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Background Having no or few confidants is found to be associated with more severe mental health problems and a higher prevalence of depression in adults, but research examining this association in adolescents is scarce. Social relationships may be particularly critical during adolescence, as it is an important developmental period during which vulnerability to mental health problems increases. The present study examined the relationship between having no or few confidants and anxiety/depressive symptoms in adolescents. Methods Cross-sectional self-report data from 17,829 Japanese students (49.7% boys) in public junior and senior high schools were analyzed. Associations between anxiety/depressive symptoms (12-item General Health Questionnaire; score range: 0–12) and the number of confidants (None, 1–3, or ≥ 4) were examined using multilevel regression analyses. The analyses were stratified by gender and school level (junior/senior high), and adjusted for experiences of physical abuse and bullying. Results Having 1–3 or no confidants was associated with more anxiety/depressive symptoms, compared to having ≥ 4 confidants (p

Background Lithium is the first‐line drug for the treatment of bipolar disorders (BDs); however, not all patients responded. Glycogen synthase kinase (GSK) 3β and brain‐derived neurotrophic factor (BDNF) play a role in the therapeutic action of lithium. Since structural variations were reported in these genes, it is possible that these genomic variations may be involved in the therapeutic responses to lithium. Method Fifty patients with BDs and 50 healthy subjects (mean age 55.0 ± 15.0 years; M/F 19/31) participated. We examined structural variation of the GSK3β and BDNF genes by real‐time PCR. We examined the influence of structural variation of these genes on the therapeutic responses to lithium and the occurrence of antidepressant‐emergent affective switch (AEAS). The efficacy of lithium was assessed using the Alda scale, and AEAS was evaluated using Young Mania Rating Scale. Results Although we examined structural variations within intron II and VII of the GSK3® gene and from the end of exon IV to intron IV and within exon IX of the BDNF gene, no structural variation was found in BDs. Whereas 5 of 50 patients exhibited three copies of the genomic region within exon IV of the BDNF gene, all healthy subjects had two copies. No difference in the therapeutic efficacy of lithium was found between patients with three and two copies. No difference in the occurrence of AEAS was found between the two groups. Conclusion The amplification of the BDNF gene influenced neither the therapeutic responses to lithium nor the occurrence of AEAS., Five of 50 patients with bipolar disorders exhibited three copies of the genomic region within exon IV of the BDNF gene. But, 50 healthy subjects had two copies. This amplification did not affect the therapeutic responses to lithium.

Recently, several epidemiologic studies have reported that lithium in drinking water may be associated with lower rates of suicide mortality, lower incidence of dementia, and lower levels of adolescents' depression and aggression at the population level. However, to our knowledge, no study has investigated lithium level in tap water in relation to psychotic experiences in a general population of adolescents. This is the first study to investigate this using a large dataset. Information on psychotic experiences, distress associated with these experiences, and depressive symptoms were collected in 24 public junior high schools in Kochi Prefecture in Japan. Samples were collected from sources that supplied drinking water to schools, and lithium levels were measured using atomic absorption spectrophotometry. The association of lithium levels with psychotic experiences, considering distress as a degree of severity, was examined using an ordinal logistic regression model with schools and depressive symptoms as random effects. In total, 3040 students responded to the self-reporting questionnaire (response rate: 91.8%). Lithium levels in tap water were inversely associated with psychotic experiences (p = 0.021). We concluded that lithium level in tap water was inversely associated with psychotic experiences among a general population of adolescents and may have a preventive effect for such experiences and distress.

Background Behavioral activation (BA) is receiving renewed interest as a stand-alone or as a component of cognitive-behavior therapy (CBT) for depression. However, few studies have examined which aspects of BA are most contributory to its efficacy. Methods This is a secondary analysis of a 9-week randomized controlled trial of smartphone CBT for patients with major depression. Depression severity was measured at baseline and at end of treatment by the Patient Health Questionnaire-9. All aspects of behavioral activation tasks that the participants had engaged in, including their expected mastery and pleasure and obtained mastery and pleasure, were recorded in the web server. We examined their contribution to improvement in depression as simple correlations and in stepwise multivariable linear regression. Results Among the 78 patients who completed at least one behavioral experiment, all aspects of expected or achieved mastery or pleasure correlated with change in depression severity. Discrepancy between the expectation and achievement, representing unexpected gain in mastery or pleasure, was not correlated. In stepwise regression, expected mastery and pleasure, especially the maximum level of the latter, emerged as the strongest contributing factors. Limitations The study is observational and cannot deduce cause-effect relationships. Conclusions It may be the expected and continued sense of pleasure in planning activities that are most meaningful and rewarding to individuals, and not the simple level or amount of obtained pleasure, that contributes to the efficacy of BA.

Purpose Social isolation is associated with suicidal ideation (SI) and self-harm (SH) among adolescents. However, the association between preference for solitude (PfS), SI, and SH is unknown. The prevalence of adolescents who have both of PfS and social isolation and the risks for SI and SH among them are also unknown. Methods Information on PfS, social isolation, SI, and SH was collected in a large-scale school-based survey on adolescents, using a self-report questionnaire. Associations between PfS, SI, and SH were examined by logistic regression analysis. The interactions between PfS and social isolation on SI and SH were also investigated. The odds of SI and SH were examined for groups defined by presence of PfS and social isolation. Results Responses from 17,437 students (89.3% of relevant classes) were available. After adjusting for demographic characteristics and social isolation, PfS was associated with increased odds of SI (odds ratio [OR] = 3.1) and SH (OR = 1.9). There was no interaction between PfS and social isolation on SI and SH. After adjusting for demographic characteristics, the odds for SI (OR = 8.6) and SH (OR = 3.8) were highest among adolescents with both PfS and social isolation (8.4% of all respondents). Conclusions PfS was associated with increased odds of SI and SH in adolescents. No interaction effect between PfS and social isolation on SI and SH was found, but adolescents with PfS and social isolation had the highest risk for SI and SH. Parents and professionals should pay attention to suicide risk in adolescents with PfS.

