Showing papers in "Psychiatry and Clinical Neurosciences in 2018"

Neural basis of major depressive disorder: Beyond monoamine hypothesis.

Abstract: The monoamine hypothesis has been accepted as the most common hypothesis of major depressive disorder (MDD) for a long period because of its simplicity and understandability. Actually, most currently used antidepressants have been considered to act based on the monoamine hypothesis. However, an important problem of the monoamine hypothesis has been pointed out as follows: it fails to explain the latency of response to antidepressants. In addition, many patients with MDD have remained refractory to currently used antidepressants. Therefore, monoamine-alternate hypotheses are required to explain the latency of response to antidepressants. Such hypotheses have been expected to contribute to identifying hopeful new therapeutic targets for MDD. Past studies have revealed that the volume of the hippocampus is decreased in patients with MDD, which is likely caused by the failure of the hypothalamic-pituitary-adrenal axis and following elevation of glucocorticoids. Two hypotheses have been proposed to explain the volume of the hippocampus: (i) the neuroplasticity hypothesis; and (ii) the neurogenesis hypothesis. The neuroplasticity hypothesis explains how the hippocampal volume is decreased by the morphological changes of hippocampal neurons, such as the shortening length of dendrites and the decreased number and density of spines. The neurogenesis hypothesis explains how the hippocampal volume is decreased by the decrease of neurogenesis in the hippocampal dentate gyrus. These hypotheses are able to explain the latency of response to antidepressants. In this review, we first overview how the neuroplasticity and neurogenesis hypotheses have been developed. We then describe the details of these hypotheses.

Circadian rhythm in bipolar disorder: A review of the literature.

Abstract: Sleep disturbances and circadian rhythm dysfunction have been widely demonstrated in patients with bipolar disorder (BD). Irregularity of the sleep-wake rhythm, eveningness chronotype, abnormality of melatonin secretion, vulnerability of clock genes, and the irregularity of social time cues have also been well-documented in BD. Circadian rhythm dysfunction is prominent in BD compared with that in major depressive disorders, implying that circadian rhythm dysfunction is a trait marker of BD. In the clinical course of BD, the circadian rhythm dysfunctions may act as predictors for the first onset of BD and the relapse of mood episodes. Treatments focusing on sleep disturbances and circadian rhythm dysfunction in combination with pharmacological, psychosocial, and chronobiological treatments are believed to be useful for relapse prevention. Further studies are therefore warranted to clarify the relation between circadian rhythm dysfunction and the pathophysiology of BD to develop treatment strategies for achieving recovery in BD patients.

Genetics and epigenetics of autism: A Review.

Abstract: Autism is a developmental disorder that starts before age 3, and children with autism has impairment in both social interaction and communication, and has restricted, repetitive and stereotyped patterns of behavior, interests and activities. There is a strong heritable component of autism and autism spectrum disorder as studies have shown that parents who have a child with ASD have a 2-18% chance of having a second child with ASD. Since the prevalence of autism and autism spectrum disorders have been increasing during the last 3 decades, much research has been carried out to understand the etiology, so as to develop novel preventive and treatment strategies. This review aims at summarizing the latest research studies related to autism and autism spectrum disorder, focusing not only on the genetics but also some epigenetic findings of autism/autism spectrum disorder. Some promising areas of research using transgenic/knockout animals and some ideas related to potential novel treatment and prevention strategies will be discussed.

Epigenetic mechanisms of major depression: Targeting neuronal plasticity

Abstract: Major depressive disorder is one of the most common mental illnesses as it affects more than 350 million people globally. Major depressive disorder is etiologically complex and disabling. Genetic factors play a role in the etiology of major depression. However, identical twin studies have shown high rates of discordance, indicating non-genetic mechanisms as well. For instance, stressful life events increase the risk of depression. Environmental stressors also induce stable changes in gene expression within the brain that may lead to maladaptive neuronal plasticity in regions implicated in disease pathogenesis. Epigenetic events alter the chromatin structure and thus modulate expression of genes that play a role in neuronal plasticity, behavioral response to stress, depressive behaviors, and response to antidepressants. Here, we review new information regarding current understanding of epigenetic events that may impact depression. In particular, we discuss the roles of histone acetylation, DNA methylation, and non-coding RNA. These novel mechanisms of action may lead to new therapeutic strategies for treating major depression.

Associations between problematic Internet use and psychiatric symptoms among university students in Japan.

