thought to be related to contextual memory function, and our results suggest that this particular hippocampal subfield plays a role in the development of PD symptoms.

Hopelessness may be associated with an increased risk of suicide. However, findings regarding the long-term predictive ability of the Beck Hopelessness Scale (BHS) for suicide are inconsistent. This study investigated the long-term predictive ability of BHS scores for subsequent self-harm episodes in individuals admitted to an emergency department after attempting suicide.The BHS was administered to 805 adult patients with a DSM-IV-TR axis I disorder admitted to an emergency department following a suicide attempt. The patients were followed for at least 18 months and up to 5 years. The incidence of the first subsequent suicidal behavior (attempt or dying by suicide) was examined and the numbers per person-year of overall repeat self-harm episodes, suicide attempt episodes, and non-suicidal self-harm episodes were evaluated.The total BHS scores showed significant associations with the overall number of self-harm episodes per person-year (incidence rate ratio [IRR], 1.05; 95% confidence interval [CI], 1.03-1.07; p0.0001), the number of suicide attempt episodes per person-year (IRR, 1.05; 95%CI, 1.03-1.08; p0.0001), and the number of non-suicidal self-harm episodes per person-year (IRR, 1.05; 95%CI, 1.03-1.07; p0.0001).The study excluded children and adolescents. The sample size, while large, was insufficient to ensure generalizability, or to allow subanalyses based on specific disorders.Hopelessness scores assessed in the emergency department after a self-harming episode were associated with a rate of repetition of suicidal behaviors after discharge. Additional strategies to address hopelessness of these patients are warranted.

Background Patients with schizophrenia have a higher mortality risk than the general population. Additionally, the autonomic nervous system (ANS) activity of patients with schizophrenia is lower and more dysfunctional than that of the general population. Nonetheless, the association between ANS dysfunction and mortality in schizophrenia is unclear. The aim of this study was to investigate the association between ANS activity and mortality in schizophrenia and to evaluate the predictive values of heart rate variability for long-term survival. Methods This study involves the 10-year follow-up of a sample population consisting of 59 Japanese inpatients with schizophrenia between 60 and 70 years of age from 2007 to 2016. The ANS activity of all patients was evaluated using heart rate variability in 2007. Results Fifty-three participants could be followed up because they stayed in the hospital during the follow-up period. Of these patients, 11 died during follow-up. Their mean age at death was 70.55 ± 3.45 years. The parasympathetic activity of nonsurvivors was significantly lower than that of survivors, and multiple logistic regression analysis showed a significant association between death and parasympathetic activity. Conclusion We suggest that decreased parasympathetic activity could be associated with 10-year all-cause mortality in older schizophrenic patients.

Background There are interindividual differences in the adverse effects of atypical antipsychotics, which include autonomic nervous system (ANS) dysfunction. Accordingly, to clarify the interindividual differences in the adverse effects of specific atypical antipsychotics in schizophrenia, we investigated the association between ANS dysfunction and ATP-binding cassette transport sub-family B member 1 (ABCB1) gene polymorphisms in patients with schizophrenia. Methods In total, 233 Japanese patients with schizophrenia participated in this study. All of the participants received an atypical antipsychotic as monotherapy: 89 participants received risperidone, 69 olanzapine, 48 aripiprazole, and 27 quetiapine. ANS activity was assessed by means of a power spectral analysis of heart rate variability. Four single nucleotide polymorphisms (SNPs) in ABCB1 (rs1045642, rs1128503, rs2032582, and rs2235048) were genotyped using the TaqMan method. Results For aripiprazole, sympathetic and total autonomic nervous activities were significantly lower in the rs1045642 T allele carrier–rs2235048 C allele carrier group than in the rs1045642 non-T allele carrier–rs2235048 non-C allele carrier group. In addition, in the aripiprazole group, the T-C-T-A haplotype (rs1045642-rs2235048-rs1128503-rs2032582) was associated with decreased ANS activity. However, there were no significant associations between ANS activity and ABCB1 gene polymorphisms in the risperidone, olanzapine, and quetiapine groups. Multiple regression analysis revealed that sympathetic and total nervous activities were significantly associated with the ABCB1 rs1045642–rs2235048 genotype and the T-C-T-A haplotype (rs1045642-rs2235048-rs1128503-rs2032582). Conclusion We suggest that ABCB1 genetic polymorphisms affect aripiprazole-related ANS dysfunction but do not affect risperidone-, olanzapine-, or quetiapine-related ANS dysfunction.

Antipsychotic drugs are associated with autonomic nervous system (ANS) dysfunction in patients with schizophrenia, but the effects of individual atypical antipsychotic drugs are not clear. This study investigated how four atypical antipsychotic drugs-risperidone, olanzapine, aripiprazole, and quetiapine-differ in their effects on ANS activity. A total of 241 Japanese patients with schizophrenia participated in this study. All of the participants received an atypical antipsychotic as monotherapy: 90 participants received risperidone, 68 olanzapine, 52 aripiprazole, and 31 quetiapine. ANS activity was assessed by means of a power spectral analysis of heart rate variability. The quetiapine group showed significantly diminished sympathetic and parasympathetic activity compared with the risperidone and aripiprazole groups and significantly lower sympathetic activity relative to olanzapine. In addition, multiple regression analysis showed that the type of antipsychotic drug significantly influenced ANS activity. We suggest that, among the antipsychotics examined-risperidone, olanzapine, aripiprazole and quetiapine-quetiapine has the strongest effect on ANS activity.