Suicide is a leading cause of death in adolescents, but detection of its risk is often challenging. Many mental illnesses share the common symptom of appetite loss and it is also known that people who suffer from these illnesses are at greater risk of suicide. However, the relationship between appetite loss and suicide risk has yet to be examined. For adolescents in particular, questions about appetite loss may be easier to answer than sensitive questions regarding mental health. The present study aims to investigate the association of appetite loss with suicidal ideation and self-harm in adolescents. Rates of adolescents with suicidal ideation or self-harm associated with appetite-loss were examined in 18,250 Japanese junior and senior high school students (aged 12-18) using a self-report questionnaire. Insomnia, a physical symptom which has previously been associated with suicide risk, was also controlled for in the analysis. Results showed that rates of adolescents with suicidal ideation or self-harm significantly increased according to the degree of self-reported appetite loss. Similar results were observed for insomnia. Odds ratios (ORs) for suicidal ideation and self-harm were 5.5 and 4.1 for adolescents with appetite loss compared to those without it, and the ORs were 5.5 and 3.5 for those with insomnia compared to those without it, respectively, adjusting for sex and age (p 0.001). ORs remained statistically significant after adjusting for depression/anxiety (General Health Questionnaire-12 score). In conclusion, self-reported appetite loss was highly associated with suicidal ideation and self-harm in adolescents; adolescents reporting physical symptoms such as loss of appetite or insomnia should be given careful attention.

Objective We investigated the association between lithium level in tap water and mental health problems, including depressive symptoms, anxiety, and aggressive and suicidal behaviors, in a general population of adolescents using a large individual-level dataset. Methods A school-based, cross-sectional survey was conducted in Kochi Prefecture in Japan between 2008 and 2009. Students in 24 public junior high schools were asked to anonymously complete a self-report questionnaire. The main outcome measures were mental health problems, including those on the 12-item General Health Questionnaire, interpersonal violence, bullying, destructive behavior, self-harm, and suicidal ideation. Samples were collected from sources that supplied drinking water to schools, and lithium levels were measured using atomic absorption spectrophotometry. The associations of lithium levels with mental health problems were examined using a generalized linear mixed model with schools as the fixed effect. Potential confounding factors were also added into the model. Results A total of 3,040 students among 3,311 students responded to the self-report questionnaire (response rate, 91.8%). The mean lithium concentration in tap water was 0.48 μg/L (SD = 0.52; range, 0.01 to 2.10; skewness = 2.01; kurtosis = 4.04), and it was relatively low compared with previous studies. In multivariable regression analysis, lithium level in tap water had an inverse association with depressive symptoms (P = .02) and interpersonal violence (P = .02) but not with suicidal behaviors (suicidal ideation, P = .82; self-harm, P = .46). Conclusions Lithium level in tap water was inversely associated with depressive symptoms and interpersonal violence among a general population of adolescents and may have antidepressive and antiaggressive effects.

Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P=6.4 × 10−9), a region known to contain regulatory genes for plasma lipid levels (FADS1/2/3). A subsequent meta-analysis of Phase I/II and the Psychiatric GWAS Consortium for BD (PGC-BD) identified another novel BD gene, NFIX (P best=5.8 × 10−10), and supported three regions previously implicated in BD susceptibility: MAD1L1 (P best=1.9 × 10−9), TRANK1 (P best=2.1 × 10−9) and ODZ4 (P best=3.3 × 10−9). Polygenicity of BD within Japanese and trans-European-Japanese populations was assessed with risk profile score analysis. We detected higher scores in BD cases both within (Phase I/II) and across populations (Phase I/II and PGC-BD). These were defined by (1) Phase II as discovery and Phase I as target, or vice versa (for ‘within Japanese comparisons’, Pbest~10−29, R2~2%), and (2) European PGC-BD as discovery and Japanese BD (Phase I/II) as target (for ‘trans-European-Japanese comparison,’ Pbest~10−13, R2~0.27%). This ‘trans population’ effect was supported by estimation of the genetic correlation using the effect size based on each population (liability estimates~0.7). These results indicate that (1) two novel and three previously implicated loci are significantly associated with BD and that (2) BD ‘risk’ effect are shared between Japanese and European populations.

Background Although depression has a high rate of recurrence, no prior studies have established a method that could identify the warning signs of its recurrence. Methods We collected digital data consisting of individual activity records such as location or mobility information (lifelog data) from 89 patients who were on maintenance therapy for depression for a year, using a smartphone application and a wearable device. We assessed depression and its recurrence using both the Kessler Psychological Distress Scale (K6) and the Patient Health Questionnaire-9. Results A panel vector autoregressive analysis indicated that long sleep time was a important risk factor for the recurrence of depression. Long sleep predicted the recurrence of depression after 3 weeks. Conclusions The panel vector autoregressive approach can identify the warning signs of depression recurrence; however, the convenient sampling of the present cohort may limit the scope towards drawing a generalised conclusion.

The serotonin transporter (5HTT) may be associated with the pathogenesis of major depressive disorder (MDD). The 5HTT-linked polymorphic region (5HTTLPR) genotype may determine how levels of 5HTT mRNA are influenced by promoter methylation. We examined the association of 5HTT gene methylation, which influences gene expression, and the 5HTTLPR genotype before antidepressant treatment and expression before and after treatment. The aims of this study were (1) to investigate the association between 5HTT methylation or expression in leukocytes and depression and (2) to investigate a possible effect of 5HTT methylation, expression, and genotype on clinical symptoms in MDD. The 5HTTLPR genotype was significantly associated with mean methylation levels in patients only (patients: r = 0.40, p = 0.035, controls: p = 0.96). The mean methylation level was significantly increased in patients compared with controls (patients: 5.30 ± 0.24, controls: 4.70 ± 0.19, unpaired t-test, p = 0.04). 5HTT expression using real-time PCR and Taqman probes was increased in unmedicated patients compared with controls and then decreased 8 weeks after antidepressant treatment. The mean 5HTT expression level was not associated with the 5HTTLPR genotype in patients or controls. Increased depressive symptoms were related to decreased levels of methylation. Copyright © 2016 John Wiley & Sons, Ltd.