Abstract: AIM Research on the adverse effects of Internet use has gained importance recently. However, there is currently insufficient data on Japanese young adults' Internet use, so we conducted a survey targeting Japanese university students to research problematic Internet use (PIU). We also investigated the relationship between PIU and multiple psychiatric symptoms. METHODS A paper-based survey was conducted at five universities in Japan. Respondents were asked to fill out self-report scales regarding their Internet dependency using the Internet Addiction Test (IAT). Sleep quality, attention-deficit hyperactivity disorder (ADHD) tendency, depression, and anxiety symptom data were also collected based on respective self-reports. RESULTS There were 1336 responses and 1258 were included in the analysis. The mean IAT score (± SD) was 37.87 ± 12.59; and 38.2% of participants were classified as PIU, and 61.8% as non-PIU. The trend level for young women showed that they were more likely to be classified as PIU than young men (40.6% and 35.2% respectively, P = 0.05). Compared to the non-PIU group, the PIU group used the Internet longer (P < 0.001), had significantly lower sleep quality (P < 0.001), had stronger ADHD tendencies (P < 0.001), had higher Depression scores (P < 0.001), and had higher Trait-Anxiety scores (P < 0.001). Based on multiple logistic regression analyses, the factors that contributed to an increased risk of PIU were: being female (odds ratio [OR] = 1.52), being older (OR = 1.17), having poor sleep quality (OR = 1.52), having ADHD tendencies (OR = 2.70), having depression (OR = 2.24), and having anxiety tendencies (OR = 1.43). CONCLUSION We found a high PIU prevalence among Japanese young adults. The factors that predicted PIU were: female sex, older age, poor sleep quality, ADHD tendencies, depression, and anxiety.

Brain morphologic changes in early stages of psychosis: Implications for clinical application and early intervention

Abstract: To date, a large number of magnetic resonance imaging (MRI) studies have been conducted in schizophrenia, which generally demonstrate gray matter reduction, predominantly in the frontal and temporo-limbic regions, as well as gross brain abnormalities (e.g., a deviated sulcogyral pattern). Although the causes as well as timing and course of these findings remain elusive, these morphologic changes (especially gross brain abnormalities and medial temporal lobe atrophy) are likely present at illness onset, possibly reflecting early neurodevelopmental abnormalities. In addition, longitudinal MRI studies suggest that patients with schizophrenia and related psychoses also have progressive gray matter reduction during the transition period from prodrome to overt psychosis, as well as initial periods after psychosis onset, while such changes may become almost stable in the chronic stage. These active brain changes during the early phases seem to be relevant to the development of clinical symptoms in a region-specific manner (e.g., superior temporal gyrus atrophy and positive psychotic symptoms), but may be at least partly ameliorated by antipsychotic medication. Recently, increasing evidence from MRI findings in individuals at risk for developing psychosis has suggested that those who subsequently develop psychosis have baseline brain changes, which could be at least partly predictive of later transition into psychosis. In this article, we selectively review previous MRI findings during the course of psychosis and also refer to the possible clinical applicability of these neuroimaging research findings, especially in the diagnosis of schizophrenia and early intervention for psychosis.

Genome‐wide association studies of bipolar disorder: A systematic review of recent findings and their clinical implications

Abstract: Recent advances in molecular genetics have enabled assessments of the associations among genetic variants (e.g., single-nucleotide polymorphisms) and susceptibility for complex diseases, including psychiatric disorders. Specifically, genome-wide association studies (GWAS), meta-analyses of the GWAS summary statistics, and mega-analyses (which use raw data, not summary statistics) of GWAS have provided revolutionary results and have identified numerous susceptibility genes or single-nucleotide polymorphisms. By using several tens of thousands of subjects, >40 genes have been identified as being associated with susceptibility for bipolar disorder so far. The purpose of this systematic review was to summarize the recent findings of bipolar disorder GWAS and discuss their clinical implications.

Amygdala real-time functional magnetic resonance imaging neurofeedback for major depressive disorder: A review

Abstract: Advances in imaging technologies have allowed for the analysis of functional magnetic resonance imaging data in real-time (rtfMRI), leading to the development of neurofeedback (nf) training. This rtfMRI-nf training utilizes functional magnetic resonance imaging (fMRI) tomographic localization capacity to allow a person to see and regulate the localized hemodynamic signal from his or her own brain. In this review, we summarize the results of several studies that have developed and applied neurofeedback training to healthy and depressed individuals with the amygdala as the neurofeedback target and the goal to increase the hemodynamic response during positive autobiographical memory recall. We review these studies and highlight some of the challenges and advances in developing an rtfMRI-nf paradigm for broader use in psychiatric populations. The work described focuses on our line of research aiming to develop the rtfMRI-nf into an intervention, and includes a discussion of the selection of a region of interest for feedback, selecting a control condition, behavioral and cognitive effects of training, and predicting which participants are most likely to respond well to training. While the results of these studies are encouraging and suggest the clinical potential of amygdala rtfMRI-nf in alleviating symptoms of major depressive disorder, larger studies are warranted to confirm its efficacy.

Epigenetics applied to psychiatry: Clinical opportunities and future challenges.

Abstract: Psychiatric disorders are clinically heterogeneous and debilitating chronic diseases resulting from a complex interplay between gene variants and environmental factors. Epigenetic processes, such as DNA methylation and histone posttranslational modifications, instruct the cell/tissue to correctly interpret external signals and adjust its functions accordingly. Given that epigenetic modifications are sensitive to environment, stable, and reversible, epigenetic studies in psychiatry could represent a promising approach to better understanding and treating disease. In the present review, we aim to discuss the clinical opportunities and challenges arising from the epigenetic research in psychiatry. Using selected examples, we first recapitulate key findings supporting the role of adverse life events, alone or in combination with genetic risk, in epigenetic programming of neuropsychiatric systems. Epigenetic studies further report encouraging findings about the use of methylation changes as diagnostic markers of disease phenotype and predictive tools of progression and response to treatment. Then we discuss the potential of using targeted epigenetic pharmacotherapy, combined with psychosocial interventions, for future personalized medicine for patients. Finally, we review the methodological limitations that could hinder interpretation of epigenetic data in psychiatry. They mainly arise from heterogeneity at the individual and tissue level and require future strategies in order to reinforce the biological relevance of epigenetic data and its translational use in psychiatry. Overall, we suggest that epigenetics could provide new insights into a more comprehensive interpretation of mental illness and might eventually improve the nosology, treatment, and prevention of psychiatric disorders.