The aim of this study was to examine the effectiveness of assertive case management intervention in preventing suicidal behaviour in self-poisoning patients. We conducted a secondary analysis of data from the ACTION-J study. Participants were self-poisoning patients with clear suicide intent admitted to emergency departments and with a primary psychiatric diagnosis (as per DSM-IV-TR axis 1). Patients were randomly assigned either to assertive case management or enhanced usual care. The primary outcome measure was the incidence of a first recurrent suicide attempt within 6 months. This study is registered at ClinicalTrials.gov (NCT00736918) and UMIN-CTR (C000000444). There were 297 self-poisoning patients in the intervention group and 295 in the control group. The primary outcome was significantly lower in the intervention group than in the control group. The incidence of a first recurrent suicide attempt within 1 and 3 months was also significantly lower in the intervention group, as was the number of overall self-harm episodes over the entire study period. Furthermore, the number of non-suicidal self-harm episodes and suicide attempts was significantly lower in the intervention group. Assertive case management is effective when promptly introduced in a hospital setting as an intervention following a suicide attempt, particularly for self-poisoning patients.

Objectives Depression is frequently observed in patients with systemic lupus erythematosus (SLE). Neuropsychiatric SLE (NPSLE) patients often exhibit cerebral hypometabolism, but the association between cerebral metabolism and depression remains unclear. To elucidate the features of cerebral metabolism in SLE patients with depression, we performed brain 18F-fluoro- d -glucose positron emission tomography (FDG-PET) on SLE patients with and without major depressive disorder. Methods We performed brain FDG-PET on 20 SLE subjects (5 male, 15 female). The subjects were divided into two groups: subjects with major depressive disorder (DSLE) and subjects without major depressive disorder (non-DSLE). Cerebral glucose metabolism was analyzed using the three-dimensional stereotactic surface projection (3D-SSP) program. Regional metabolism was evaluated by stereotactic extraction estimation (SEE), in which the whole brain was divided into segments. Results Every SLE subject exhibited cerebral hypometabolism, in contrast to the normal healthy subjects. Regional analysis revealed a significantly lower ER in the left medial frontal gyrus (p = 0.0055) and the right medial frontal gyrus (p = 0.0022) in the DSLE group than in the non-DSLE group. Conclusion Hypometabolism in the medial frontal gyrus may be related to major depressive disorder in SLE. Larger studies are needed to clarify this relationship.

AIM Repetitive transcranial magnetic stimulation (rTMS) has been applied as a treatment for patients with treatment-resistant depression in recent years, and a large body of evidence has demonstrated its therapeutic efficacy through stimulating neuronal plasticity. The aim of this study was to investigate structural alterations in the hippocampus (HIPP) and amygdala (AM) following conventional rTMS in patients with depression. METHODS Twenty-eight patients with depression underwent 10 daily 20-Hz left prefrontal rTMS over 2 weeks. The left dorsolateral prefrontal cortex (DLPFC) was identified using magnetic resonance imaging (MRI)-guided neuronavigation prior to stimulation. MRI scans were obtained at baseline and after the completion of rTMS sessions. The therapeutic effects of rTMS were evaluated with the 17-item Hamilton Depression Rating Scale (HAM-D17), and the volumes of the HIPP and AM were measured by a manual tracing method. RESULTS Statistical analyses revealed a significant volume increase in the left HIPP (+3.4%) after rTMS but no significant volume change in the AM. No correlation was found between the left HIPP volume increase and clinical improvement, as measured by the HAM-D17. CONCLUSION The present study demonstrated that conventional left prefrontal rTMS increases the HIPP volume in the stimulated side, indicating a remote neuroplastic effect through the cingulum bundle.

Background To analyze voxel-wise correlation between cerebral blood flow (CBF) measured using ASL-MRI and cognition in patients with Alzheimer’s disease (AD). Methods Forty-one patients diagnosed with AD or mild cognitive impairment due to AD were recruited for this study. CBF images were obtained using ASL-MRI (n = 41) with a post-labeling delay (PLD) of 1.5 and 2.5 s (PLD1.5 and PLD2.5, respectively) using a 3 T scanner, in addition to brain perfusion SPECT with N-isopropyl-4-[I-123]iodoamphetamine (n = 28). Voxel-based analyses were performed for ASL-MRI and SPECT using Mini-Mental State Examination (MMSE) scores as covariates. Differences in CBF between PLD1.5 and PLD2.5 were assessed using a paired t-test with SPM12. Results Significant positive correlations were observed between MMSE scores and CBF at PLD1.5 in the right posterior cingulate cortex (PCC), and both temporo-parietal association cortexes. At PLD2.5, significant positive correlations were determined for MMSE scores and CBF in the superior parietal lobule and the right temporo-parietal association cortex. SPECT showed significant positive correlations in the PCC and both temporo-parietal association cortexes (right-side dominant). PLD1.5 showed significantly higher CBF than PLD2.5 in the proximal areas of vascular territories of the anterior, middle, and posterior cerebral arteries. Conclusions Significant positive correlations in CBF, measured with both ASL-MRI and SPECT, with cognition were found in the PCC and temporo-parietal association cortexes. PLD1.5 and PLD2.5 showed similar correlations with cognition, although the CBF images had significant differences.