Sleep problems during adolescence affect current and subsequent mental health and are associated with experiences of psychotic symptoms. Recent studies have suggested that short sleep duration increases the risk of experiencing psychotic symptoms in the general adolescent population; however, whether long sleep duration is associated with an increased risk of psychotic symptoms in adolescence remains unclear. The present study aimed to examine the relationships between long sleep duration, short sleep duration, and the risk of experiencing psychotic symptoms in adolescence. Cross-sectional survey data from 15,786 junior and senior high school students (12- to 15-year-olds and 15- to 18-year-olds, respectively) in Japan were collected and analyzed using logistic regression analysis after controlling for covariates, including depressive symptoms. Long sleep duration was associated with a 1.6- to 2.8-fold increased risk of psychotic symptoms in male but not in female adolescents. Short sleep duration was also related with a 1.6- to 2.9-fold increased risk of experiencing psychotic symptoms, except for 15- to 18-year-old female adolescents. The present study suggested that adolescents with long and short sleep duration should be assessed for their risk of experiencing psychotic symptoms regardless of concurrent depressive symptoms.

Background Identifying the predictors of relapse could help to develop more individualized treatment strategies for major depression. The study aim was to explore predictors of depression relapse after remission using data from our previous multicenter randomized practical trial of patients with major depression. Methods Our cohort comprised subjects with Patient Health Questionnaire (PHQ-9) scores less than 5 after antidepressant treatment for 9 weeks. Relapse was defined as a PHQ-9 score of 5 or more at week 25. We examined patient demographic and clinical characteristics at baseline (age, sex education, job status, marital status, onset age at first depressive episode, number of previous episodes, length of current episode, scores on the nine PHQ-9 criteria at week 0) and Frequency, Intensity, and Burden of Side Effects Rating Scale and PHQ-9 total scores at week 9 (residual symptoms) as potential predictors of depression relapse at week 25. Results Of 494 patients remitted at week 9, 71 (14.4%) experienced relapse at week 25. Logistic regression analysis showed that lower PHQ-9 depressive mood score at week 0, higher suicidal ideation score at week 0, and total PHQ-9 score at week 9, and greater severity of side effects at week 9 were significant predictors. On the other hand, when relapse was defined as a PHQ-9 score of 10 or more at week 25, there were no significant predictors. Limitations There may be other important predictors that this study failed to identify and the findings obtained may be sensitive to the specific definition of relapse. Conclusions Approximately one-seventh of subjects who remitted after 2 months of acute-phase treatment experienced depression relapse within 4 months of remission. Lower depressive mood and higher suicidal ideation upon development of the current depression episode, the presence of residual symptoms, and greater severity of side effects at remission may predict subsequent depression relapse.

Background: Alterations in one-carbon metabolism have been associated with schizophrenia, and vitamin B6 is one of the key components in this pathway. Methods: We first conducted a case–control study of serum pyridoxal levels and schizophrenia in a large Japanese cohort (n = 1276). Subsequently, we conducted a meta-analysis of association studies (n = 2125). Second, we investigated whether rs4654748, which was identified in a genome-wide association study as a vitamin B6-related single nucleotide polymorphism, was genetically implicated in patients with schizophrenia in the Japanese population (n = 10 689). Finally, we assessed the effect of serum pyridoxal levels on schizophrenia risk using a Mendelian randomization (MR) approach. Results: Serum pyridoxal levels were significantly lower in patients with schizophrenia than in controls, not only in our cohort, but also in the pooled data set of the meta-analysis of association studies (standardized mean difference –0.48, 95% confidence interval [CI] –0.57 to –0.39, p = 9.8 × 10–24). We failed to find a significant association between rs4654748 and schizophrenia. Furthermore, an MR analysis failed to find a causal relationship between pyridoxal levels and schizophrenia risk (odds ratio 0.99, 95% CI 0.65–1.51, p = 0.96). Limitations: Food consumption and medications may have affected serum pyridoxal levels in our cross-sectional study. Sample size, number of instrumental variables and substantial heterogeneity among patients with schizophrenia are limitations of an MR analysis. Conclusion: We found decreased serum pyridoxal levels in patients with schizophrenia in this observational study. However, we failed to obtain data supporting a causal relationship between pyridoxal levels and schizophrenia risk using the MR approach.

Many observational studies have shown elevated blood CRP levels in schizophrenia compared with controls, and one population-based prospective study has reported that elevated plasma CRP levels were associated with late- and very-late-onset schizophrenia. Furthermore, several clinical studies have reported the efficacy of anti-inflammatory drugs on the symptoms in patients with schizophrenia. However, whether elevated CRP levels are causally related to schizophrenia is not still established because of confounding factors and reverse causality. In the present study, we demonstrated that serum CRP levels were significantly higher in patients with schizophrenia than in the controls by conducting a case-control study and a meta-analysis of case-control studies between schizophrenia and serum CRP levels. Furthermore, we provided evidence for a causal association between elevated CRP levels and increased schizophrenia risk by conducting a Mendelian randomization analysis. Our findings suggest that elevated CRP itself may be a causal risk factor for schizophrenia.