Development and validation of the 25-item Hikikomori Questionnaire (HQ-25)

Abstract: Aim Hikikomori, a form of severe social withdrawal, is an emerging issue in mental health, for which validated measurement tools are lacking. The object was to develop a self-report scale of hikikomori, and assess its psychometric properties and diagnostic accuracy. Methods A sample of 399 participants from clinical and community settings completed measures. Psychometric properties were assessed with factor analysis; diagnostic accuracy was compared against a semi-structured diagnostic interview. Results The Hikikomori Questionnaire contained 25 items across three subscales representing socialization, isolation, and emotional support. Internal consistency, test-retest reliability, and convergent validity were all satisfactory. The area under the curve was 0.86 (95% confidence interval, 0.80-0.92). A cut-off score of 42 (out of 100) was associated with a sensitivity of 94%, specificity of 61%, and positive predictive value of 17%. Conclusion The 25-item Hikikomori Questionnaire (HQ-25) possesses robust psychometric properties and diagnostic accuracy in an initial sample of Japanese adults. Additional research on its psychometric properties and ability to support clinical assessment of hikikomori is warranted.

Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia in Japan: A 6-week, randomized, double-blind, placebo-controlled study.

Abstract: Aim This study aimed to evaluate the efficacy, safety, and tolerability of brexpiprazole compared to placebo in Japanese patients with acute schizophrenia (SCZ). Methods We conducted a 6-week, multicenter, double-blind, placebo-controlled, phase 2/3 study in Japan. Patients with acute SCZ were randomized (1:1:1:1) to receive brexpiprazole 1 mg, 2 mg, 4 mg, or placebo once a day. The primary endpoint was the change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total scores. Results In the 459 patients that were randomized, brexpiprazole 2 mg showed a significant improvement versus placebo (treatment difference: -7.32, P = 0.0124), although brexpiprazole 4 mg showed numerical improvements (treatment difference: -3.86, P = 0.1959), and brexpiprazole 1 mg showed only minimal change (treatment difference: -0.63, P = 0.8330). Treatment-emergent adverse events with an incidence of ≥5% and ≥2 times the rate of placebo in the brexpiprazole groups were vomiting, elevated blood prolactin, diarrhea, nausea, and dental caries. Most treatment-emergent adverse events were mild or moderate in severity. There were no clinically significant changes in electrocardiogram parameters, bodyweight, laboratory values, or vital signs in the brexpiprazole groups. Conclusion Brexpiprazole was efficacious and well tolerated in Japanese adult patients with acute SCZ.

iPlasticity: Induced juvenile-like plasticity in the adult brain as a mechanism of antidepressants.

Abstract: The network hypothesis of depression proposes that mood disorders reflect problems in information processing within particular neural networks. Antidepressants (AD), including selective serotonin reuptake inhibitors (SSRI), function by gradually improving information processing within these networks. AD have been shown to induce a state of juvenile-like plasticity comparable to that observed during developmental critical periods: Such critical-period-like plasticity allows brain networks to better adapt to extrinsic and intrinsic signals. We have coined this drug-induced state of juvenile-like plasticity 'iPlasticity.' A combination of iPlasticity induced by chronic SSRI treatment together with training, rehabilitation, or psychotherapy improves symptoms of neuropsychiatric disorders and issues underlying the developmentally or genetically malfunctioning networks. We have proposed that iPlasticity might be a critical component of AD action. We have demonstrated that iPlasticity occurs in the visual cortex, fear erasure network, extinction of aggression caused by social isolation, and spatial reversal memory in rodent models. Chronic SSRI treatment is known to promote neurogenesis and to cause dematuration of granule cells in the dentate gyrus and of interneurons, especially parvalbumin interneurons enwrapped by perineuronal nets in the prefrontal cortex, visual cortex, and amygdala. Brain-derived neurotrophic factor (BDNF), via its receptor tropomyosin kinase receptor B, is involved in the processes of synaptic plasticity, including neurogenesis, neuronal differentiation, weight of synapses, and gene regulation of synaptic formation. BDNF can be activated by both chronic SSRI treatment and neuronal activity. Accordingly, the BDNF/tropomyosin kinase receptor B pathway is critical for iPlasticity, but further analyses will be needed to provide mechanical insight into the processes of iPlasticity.

Therapeutic role of rifampicin in Alzheimer's disease.

