Correction: Association of serum BDNF levels and the BDNF Val66Met polymorphism with the sleep pattern in healthy young adults.

[This corrects the article DOI: 10.1371/journal.pone.0199765.].

Association of serum BDNF levels and the BDNF Val66Met polymorphism with the sleep pattern in healthy young adults.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is widely expressed in the brain and plays an important role in neuronal maintenance, plasticity, and neurogenesis. Prior studies have found that decreased serum BDNF levels are associated with perceived stress, depression, or sleep disturbances in humans. STUDY OBJECTIVES: To elucidate whether the serum BDNF levels and BDNF genotype were associated with the sleep pattern in healthy young adults. METHODS: The study group consisted of 79 healthy paid volunteers (45 men, 34 women) aged 20 to 29 years. Serum BDNF levels were measured with an enzyme-linked immunosorbent assay, and a single-nucleotide polymorphism (Val66Met) in the BDNF gene was assessed with a TaqMan assay. Details of the sleep pattern were obtained from 1-week sleep/wake records. RESULTS: Serum BDNF levels were significantly associated with sleep parameters on weekends, whereas no such association was found on weekdays. On weekends, longer total sleep time and time in bed, and later mid-sleep time were associated with lower serum BDNF levels. The difference between mid-sleep time on weekdays and that on weekends, otherwise known as social jetlag, was negatively associated with serum BDNF levels. Met/Met homozygotes of the BDNF Val66Met polymorphism had significantly longer time in bed on weekends than Val/Val homozygotes. Heterozygotes did not differ from Val/Val homozygotes. CONCLUSIONS: We first found that serum BDNF levels and the BDNF Val66Met polymorphism in healthy young adults were associated with the sleep pattern on weekends but not with that on weekdays, suggesting that the systems involved in BDNF control may be linked to endogenous sleep characteristics rather than the socially constrained sleep schedule in healthy young adults.

Unhealthy lifestyle factors and depressive symptoms: A Japanese general adult population survey.

OBJECTIVE: To investigate the relationship between unhealthy lifestyles factors and depressive symptoms among the general adult population in Japan. METHOD: Participants were randomly selected from the Japanese general adult population. Data from 2334 people aged 20 years or older were analyzed. This cross-sectional survey was conducted in August and September 2009. Participants completed a face-to-face interview about unhealthy lifestyle factors, including lack of exercise, skipping breakfast, a poorly balanced diet, snacking between meals, insufficient sleep, current smoking, alcohol drinking, and obesity. Presence of depressive symptoms was defined as a score of ≥ 16 on the Japanese version of the Center for Epidemiologic Studies Depression Scale (CES-D). Relationships between unhealthy lifestyle factors and depressive symptoms were evaluated by multivariate logistic regression analysis adjusting for sociodemographic variables and other unhealthy lifestyle factors. RESULTS: Multivariate logistic regression analysis revealed that insufficient sleep, a poorly balanced diet, snacking between meals and lack of exercise were significantly associated with the prevalence of depressive symptoms, with odds ratios ranging from 1.56 for lack of exercise to 3.98 for insufficient sleep. LIMITATIONS: Since this study was a cross-sectional study, causal relationships could not be determined. CONCLUSION: These results suggest that promoting a healthy lifestyle focused on sleep, food intake and exercise may be important for individuals with depressive symptoms.

One-Year Follow-Up of Serum Prolactin Level in Schizophrenia Patients Treated with Blonanserin: A Case Series.

In our previous study, a prolactin elevation was more frequently in risperidone than in blonanserin; however, it was more often in blonanserin than in olanzapine. Therefore, while a rate of PRL rising is low to moderate, hyperprolactinemia is a considerable adverse effect in the blonanserin treatment. In this study, to examine detailed characteristics of hyperprolactinemia of blonanserin, we analyzed the prolactin data in six schizophrenic patients who were switched to blonanserin from other antipsychotics and followed for one year. As a result, blonanserin dose was clearly associated with serum prolactin level. The average prolactin level was almost normal when the mean blonanserin dosage was 8.0 mg/day. Regardless of the dose decrease of blonanserin, there were no remarkable changes in symptoms and social functions. Based on our findings, we conclude that low dose blonanserin medication may be useful for schizophrenia maintenance treatment without hyperprolactinemia and a high rate of relapse.

Meta-analysis of data from the Psychiatric Genomics Consortium and additional samples supports association of CACNA1C with risk for schizophrenia.