Background For patients starting treatment for depression, current guidelines recommend titrating the antidepressant dosage to the maximum of the licenced range if tolerated. When patients do not achieve remission within several weeks, recommendations include adding or switching to another antidepressant. However, the relative merits of these guideline strategies remain unestablished. Methods This multi-centre, open-label, assessor-blinded, pragmatic trial involved two steps. Step 1 used open-cluster randomisation, allocating clinics into those titrating sertraline up to 50 mg/day or 100 mg/day by week 3. Step 2 used central randomisation to allocate patients who did not remit after 3 weeks of treatment to continue sertraline, to add mirtazapine or to switch to mirtazapine. The primary outcome was depression severity measured with the Patient Health Questionnaire-9 (PHQ-9) (scores between 0 and 27; higher scores, greater depression) at week 9. We applied mixed-model repeated-measures analysis adjusted for key baseline covariates. Results Between December 2010 and March 2015, we recruited 2011 participants with hitherto untreated major depression at 48 clinics in Japan. In step 1, 970 participants were allocated to the 50 mg/day and 1041 to the 100 mg/day arms; 1927 (95.8%) provided primary outcomes. There was no statistically significant difference in the adjusted PHQ-9 score at week 9 between the 50 mg/day arm and the 100 mg/day arm (0.25 point, 95% confidence interval (CI), − 0.58 to 1.07, P = 0.55). Other outcomes proved similar in the two groups. In step 2, 1646 participants not remitted by week 3 were randomised to continue sertraline (n = 551), to add mirtazapine (n = 537) or to switch to mirtazapine (n = 558): 1613 (98.0%) provided primary outcomes. At week 9, adding mirtazapine achieved a reduction in PHQ-9 scores of 0.99 point (0.43 to 1.55, P = 0.0012); switching achieved a reduction of 1.01 points (0.46 to 1.56, P = 0.0012), both relative to continuing sertraline. Combination increased the percentage of remission by 12.4% (6.1 to 19.0%) and switching by 8.4% (2.5 to 14.8%). There were no differences in adverse effects. Conclusions In patients with new onset depression, we found no advantage of titrating sertraline to 100 mg vs 50 mg. Patients unremitted by week 3 gained a small benefit in reduction of depressive symptoms at week 9 by switching sertraline to mirtazapine or by adding mirtazapine. Trial registration ClinicalTrials.gov, NCT01109693. Registered on 23 April 2010. Electronic supplementary material The online version of this article (10.1186/s12916-018-1096-5) contains supplementary material, which is available to authorized users.

BACKGROUND A strong and growing body of evidence has demonstrated the effectiveness of cognitive behavioral therapy (CBT), either face-to-face, in person, or as self-help via the Internet, for depression. However, CBT is a complex intervention consisting of several putatively effective components, and how each component may or may not contribute to the overall effectiveness of CBT is poorly understood. OBJECTIVE The aim of this study was to investigate how the users of smartphone CBT use and benefit from various components of the program. METHODS This is a secondary analysis from a 9-week, single-blind, randomized controlled trial that has demonstrated the effectiveness of adjunctive use of smartphone CBT (Kokoro-App) over antidepressant pharmacotherapy alone among patients with drug-resistant major depressive disorder (total n=164, standardized mean difference in depression severity at week 9=0.40, J Med Internet Res). Kokoro-App consists of three cognitive behavioral skills of self-monitoring, behavioral activation, and cognitive restructuring, with corresponding worksheets to fill in. All activities of the participants learning each session of the program and completing each worksheet were uploaded onto Kokoro-Web, which each patient could use for self-check. We examined what use characteristics differentiated the more successful users of the CBT app from the less successful ones, split at the median of change in depression severity. RESULTS A total of 81 patients with major depression were allocated to the smartphone CBT. On average, they completed 7.0 (standard deviation [SD] 1.4) out of 8 sessions of the program; it took them 10.8 (SD 4.2) days to complete one session, during which they spent 62 min (SD 96) on the app. There were no statistically significant differences in the number of sessions completed, time spent for the program, or the number of completed self-monitoring worksheets between the beneficiaries and the nonbeneficiaries. However, the former completed more behavioral activation tasks, engaged in different types of activities, and also filled in more cognitive restructuring worksheets than the latter. Activities such as “test-drive a new car,” “go to a coffee shop after lunch,” or “call up an old friend” were found to be particularly rewarding. All cognitive restructuring strategies were found to significantly decrease the distress level, with “What would be your advice to a friend who has a similar problem?” found more helpful than some other strategies. CONCLUSIONS The CBT program offered via smartphone and connected to the remote server is not only effective in alleviating depression but also opens a new avenue in gathering information of what and how each participant may utilize the program. The activities and strategies found useful in this analysis will provide valuable information in brush-ups of the program itself and of mobile health (mHealth) in general. CLINICALTRIAL Japanese Clinical Trials Registry UMIN CTR 000013693; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ ctr_view.cgi?recptno=R000015984 (Archived by WebCite at http://www.webcitation.org/6u6pxVwik)