Abstract: Rifampicin exerts significant brain protective functions in multiple experimental models. Here we summarize the underlying mechanisms of the neuroprotective and pro-cognitive effects of rifampicin that are mediated by its anti-inflammatory, anti-tau, anti-amyloid, and cholinergic effects. Beyond suggesting that rifampicin shows strong brain protective effects in preclinical models of Alzheimer's disease, we also provide substantial clinical evidence for the neuroprotective and pro-cognitive effects of rifampicin. Future neuroimaging studies combined with clinical assessment scores are the following steps to be taken in this field of research.

Prevalence rate of Internet addiction among Japanese college students: Two cross-sectional studies and reconsideration of cut-off points of Young's Internet Addiction Test in Japan.

Abstract: AIM Due to variation in estimates of the prevalence of Internet addiction (IA) in prior research, we conducted two cross-sectional studies over 2 years investigating the prevalence rate of IA in college students in Japan and reconsidered appropriate cut-off points of a self-rating scale to screen possible IA. METHODS This study was composed of two parts: survey I in 2014 and survey II in 2016, which were conducted in the same schools with an interval of 2 years. The study questionnaire included questions about demographics and Internet use, and Young's Internet Addiction Test (IAT). Additionally, the subjects in survey II were asked about self-reported IA. RESULTS There were 1005 respondents in total with a mean age (± SD) of 18.9 ± 1.3 years. The mean IAT scores remained stable between 2014 and 2016: 45.2 ± 12.6 in survey I and 45.5 ± 13.1 in survey II (overall mean IAT score of 45.4 ± 13.0). With respect to self-reported IA in survey II, a total of 21.6% admitted to having IA (score of 5 or 6 on a 6-point Likert scale). We categorized these subjects as IA, and the remainder as non-IA. The mean IAT score showed a significant difference between these two groups (57.8 ± 14.3 vs 42.1 ± 10.7, P < 0.001). CONCLUSION The severity of IA symptoms among Japanese college students has appeared stable in recent years, with mean IAT scores of over 40. Our results suggest that a screening score cut-off of 40 on the IAT could be reconsidered and that 50 might be proposed for the cut-off.

Preventing Wernicke's encephalopathy in anorexia nervosa: A systematic review

Abstract: Anorexia nervosa (AN) is a common eating disorder that affects 2.9 million people worldwide. Not eating a balanced diet or fasting can cause neurological complications after severe vitamin B1 malnourishment, although the precise signs and symptoms of Wernicke's encephalopathy (WE) are not clear. Our aim was to review the signs and symptoms of WE in patients with AN. We searched MEDLINE, EMBASE, Scopus, and PiCarta on all case descriptions of WE following AN. All case descriptions of WE in AN, irrespective of language, were included. Twelve WE cases were reviewed, suggesting that WE following AN is still a relatively rare neuropsychiatric disorder. WE is characterized by a triad of: mental status change, ocular signs, and ataxia. In alcoholism, this triad is present in 16% of cases, but eight out of 12 AN cases presented themselves with a full triad of symptomatology. Importantly, patients often had a more complex triad than has been previously described, involving vertigo, diplopia, and the consequences of refeeding syndrome. The development of a full triad and additional symptomatology suggests a late recognition of signs and symptoms of WE in AN. A complicating factor is the overlap between symptoms of thiamine deficiency and the symptoms of WE. Specifically, patients who show rapid weight loss are vulnerable for the development of WE. Eating disorders, such as AN, can lead to WE. Prophylactic thiamine checks and treatment in patients with AN are relevant, and in case of suspicion of WE, adequate parenteral thiamine supplementation is necessary.

Systematic review and meta-analysis of reported adverse events of long-term intranasal oxytocin treatment for autism spectrum disorder.

Abstract: Recent studies have suggested oxytocin as a possible drug to treat social deficits caused by autism spectrum disorder (ASD), but the safety of intranasal oxytocin in autistic patients has not been established. The aim of this review was to characterize the side-effect profile of long-term intranasal oxytocin in treatment of ASD compared to placebo. All randomized controlled trials of intranasal oxytocin in the treatment of ASD published before 1 January 2017 that reported safety data were identified from databases, including PubMed, Embase, Cochrane Library, and International Pharmaceutical Abstract. Relevant data from the selected studies were then extracted for meta-analysis to estimate the pooled risk ratio for the most common adverse events. Descriptive analysis of severe adverse events was also conducted. Of the 223 participants in the five included studies, 123 were given oxytocin and 100 were given placebos. Nasal discomfort (14.3%), tiredness (7.2%), irritability (9.0%), diarrhea (4.5%), and skin irritation (4.5%) were the most common adverse events. None of these common adverse events was statistically associated with treatment allocation according to meta-analysis using pooled data (all P-values > 0.1). Five severe adverse events were reported, namely aggression (one in placebo, two in oxytocin) and seizures (one in placebo, one in oxytocin). Results from this systematic review support intranasal oxytocin as well tolerated and safe for use in the ASD population. Larger clinical trials should be conducted to establish the efficacy of intranasal oxytocin as a treatment of ASD.

Polypharmacy and psychotropic drug loading in patients with schizophrenia in Asian countries: Fourth survey of Research on Asian Prescription Patterns on antipsychotics.

