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Background Cognitive impairment is common in people with mental disorders, leading to transdiagnostic classification based on cognitive characteristics. However, few studies have used this approach for intellectual abilities and functional outcomes. Aims The present study aimed to classify people with mental disorders based on intellectual abilities and functional outcomes in a data-driven manner. Method Seven hundred and forty-nine patients diagnosed with schizophrenia, bipolar disorder, major depression disorder or autism spectrum disorder and 1030 healthy control subjects were recruited from facilities in various regions of Japan. Two independent k-means cluster analyses were performed. First, intelligence variables (current estimated IQ, premorbid IQ, and IQ discrepancy) were included. Second, number of work hours per week was included instead of premorbid IQ. Results Four clusters were identified in the two analyses. These clusters were specifically characterised in terms of IQ discrepancy in the first cluster analysis, whereas the work variable was the most salient feature in the second cluster analysis. Distributions of clinical diagnoses in the two cluster analyses showed that all diagnoses were unevenly represented across the clusters. Conclusions Intellectual abilities and work outcomes are effective classifiers in transdiagnostic approaches. The results of our study also suggest the importance of diagnosis-specific strategies to support functional recovery in people with mental disorders.

Higher cortisol levels due to a hyperactive hypothalamic–pituitary–adrenal axis have been reported in patients with major depressive disorder (MDD). Increased cortisol levels change both the brain morphology and function in MDD patients. The multivariate source-based morphometry (SBM) technique has been applied to investigate neuroanatomical changes in some neuropsychiatric diseases, but not MDD. We aimed to examine the alterations in gray matter (GM) networks and their relationship with serum cortisol levels in first-episode, drug-naïve MDD patients using SBM. Forty-two patients with MDD and 39 controls were recruited via interviews. Morning serum cortisol levels were measured, and high-resolution T1-weighted imaging followed by SBM analysis was performed in all participants. The patients had significantly higher serum cortisol levels than the controls. We found two GM sources, which were significantly different between patients with MDD and controls (prefrontal network, p

BackgroundThe present study aimed to determine whether the number of hospitalizations in schizophrenia patients is associated with reduced cognitive performance, which may in turn imply that recurrences indirectly lead to a worsening in the disorder’s progression.MethodsCognitive performance in stable schizophrenia patients was assessed using the Brief Assessment of Cognition in Schizophrenia, Japanese-language version, on 30 patients who had not experienced any hospitalizations (G0), 57 patients who had experienced only one hospitalization (G1), 47 patients with two hospitalizations (G2), and 59 patients with three or more hospitalizations (G3).ResultsSignificant differences in motor function and attention and processing speed were found between patients with G0 and those with G1. Significant differences in working memory and verbal fluency were found between patients with G1 and those with G2. Patients with G3 performed even more poorly in comparison with those with G1, showing deficits in verbal memory, working memory, executive function, and composite score. The patients with G3 displayed a greater range of impairment and demonstrated deficits in executive function compared with patients with G2. Finally, G2 and G3 performed more poorly than G0, with deficits in the various cognitive areas.ConclusionThe number of hospitalizations predicted cognitive performance, which suggests that relapse or recurrence may have a long-term neuropsychological impact. Prospective follow-up studies must be completed to explore this effect further because better treatment adherence may have a protective effect on neurocognitive function.

Objectives The aim of this study was to develop a consensus guideline by certified experts of the Japanese Society of Clinical Neuropsychopharmacology on the psychopharmacological treatment for bipolar disorders I and II (BP‐I and BP‐II), in order to fill the gap in the literature and provide more concrete guidance for challenging and controversial real‐world situations. Methods Experts were asked to assess treatment options regarding 19 clinical situations of bipolar disorder with a nine‐point Likert scale (one = “disagree” and nine = “agree”). According to the responses from 119 experts, the options were categorized into the first‐, second‐, and third‐line treatments. Results For the treatment of BP‐I, lithium monotherapy was categorized as a first‐line treatment for manic episodes (mean ± standard deviation score, 7.0 ± 2.2), depressive episodes (7.1 ± 2.0), and the maintenance phase (7.8 ± 1.8). Combination therapy of lithium and an atypical antipsychotic was endorsed for manic episodes (7.7 ± 1.7), depressive episodes with (7.1 ± 2.0) and without mixed features (6.9 ± 2.2), and the maintenance phase (6.9 ± 2.1). Similarly, in BP‐II, lithium monotherapy was categorized as a first‐line treatment for hypomanic episodes (7.3 ± 2.2), depressive episodes (7.0 ± 2.2), and the maintenance phase (7.3 ± 2.3), while combination therapy of lithium and an atypical antipsychotic was recommended for hypomanic episodes (6.9 ± 2.4).No antipsychotic monotherapy or antidepressant treatment was categorized as a first‐line treatment for any type of episode. Conclusions These recommendations reflect the current evidence and represent the experts' consensus on using lithium for the treatment of bipolar disorder. Clinicians should consider the effectiveness and adverse effects of antipsychotic and antidepressant medications for the treatment of bipolar disorder.