Background A strong and growing body of evidence has demonstrated the effectiveness of cognitive behavioral therapy (CBT), either face-to-face, in person, or as self-help via the Internet, for depression. However, CBT is a complex intervention consisting of several putatively effective components, and how each component may or may not contribute to the overall effectiveness of CBT is poorly understood. Objective The aim of this study was to investigate how the users of smartphone CBT use and benefit from various components of the program. Methods This is a secondary analysis from a 9-week, single-blind, randomized controlled trial that has demonstrated the effectiveness of adjunctive use of smartphone CBT (Kokoro-App) over antidepressant pharmacotherapy alone among patients with drug-resistant major depressive disorder (total n=164, standardized mean difference in depression severity at week 9=0.40, J Med Internet Res). Kokoro-App consists of three cognitive behavioral skills of self-monitoring, behavioral activation, and cognitive restructuring, with corresponding worksheets to fill in. All activities of the participants learning each session of the program and completing each worksheet were uploaded onto Kokoro-Web, which each patient could use for self-check. We examined what use characteristics differentiated the more successful users of the CBT app from the less successful ones, split at the median of change in depression severity. Results A total of 81 patients with major depression were allocated to the smartphone CBT. On average, they completed 7.0 (standard deviation [SD] 1.4) out of 8 sessions of the program; it took them 10.8 (SD 4.2) days to complete one session, during which they spent 62 min (SD 96) on the app. There were no statistically significant differences in the number of sessions completed, time spent for the program, or the number of completed self-monitoring worksheets between the beneficiaries and the nonbeneficiaries. However, the former completed more behavioral activation tasks, engaged in different types of activities, and also filled in more cognitive restructuring worksheets than the latter. Activities such as “test-drive a new car,” “go to a coffee shop after lunch,” or “call up an old friend” were found to be particularly rewarding. All cognitive restructuring strategies were found to significantly decrease the distress level, with “What would be your advice to a friend who has a similar problem?” found more helpful than some other strategies. Conclusions The CBT program offered via smartphone and connected to the remote server is not only effective in alleviating depression but also opens a new avenue in gathering information of what and how each participant may utilize the program. The activities and strategies found useful in this analysis will provide valuable information in brush-ups of the program itself and of mobile health (mHealth) in general. Trial Registration Japanese Clinical Trials Registry UMIN CTR 000013693; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ ctr_view.cgi?recptno=R000015984 (Archived by WebCite at http://www.webcitation.org/6u6pxVwik)

Objectives Women have higher rates of auditory verbal hallucinations (AVH) than men; however, less is known about sex differences in the prevalence of AVH in early, middle and late adolescence. We sought to elucidate the differences in the prevalence of AVH and to examine the degree to which these differences could be explained by differences in levels of depressive symptoms. Design We used a cross-sectional design and a self-reported questionnaire. Setting Participants were recruited from public junior and senior high schools in Tsu, Mie Prefecture and Kochi Prefecture, Japan. Participants In total, 19 436 students were contacted and 18 250 participated. Responses from 17 451 students with no missing data were analysed (aged 12–18 years, Mage=15.2 years (SD=1.7), 50.6% girls). Measures AVH were assessed through one of four items adopted from the schizophrenia section of the Japanese version of the Diagnostic Interview Schedule for Children. Depressive symptoms were assessed using the 12-item General Health Questionnaire. Results The prevalence of AVH was 7.0% among early adolescents (aged 12–13 years), 6.2% among middle adolescents (aged 14–15 years) and 4.8% among late adolescents (aged 16–18 years). Being female was significantly associated with a higher prevalence of AVH through adolescence (OR=1.71, 95% CI 1.31 to 2.23 in early adolescence; OR=1.42, 95% CI 1.14 to 1.76 in middle adolescence; OR=1.52, 95% CI 1.23 to 1.87 in late adolescence); however, these differences became non-significant after adjusting for depressive symptoms (OR=1.21, 95% CI 0.92 to 1.60; OR=1.00, 95% CI 0.80 to 1.25; OR=1.16, 95% CI 0.93 to 1.44, respectively). Conclusions Sex differences in auditory hallucinations are seen in both adult and youth populations. The higher rates of auditory verbal hallucinations seen in girls may be secondary to the differences in the rate of depressive symptoms.

AIM: Although the efficacy of cognitive behavioral therapy for insomnia has been confirmed, dissemination depends on the balance of benefits and costs. The study aimed to examine the cost-effectiveness of cognitive behavioral therapy for insomnia consisting of 4 weekly individual sessions. METHODS: We conducted a 4-week randomized controlled trial with 4-week follow-up in outpatient clinics in Japan. Thirty-seven patients diagnosed as major depressive disorder with DSM-IV and suffering from chronic insomnia were randomized to either treatment as usual (TAU) alone or TAU plus cognitive behavioral therapy for insomnia. Effectiveness was evaluated as Quality-Adjusted Life Years (QALYs) over 8 weeks' time, estimated by bootstrapping of the observed total scores of the Hamilton Depression Rating scale. Direct medical costs for cognitive behavioral therapy for insomnia and TAU were also evaluated. We calculated the incremental cost-effectiveness ratio. RESULTS: Over 8 weeks of the study, cognitive behavioral therapy for insomnia plus TAU group had significantly higher QALYs (P=0.002) than the TAU alone group with an incremental value of 0.019 (SD 0.006), and had non-significantly higher costs with an incremental value of 254 (SD 203) USD in direct costs. The incremental cost-effectiveness ratio was 13,678 USD (95%CI: -5,691 to 71,316). Adding cognitive behavioral therapy for insomnia demonstrated an approximately 95% chance of gaining one more QALY if a decision-maker was willing to pay for 60,000 USD, and approximately 90% for 40,000. CONCLUSION: Adding cognitive behavioral therapy for insomnia is highly likely to be cost-effective for patients with residual insomnia and concomitant depression. Language: en

DNA methylation, which is the transference of a methyl group to the 5′-carbon position of the cytosine in a CpG dinucleotide, is one of the major mechanisms of epigenetic modifications. A number of studies have demonstrated altered DNA methylation of peripheral blood cells in schizophrenia (SCZ) in previous studies. However, most of these studies have been limited to the analysis of the CpG sites in CpG islands in gene promoter regions, and cell-type proportions of peripheral leukocytes, which may be one of the potential confounding factors for DNA methylation, have not been adjusted in these studies. In this study, we performed a genome-wide DNA methylation profiling of the peripheral leukocytes from patients with SCZ and from non-psychiatric controls (N = 105; 63 SCZ and 42 control subjects) using a quantitative high-resolution DNA methylation microarray which covered across the whole gene region (485,764 CpG dinucleotides). In the DNA methylation data analysis, we first estimated the cell-type proportions of each sample with a published algorithm. Next, we performed a surrogate variable analysis to identify potential confounding factors in our microarray data. Finally, we conducted a multiple linear regression analysis in consideration of these factors, including estimated cell-type proportions, and identified aberrant DNA methylation in SCZ at 2,552 CpG loci at a 5 % false discovery rate correction. Our results suggest that altered DNA methylation may be involved in the pathophysiology of SCZ, and cell heterogeneity adjustments may be necessary for DNA methylation analysis.