Suicide is one of the common severe accidents occurring in hospitals. This study aimed to investigate inpatient suicides simultaneously in medical and psychiatric settings in a large number of hospitals and to examine the prevalence of common suicide risk factors, related symptoms in inpatients who had died by suicide and the differences in inpatient suicides between both settings. We conducted a survey of hospitals in Japan that belonged to the nationwide standard-setting and accrediting body. The questionnaire covered the: 1) presence or absence of inpatient suicides in each hospital from 2012 to 2015; 2) number of inpatient suicides; 3) method, location, and timing of inpatient suicides; and 4) characteristics of inpatients who died by suicide. In total, 529 hospitals reported 262 inpatient suicides during the 3-year period: 131 were in medical settings and 131 were in psychiatric settings. The prevalence of common suicide risk factors was frequent in inpatient suicides. Inpatients had characteristics and suicide risk factors specific to those settings such as worsening of physical health in medical settings. Therefore, recognizing common suicide risk factors and understanding differences in inpatient suicides between both settings are important to prevent inpatient suicides.

Background : Although the pathogenesis of panic attacks has been well studied in patients with panic disorder (PD), the neurobiological basis of the long-term fear memories and avoidance behavior that are often observed in PD have not been well investigated. Recent animal studies have suggested that nucleus accumbens (NAcc) plays an important role in neurobiological basis of long-term fear memories and avoidance behavior. Methods : Thirty-eight patients with PD and 38 matched healthy control subjects (HC) participated in this study. Differences in relative volumes and shape deformations of NAcc were evaluated between groups. Correlation analyses were conducted to quantify the association between structural abnormalities in the NAcc and trait, state anxiety measured by the State-Trait Anxiety Inventory (STAI). Results : Significant volume reductions were observed in the bilateral NAcc in the patients with PD, relative to the HC. In terms of shape differences, the PD patients demonstrated significant inward deformation of the NAcc bilaterally, compared to the HC. Degree of shape deformation in the right NAcc was associated with higher scores of the STAI-Trait, and STAI-State measures in the PD patients. Limitations : All the patients received medication such as Psychotropic drug. Conclusion : Patients with PD showed reduced volumes in the NAcc, especially in lateral regions, compared with HC. Furthermore, shape deformation in the right NAcc was associated with trait anxiety and state anxiety, which has been associated with avoidance behavior.

Background People with depression have autonomic function disturbances. In Japan, workers who take leave due to depression often undergo a work-focused intervention program called the return to work (RTW) program at a mental health hospital during their leave of absence. However, its biological efficacy remains unclear. We investigated the biological efficacy of the RTW program, including changes in autonomic nervous system (ANS) activity, in workers on sick leave due to depression in Japan. Methods The study involved 104 workers on sick leave due to major depressive disorder or bipolar disorder who underwent the RTW program for 3 months in Yokohama City University Hospital. The ANS activity of all patients was evaluated using heart rate variability at the beginning and end of the 3-month RTW program. Psychiatric symptoms were evaluated using the Montgomery-Asberg Depression Rating Scale-Japanese (MADRS-J) and Social Adaptation Self-evaluation Scale (SASS). We followed up 3 months after the end of the program and investigated the association between the success in returning to work within 3 months after the end of the RTW program and several factors, including ANS activity, depressive symptoms, and demographic factors. Results Parasympathetic activity was significantly higher and depressive symptom severity was significantly lower at program end than at baseline. Logistic regression analysis showed that the change in depressive symptoms was significantly associated with success in returning to work. Conclusion We suggest that the RTW program improves parasympathetic activity as well as psychiatric symptoms. ANS activity was not a predictor of a successful return to work within 3 months after the end of the program in workers on sick leave due to depression, but further studies with a larger sample size are needed.

OBJECTIVE The aim of the present study was to perform a subgroup analysis of data from a phase II global, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of bitopertin, a glycine reuptake inhibitor that activates N-methyl-D-aspartate receptors by increasing the concentration of glycine in the synaptic cleft, in Japanese and non-Japanese patients with schizophrenia and predominant negative symptoms. METHODS Patients with schizophrenia and predominant negative symptoms on one or two antipsychotic drugs, including atypical antipsychotic drugs (olanzapine, risperidone, quetiapine, aripiprazole, and paliperidone) as the primary treatment, received bitopertin (10, 30, or 60 mg/day) or placebo once daily for 8 weeks as an add-on treatment. Efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS) negative symptom factor score (NSFS). RESULTS The efficacy of bitopertin (10 mg and 30 mg) was similar between Japanese and non-Japanese patients. In the bitopertin 60-mg group, no difference from the placebo group was observed in Japanese or non-Japanese patients. The response to placebo was lower in Japanese patients, and there was a trend towards a greater difference in the change in PANSS NSFS between the placebo group and the 10-mg and 30-mg groups among Japanese patients. The safety profile of bitopertin was favorable in Japanese and non-Japanese patients. CONCLUSION According to this subgroup analysis from a global phase II study of bitopertin, there was no difference in terms of efficacy and safety between Japanese and non-Japanese patients.