The response to antidepressants varies significantly among individuals and is difficult to predict before treatment. In this randomised control trial, we explored cytokines that correlate with the therapeutic effect of mirtazapine (MIR) and selective serotonin reuptake inhibitors (SSRIs) and whether they could be predictors of remission for each antidepressant. Plasma cytokines, such as tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were assayed in 95 participants before medication and assayed by the enzyme-linked immunosorbent assay. The Hamilton Rating Scale for Depression assessed depressive symptoms over 4 weeks. In the SSRI group, the baseline GM-CSF level was significantly higher in the remission group than in the non-remission group (p = .022). In the MIR group, the baseline level of TNF-α was significantly higher (p = .039) and IL-2 was lower (p = .032) in the remission group than in the non-remission group. In patients prescribed with MIR, the cut-off values of TNF-α (10.035 pg/mL) and IL-2 (1.170 pg/mL) calculated from the receiver operating characteristic curve suggested that the remission rate, which corresponds to a positive predictive value, could be increased from 31.3% to 60.0% and 50.0%, respectively. For those prescribed with SSRIs, the remission rate was 37.0% and using the cut-off value of GM-CSF (0.205 pg/mL), the remission rate could be almost doubled to 70%. Our study shows that pre-treatment plasma concentrations of TNF-α, IL-2, and GM-CSF may suggest the predictability of remission by SSRIs or MIR.

Objective Recently, a genome-wide association study successfully identified genetic variants associated with major depressive disorder (MDD). The study identified 17 independent single-nucleotide polymorphisms (SNPs) significantly associated with diagnosis of MDD. These SNPs were predicted to be enriched in genes that are expressed in the central nervous system and function in transcriptional regulation associated with neurodevelopment. The study aimed to investigate associations between 17 SNPs and brain morphometry using magnetic resonance imaging (MRI) in drug-naive patients with MDD and healthy controls (HCs). Methods Forty-seven patients with MDD and 42 HCs were included. All participants underwent T1-weighted structural MRI and genotyping. The genotype–diagnosis interactions associated with regional cortical thicknesses were evaluated using voxel-based morphometry for the 17 SNPs. Results Regarding rs301806, an SNP in the RERE genomic regions, we found a significant difference in a genotype effect in the right-lateral orbitofrontal and postcentral lobes between diagnosis groups. After testing every possible diagnostic comparison, the genotype–diagnosis interaction in these areas revealed that the cortical thickness reductions in the MDD group relative to those in the HC group were significantly larger in T/T individuals than in C-carrier ones. For the other SNPs, no brain area was noted where a genotype effect significantly differed between the two groups. Conclusions We found that a RERE gene SNP was associated with cortical thickness reductions in the right-lateral orbitofrontal and postcentral lobes in drug-naive patients with MDD. The effects of RERE gene polymorphism and gene–environment interactions may exist in brain structures of patients with MDD.

Purpose: Compared with healthy subjects (HS), patients with major depressive disorder (MDD) exhibit volume differences that affect the volume changes in several areas such as the limbic, cortical, subcortical, and white matter. Catechol-O-methyltransferase (COMT) is a methylation enzyme that catalyzes endogenous catecholamines. The Val158Met polymorphism of COMT has been reported to affect the dopamine (DA) levels, which plays an important role in psychiatric diseases. However, the relationships among both DA levels, COMT genotype, and brain morphology are complicated and controversial. In previous studies that investigated the hippocampal subfields, the greatest brain abnormalities in MDD patients were observed in Cornu Ammonis (CA)1 and the subiculum, followed by that in CA2-3. We have prospectively demonstrated the relationship between the single-nucleotide polymorphism of the Val158Met COMT gene (rs4680) and the hippocampal subfields in drug-naive MDD patients. Patients and methods: In this study, we compared 27 MDD patients and 42 HS who were divided into groups based on their COMT genotype. The effects of the diagnosis, genotype, and genotype-diagnosis interaction related to CA1 and the subiculum volumes, as well as the whole-brain cortical thickness, were evaluated by performing a FreeSurfer statistical analysis of high-resolution magnetic resonance imaging (MRI) findings. Results: The results revealed that there was a statistically significant interaction between the effects of diagnosis and genotype on the right subiculum (a component of the hippocampus). Conclusion: This Val158Met COMT polymorphism may influence the subiculum volume in drug-naive, first-episode MDD patients.

Introduction Conventional treatment guidelines of schizophrenia do not necessarily provide solutions on clinically important issues. Methods A total of 141 certified psychiatrists of the Japanese Society of Clinical Neuropsychopharmacology evaluated treatment options regarding 19 clinically relevant situations in the treatment of schizophrenia with a 9-point scale (1=“disagree” and 9=“agree”). Results First-line antipsychotics varied depending on predominant symptoms: risperidone (mean±standard deviation score, 7.9±1.4), olanzapine (7.5±1.6), and aripiprazole (6.9±1.9) were more likely selected for positive symptoms; aripiprazole (7.6±1.6) for negative symptoms; aripiprazole (7.3±1.9), olanzapine (7.2±1.9), and quetiapine (6.9±1.9) for depression and anxiety; and olanzapine (7.9±1.5) and risperidone (7.5±1.5) for excitement and aggression. While only aripiprazole was categorized as a first-line treatment for relapse prevention (7.6±1.0) in patients without noticeable symptoms, aripiprazole (8.0±1.6) and brexpiprazole (6.9±2.3) were categorized as such for social integration. First-line treatments in patients who are vulnerable to extrapyramidal symptoms include quetiapine (7.5±2.0) and aripiprazole (6.9±2.1). Discussion These clinical recommendations represent the expert consensus on the use of a particular antipsychotic medication for a particular situation, filling a current gap in the literature.