The efficacy of cognitive behavioral therapy for insomnia (CBT-I) has been suggested for insomnia concomitant with depression, but its impact on quality of life (QoL) has not been adequately evaluated. The study aimed to determine which aspects of QoL could be affected by CBT-I and how any changes in QoL were mediated by changes in insomnia and depression.We conducted a 4-week randomized controlled trial with 4-week follow-up in outpatient clinics in Japan. Thirty-seven patients with DSM-IV diagnosis of major depressive disorder concomitant with chronic insomnia were randomly assigned to the treatment-as-usual (TAU) alone arm or the TAU with brief behavioral therapy for insomnia (TAU plus psychotherapy) arm using modified CBT-I consisting of 4 weekly individual sessions. We evaluated QoL using norm-based scoring of the Short Form-36 at baseline and at 8 weeks. We also examined associations between QoL subscales and remission in insomnia or depression while controlling for baseline scores of the entire sample.We tested group effects while controlling for baseline scores. TAU plus psychotherapy resulted in significantly better scores on physical functioning (p = 0.006), social functioning (p = 0.002), and mental health (p = 0.041) subscales than TAU alone at 8 weeks. Patients with either remitted insomnia or depression showed higher QoL scores than non-remitted patients; scores approximated those within the normal range.For patients with insomnia in depression, adding CBT-I to TAU can produce substantive benefits in some aspects of QoL.ClinicalTrials.gov Identifier: NCT00610259, http://www.clinicaltrials.gov/.

Previous studies suggest that elevated blood homocysteine levels and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism are risk factors for schizophrenia. However, the effects of gender and MTHFR C677T genotypes on blood homocysteine levels in schizophrenia have not been consistent. We first investigated whether plasma total homocysteine levels were higher in patients with schizophrenia than in controls with stratification by gender and by the MTHFR C677T genotypes in a large cohort (N = 1379). Second, we conducted a meta-analysis of association studies between blood homocysteine levels and schizophrenia separately by gender (N = 4714). Third, we performed a case-control association study between the MTHFR C677T polymorphism and schizophrenia (N = 4998) and conducted a meta-analysis of genetic association studies based on Japanese subjects (N = 10 378). Finally, we assessed the effect of plasma total homocysteine levels on schizophrenia by a mendelian randomization approach. The ANCOVA after adjustment for age demonstrated a significant effect of diagnosis on the plasma total homocysteine levels in all strata, and the subsequent meta-analysis for gender demonstrated elevated blood homocysteine levels in both male and female patients with schizophrenia although antipsychotic medication might influence the outcome. The meta-analysis of the Japanese genetic association studies demonstrated a significant association between the MTHFR C677T polymorphism and schizophrenia. The mendelian randomization analysis in the Japanese populations yielded an OR of 1.15 for schizophrenia per 1-SD increase in plasma total homocysteine. Our study suggests that increased plasma total homocysteine levels may be associated with an increased risk of schizophrenia.

Various psychological therapies have been shown to be effective for the treatment of mood disorders. Among them, family psychoeducation has demonstrated efficacy in reducing symptom severity and extending the time to relapse. We tested the efficacy of adding psychoeducation focussed on how to deal with the family's expressed emotion to treatment as usual (TAU) to prevent relapse among patients with remitted major depression. A total of 34 patients with major depressive disorders in full or partial remission were randomised to receive either group psychoeducation over six sessions, each consisting of a didactic lecture and group problem-solving (n=19), plus TAU or TAU alone (n=15). The primary outcome was relapse by Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV) criteria. Masked raters administered the Hamilton Rating Scale for Depression-17 (HRSD-17). As many as 18 patients in the intervention group and 14 patients in the control group completed the study. Time to relapse was significantly longer in the intervention group than in the control group, with a risk ratio (RR) of relapse by 9 months of 0.12. At 9 months, there was a significantly greater decrease in the HRSD-17 score in the intervention group than in the control group. We demonstrated the effectiveness of patient psychoeducation on the course and outcome of major depressive disorders.

Schizophrenia (SCZ) is a devastating psychiatric disorder with a median lifetime prevalence rate of 0.7-0.8%. Elevated plasma total homocysteine has been suggested as a risk factor for SCZ, and various biological effects of hyperhomocysteinemia have been proposed to be relevant to the pathophysiology of SCZ. As increased attention is paid to aberrant DNA methylation in SCZ, homocysteine is attracting additional interest as a potential key substance. Homocysteine is formed in the methionine cycle, which is involved in one-carbon methyl group-transfer metabolism, and it acts as a methyl donor when it is converted to S-adenosyl-methionine. To date, no studies have examined the relationship between homocysteine and genome-wide DNA methylation in SCZ. We examined the relationship between plasma total homocysteine and DNA methylation patterns in the peripheral leukocytes of patients with SCZ (n = 42) using a quantitative high-resolution DNA methylation array (485,764 CpG sites). Significant homocysteine-related changes in DNA methylation were observed at 1,338 CpG sites that were located across whole gene regions, including promoters, gene bodies and 3'-untranslated regions. Of the 1,338 sites, 758 sites (56.6%) were located in the CpG islands (CGIs) and in the regions flanking CGIs (CGI: 15.8%; CGI shore: 28.2%; CGI shelf: 12.6%), and positive correlations between plasma total homocysteine and DNA methylation were observed predominantly at CpG sites in the CGIs. Our results suggest that homocysteine might play a role in the pathogenesis of SCZ via a molecular mechanism that involves alterations to DNA methylation.