Recently, numerous genome-wide association studies (GWASs) have identified numerous risk loci for schizophrenia, but follow-up studies are still essential to confirm those results. Therefore, we followed up on top GWAS hits by genotyping implicated loci in additional schizophrenia family samples from our own collection. Five-hundred thirty-six Asian families (comprising 1633 members including 698 schizophrenics) were genotyped in this study. We analyzed 12 single nucleotide polymorphisms (SNPs) in strongly implicated candidate genes revealed by GWASs and their follow-up studies. We then used meta-analysis to combine our results with those of the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC). In our newly genotyped samples, there were no significant associations of any of the 12 candidate SNPs with schizophrenia; however, all genome-wide significant results from the schizophrenia PGC analysis were maintained after combination with our new data by meta-analysis. One SNP (rs4765905 in CACNA1C) showed a stronger effect and decreased p-value (5.14e-17) after meta-analysis relative to the original PGC results, with no significant between-study heterogeneity. The findings of this study support the significant results in the PGC, especially for CACNA1C. The sample size in our study was considerably smaller than that in the PGC-SCZ study; thus, the weights carried by our samples in the meta-analysis were small. Therefore, our data could not vastly reduce PGC association signals. However, we considered that the well replicated results from the PGC hold up in our new samples, and may suggest that the top hits from the PGC are generalizable, even to other ancestral groups.

Case history and genome-wide scans for copy number variants in a family with patient having 15q11.1-q11.2 duplication and 22q11.2 deletion, and schizophrenia.

Many studies have indicated that chromosomes 15q11 and 22q11 may be associated with the genetic etiologies of schizophrenia. We have followed an adult schizophrenia case with 15q11.1-q11.2 duplication and 22q11.2 deletion. Here we report his clinical history, and copy number variants (CNVs) identified by microarray and real-time PCR in the patient and his parents. This is the first report describing a detailed phenotype of an adult schizophrenic case with both 15q11 and 22q11 CNVs as revealed by novel and trustworthy technologies. Subjects were a 33-year-old male patient with 15q11 and 22q11 CNVs, and his normal parents. He fulfilled the DSM-IV criteria for schizophrenia at age 18 years. He was also diagnosed with 22q11.2 deletion syndrome by fluorescence in situ hybridization (FISH) at age 18 years. To search for CNVs in more detail, whole-genome array-CGH analyses including ∼ 420,000 probes were carried out in the patient and his parents. For validations of the CNVs detected by array-CGH, real-time PCR analyses of these CNVs were performed. The patient had two disease-specific CNVs, 15q11.1-q11.2 duplication (∼ 2.7 Mb) and 22q11.21 deletion (∼ 2.9 Mb). These two regions are important for the development of schizophrenia, and this patient had shown symptoms of schizophrenia. Thus, the two areas may contain causal genes for schizophrenia.

Heterogeneity of schizophrenia: Genetic and symptomatic factors.

Schizophrenia may have etiological heterogeneity, and may reflect common symptomatology caused by many genetic and environmental factors. In this review, we show the potential existence of heterogeneity in schizophrenia based on the results of our previous studies. In our study of the NOTCH4 gene, there were no significant associations between any single nucleotide polymorphisms (SNPs) of NOTCH4 and schizophrenia. However, exploratory analyses suggested that the SNP, rs3134928 may be associated with early-onset schizophrenia, and that rs387071 may be associated with schizophrenia characterized by negative symptoms. In our highly familial schizophrenia study, the African-American cohort without environmental exposure showed a possible linkage at marker 8p23.1 in the dominant model and in the European-American cohort, a marker at 22q13.32 showed a probable linkage in the recessive model. In the less familial schizophrenia families, these linkages were not shown. Based on our eye movement study, a putative subtype of schizophrenia with severe symptoms related to excitement/hostility, negative symptoms and disorganization may be associated with chromosome 22q11. We consider that a sample stratification approach may clarify the heterogeneity of schizophrenia. Therefore, this approach may lead to a more straightforward way of identifying susceptibility genes of schizophrenia.

One-year follow-up study of psychotic patients treated with blonanserin: a case series.

INTRODUCTION: Blonanserin is a relatively new atypical antipsychotic drug, and has been used in Korea and Japan for 1 and 3 years, respectively. Therefore, the clinical characteristics of blonanserin remain unclear. In this study, to clarify the features of blonanserin, we performed prospective and long-term comparative investigations of patients treated with blonanserin. METHODS: We followed 10 psychiatric patients who were switched to blonanserin from other antipsychotics for 1 year (schizophrenia: 8; mental retardation: 2). In the light of quality of life, we focused on adverse effects of patients during the follow-up. RESULTS: In the long-term follow-up, (i) hyperprolactinemia is more frequently in risperidone than in blonanserin; however, it is more often in blonanserin than in olanzapine; and (ii) weight gain is more common in olanzapine than in blonanserin. DISCUSSION: We switched to blonanserin from other antipsychotic drugs within the same case, and then followed the case for 1 year. We consider that long-term observations within the same case lead to obvious comparisons among drugs. On the basis of our findings, we conclude that blonanserin may be useful for the maintenance treatment of schizophrenia without inducing hyperprolactinemia and weight gain.