Understanding the neural correlates of the neurotic brain is important because neuroticism is a risk factor for the development of psychopathology. We examined the correlation between brain structural networks and neuroticism based on NEO Five-Factor Inventory (NEO-FFI) scores. Fifty-one healthy participants (female, n = 18; male, n = 33; mean age, 38.5 ± 11.7 years) underwent the NEO-FFI test and magnetic resonance imaging (MRI), including diffusion tensor imaging and 3D T1WI. Using MRI data, for each participant, we constructed whole-brain interregional connectivity matrices by deterministic tractography and calculated the graph theoretical network measures, including the characteristic path length, global clustering coefficient, small-worldness, and betweenness centrality (BET) in 83 brain regions from the Desikan-Killiany atlas with subcortical segmentation using FreeSurfer. In relation to the BET, neuroticism score had a negative correlation in the left isthmus cingulate cortex, left superior parietal, left superior temporal, right caudal middle frontal, and right entorhinal cortices, and a positive correlation in the bilateral frontal pole, left caudal anterior cingulate cortex, and left fusiform gyrus. No other measurements showed significant correlations. Our results imply that the brain regions related to neuroticism exist in various regions, and that the neuroticism trait is likely formed as a result of interactions among these regions. This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) from the Ministry of Education, Science, Sports and Culture of Japan.

Introduction We conducted an updated systematic review and meta-analysis of randomized controlled trials (RCTs) comparing blonanserin with other antipsychotics (amisulpride, aripiprazole, haloperidol, paliperidone, and risperidone). Methods Weighted mean difference (WMD), risk ratio, and number needed to harm (NNH) with 95% confidence intervals (95% CIs) were calculated using random-effects model. Results Ten RCTs (n=1521) were included in this study. Blonanserin was superior to aripiprazole in improvement of Positive and Negative Syndrome Scale total scores (WMD=−10.62, 95% CI=−17.67 to −3.560, p=0.003). Blonanserin was associated with a higher incidence of all-cause discontinuation (RR=1.373, 95% CI=1.088–1.734, p=0.008, NNH=11), akathisia, extrapyramidal disorder, and agitation/excitement and a lower risk of hyperprolactinemia compared with risperidone + paliperidone. Discussion The current meta-analytic study did not update the comparison of blonanserin vs. haloperidol because there were no new RCTs. Our results suggest that the efficacy of blonanserin for schizophrenia is comparable with that of other antipsychotics, and blonanserin seems to be well tolerated.

Background The effect of duration of illness and antipsychotic medication on the volumes of subcortical structures in schizophrenia is inconsistent among previous reports. We implemented a large sample analysis utilizing clinical data from 11 institutions in a previous meta-analysis. Methods Imaging and clinical data of 778 schizophrenia subjects were taken from a prospective meta-analysis conducted by the COCORO consortium in Japan. The effect of duration of illness and daily dose and type of antipsychotics were assessed using the linear mixed effect model where the volumes of subcortical structures computed by FreeSurfer were used as a dependent variable and age, sex, duration of illness, daily dose of antipsychotics and intracranial volume were used as independent variables, and the type of protocol was incorporated as a random effect for intercept. The statistical significance of fixed-effect of dependent variable was assessed. Results Daily dose of antipsychotics was positively associated with left globus pallidus volume and negatively associated with right hippocampus. It was also positively associated with laterality index of globus pallidus. Duration of illness was positively associated with bilateral globus pallidus volumes. Type of antipsychotics did not have any effect on the subcortical volumes. Discussion A large sample size, uniform data collection methodology and robust statistical analysis are strengths of the current study. This result suggests that we need special attention to discuss about relationship between subcortical regional brain volumes and pathophysiology of schizophrenia because regional brain volumes may be affected by antipsychotic medication., Graphical abstract Image 2, Highlights • The imaging data as well as prescription data and demographics from 778 patients with schizophrenia from 11 institutions were included. • The effect of protocol was cooperated as random-effect in the linear mixed-effect model. • Significant positive association were found between daily dose of antipsychotics and left globus pallidus volume. • Significant negative association was found between daily dose of antipsychotics and right hippocampus volume. • Significant positive associations were found between duration of illness and bilateral volumes of globus pallidus.

Individuals with s/s genotype of serotonin transporter gene-linked promotor region (5-HTTLPR), which appear with a high frequency in Japanese, exhibit more diagnosable depression in relation to stressful life events than those with the s/l or l/l genotype. We prospectively investigated the brain volume changes in first-episode and medication naïve major depression disorder patients (MDD) with the s/s genotype in Japanese. We assessed the differences between 27 MDD with the s/s genotype and 44 healthy subjects (HS) with the same genotype using a whole-brain voxel-by-voxel statistical analysis of MRI. Gray matter volume in a brain region with significant clusters obtained via voxel-based morphometry analysis were measured and, as an exploratory analysis, evaluated for relationships to the subcategory scores (core, sleep, activity, psychic, somatic anxiety, delusion) of the Hamilton Depression Rating Scale (HAM-D) and the Social Readjustment Rating Scale (SRRS). The brain volume in the left insula lobe was significantly smaller in the MDD than in the HS. The left insula lobe volume correlated negatively with the “psychic” score of HAM-D and the SRRS. In a Japanese population with the s/s genotype, we found an atrophy of the insula in the MDD, which might be associated with “psychic” symptom and stress events.