STUDY OBJECTIVES To investigate sleep duration associated with the least depression/anxiety in adolescence. METHODS Grades 7-12 Japanese students (n = 18,250, aged 12-18 y) from public junior high/high schools were studied in a cross-sectional design. Due to missing/implausible data, 15,637 out of the 18,250 students were statistically analyzed. Relationship between sleep duration on school nights and depression/anxiety, measured using self-report questionnaires, including the General Health Questionnaire-12 (GHQ-12), were studied by sex and grade, controlling for bedtime regularity. RESULTS When sleep duration was classified by 1-h intervals, rate of adolescents with a GHQ-12 score ≥ 4 was the lowest in males and females who slept 8.5-9.5 h and 7.5-8.5 h, respectively, (designated "references") in both grades 7-9 and 10-12. The rate was significantly higher than the references in both males and females who slept < 7.5 h, regardless of grade (P < 0.05, logistic regression). GHQ-12 tended to be worse in adolescents (2.0%-13.5%) who slept longer than the references. Sleep duration for the minimum GHQ-12 score was estimated to be 8.8 and 8.5 h in males, and 8.0 and 7.5 h in females, in grades 7-9 and 10-12, respectively, using the General Additive Model. CONCLUSIONS Sleep duration of ≥ 8.5 h on school nights may be associated with the lowest risk of depression/anxiety on average in male adolescents. Although the duration was estimated to be shorter in females (≥ 7.5 h) than males, this should be interpreted carefully. Most adolescents may currently be sleeping less than the optimal duration. COMMENTARY A commentary on this article appears in this issue on page 1491.

Many observational studies have shown elevated blood CRP levels in schizophrenia compared with controls and one population-based prospective study has reported that elevated plasma CRP levels were associated with late- and very-late-onset schizophrenia. Furthermore, several clinical studies have reported the efficacy of anti-inflammatory drugs on the symptoms in patients with schizophrenia. However, whether elevated CRP levels are causally related to schizophrenia is not still established because of confounding factors and reverse causality. In the present study, we demonstrated that serum CRP levels were significantly higher in patients with schizophrenia than in the controls by conducting a case-control study and a meta-analysis of case-control studies between schizophrenia and serum CRP levels. Furthermore, we provided evidence for a causal association between elevated CRP levels and increased schizophrenia risk by conducting a Mendelian randomization analysis. Our findings suggest that elevated CRP itself may be a causal risk factor for schizophrenia.

Although several studies have reported that child physical abuse increased the risk for bullying involvement, the effect of current violence from adult family members (CVA) on bullying involvement and suicidal feelings among adolescents has not been sufficiently examined. This study investigated the association of CVA with adolescent bullying involvement and the interaction effect of CVA and bullying involvement on suicidal feelings. This cross-sectional study used data from a school-based survey with a general population of adolescents (grades 7 to 12). Data were collected using a self-report questionnaire completed by 17,530 students. Logistic regression analyses were performed to explore the association of CVA with adolescent bullying involvement and suicidal feelings. The overall response rate was 90.2%. The odds of students being characterized as bullies, victims, and bully-victims were higher among adolescents with CVA than without CVA (odds ratios (OR) = 2.9, 95% confidence interval (CI), [2.3–3.7], 4.6 [3.6–5.8], and 5.8 [4.4–7.6], respectively). Both CVA (OR = 3.4 [95% CI 2.7–4.3]) and bullying (bullies, victims, and bully-victims; OR = 2.0 [95% CI 1.6–2.6], 4.0 [3.1–5.1], 4.1 [3.0–5.6], respectively), were associated with increased odds of current suicidal feelings after adjusting for confounding factors. Furthermore, positive additive effects of CVA and all three types of bullying involvement on suicidal feelings were found. For example, bully-victims with CVA had about 19-fold higher odds of suicidal feelings compared with uninvolved adolescents without CVA. This study, although correlational, suggested that CVA avoidance might prevent bullying involvement and suicidal feelings in adolescents.

Schizophrenia (SCZ) is a complex psychiatric disease with a lifetime morbidity rate of 0.5-1.0 %. To date, aberrant DNA methylation in SCZ has been reported in several studies. However, no comprehensive studies using medication-free subjects with SCZ have been conducted. In addition, most of these studies have been limited to the analysis of the CpG sites in CpG islands (CGIs) in the gene promoter regions, so little is known about the DNA methylation signatures across the whole genome in SCZ. Genome-wide DNA methylation profiling (485,764 CpG sites) of peripheral leukocytes was conducted in the first set of samples (24 medication-free patients with SCZ and 23 non-psychiatric controls) using Infinium HumanMethylation450 Beadchips. Second, a monozygotic twin study was performed using three pairs of monozygotic twins that were discordant for SCZ. Finally, the data from these two independent cohorts were compared. A total of 234 differentially methylated CpG sites that were common between these two cohorts were identified. Of the 234 CpG sites, 153 sites (65.4 %) were located in the CGIs and in the regions flanking CGIs (CGI: 40.6 %; CGI shore: 13.3 %; CGI shelf: 11.5 %). Of the 95 differently methylated CpG sites in the CGIs, most of them were located in the promoter regions (promoter: 75.8 %; gene body: 14.7 %; 3'-UTR: 2.1 %). Aberrant DNA methylation in SCZ was identified at numerous loci across the whole genome in peripheral leukocytes using two independent sets of samples. These findings support the notion that altered DNA methylation could be involved in the pathophysiology of SCZ.