Abstract: Aim The aim of the present study was to survey the prevalence of antipsychotic polypharmacy and combined medication use across 15 Asian countries and areas in 2016. Methods By using the results from the fourth survey of Research on Asian Prescription Patterns on antipsychotics, the rates of polypharmacy and combined medication use in each country were analyzed. Daily medications prescribed for the treatment of inpatients or outpatients with schizophrenia, including antipsychotics, mood stabilizers, anxiolytics, hypnotics, and antiparkinson agents, were collected. Fifteen countries from Asia participated in this study. Results A total of 3744 patients' prescription forms were examined. The prescription patterns differed across these Asian countries, with the highest rate of polypharmacy noted in Vietnam (59.1%) and the lowest in Myanmar (22.0%). Furthermore, the combined use of other medications, expressed as highest and lowest rate, respectively, was as follows: mood stabilizers, China (35.0%) and Bangladesh (1.0%); antidepressants, South Korea (36.6%) and Bangladesh (0%); anxiolytics, Pakistan (55.7%) and Myanmar (8.5%); hypnotics, Japan (61.1%) and, equally, Myanmar (0%) and Sri Lanka (0%); and antiparkinson agents, Bangladesh (87.9%) and Vietnam (10.9%). The average psychotropic drug loading of all patients was 2.01 ± 1.64, with the highest and lowest loadings noted in Japan (4.13 ± 3.13) and Indonesia (1.16 ± 0.68), respectively. Conclusion Differences in psychiatrist training as well as the civil culture and health insurance system of each country may have contributed to the differences in these rates. The concept of drug loading can be applied to other medical fields.

Delirium detection by a novel bispectral electroencephalography device in general hospital

Abstract: Aim Delirium is common and dangerous among elderly inpatients; yet, it is underdiagnosed and thus undertreated. This study aimed to test the diagnostic characteristics of a noninvasive point-of-care device with two-channel (bispectral) electroencephalography (EEG) for the screening of delirium in the hospital. Methods Patients admitted to the University of Iowa Hospitals and Clinics were assessed for the presence of delirium with a clinical assessment, the Confusion Assessment Method for Intensive Care Unit and Delirium Rating Scale. Subsequently, we obtained a 10-min bispectral EEG (BSEEG) recording from a hand-held electroencephalogram device during hospitalization. We performed power spectral density analysis to differentiate between those patients with and without delirium. Results Initially 45 subjects were used as a test dataset to establish a cut-off. The BSEEG index was determined to be a significant indicator of delirium, with sensitivity 80% and specificity 87.7%. An additional independent validation dataset with 24 patients confirmed the validity of the approach, with a sensitivity of 83.3% and specificity of 83.3%. Conclusion In this pilot study, the BSEEG method was able to distinguish delirious patients from non-delirious patients. Our data showed the feasibility of this technology for mass screening of delirium in the hospital.

Pyridoxamine: A novel treatment for schizophrenia with enhanced carbonyl stress.

Abstract: Aim The aim of this clinical trial was to obtain proof of concept for high-dose pyridoxamine as a novel treatment for schizophrenia with enhanced carbonyl stress. Methods Ten Japanese schizophrenia patients with high plasma pentosidine, which is a representative biomarker of enhanced carbonyl stress, were recruited in a 24-week, open trial in which high-dose pyridoxamine (ranging from 1200 to 2400 mg/day) was administered using a conventional antipsychotic regimen. Main outcomes were the total change in Positive and Negative Syndrome Scale score and the Brief Psychiatric Rating Scale score from baseline to end of treatment at week 24 (or at withdrawal). Results Decreased plasma pentosidine levels were observed in eight patients. Two patients showed marked improvement in their psychological symptoms. A patient who harbors a frameshift mutation in the Glyoxalase 1 gene also showed considerable reduction in psychosis accompanied with a moderate decrease in plasma pentosidine levels. A reduction of greater than 20% in the assessment scale of drug-induced Parkinsonism occurred in four patients. Although there was no severe suicide-related ideation or behavior, Wernicke's encephalopathy-like adverse drug reactions occurred in two patients and were completely suppressed by thiamine supplementation. Conclusion High-dose pyridoxamine add-on treatment was, in part, effective for a subpopulation of schizophrenia patients with enhanced carbonyl stress. Further randomized, placebo-controlled trials with careful monitoring will be required to validate the efficacy of high-dose pyridoxamine for these patients.