Aim To determine characteristics of MCI that can predict whether patients will go on to develop AD or DLB. Methods Ninety-three patients diagnosed with MCI underwent neuropsychological and neuroimaging examinations, and were followed-up for a mean of 44.9±19.3months. They were divided into four MCI subtypes (amnestic/non-amnestic MCI, single/multiple domain) according to neuropsychological findings, and into three other MCI categories (AD-type PET, DLB-type PET, and unknown-type PET) based on 18 F-fluorodeoxyglucose PET findings. Patients who were eventually diagnosed with AD, DLB, other dementia, or remained MCI were analyzed in relation to the groups to which they had initially been allocated at the MCI stage. Results Clinical diagnosis after follow-up determined AD in 21 patients (22.6%), DLB in 12 patients (12.9%), other dementia in 2 patients (2.2%), and non-converter in 58 patients (62.3%). Amnestic single-domain MCI and AD-type PET tended to convert into AD. Amnestic multiple-domain MCI and DLB-type PET tended to convert into DLB. A few patients with AD-type PET later developed DLB, and some with DLB-type PET later developed AD. Conclusions Predicting which type of dementia a person with MCI will later develop might be possible based on early assessment with clinical symptoms in conjunction with neuropsychological and 18 F-fluorodeoxyglucose PET findings.

The accumulation of α-synuclein (ASyn) has been observed in several lysosomal storage diseases (LSDs) but it remains unclear if ASyn accumulation contributes to LSD pathology. ASyn also accumulates in the neurons of Sandhoff disease (SD) patients and SD model mice (Hexb-/- ASyn+/+ mice). SD is a lysosomal storage disorder caused by the absence of a functional β-subunit on the β-hexosaminidase A and B enzymes, which leads to the accumulation of ganglioside in the central nervous system. Here, we explored the role of accumulated ASyn in the progression of Hexb-/- mice by creating a Hexb-/- ASyn-/- double-knockout mice. Our results show that Hexb-/- ASyn-/- mice demonstrated active microglia levels and less dopaminergic neuron loss, without altering the neuronal storage of ganglioside. The autophagy and ubiquitin proteasome pathways are defective in the neurons of Hexb-/- ASyn+/+ mice. In ultrastructural physiological studies, the mitochondria structures look degenerated and dysfunctional. As a result, expression of manganese superoxide dismutase 2 are reduced, and reactive oxygen species-mediated oxidative damage in the neurons of Hexb-/- ASyn+/+ mice. Interestingly, these dysfunctions improved in Hexb-/- ASyn-/- mice. But any clinical improvement were hardly observed in Hexb-/- ASyn-/- mice. Taken together, these findings suggest that ASyn accumulation plays an important role in the pathogenesis of neuropathy in SD and other LSDs, and is therefore a target for novel therapies.

Aim Numerous reports have described differences in the distribution of orbitofrontal cortex (OFC) sulcogyral patterns between patients with schizophrenia (SZ patients) and healthy controls (HC). Alterations in OFC morphology are also observed in those at high risk for developing SZ and in first-episode SZ, suggesting that genetic associations may be extant in determining OFC sulcogyral patterns. We investigated the association between single nucleotide polymorphisms (SNP) in NRG1 and OFC sulcogyral patterns. Methods A total of 59 Japanese patients diagnosed with SZ and 60 HC were scanned on a 1.5-T magnet. Patients were also assessed clinically. OFC sulcogyral patterns were evaluated for each participant, and genotyping was performed for four SNP in NRG1 ( SNP8NRG243177 , SNP8NRG221533 , SNP8NRG241930 , and rs1081062 ). Results There were significant differences in the distribution of OFC sulcogyral patterns between SZ patients and HC (χ2 = 6.52, P = 0.038). SZ patients showed an increase in the frequency of Type III expression, which was associated with an earlier age of disease onset (β = −0.302, F = 4.948, P = 0.030). Although no difference was found in genotype frequencies between SZ patients and HC, an NRG1 SNP, SNP8NRG243177, was associated with Type II expression in SZ patients (β = 0.237, F = 4.120, P = 0.047). Conclusion Our results suggest that OFC sulcogyral pattern formation in schizophrenia may be associated with NRG1 allele frequency, which is closely related to neurodevelopment.

Both (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and (123)I-iodoamphetamine (IMP) single-photon emission computed tomography (SPECT) have been used for the differential diagnosis of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Less information is available, however, regarding the differential diagnosis of mild cognitive impairment (MCI) due to AD and MCI due to DLB. We examined nine AD patients (AD group), nine DLB patients (DLB group), eight MCI due to AD patients (MCI-AD group), and nine MCI due to DLB patients (MCI-DLB group) with FDG PET and IMP SPECT using a well-characterized normal database and a stereotactic extraction estimation method. In the AD and DLB groups, receiver operating characteristic (ROC) analysis in the occipital regions showed significant accuracy of both FDG PET and IMP SPECT for the differential diagnosis. In the MCI-AD and MCI-DLB groups, ROC analysis showed significant accuracy of only FDG PET for the differential diagnosis. Both FDG PET and IMP SPECT would be useful for the differential diagnosis between AD and DLB. For the differential diagnosis of MCI-AD versus MCI-DLB, FDG PET would be more useful than IMP SPECT.