Although the effects of atypical antipsychotics with regard to improving neurocognitive function are not sufficiently high. The present study applied an atypical antipsychotic monotherapy for patients with acute schizophrenia to (1) examine the percentage of patients who respond well to this treatment, (2) explore the factors that predict response (e.g. the improvement of neurocognition), and (3) identify the factors associated with improved neurocognitive function. We studied 40 patients with acute schizophrenia who had received atypical antipsychotic monotherapy for 24 weeks. The following parameters were evaluated at baseline and 24 weeks after the start of treatment: psychotic symptoms, neurocognitive function, and blood biological markers including homovanillic acid, 3-methoxy-4-hydroxyphenylglycol, and brain-derived neurotrophic factor. Marked improvements in neurocognitive function were noted in 7.5%-25% of patients. The factors that significantly predicted neurocognitive function improvement were the frequency of hospitalization (verbal memory and verbal fluency), 3-methoxy-4-hydroxyphenylglycol (verbal fluency and executive function), and verbal memory (working memory). Approximately 20% of the patients showed good response to treatment with antipsychotics. Frequency of hospitalization, 3-methoxy-4-hydroxyphenylglycol level, and other parameters predicted responsiveness to these drug therapies. Thus, it might be useful to apply these factors to predict responses to treatment.

Background : Clinically relevant issues in the real-world treatment of depression have not always been captured by conventional treatment guidelines. Methods : Certified psychiatrists of the Japanese Society of Clinical Neuropsychopharmacology were asked to evaluate treatment options regarding 23 clinical situations in the treatment of depression using a 9-point Likert scale (1=“disagree” and 9=“agree”). According to the responses of 114 experts, the options were categorized into first-, second-, and third-line treatments. Results : First-line antidepressants varied depending on predominant symptoms: escitalopram (mean ± standard deviation score, 7.8±1.7) and sertraline (7.3±1.7) were likely selected for anxiety; duloxetine (7.6±1.9) and venlafaxine (7.2±2.1) for loss of interest; mirtazapine for insomnia (8.2±1.6), loss of appetite (7.9±1.9), agitation and severe irritation (7.4±2.0), and suicidal ideation (7.5±1.9). While first-line treatment was switched to either an SNRI (7.7±1.9) or mirtazapine (7.4±2.0) in the case of non-response to an SSRI, switching to mirtazapine (7.1±2.2) was recommended in the case of non-response to an SNRI, and vice versa (switching to an SNRI (7.0±2.0) in the case of non-response to mirtazapine). Augmentation with aripiprazole was considered the first-line treatment for partial response to an SSRI (7.1±2.3) or SNRI (7.0±2.5). Limitations : The evidence level of expert consensus is considered low. All included experts were Japanese. Conclusions : Recommendations made by experts in the field are useful and can supplement guidelines and informed decision making in real-world clinical practice. We suggest that pharmacological strategies for depression be flexible and that each patient's situational needs as well as the pharmacotherapeutic profile of medications be considered.

We aimed to evaluate the convergent validity and responsiveness of the work functioning impairment scale (WFun) in patients with depression, a major disease causing presenteeism.Baseline testing was performed using WFun, the Quick Inventory of Depressive Symptomatology (QIDS), 17-item Hamilton Depression Rating Scale (HAM-D), and Montgomery-Asberg Depression Rating Scale (MADRS) in 37 outpatients with major depression or bipolar disorder who were working. The QIDS and WFun scores were measured several times for responsiveness evaluation.Regression analyses showed significant positive correlations between baseline WFun and HAM-D and MADRS scores. Changes in WFun and QIDS scores were positively correlated for QIDS scores.Our results suggest that WFun is convergently valid and responsive for determining the clinical severity of depression in workers treated as psychiatric outpatients.

Objective Recently, a genome-wide association study successfully identified genetic variants associated with major depressive disorder (MDD). The study identified 17 independent single-nucleotide polymorphisms (SNPs) significantly associated with diagnosis of MDD. These SNPs were predicted to be enriched in genes that are expressed in the central nervous system and function in transcriptional regulation associated with neurodevelopment. The study aimed to investigate associations between 17 SNPs and brain morphometry using magnetic resonance imaging (MRI) in drug-naïve patients with MDD and healthy controls (HCs). Methods Forty-seven patients with MDD and 42 HCs were included. All participants underwent T1-weighted structural MRI and genotyping. The genotype–diagnosis interactions associated with regional cortical thicknesses were evaluated using voxel-based morphometry for the 17 SNPs. Results Regarding rs301806, an SNP in the RERE genomic regions, we found a significant difference in a genotype effect in the right-lateral orbitofrontal and postcentral lobes between diagnosis groups. After testing every possible diagnostic comparison, the genotype–diagnosis interaction in these areas revealed that the cortical thickness reductions in the MDD group relative to those in the HC group were significantly larger in T/T individuals than in C-carrier ones. For the other SNPs, no brain area was noted where a genotype effect significantly differed between the two groups. Conclusions We found that a RERE gene SNP was associated with cortical thickness reductions in the right-lateral orbitofrontal and postcentral lobes in drug-naïve patients with MDD. The effects of RERE gene polymorphism and gene–environment interactions may exist in brain structures of patients with MDD.