Plasma metabolome analysis of patients with major depressive disorder

Abstract: Aim This study sought to characterize the plasma metabolite profiling of patients with major depressive disorder (MDD). Methods Psychiatric assessments were made with the Structured Clinical Interview for DSM-IV Axis I Disorders. In the exploratory cohort, plasma metabolite profiles of 34 MDD patients and 31 mentally healthy controls were compared using capillary electrophoresis-mass spectrometry. Among the candidate metabolites, we focused on a metabolite showing the largest difference. The absolute concentrations were measured in two cohorts from a psychiatric primary care clinic to characterize the accuracy of the metabolite biomarker. Results Among 23 metabolites significantly lower in the MDD group than in healthy controls, we focused on phosphoethanolamine (PEA) as a candidate. The reduction of PEA levels in MDD was checked in independent clinical sample sets. An ion-chromatography-fluorescence detection method was developed to measure plasma PEA levels. In the preliminary cohort, we examined 34 MDD and 43 non-MDD subjects. The area under the receiver-operator curve (AUC) was 0.92, with sensitivity/specificity greater than 88%, at a cut-off of 1.46 μM. In the checking cohort, with 10 MDD and 13 non-MDD subjects, AUC was 0.89, with sensitivity/specificity of 86% and 100%, respectively, at a cut-off of 1.48 μM. Plasma PEA inversely correlated with MDD severity, depressed mood, loss of interest, and psychomotor retardation. Conclusion These results suggest that plasma PEA level could be a candidate biomarker of MDD in the clinical setting. Further studies comparing MDD and mentally healthy controls are needed to confirm the utility of PEA as a biomarker for depression.

MEF2C mRNA expression and cognitive function in Japanese patients with Alzheimer's disease.

Abstract: Aim Despite continuing research into Alzheimer's disease (AD), its pathological mechanisms and modulating factors remain unknown. Several genes influence AD pathogenesis by affecting inflammatory pathways. Myocyte-enhancer factor 2C (MEF2C) is one such candidate gene for AD. Methods We examined MEF2C mRNA expression levels and methylation rates of CpG on its promoter region in peripheral leukocytes from Japanese AD patients compared with age- and sex-matched control subjects. Results In peripheral leukocytes, MEF2C mRNA expression levels in AD subjects were significantly lower than those in control subjects (0.86 ± 0.25 vs 0.99 ± 0.27, respectively, P = 0.007) and were correlated with the Alzheimer's Disease Assessment Scale (r = -0.345, P = 0.049) and the Mini Mental State Examination (r = 0.324, P = 0.02). No significant differences were found in methylation rates between AD and control subjects. Conclusion MEF2C mRNA expression in leukocytes may be a biological marker for cognitive decline in AD.

Association between iron-deficiency anemia and depression: A web-based Japanese investigation.

Abstract: AIM This web-based survey aimed to examine the relation between iron-deficiency anemia and depression in 11 876 Japanese participants. METHODS Participants consisted of 1000 individuals with self-reported history of depression (mean age, 41.4 ± 12.3 years; 499 women) and 10 876 population-based controls (mean age, 45.1 ± 13.6 years; 5185 women). The 6-item Kessler Scale (K6) score was used as a psychological distress scale. The design of the study was cross-sectional. RESULTS The rate of self-reported lifetime history of iron-deficiency anemia was higher in the depression group in both men (depression, 7.2%; control, 4.0%; P < 0.001; odds ratio [OR], 1.86; 95% confidence interval [CI], 1.30-2.68) and women (depression, 33.4%; control, 25.8%; P < 0.001; OR, 1.45; 95%CI, 1.19-1.76). The K6 score in participants with self-reported history of iron-deficiency anemia was higher in both the depression (P = 0.004) and control (P < 0.001) groups. In addition, in all participants, the rate of individuals who showed a K6 cut-off score of 13 or more was higher in those with a self-reported history of iron-deficiency anemia (P < 0.001; OR, 1.47; 95%CI, 1.31-1.65). Logistic regression analyses revealed that self-reported history of depression and the K6 score were positively associated with self-reported history of iron-deficiency anemia (all P < 0.01). CONCLUSION Self-reported history of iron-deficiency anemia was associated with self-reported history of depression. Furthermore, self-reported history of iron-deficiency anemia was associated with higher psychological distress.

Evaluation of the neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and mean platelet volume as inflammatory markers in children with attention-deficit hyperactivity disorder.

Abstract: Aim The neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), monocyte/lymphocyte ratio (MLR), and mean platelet volume (MPV) have recently been used as indicators of a systemic inflammatory response. The aim of this study was to investigate the relations of the NLR, PLR, MLR, and MPV with attention-deficit hyperactivity disorder (ADHD). Methods The study group consisting of 82 children diagnosed with ADHD was compared with a healthy control (HC) group of 70 age-, sex-, and body-mass-index-matched subjects. The NLR, PLR, MLR, and MPV were measured according to the complete blood count. Results The NLR, PLR, MLR, MPV, and neutrophil count of the ADHD group were significantly higher than those of the HC group. The lymphocyte counts of the patients were significantly lower than those of the HC group. Conclusion Inflammation might play a role in the etiopathogenesis of ADHD. The NLR, PLR, MLR, and MPV may be potential inflammation markers for ADHD in children.

Effects of maternal separation and antidepressant drug on epigenetic regulation of the brain-derived neurotrophic factor exon I promoter in the adult rat hippocampus.