Akira Suda,1 Saki Hattori,1 Ikuko Kishida,1,2 Masatoshi Miyauchi,1 Yohko Shiraishi,1 Mami Fujibayashi,3 Natsuki Tsujita,4 Chie Ishii,2 Norio Ishii,2 Toshio Moritani,5 Yoshio Hirayasu1,6 1Department of Psychiatry, Yokohama City University School of Medicine, Yokohama, 2Department of Psychiatry, Fujisawa Hospital, Kanagawa, 3Division of Physical and Health Education, Setsunan University, Osaka, 4Graduate School of Human and Environmental Studies, Kyoto University, 5Department of Health and Sports Sociology, Faculty of General Education, Kyoto Sangyo University, Kyoto, 6Department of Psychiatry, Hirayasu Hospital, Okinawa, Japan Objective: Long-acting injections (LAIs) of antipsychotics show distinct pharmacokinetic profiles from oral antipsychotics (OAPs). Although there may be differences in adverse event frequency, any differences in their effects on autonomic nervous system (ANS) remain unclear. Patients and methods: In total, 270 schizophrenic patients were recruited in this study: 241 received OAPs (risperidone, olanzapine, quetiapine, or aripiprazole) and 29 received LAIs (risperidone LAI, aripiprazole LAI, or paliperidone palmitate) as monotherapy. Heart rate variability was measured as an index of ANS activity, and the low-frequency (0.03–0.15Hz) component, high-frequency (0.15–0.40Hz) component, and total power (0.03–0.40Hz) were calculated. Components were compared between the groups using t-tests. Results: A significant difference was detected in the low-frequency component between the OAP and LAI groups (P=0.046). No significant difference was found in total power or the high-frequency component between the two groups. Conclusion: Compared with OAPs, LAIs have fewer adverse effects on ANS activity, particularly the low-frequency component, as determined using a spectral analysis of heart rate variability. Keywords: long-acting injectable antipsychotics, autonomic nervous system, heart rate variability, adverse effect

The amygdala plays an important functional role in fear and anxiety. Abnormalities in the amygdala are believed to be involved in the neurobiological basis of panic disorder (PD). Previous structural neuroimaging studies have found global volumetric and morphological abnormalities in the amygdala in patients with PD. Very few studies, however, have explored for structural abnormalities in various amygdala sub-regions, which consist of various sub-nuclei, each with different functions. This study aimed to evaluate for volumetric abnormalities in the amygdala sub-nuclei, in order to provide a better understanding neurobiological basis of PD. Thirty-eight patients with PD and 38 matched healthy control (HC) participants underwent structural MRI scanning. The volume of the whole amygdala, as well as its consistent sub-nuclei, were calculated using FreeSurfer software. Relative volumes of these amygdala sub-regions were compared between the two groups. Results showed significantly smaller volumes in the right lateral and basal nuclei in the patients with PD compared with the HC. Lateral and basal nuclei are thought to play crucial role for processing sensory information related with anxiety and fear. Our results suggest that these particular amygdala sub-regions play a role in the development of PD symptoms.

Aims In this study, we implemented the Illness Management and Recovery (IMR) program for middle-aged and older patients with schizophrenia hospitalized for long periods and assessed the effect of the IMR program on psychiatric symptoms and psychosocial function. The effects of the IMR program on brain structure were also evaluated. Methods The IMR program was implemented for 19 patients with schizophrenia; 17 patients with schizophrenia receiving treatment as usual (TAU) were also recruited as controls. In all patients, mean age was 61.4 years (range, 50-77 years) and mean hospitalization duration was 13.1 years (range, 1-31 years) at enrollment. Structural magnetic resonance images and Positive and Negative Syndrome Scale (PANSS) and Global Assessment of Functioning (GAF) scores as clinical variables were obtained at the beginning and end of the IMR program. Longitudinal analyses were performed to compare the effects of the IMR program on clinical symptoms and cortical thickness in the superior temporal gyrus (STG) between the IMR and TAU groups. Results Significant improvements in GAF scores and the total, Insight and Judgment, and Positive components of the PANSS were found in the IMR group compared with the TAU group. Cortical thickness in the left STG was preserved in the IMR group compared with the TAU group. Conclusions This is the first report demonstrating the effectiveness of the IMR program for improving psychotic symptoms and psychosocial function and protecting brain structure in middle-aged and older inpatients with schizophrenia hospitalized for long periods.

Background: Patients with schizophrenia have abnormal autonomic nervous system (ANS) activity compared with the general population. One reason for this difference is the muscarinic affinity for antipsychotic drugs; therefore, single nucleotide polymorphisms (SNPs) of the muscarinic receptor gene influence this ANS dysfunction. This study sought to determine the effect of SNPs of the cholinergic muscarinic receptor (CHRM) gene on ANS activity in patients with schizophrenia receiving antipsychotic drugs. Methods: A total of 173 Japanese patients with schizophrenia were included in this study. Heart rate variability (HRV) was measured as an index of ANS activity. SNPs in CHRM1 (rs542269 and rs2075748), CHRM2 (rs324640, rs8191992, rs1824024, and rs7810473), and CHRM3 (rs3738435, rs4620530, and rs6429157) were genotyped using the TaqMan® method. Patients were grouped according to standard equivalent conversions of chlorpromazine (CP) into a high-CP group (HG; ≥1,000 mg) and a low-CP group (LG; p value was Results: The A allele of the CHRM2 rs8191992 polymorphism in HG was associated with decreased ANS activity. Conclusion: Our results show reduced ANS activity in association with the CHRM2 rs8191992 polymorphism in patients with schizophrenia on high-dose antipsychotics. CHRM2 polymorphisms may play an important role in ANS activity in patients with schizophrenia.