The association between sleep problems and perceived health status: a Japanese nationwide general population survey.

OBJECTIVE: Sleep problems in humans have been reported to impact seriously on daily function and to have a close association with well-being. To examine the effects of individual sleep problems on physical and mental health, we conducted a nationwide epidemiological survey and examined the associations between sleep problems and perceived health status. METHODS: Cross-sectional surveys with a face-to-face interview were conducted in August and September, 2009, as part of the Nihon University Sleep and Mental Health Epidemiology Project (NUSMEP). Data from 2559 people aged 20 years or older were analyzed (response rate 54.0%). Participants completed a questionnaire on perceived physical and mental health statuses, and sleep problems including the presence or absence of insomnia symptoms (i.e., difficulty initiating sleep [DIS], difficulty maintaining sleep [DMS], and early morning awakening [EMA]), excessive daytime sleepiness (EDS), poor sleep quality (PSQ), short sleep duration (SSD), and long sleep duration (LSD). RESULTS: The prevalence of DIS, DMS, and EMA was 14.9%, 26.6%, and 11.7%, respectively, and 32.7% of the sample reported at least one of them. At the complaint level, the prevalence of EDS, PSQ, SSD, and LSD was 1.4%, 21.7%, 4.0%, and 3.2%, respectively. Multiple logistic regression analyses revealed that DMS, PSQ, SSD, and LSD were independently associated with poor perceived physical health status; DIS, EDS, and PSQ were independently associated with poor perceived mental health status. CONCLUSIONS: This study has demonstrated that sleep problems have individual significance with regard to perceived physical or mental health status.

Relationships between exploratory eye movement dysfunction and clinical symptoms in schizophrenia.

AIM: Many psychophysiological tests have been widely researched in the search for a biological marker of schizophrenia. The exploratory eye movement (EEM) test involves the monitoring of eye movements while subjects freely view geometric figures. Suzuki et al. (2009) performed discriminant analysis between schizophrenia and non-schizophrenia subjects using EEM test data; consequently, clinically diagnosed schizophrenia patients were identified as having schizophrenia with high probability (73.3%). The aim of the present study was to investigate the characteristics of schizophrenia patients who were identified as having schizophrenia on EEM discriminant analysis (SPDSE) or schizophrenia patients who were identified as not having schizophrenia on EEM discriminant analysis (SPDNSE). METHODS: The data for the 251 schizophrenia subjects used in the previous discriminant-analytic study were analyzed, and the demographic or symptomatic characteristics of SPDSE and SPDNSE were investigated. As for the symptomatic features, a factor analysis of the Brief Psychiatric Rating Scale (BPRS) rating from the schizophrenia subjects was carried out. RESULTS: Five factors were found for schizophrenia symptoms: excitement/hostility; negative symptoms; depression/anxiety; positive symptoms; and disorganization. SPDSE had significantly higher factor scores for excitement/hostility, negative symptoms and disorganization than SPDNSE. Furthermore, the BPRS total score for the SPDSE was significantly higher than that for the SPDNSE. CONCLUSION: SPDSE may be a disease subtype of schizophrenia with severe symptoms related to excitement/hostility, negative symptoms and disorganization, and EEM parameters may detect this subtype. Therefore, the EEM test may be one of the contributors to the simplification of the heterogeneity of schizophrenia.

Self-help behaviors for sleep and depression: a Japanese nationwide general population survey.

OBJECTIVE: The aim of this study was to examine the relationship between self-help behaviors for sleep (SHBS) and depression among the general adult population in Japan. METHODS: The survey was conducted in June 2000 using self-administered questionnaires for subjects living in 300 communities randomly selected throughout Japan. A total of 24,686 responses were analyzed from individuals aged 20 years or older. The Center for Epidemiologic Studies Depression Scale was used to assess the prevalence of depression with two cut-off points: 16 and 25. Details of 6 types of SHBS were asked, based on given examples of actual behavior and frequency. RESULTS: After adjusting for sociodemographic variables, sleep problems and other SHBS, multiple logistic regression analyses revealed that "snacking on food and/or beverages" was independently associated with an increased odds ratio for depression, whereas "maintaining lifestyle regularity" was independently associated with a decreased odds ratio for depression. "Drinking alcoholic beverages," "having a bath," and "reading books or listening to music" were associated with an increased odds ratio for depression in crude analyses, but the significance of the association disappeared after adjusting for sociodemographic variables, sleep problems and other SHBS. LIMITATION: Complex constructs are being correlated. CONCLUSIONS: These results suggest that individual SHBS are differentially associated with depression, thus providing important clues for establishing sleep hygiene for treatment and prevention of depression.