The Specific Levels of Functioning Scale (SLOF) has been reported to provide a measure of social function in patients with schizophrenia. The aim of this multi-center study was to determine convergent validity of the Japanese version of SLOF, and if cognitive insight would be associated with social function. Fifty-eight patients with schizophrenia participated in the study. Social function, neurocognition, and daily activity skills were evaluated by the Social Functioning Scale (SFS), Brief Assessment of Cognition in Schizophrenia (BACS) and UCSD Performance-based Skills Assessment-Brief (UPSA-B), respectively. We also assessed cognitive insight with the Beck Cognitive Insight Scale (BCIS). Significant relationships were noted between scores on the SLOF vs. those of the SFS, BACS, UPSA-B, and BCIS. Specifically, the correlation between performance on the UPSA-B and SLOF scores was significantly more robust compared to the correlation between performance on the UPSA-B and scores on the SFS. Similarly, the correlation between scores on the BACS and SLOF tended to be more robust than that between the BACS and SFS. Importantly, while the correlation between scores on the BCIS and SLOF reached significance, it was not so between scores on the BCIS and SFS. The SLOF Japanese version was found to provide a measure of social consequences in patients with schizophrenia. Importantly, this study is the first to indicate the relationship between cognitive insight and social function evaluated by the SLOF. This finding is consistent with the observation that SLOF scores were considerably associated with performances on objective functional measures.

Catecholamines, brain-derived neurotrophic factor (BDNF) and cytokines may be involved in the pathophysiology of schizophrenia. The aim of this study was to examine the associations between serum BDNF levels, plasma catecholamine metablolites, cytokines and the cognitive functions of patients with schizophrenia treated with atypical antipsychotic monotherapy.One hundred and forty-six patients with schizophrenia and 51 age- and sex-matched healthy controls were examined for peripheral biological markers and neurocognitive test.There were positive correlations between serum BDNF levels and scores for verbal memory and attention and processing speed as well as between serum BDNF levels and negative symptoms. Furthermore, there was a negative correlation between the plasma homovanillic acid (HVA) level and motor function and a positive correlation between the plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) level and attention and processing speed. There were no significant correlations between interleukin-6 or tumour necrosis factor alpha and cognitive function. Moreover, there were no significant correlations between the plasma levels of HVA, MHPG, cytokines and clinical symptoms.Serum BDNF levels are positively related to the impairment of verbal memory and attention, plasma HVA levels are positively related to motor function, and plasma MHPG levels are positively related to attention in patients with schizophrenia.

BackgroundHigher daytime cortisol levels because of a hyperactive hypothalamic–pituitary–adrenal axis have been reported in patients with major depressive disorder (MDD). The elevated glucocorticoids inhibit the proliferation of the oligodendrocytes that are responsible for myelinating the axons of white matter fibre tracts.AimsTo evaluate the relationship between white matter integrity and serum cortisol levels during a first depressive episode in drug-naive patients with MDD (MDD group) using a tract-based spatial statistics (TBSS) method.MethodThe MDD group (n= 29) and a healthy control group (n= 47) underwent diffusion tensor imaging (DTI) scans and an analysis was conducted using TBSS. Morning blood samples were obtained from both groups for cortisol measurement.ResultsCompared with the controls, the MDD group had significantly reduced fractional anisotropy values (PPConclusionsOur findings indicate that the elevated cortisol levels in the MDD group may injure the white matter integrity in the frontal–subcortical and frontal–limbic circuits.

Meige syndrome is a relatively rare type of oral facial dystonia. The dominant symptoms involve involuntary eye blinking and chin thrusting. Some patients may experience excessive tongue protrusion, squinting, muddled speech, or uncontrollable contraction of the platysma muscle. A 44-year-old Japanese male was suffering from schizophrenia. The initial presentation of his psychosis consisted of auditory hallucinations, delusions of persecution, psychomotor excitement, loosening association, and restlessness. After being prescribed several antipsychotic drugs, risperidone was started and gradually increased to 4 mg/day. The above symptoms were relieved, particularly auditory hallucination and excitement were promptly improved. Persecutory delusion, however persisted, and deteriorated. At one year after the start of this risperidone regimen, he exhibited severe blepharospasm symptoms (increased rate of eye blinking, light sensitivity) and oromandibular symptoms (trismus, jaw pain, dysarthria). He was diagnosed with Meige syndrome. His antipsychotic drug was changed from risperidone to paliperidone. Two months after switching from risperidone to paliperidone, his eye blinking, light sensitivity, jaw pain, and trismus gradually improved, although the dysarthria persisted. Six months after starting paliperidone, his symptoms of Meige syndrome were completely remitted. He has been well without relapse at 12 mg/day of paliperidone. The case suggests that Meige syndrome is relieved by changing from risperidone to paliperidone. The precise mechanism of the relief remains, however, unknown.