Background and Aim Major depressive disorder (MDD) is an important public health problem, and it is often comorbid with many chronic diseases. The purpose of this study was to identify the clinical features of non-alcoholic fatty liver disease (NAFLD) patients comorbid with MDD and to investigate the influence of MDD on the effect of treatment in patients with NAFLD. Methods A total of 258 patients with biopsy-proven NAFLD were included. MDD was diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision. The patients were followed up for 48 weeks under standard care for NAFLD, which consisted mainly of lifestyle modification. Results There were 32 patients comorbid with MDD. They were characterized by more severe histological steatosis and higher NAFLD activity score, and also significantly higher levels of serum aminotransferase, γ-glutamyl transpeptidase and ferritin, than age-and-sex-matched NAFLD patients without MDD. Moreover, NAFLD patients with MDD showed poor response to the standard care for NAFLD, in body weight loss and in other parameters. Particularly, NAFLD patients with unstable MDD (not in full/partial remission) showed severe resistance to the treatment. Conclusion This is the first study to demonstrate the clinical features and response to therapy of NAFLD patients comorbid with MDD. The comorbid state of MDD was associated with more severe histological liver steatosis and worse treatment outcomes in patients with NAFLD. Further investigations are required to develop new lifestyle modification programs that enable NAFLD patients with MDD to achieve the treatment goal.

Background Panic disorder (PD), an anxiety disorder characterized by the recurrence of panic attacks, has been reported to be associated with volumetric changes in several brain regions. There are, however, very few studies investigating abnormalities in cortical thickness, and little is known about the relationship between cortical thickness and social dysfunction in PD. Methods Thirty-eight patients with PD and 38 healthy control participants (HC) were recruited for this study. A whole-brain analysis was performed to evaluate groupwise differences in cortical thickness using the FreeSurfer software. Symptom severity and social functioning were evaluated with the Panic Disorder Severity Scale (PDSS) and the Global Assessment of Functioning (GAF) scale. Results The patients with PD demonstrated a significant reduction in cortical thickness in the left rostral middle frontal cortex (MFC), compared with the HC. Correlational analyses revealed that cortical thickness in the left rostral MFC showed a significant negative relationship with PDSS score and a significant positive relationship with GAF scores in the PD patients. Limitations All the patients received medication. Conclusion PD patients showed reduced cortical thickness in the left rostral MFC compared with HC. Furthermore, cortical thickness in this region was associated with patients’ symptom severity and degree of social dysfunction.

The thalamus is believed to play crucial role in processing viscero-sensory information, and regulating the activity of amygdala in patients with panic disorder (PD). Previous functional neuroimaging studies have detected abnormal activation in the thalamus in patients with PD compared with healthy control subjects (HC). Very few studies, however, have investigated for volumetric abnormalities in the thalamus in patients with PD. Furthermore, to the best of our knowledge, no previous study has investigated for shape abnormalities in the thalamus in patients with PD. Twenty-five patients with PD and 25 HC participants (all female) were recruited for the study. A voxel-wise volume comparison analysis and a vertex-wise shape analysis were conducted to evaluate structural abnormalities in the PD patients compared to HC. The patients with PD demonstrated significant gray matter volume reductions in the thalamus bilaterally, relative to the HC. The shape analysis detected significant inward deformation in some thalamic regions in the PD patients, including the anterior nucleus, mediodorsal nucleus, and pulvinar nucleus. PD patients showed shape deformations in key thalamic regions that are believed to play a role in regulating emotional and cognitive functions.

Received June 3, 2013; revised June 26, 2013; accepted June 27, 2013. From Department of Psychiatry, Yokohama City University School of Medicine, Yokohama, Japan (YC, OK, HF, AK, TS, TI, YH); Department of Pediatrics, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan (YT); Department of Neurology, Yokohama City University School of Medicine, Yokohama, Japan (MK); Department of Internal Medicine and Clinical Immunology, Yokohama City University School of Medicine, Yokohama, Japan (MT). Send correspondence and reprint requests toOmiKatsuse,M.D., Ph.D.,Department of Psychiatry, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; e-mail: oxm08@yahoo.co.jp & 2015 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved. Introduction

We examined whether abnormal volumes of several brain regions as well as their mutual associations that have been observed in patients with schizophrenia, are also present in individuals at clinical high-risk (CHR) for developing psychosis. 3T magnetic resonance imaging was acquired in 19 CHR and 20 age- and handedness-matched controls. Volumes were measured for the body and temporal horns of the lateral ventricles, hippocampus and amygdala as well as total brain, cortical gray matter, white matter, and subcortical gray matter volumes. Relationships between volumes as well as correlations between volumes and cognitive and clinical measures were explored. Ratios of lateral ventricular volume to total brain volume and temporal horn volume to total brain volume were calculated. Volumetric abnormalities were lateralized to the left hemisphere. Volumes of the left temporal horn, and marginally, of the body of the left lateral ventricle were larger, while left amygdala but not hippocampal volume was significantly smaller in CHR participants compared to controls. Total brain volume was also significantly smaller and the ratio of the temporal horn/total brain volume was significantly higher in CHR than in controls. White matter volume correlated positively with higher verbal fluency score while temporal horn volume correlated positively with a greater number of perseverative errors. Together with the finding of larger temporal horns and smaller amygdala volumes in the left hemisphere, these results indicate that the ratio of lateral ventricle the ratio of temporal horns volume to brain volume is abnormal in CHR compared to controls. These abnormalities present in CHR individuals may constitute the biological basis for at least some of the CHR syndrome.