Abstract: Aim Early life stress can induce epigenetic changes through genetic and environmental interactions and is a risk factor for depression. Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of depression and antidepressant drug action. We investigated epigenetic changes at the BDNF exon I promoter in the hippocampus of adult rats subjected to maternal separation (MS) during early life and treated with an antidepressant drug as adults. Methods Rat pups were subjected to MS from postnatal day 1 to 21 and received chronic escitalopram (ESC) as adults. We assessed the effects of MS and ESC on BDNF exon I and DNA methyltransferases (DNMTs) mRNA levels (quantitative reverse-transcription polymerase chain reaction [qRT-PCR]), acetylated histone H3 and MeCP2 binding to the BDNF promoter I (chromatin immunoprecipitation followed by real-time PCR), and BDNF protein levels (enzyme-linked immunosorbent assay). Results The levels of BDNF protein, exon I mRNA, histone H3 acetylation, and DNMT1 and DNMT3a mRNA were altered in the MS group compared with the control group. Significant decreases were observed in the BDNF protein, exon I mRNA, and histone H3 acetylation levels and significant increases in DNMT1 and DNMT3a mRNA levels. The comparison between the MS + ESC and MS groups revealed significant increases in BDNF protein, exon I mRNA, and histone H3 acetylation levels and significant decreases in MeCP2 and DNMT1 and DNMT3a mRNA levels. Conclusion These findings indicate that MS induced epigenetic changes at the BDNF exon I promoter and these changes were prevented by antidepressant drug treatment during adulthood.

Lactate in bipolar disorder: A systematic review and meta-analysis.

Abstract: Bipolar disorder (BD) is a debilitating mood disorder with no specific biological marker. No novel treatment has been developed specifically for BD in the last several decades. Although the pathophysiology of BD remains unclear, there is strong evidence in the literature supporting the role of mitochondrial dysfunction in BD. In this systematic review, we identified and investigated 12 studies that measure lactate, which is a direct marker for mitochondrial dysfunction, in BD patients and healthy controls. Six studies measured lactate levels in the brain through proton echo-planar spectroscopy or magnetic resonance spectroscopy and five of these studies reported significantly elevated lactate levels in patients with BD. Two studies reporting cerebrospinal fluid lactate levels also found significantly elevated lactate in BD compared to healthy controls. Two other studies that reported peripheral lactate levels did not demonstrate significant findings. The meta-analysis, using standardized means and a random-effect model for five studies that measured brain lactate levels, corroborated the findings of the systematic review. Although the meta-analysis had a nearly significant overall effect (Z = 1.97, P = 0.05), high statistical heterogeneity (I2 = 86%) and possible publication bias suggest that the results should be interpreted with caution. To validate lactate abnormalities in BD, further studies should be carried out, including larger sample sizes, not excluding female patients, and using standardized methodologies. Peripheral lactate levels and other bioenergetic markers should be thoroughly studied to better understand the role of mitochondrial dysfunction in BD and to help develop more objective diagnostic tools.

Critical reappraisal of mechanistic links of copy number variants to dimensional constructs of neuropsychiatric disorders in mouse models.

Abstract: Copy number variants are deletions and duplications of a few thousand to million base pairs and are associated with extraordinarily high levels of autism spectrum disorder, schizophrenia, intellectual disability, or attention-deficit hyperactivity disorder. The unprecedented levels of robust and reproducible penetrance of copy number variants make them one of the most promising and reliable entry points to delve into the mechanistic bases of many mental disorders. However, the precise mechanistic bases of these associations still remain elusive in humans due to the many genes encoded in each copy number variant and the diverse associated phenotypic features. Genetically engineered mice have provided a technical means to ascertain precise genetic mechanisms of association between copy number variants and dimensional aspects of mental illnesses. Molecular, cellular, and neuronal phenotypes can be detected as potential mechanistic substrates for various behavioral constructs of mental illnesses. However, mouse models come with many technical pitfalls. Genetic background is not well controlled in many mouse models, leading to rather obvious interpretative issues. Dose alterations of many copy number variants and single genes within copy number variants result in some molecular, cellular, and neuronal phenotypes without a behavioral phenotype or with a behavioral phenotype opposite to what is seen in humans. In this review, I discuss technical and interpretative pitfalls of mouse models of copy number variants and highlight well-controlled studies to suggest potential neuronal mechanisms of dimensional aspects of mental illnesses. Mouse models of copy number variants represent toeholds to achieve a better understanding of the mechanistic bases of dimensions of neuropsychiatric disorders and thus for development of mechanism-based therapeutic options in humans.

Longitudinal characteristics of resilience among adolescents: A high school student cohort study to assess the psychological impact of the Great East Japan Earthquake.

Abstract: Aim Resilience, the ability to cope with disasters and significant life adversity, is an important factor to consider when studying the mental health of populations affected by a disaster. Although high school students in a community affected by a disaster should have specific characteristics of resilience, little has been reported on the issue. This study was designed to provide initial data regarding characteristics of the resilience of high school students affected by a catastrophe. Methods A total of 760 high school students in Natori City, which was devastated by the Great East Japan Earthquake in 2011, were profiled, and a 3-year longitudinal study was conducted with 254 students who had entered the school in 2012. Resilience was evaluated with the 10-item Connor-Davidson Resilience Scale. The Quick Inventory of Depressive Symptomatology-Japanese version, the Zung Self-Rating Anxiety Scale, and the Impact of Event Scale-Revised were also administered to assess the students' mental health. Results Among the students who entered the high school in 2012, 28.6% showed high resilience, and the proportion increased to 42.9% in 2013 and 46.6% in 2014. The Quick Inventory of Depressive Symptomatology-Japanese version and Impact of Event Scale-Revised scores decreased significantly over the 3-year study period, but there were no significant differences in the Zung Self-Rating Anxiety Scale scores over time. Conclusion This initial study profiling the characteristics of resilience among adolescents suggests that resilience is a highly changeable component of mental health among people who have faced adversity. Resilience can be a useful indicator of recovery from adversity and a target of interventions for improving mental health conditions.