Background Although structural correlation network (SCN) analysis is an approach to evaluate brain networks, the neurobiological interpretation of SCNs is still problematic. Brain-derived neurotrophic factor (BDNF) is well-established as a representative protein related to neuronal differentiation, maturation, and survival. Since a valine-to-methionine substitution at codon 66 of the BDNF gene (BDNF Val66Met single nucleotide polymorphism (SNP)) is well-known to have effects on brain structure and function, we hypothesized that SCNs are affected by the BDNF Val66Met SNP. To gain insight into SCN analysis, we investigated potential differences between BDNF valine (Val) homozygotes and methionine (Met) carriers in the organization of their SCNs derived from inter-regional cortical thickness correlations. Methods Forty-nine healthy adult subjects (mean age = 41.1 years old) were divided into two groups according to their genotype (n: Val homozygotes = 16, Met carriers = 33). We obtained regional cortical thickness from their brain T1 weighted images. Based on the inter-regional cortical thickness correlations, we generated SCNs and used graph theoretical measures to assess differences between the two groups in terms of network integration, segregation, and modularity. Results The average local efficiency, a measure of network segregation, of BDNF Met carriers’ network was significantly higher than that of the Val homozygotes’ (permutation p-value = 0.002). Average shortest path lengths (a measure of integration), average local clustering coefficient (another measure of network segregation), small-worldness (a balance between integration and segregation), and modularity (a representative measure for modular architecture) were not significantly different between group (permutation p-values ≧ 0.01). Discussion and Conclusion Our results suggest that the BDNF Val66Met polymorphism may potentially influence the pattern of brain regional morphometric (cortical thickness) correlations. Comparing networks derived from inter-regional cortical thickness correlations, Met carrier SCNs have denser connections with neighbors and are more distant from random networks than Val homozygote networks. Thus, it may be necessary to consider potential effects of BDNF gene mutations in SCN analyses. This is the first study to demonstrate a difference between Val homozygotes and Met carriers in brain SCNs.

There has been a growing interest in the abnormality of networks across the brain in major depressive disorder (MDD). We aimed to investigate the structural covariance networks in patients with first-episode and drug-naïve MDD using structural imaging. A total of 77 patients with first-episode and drug-naïve MDD and 79 healthy subjects (HS) were recruited, from whom high-resolution T1-weighted images were analysed. Incident component analysis was used to calculate the brain networks based on grey matter volume covariance. There were significant differences in salience network, medial temporal lobe network, default mode network and central executive network between MDD and HS (p 0.05). Further, the disturbance of medial temporal lobe network was significantly correlated with the severity of depressive symptoms (p 0.05). In conclusion, we found a novel abnormality in the brain network in the medial temporal lobe primarily involving the hippocampus and parahippocampal gyrus in patients with first-episode and treatment-naïve MDD.

Purpose: Compared with healthy subjects (HS), patients with major depressive disorder (MDD) exhibit volume differences that affect the volume changes in several areas such as the limbic, cortical, subcortical, and white matter. Catechol-O-methyltransferase (COMT) is a methylation enzyme that catalyzes endogenous catecholamines. The Val158Met polymorphism of COMT has been reported to affect the dopamine (DA) levels, which plays an important role in psychiatric diseases. However, the relationships among both DA levels, COMT genotype, and brain morphology are complicated and controversial. In previous studies that investigated the hippocampal subfields, the greatest brain abnormalities in MDD patients were observed in Cornu Ammonis (CA)1 and the subiculum, followed by that in CA2-3. We have prospectively demonstrated the relationship between the single-nucleotide polymorphism of the Val158Met COMT gene (rs4680) and the hippocampal subfields in drug-naive MDD patients. Patients and methods: In this study, we compared 27 MDD patients and 42 HS who were divided into groups based on their COMT genotype. The effects of the diagnosis, genotype, and genotype–diagnosis interaction related to CA1 and the subiculum volumes, as well as the whole-brain cortical thickness, were evaluated by performing a FreeSurfer statistical analysis of high-resolution magnetic resonance imaging (MRI) findings. Results: The results revealed that there was a statistically significant interaction between the effects of diagnosis and genotype on the right subiculum (a component of the hippocampus). Conclusion: This Val158Met COMT polymorphism may influence the subiculum volume in drug-naive, first-episode MDD patients.

Recently, accumulated evidence has indicated a role of inflammation in the pathogenesis of major depressive disorder (MDD). Therefore, we evaluated the relationship between white matter integrity and serum cytokine levels during the first depressive episode in drug-naive MDD patients, using a tract-based spatial statistics (TBSS) method. A total of 35 drug-naive MDD patients with a first depressive episode and 35 healthy subjects (HS) underwent diffusion tensor imaging, and an analysis was conducted using TBSS. We measured serum cytokine levels (interleukin [IL]-1β, IL-6, interferon-γ, and tumor necrosis factor-α). Fractional anisotropy (FA) values of the bilateral inferior fronto-occipital fasciculus (IFOF) and genu of the corpus callosum in MDD patients were decreased significantly to the HS (p < 0.05 with family-wise error [FWE] correction) and were significantly inversely correlated with the IL-1β levels (p < 0.05, with FWE correction). No regions showed a correlation between FA values and other serum cytokine levels. Our results suggested that the microstructural changes in IFOF and genu of the corpus callosum are associated with the high IL-1β levels in the early stage of MDD.