BACKGROUND AND PURPOSE: Arterial spin-labeling MR imaging has been recently developed as a noninvasive technique with magnetically labeled arterial blood water as an endogenous contrast medium for the evaluation of CBF. Our aim was to compare arterial spin-labeling MR imaging and SPECT in the visual assessment of CBF in patients with Alzheimer disease. MATERIALS AND METHODS: In 33 patients with Alzheimer disease or mild cognitive impairment due to Alzheimer disease, CBF images were obtained by using both arterial spin-labeling–MR imaging with a postlabeling delay of 1.5 seconds and 2.5 seconds (PLD(1.5) and PLD(2.5), respectively) and brain perfusion SPECT. Twenty-two brain regions were visually assessed, and the diagnostic confidence of Alzheimer disease was recorded. RESULTS: Among all arterial spin-labeling images, 84.9% of PLD(1.5) and 9% of PLD(2.5) images showed the typical pattern of advanced Alzheimer disease (ie, decreased CBF in the bilateral parietal, temporal, and frontal lobes). PLD(1.5), PLD(2.5), and SPECT imaging resulted in obviously different visual assessments. PLD(1.5) showed a broad decrease in CBF, which could have been due to an early perfusion. In contrast, PLD(2.5) did not appear to be influenced by an early perfusion but showed fewer pathologic findings than SPECT. CONCLUSIONS: The distinctions observed by us should be carefully considered in the visual assessments of Alzheimer disease. Further studies are required to define the patterns of change in arterial spin-labeling–MR imaging associated with Alzheimer disease.

The feasibility of shared decision making (SDM) for patients with schizophrenia remains controversial due to the assumed inability of patients to cooperate in treatment decision making. This study evaluated the feasibility and efficacy of SDM in patients upon first admission for schizophrenia. This was a randomized, parallel-group, two-arm, open-label, single-center study conducted in an acute psychiatric ward of Numazu Chuo Hospital, Japan. Patients with the diagnosis of schizophrenia upon their first admission were randomized into a SDM intervention group or a usual treatment group in a 1:1 ratio. The primary outcome was patient satisfaction at discharge. The secondary outcomes were attitudes toward medication at discharge and treatment continuation at 6 months after discharge. Twenty-four patients were randomly assigned. The trial was prematurely terminated due to slow enrollment. At discharge, the mean score on satisfaction was 23.7 in the SDM group and 22.1 in the usual care group (unadjusted mean difference: 1.6; 95% CI: −5.2 to 2.0). Group differences were not observed in attitude toward medication and treatment continuation. There was no statistically significant difference between the groups for the mean Global Assessment of Functioning score at discharge or length of stay as safety endpoint. No statistical differences were found between the SDM group and usual care group in the efficacy outcomes and safety endpoints. Large trials are needed to confirm the efficacy of the SDM program upon first admission for schizophrenia. The study has been registered with ClinicalTrials.gov as NCT01869660 (registered 27 May, 2013).

The patient was a 72-year-old Japanese woman. At the age of 57, she started having difficulty performing daily work and developed agraphia. She also exhibited restlessness and loss of interest, and began to speak less. Thereafter, stereotypical behavior, gait disturbance and dysphagia were noted. CT scan demonstrated left-dominant frontal and temporal lobe atrophy. She died at the age of 72, about 16 years after the onset of symptoms. Neuropathologically, the brain weighed 867 g, and showed remarkable cerebral atrophy with degeneration of the white matter, predominantly in the left dorsal frontal lobe and anterior temporal lobe. Microscopically, severe neuronal loss and gliosis with rarefaction were found in the cerebral cortex, and severe destruction of myelin and axons was observed in the cerebral white matter. Moderate neuronal loss with gliosis was also found in the pallidum and substantia nigra. Gallyas-Braak staining and tau immunostaining revealed pretangle neurons, NFTs, ballooned neurons and astrocytic plaques in the cerebral cortex, subcortical nuclei and brainstem, and argyrophilic threads and coiled bodies in the subcortical white matter. Tau isoform-specific immunostaining revealed that most tau-immunoreactive structures were positive for 4-repeat (4R) tau, but some of the NFTs were positive for 3-repeat (3R) tau in the cerebral neocortex. Immunoblotting demonstrated an accumulation of 4R tau in the cerebral cortex and subcortical white matter. The patient was pathologically diagnosed as having corticobasal degeneration. Her long survival course likely accounts for the severe white matter degeneration and accumulation of 3R tau in NFTs.