DNA methylation analyses of the candidate genes identified by a methylome-wide association study revealed common epigenetic alterations in schizophrenia and bipolar disorder.

Abstract: Aim Schizophrenia (SZ) and bipolar disorder (BD) have been known to share genetic and environmental risk factors, and complex gene-environmental interactions may contribute to their pathophysiology. In contrast to high genetic overlap between SZ and BD, as revealed by genome-wide association studies, the extent of epigenetic overlap remains largely unknown. In the present study, we explored whether SZ and BD share epigenetic risk factors in the same manner as they share genetic components. Methods We performed DNA methylation analyses of the CpG sites in the top five candidate regions (FAM63B, ARHGAP26, CTAGE11P, TBC1D22A, and intergenic region [IR] on chromosome 16) reported in a previous methylome-wide association study (MWAS) of SZ, using whole blood samples from subjects with BD and controls. Results Among the five candidate regions, the CpG sites in FAM63B and IR on chromosome 16 were significantly hypomethylated in the samples from subjects with BD as well as those from subjects with SZ. On the other hand, the CpG sites in TBC1D22A were hypermethylated in the samples from subjects with BD, in contrast to hypomethylation in the samples from subjects with SZ. Conclusion Hypomethylation of FAM63B and IR on chromosome 16 could be common epigenetic risk factors for SZ and BD. Further comprehensive epigenetic studies for BD, such as MWAS, will uncover the extent of similarity and uniqueness of epigenetic alterations.

Randomized, double-blind, placebo-controlled 8-week trial of the efficacy, safety, and tolerability of 5, 10, and 20 mg/day vortioxetine in adults with major depressive disorder.

Abstract: Aim This study assessed the efficacy and safety of vortioxetine in adults with major depressive disorder. Methods In this double-blind, placebo-controlled study, 600 patients with major depressive disorder were randomly assigned (1:1:1:1) to receive vortioxetine 5, 10, or 20 mg, or placebo once daily for 8 weeks. The primary end-point was change from baseline in Montgomery–Asberg Depression Rating Scale (MADRS) total score at week 8, evaluated by the last-observation-carried-forward method. Secondary end-points included response (≥ 50% decrease in the MADRS total score from baseline) and remission (MADRS total score ≤ 10), Clinical Global Impression Scale-Improvement, and change from baseline in Sheehan Disability Scale. Adverse events were summarized. Results Vortioxetine failed to show significant differences from placebo in the primary end-point. Nominally significant improvements over placebo were observed for vortioxetine doses of 10 and 20 mg when the primary end-point was evaluated using the mixed model for repeated measures as the secondary analysis, and 10 mg in secondary measures of response and patient functioning. Vortioxetine was well tolerated. Nausea, constipation, dry mouth, dizziness, and insomnia each occurred at a >twofold higher rate than placebo. Discontinuation symptom scores were comparable between all groups after 1 and 2 weeks following withdrawal of the study drug. Conclusion While vortioxetine failed to meet significance versus placebo in the primary efficacy analysis, there was evidence of efficacy for the 10- and 20-mg doses in secondary analyses. Vortioxetine was safe and well tolerated. Additional studies appear warranted.

Comparative effects of aripiprazole and selected antipsychotic drugs on lipid peroxidation in plasma.

Abstract: Aim The aim of the present study was to evaluate and compare the effects of a new antipsychotic, aripiprazole (unique due to its mechanism of action), with the effects of selected antipsychotic drugs, such as quetiapine, olanzapine, clozapine, risperidone, and ziprasidone (at the final concentrations corresponding to clinically effective doses used for the treatment of acute episodes of schizophrenia) on lipid peroxidation in human plasma measured by the level of thiobarbituric acid reactive substances (TBARS), which is a marker of oxidative stress. Methods The levels of TBARS were measured spectrophotometrically, according to the modification of the Rice-Evans method. Results Our results indicate that antipsychotics at doses recommended for the treatment of acute episodes of schizophrenia may induce distinct changes in the levels of lipid peroxidation products (TBARS) in plasma. Aripiprazole had no effect on the level of a lipid peroxidation marker in plasma, although used at lower doses it showed insignificant prooxidative properties similar to clozapine. Quetiapine had the strongest antioxidant properties, contrary to prooxidative action of risperidone, ziprasidone or haloperidol, and clozapine at lower doses. Olanzapine reduced the level of TBARS in plasma only at a lower dose. Conclusion Antipsychotics at doses recommended for the treatment of acute episode in schizophrenia may induce the distinct changes in plasma lipid peroxidation. Aripiprazole did not induce significant changes in plasma lipid peroxidation. In further studies, the role of oxidative stress in schizophrenic patients together with their clinical symptomatology and use of antipsychotics should be taken into account.