Vascular endothelial growth factor (VEGF) is involved in the development of major depressive disorder (MDD). Recently, a genome-wide association study has revealed that four VEGF-related single nucleotide polymorphisms (SNPs) (i.e., rs4416670, rs6921438, rs6993770 and rs10738760) were independently associated with circulating VEGF levels. The current study investigated the relationship between brain volume and these four SNPs in first-episode drug-naive MDD patients. A total of 38 first-episode drug-naive MDD patients and 39 healthy subjects (HS) were recruited and underwent high-resolution T1-weighted imaging. Blood samples were collected from all the participants for serum VEGF assays and VEGF-related SNPs genotyping. Genotype–diagnosis interactions related to whole-brain cortical thickness and hippocampal subfield volumes were evaluated for the four SNPs. The results revealed a genotype–diagnosis interaction only for rs6921438 (i.e., the MDD patients and HS with the G/G genotype versus the MDD patients and HS with A-carrier genotype) in the subiculum of the left hippocampus (p

There is a growing body of evidence to support the involvement of proinflammatory cytokines in the pathophysiology of depression; however, no previous studies have examined the relationship between cytokines and the brain morphology of patients with major depressive disorder (MDD). We therefore evaluated the relationship between serum cytokine levels and cortical thinning during the first depressive episode in drug-naïve patients with MDD. We measured the serum cytokine levels (IL-1β, IL-6, IFN-γ, and TNFα), and whole-brain cortical thickness and hippocampal subfield volumes on brain magnetic resonance imaging (MRI) using surface-based morphometry in 40 patients with MDD and 47 healthy volunteers (controls). Only the serum IL-6 level was significantly higher in patients with MDD than in controls. The prefrontal cortex (PFC) thickness was significantly reduced in patients with MDD, and showed a significant inverse correlation with the serum IL-6 level. Although high serum IL-6 levels were correlated with reduced left subiculum and right CA1, CA3, CA4, GC-DG, subiculum, and whole hippocampus volumes, the presence or absence of MDD had no effect on the volume of any hippocampal subfields. Our results suggest that IL-6 may play a key role in the morphological changes in the PFC during the early stage of MDD.

Background: Cognitive impairment in schizophrenia can result in considerable difficulty in performing functions of daily life or social rehabilitation. Cognitive impairment in schizophrenia is related to various factors, such as the psychotic severity, aging, medication, and brain-derived neurotrophic factor (BDNF). To date, however, no studies investigating the impact of these factors on cognitive functioning in chronic schizophrenia patients have been performed. Objective: The aim of this study is to identify those factors that influence the cognitive functioning in patients with chronic schizophrenia. Methods: Sixty-five of 116 long-term hospitalized chronic schizophrenia patients (63.8 ± 12.1 years old, M/F = 29/36) were enrolled this cross-sectional study. We investigated the relationship among the patients' age, psychotic severity, treatment medication, serum BDNF levels, and cognitive functioning (measured by the Japanese-language version of the Brief Assessment of Cognition in Schizophrenia; BACS-J). Additionally, we performed a multivariable linear regression analysis. Results: According to the partial correlation analysis, certain parameters [i.e., age, chlorpromazine (CP) equivalent, biperiden (BP) equivalent, and serum BDNF] were significantly correlated with cognitive functioning, including working memory (WM), motor function (MF), attention and processing speed (AP), and executive function (EF). For the multivariate analysis, the MF component, which had the highest correlation, was selected as the dependent variable, and the independent variables included age, Manchester Scale for chronic psychosis (ManS) total score, CP equivalent, BP equivalent, serum BDNF, estimated full scale IQ, and years of education. According to the multiple regression analysis of this model, R (multiple regression coefficient) was 0.542, the adjusted R2 (coefficient of determination) was 0.201, and only BP equivalent (β = −0.305, p = 0.030), but not age, ManS score, CP equivalent, or serum BDNF, could significantly explain MF at the 5% significant level. Conclusion: In conclusion, aging, medication (administering more antipsychotics or anticholinergics), and serum BDNF concentration are significantly correlated with cognitive dysfunction in chronic schizophrenia patients but not with the severity of psychotic symptoms. Furthermore, only the anticholinergic dosage had a significant causal relationship with MF. Thus, the use of anticholinergics in chronic schizophrenia patients with deteriorating cognitive functioning must be reconsidered.

Objectives: Risperidone is the first new generation antipsychotic drug to become available as a long-acting injection (LAI). The purpose of this study was to evaluate the effects of switching from oral risperidone to risperidone LAI (RLAI) on cognitive function in stable schizophrenia patients compared with the effects of continuing oral risperidone. Methods: Sixteen stable patients who had received risperidone monotherapy for at least 3 months were enrolled (the RLAI group). Before and 24 weeks after switching to RLAI, the Japanese-language version of the Brief Assessment of Cognition in Schizophrenia (BACS-J) and the Positive and Negative Syndrome Scale (PANSS) were administered. To exclude the possibility of learning effects on the BACS-J results, 14 age- and sex-matched patients with stable schizophrenia who continued oral risperidone treatment were also assessed (the RIS group). Results: The two groups did not differ with respect to changes in the PANSS score, and no emergent side effects, including extrapyramidal symptoms, were observed. The BACS-J score for verbal memory exhibited greater improvement in the RLAI group than in the RIS group (p=0.047). Conclusions: The results of this preliminary study suggest that switching from oral risperidone to RLAI may improve verbal capability more than continuing with oral risperidone. However, these findings must be replicated in a larger, double-blind study.