Summary Background Non-fatal suicide attempt is the most important risk factor for later suicide. Emergency department visits for attempted suicide are increasingly recognised as opportunities for intervention. However, no strong evidence exists that any intervention is effective at preventing repeated suicide attempts. We aimed to investigate whether assertive case management can reduce repetition of suicide attempts in people with mental health problems who had attempted suicide and were admitted to emergency departments. Methods In this multicentre, randomised controlled trial in 17 hospital emergency departments in Japan, we randomly assigned people aged 20 years and older with mental health problems who had attempted suicide to receive either assertive case management (based on psychiatric diagnoses, social risks, and needs of the patients) or enhanced usual care (control), using an internet-based randomisation system. Interventions were provided until the end of the follow-up period (ie, at least 18 months and up to 5 years). Outcome assessors were masked to group allocation, but patients and case managers who provided the interventions were not. The primary outcome was the incidence of first recurrent suicidal behaviour (attempted suicide or completed suicide); secondary outcomes included completed suicide and all-cause mortality. This study is registered at ClinicalTrials.gov (NCT00736918) and UMIN-CTR (C000000444). Findings Between July 1, 2006, and Dec 31, 2009, 914 eligible participants were randomly assigned, 460 to the assertive case management group and 456 to the enhanced usual care group. We noted no significant difference in incidence of first recurrent suicidal behaviour between the assertive case management group and the enhanced usual care group over the full study period (log-rank p=0·258). Because the proportional hazards assumption did not hold, we did ad-hoc analyses for cumulative incidence of the primary outcome at months 1, 3, 6, 12, and 18 after randomisation, adjusting for multiplicity with the Bonferroni method. Assertive case management significantly reduced the incidence of first recurrent suicidal behaviour up to the 6-month timepoint (6-month risk ratio 0·50, 95% CI 0·32–0·80; p=0·003), but not at the later timepoints. Prespecified subgroup analyses showed that the intervention had a greater effect in women (up to 18 months), and in participants younger than 40 years and those with a history of previous suicide attempts (up to 6 months). We did not identify any differences between the intervention and control groups for completed suicide (27 [6%] of 460 vs 30 [7%] of 454, log-rank p=0·660) or all-cause mortality (46 [10%] of 460 vs 42 [9%] of 454, log-rank p=0·698). Interpretation Our results suggest that assertive case management is feasible in real-world clinical settings. Although it was not effective at reducing the incidence of repetition of suicide attempts in the long term, the results of our ad-hoc analyses suggested that it was effective for up to 6 months. This finding should be investigated in future research. Funding The Ministry of Health, Labour, and Welfare of Japan.

Objectives It is well known that Alzheimer's disease (AD)-type pathology is commonly present in dementia with Lewy bodies (DLB) brains and that the degree of AD-type pathology has an influence on the clinical characteristics of DLB. Although significant hypometabolism in the temporoparietal/precuneus on [18F]fluoro-d-glucose (18F-FDG) positron emission tomography (PET) scans is considered to support a diagnosis of AD, some DLB patients also exhibit this metabolic pattern. The clinical significance of the metabolic pattern on DLB remains unknown. Methods Twenty-three DLB patients, 10 AD patients, and 11 controls underwent 18F-FDG PET scans. According to the degree of hypometabolism in the parietal/precuneus regions, representing the AD-like metabolic pattern, 12 patients were placed in the DLB-AD(+) group and 11 patients were placed in the DLB-AD(−) group. The demographics and clinical variables were compared among the four groups. Results In addition to the parietal/precuneus regions, the DLB-AD(+) group exhibited significantly greater posterior cingulate hypometabolism than the DLB-AD(−) group, although occipital metabolism did not differ. The prevalence of visual hallucinations and extracampine hallucinations, and the Bender–Gestalt test score were significantly higher in the DLB-AD(+) group than the DLB-AD(−) group, although there were no differences in the demographics and other examined clinical variables between the two DLB groups. These clinical differences were absent in the DLB-AD(−) group, AD group, and controls. Conclusions Parietal/precuneus hypometabolism may be associated with clinical characteristics in DLB patients. Further multiple imaging modalities that are sensitive to AD-type pathology are needed to reveal the neurobiological basis of the AD-like metabolic pattern. Copyright © 2014 John Wiley & Sons, Ltd.

We report here an autopsy case of concurrent Huntington's disease (HD) and neurofibromatosis type 1 (NF1), also known as von Recklinghausen's disease. The patient was a Japanese woman with a significant hereditary burden: seven of her family members within four generations were affected by either NF1 or concurrent HD and NF1. She was diagnosed as having NF1 at age 24. At age 40, she showed signs of irritability, aggressive and childish behaviour, which became progressively worse. At age 48, rigidity and spastic gait were observed. One year later, choreoathetoid involuntary movements became apparent. Diagnosis of HD was made by identification of the abnormally expanded cytosine-adenine-guanine repeats in the Huntington's disease gene. Her condition deteriorated gradually to an apallic state and she died at age 60. Post-mortem examination revealed extensive brain atrophy, which was particularly severe in the frontal and temporal cortices and the striatum. The degree of neurodegenerative change seemed to correspond to grade IV. Polyglutamine positive inclusions were seen frequently in all layers of the cerebral cortex and in the amygdala and hippocampus. Inclusions were also present in the striatum, but there were fewer than in the cortex. Remarkably, neuronal intranuclear inclusions were present in the cerebellum, although they are usually not seen in HD. Features associated with the central nervous system involvement of NF1 were not found in the brain, but HD pathology might have been accelerated by the concurrence of NF1. This is the third report of a case with concurrent HD and NF1 in the world, and the first study in which occurrence of polyglutamine inclusions was confirmed on post-mortem examination.