[Management of insomnia and hypersomnia associated with psychiatric disorders].

Most psychiatric disorders, such as schizophrenia, mood disorders, or neurotic disorders are associated with sleep disorders of various kinds, among which insomnia is most prevalent and important in psychiatric practice. Almost all patients suffering from major depression complain of insomnia. Pharmacological treatment of insomnia associated with major depression shortens the duration to achieve remission of depression. Insomnia has been recently reported to be a risk factor for depression. Hypersomnia is also a major sleep problem in patient suffering from depression. There have been no clinical guide to treat the symptoms of hypersomnia in depression, but some clinical trials treating them with NDRI or adjunctive administration of psychostimulants. In patients with schizophrenia, insomnia is often an early indicator of the aggravation of psychotic symptoms. Electroencephalographic sleep studies have also revealed sleep abnormalities characteristic to mood disorders, schizophrenia and anxiety disorders. A shortened REM sleep latency has been regarded as a biological marker of depression. Reduced amount of deep Non-REM sleep has been reported to be correlated with negative symptoms of schizophrenia. Recently, REM sleep abnormalities were found in teenagers having post-traumatic stress disorder after a boat accident. Although these facts indicate that insomnia plays an important role in the development of psychiatric disorders, there are few hypotheses explaining the cause and effect of insomnia in these disorders. Here, we reviewed recent articles on insomnia and hypersomnia associated with psychiatric disorders together with their clinical managements.

Coping strategies and their correlates with depression in the Japanese general population.

This study's aim was to examine the relation between depression and stress-coping strategy among the general population. The survey was conducted in June 2000, using a large sample representative of the Japanese general population. A total of 24,551 responses from individuals aged 20 years or older were analyzed. The Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess the prevalence of depression with two different cut-off points; 16 and 26. Stress-coping strategies were asked based on given examples of actual behaviors covering problem-focused, emotion-focused, and avoidant ones. There was no marked gender difference in the prevalence of a problem-solving strategy, while various types of gender differences were found with respect to the prevalence of emotion-focused and avoidant strategies. In relation to depression, multivariate logistic regression analyses revealed the significantly highest odds ratios (OR) for avoidant coping strategies and the lowest OR for problem-focused ones in both genders. The fact that depression was associated positively with avoidant strategies but negatively with problem-solving strategies indicates that individual stress-coping strategies have their own significance with respect to depression, and may be utilized in establishing an evidence-based cognitive behavioral approach to depressive patients.

Exploratory eye movement dysfunction as a discriminator for schizophrenia : a large sample study using a newly developed digital computerized system.

In our previous studies, we identified that exploratory eye movement (EEM) dysfunction appears to be specific to schizophrenia. The availability of a biological marker specific to schizophrenia would be useful for clinical diagnosis of schizophrenia. Consequently, we performed the discriminant analysis between schizophrenics and non-schizophrenics on a large sample using the EEM test data and examined an application of the EEM for clinical diagnosis of schizophrenia. EEM performances were recorded in 251 schizophrenics and 389 non-schizophrenics (111 patients with mood disorders, 28 patients with neurotic disorders and 250 normal controls). The patients were recruited from eight university hospitals and three affiliated hospitals. For this study with a large sample, we developed a new digital computerized version of the EEM test, which automatically handled large amounts of data. We measured four parameters: number of eye fixations (NEF), total eye scanning length (TESL), mean eye scanning length (MESL) and responsive search score (RSS). These parameters of schizophrenics differed significantly from those of the other three groups. The stepwise regression analysis selected the TESL and the RSS as the valid parameters for discriminating between schizophrenics and non-schizophrenics. In the discriminant analysis using the RSS and TESL as prediction parameters, 184 of the 251 clinically diagnosed schizophrenics were discriminated as having schizophrenia (sensitivity 73.3%); and 308 of the 389 clinically diagnosed non-schizophrenic subjects were discriminated as non-schizophrenics (specificity 79.2%). Based on our findings we believe that the EEM measures may be useful for the clinical diagnosis of schizophrenia.