Objective: Benzodiazepines are sometimes co-prescribed with antidepressants for patients with major depressive disorder (MDD) who have symptoms such as sleep disturbance, restlessness, or anxiety. The aim of the present study was to examine whether serum levels of brain-derived neurotrophic factor (BDNF) differed between patients with MDD treated with fluvoxamine alone and those treated with a fluvoxamine and benzodiazepine combination. Methods: Twenty-eight first-episode patients with MDD were enrolled in the present study. Thirteen patients were male, and 15 were female, with ages ranging from 29 to 70 (mean ± standard deviation [SD], 47.9 ± 11.6) years. All the patients met the DSM-5 criteria for MDD; were physically healthy; and were free of alcohol or drug abuse, comorbid anxiety, or personality disorders at the time of the study. The patients were administered fluvoxamine monotherapy for eight weeks at doses that varied among the patients and were not fixed for ethical reasons. In the benzodiazepine co-administration group, the dose of benzodiazepines was kept constant during the experimental period. Depression was assessed using the Structured Interview Guide for the 17-item Hamilton Depression Rating Scale (HAMD17). Serum BDNF and plasma fluvoxamine levels were measured. Results: The HAMD17 scores in all subjects were significantly decreased after treatment with fluvoxamine. No significant difference was found between the two groups (fluvoxamine versus fluvoxamine and benzodiazepines) regarding the reduction in HAMD17 scores. Serum BDNF levels in all subjects were significantly increased after treatment with fluvoxamine. No difference was observed between the groups regarding the increase in serum BDNF levels. Conclusion: These results suggest that benzodiazepine co-administration did not influence serum BDNF levels or clinical improvement in MDD patients.

Catechol-O-methyltransferase (COMT) is a methylation enzyme engaged in the degradation of dopamine and noradrenaline by catalyzing the transfer of a methyl group from S-adenosylmethionine. An association was found between the Valine (Val) 108/158Methionine (Met) COMT polymorphism (rs4680) and major depressive disorder (MDD). The authors prospectively investigated the relationship between the Val108/158Met COMT genotype and voxel-based morphometry (VBM) findings for patients with first-episode and treatment-naïve MDD and healthy subjects (HS). Participants comprised 30 MDD patients and 48 age- and sex-matched HS who were divided according to the COMT genotype. Effects of diagnosis, COMT genotype, and the genotype-diagnosis interaction in relation to brain morphology in the Val/Met and Val/Val individuals were evaluated using a VBM analysis of high-resolution magnetic resonance imaging findings. Among the Val/Met individuals, the volume of the bilateral caudate was significantly smaller for MDD patients than for HS. In the Val/Val individuals, the caudate volume was comparable between MDD patients and HS. Significant genotype-diagnosis interaction effects on brain morphology were noted in the right caudate.

Objective In major depressive disorder (MDD) patients, higher morning cortisol levels due to a hyperactive hypothalamic–pituitary–adrenal (HPA) axis have been reported. The aim of the present study was to evaluate the relationship between cortical thinning and the serum cortisol levels during the first depressive episode in drug-naive MDD patients using an automated surface-based morphometry (SBM) method. Methods The institutional review board approved this prospective study. MR imaging data were obtained using a 3T scanner by a three-dimensional fast-spoiled gradient recalled acquisition with steady state (3D-FSPGR). Thirty drug-naive patients with MDD and 41 age- and gender-matched healthy subjects (controls) were enrolled. We then used the SBM method (Freesurfer) to generate cortical thickness maps, and measured the cortical thickness in each subject. Morning blood samples were drawn from all participants for cortisol measurements. Results We found the serum cortisol levels were significantly higher in the MDD patients than in the controls. The MDD patients manifested significant thinning of the left lateral orbitofrontal cortex compared with the controls. There was a significant negative linear correlation between the thickness of the left lateral orbitofrontal cortex and the serum cortisol levels in the MDD patients. Conclusions In the early stage of MDD, the thickness of the lateral orbitofrontal cortex was significantly reduced, and also showed a significant inverse correlation with the serum cortisol levels. Since the lateral orbitofrontal cortex contains a high concentration of glucocorticoid receptor, glucocorticoid receptor-mediated signaling transductions could contribute to neurotoxicity, which might occur when there are high cortisol levels in patients with MDD.

A 54-year-old Japanese woman was diagnosed with major depressive disorder and prescribed paroxetine 20 mg/day. In around May 2013, the patient experienced gastric discomfort, so metoclopramide was prescribed. Beginning on June 4, 2013, the patient was given metoclopramide, 10 mg intravenously, twice per week. On the seventh day after beginning metoclopramide, facial hot flushes, increased sweating, muscle rigidity, and galactorrhea were noted. Extrapyramidal symptoms (EPS) rapidly subsided in response to an intramuscular injection of biperiden. Blood biochemical tests revealed an elevated serum prolactin level of 44 ng/mL. After stopping metoclopramide, EPS disappeared. Serum prolactin level decreased to 15 ng/mL after 4 weeks. In our case, although no adverse reactions had previously occurred following the administration of metoclopramide, the patient developed EPS and hyperprolactinemia following the administration of this antiemetic in combination with paroxetine. Paroxetine and metoclopramide are mainly metabolized by CYP2D6, and they are inhibitors for CYP2D6. We report a case with EPS and hyperprolactinemia whose plasma paroxetine and metoclopramide level rapidly increased after the addition of metoclopramide. Our experience warrants the issuing of a precaution that adverse reactions may arise following the coadministration of metoclopramide and paroxetine even at their respective standard dose levels.