To study prospectively influences of donepezil, an acetylcholinesterase inhibitor against Alzheimer disease, on cardiovascular system, we evaluated cardiovascular changes occurring during new initialized treatment with donepezil in 49 dementia patients over 6 months. No patient suffered from cardiovascular events. In clinical changes between baseline and the first evaluation after donepezil treatment, heart rate and plasma brain natriuretic peptide (BNP) levels as a marker for heart failure did not change (BNP: 59.62 ± 62.71 pg/mL at baseline to 53.18 ± 42.34 pg/mL at first evaluation; P = 0.262). We further examined plasma BNP levels in 2 groups into which the patients were divided at baseline according to the cut-off plasma BNP level of 60 pg/mL. In patients with high level of BNP, the BNP levels decreased after administration of donepezil (116.39 ± 76.58 pg/mL at baseline to 82.24 ± 46.64 pg/mL at first evaluation; P = 0.011) with the tendency to be reduced in the follow-up period. BNP did not change in patients with low level of BNP. Donepezil seemed to be safe in patients with dementia without symptomatic heart disease and significantly decreased plasma BNP levels in patients with subclinical chronic heart failure.

Little is known about accurate prevalence and associated factors of deliberate self-harm (DSH) among adolescents in Asian countries. In this study, the prevalence and associated factors of DSH among adolescents in Japan were examined. Data were derived from a cross-sectional survey using an anonymous self-report questionnaire and enrolling 8,620 adolescents aged 12-15 and 9,484 aged 15-18. DSH in the previous 12 months was reported by 3.3% (95% CI, 2.9-3.7) of junior and 4.3% (3.9%-4.7%) of senior high school respondents. The prevalence was more than four times as high among girls as among boys for both age groups. DSH was further strongly associated with having suicidal thoughts, having depression/anxiety symptoms, and having used recreational drugs. These associated factors were similar for both sexes and for both older and younger teenagers. A substantial minority of adolescents present with DSH, even among those aged 12-15. The prevalence of DSH in Japan was in the lower ranges of those reported for Western countries. The identified associated factors were not dissimilar from those reported in the West.

Objectives There is an increasing recognition that pain often coexists with depression. The current survey was undertaken to ascertain patients' and clinicians' perceptions of pain as a physical symptom associated with depression in everyday clinical practices in Japan. Methods Web-based surveys were undertaken by a market research company for patients with depression and for physicians treating patients with depression (psychiatrists, psychosomatic physicians, general internists). Results A total of 848 patients aged 20 to 59 years entered the main survey, of whom 663 returned the completed survey (78.2%). Of the respondents, 424 (64.0%) experienced at least 1 painful symptom, with almost three quarters (72.1%) reporting that the pain affected mental symptoms and 68.6% indicating that it prevented recovery from depression itself. Among 337 patients who discussed their painful symptoms with their physician, 52.5% initiated the discussion. Four hundred fifty-six physicians completed the physician survey. When asked about the influence of pain associated with depression, 61.7% of physicians indicated that they ask their patients about pain during a consultation, 79.9% considered that painful symptoms might disturb the patients' daily life, and 52.8% felt that they would delay recovery from depression. With regard to treatment, 73.2% of physicians considered that they would “like to treat if depressed patients talked about their pain” and 64.7% considered that treatment “would be more effective when patients talked about pain symptoms.” Conclusions The survey provides further evidence of the association between depression and pain, highlighting the fact that pain is prevalent in this patient population. An increased patient and physician awareness of pain in association with depression and improved physician-patient communication, enabling patients to discuss painful symptoms with their physicians and vice versa, should lead to a better overall management and treatment strategies.

OBJECTIVE: To study association between nocturnal mobile phone use and mental health, suicidal feelings, and self-injury in adolescents. METHODS: Associations of mobile phone use after lights out with mental health, suicidal feelings, and self-injury were cross-sectionally examined in 17,920 adolescents using a self-report questionnaire. A series of logistic regression analyses were separately conducted for early (grades 7-9) and late (grades 10-12) adolescents. RESULTS: Sleep length was significantly associated with the mobile phone use only in early adolescents. Logistic regression showed significant associations of the nocturnal mobile phone use with poor mental health, suicidal feelings, and self-injury after controlling for sleep length and other confounders. CONCLUSIONS: Mobile phone use after lights out may be associated with poor mental health, suicidal feelings, and self-injury in both early and late adolescents. Association between reduced sleep and the mobile phone use was confined to early adolescents. Language: en

Introduction Public speaking fears (PSF) are highly prevalent in the general population. They are also among the most common symptoms of social anxiety disorder, which typically has an adolescent onset and has recently been increasingly recognized as a persistent and impairing disorder across various cultures in the world. Methods This study examined PSF and their associated factors among 17,615 adolescents, aged 12–18, in a large-scale school-based community survey in Japan. Results PSF was noted in 7.3% of the students. The prevalence was higher among girls than among boys, and it had a tendency to decrease with age. Across the gender and age groups, PSF was associated with psychopathology, including depression and anxiety, suicidal thoughts, deliberate self-harm, violence towards objects and people, and increased difficulties at school. Discussion We should no longer make light of public speaking fears among adolescents as transient, common-sense phenomena.

Whether a low body mass index (BMI) is directly associated with a high risk of suicidal ideation or self-harming behavior in adolescents is still inconclusive. This study has, therefore, evaluated the relevance of BMI to suicidal ideation and self-harming behavior after controlling for body weight perception (BWP) and other potential confounding factors. BMI, BWP, suicidal ideation, and self-harming behavior were all assessed using a self-report questionnaire administered to 18,104 Japanese adolescents. Potential confounding factors were also evaluated. The data were then analyzed using bi-variate and multivariate logistic regression. Low BMI was associated with suicidal ideation and deliberate self-harm when controlling for sex, age, drug use, emotional distress, and BWP. Low BMI may be an independent risk factor for suicidal ideation and deliberate self-harming behavior in Japanese adolescents., Article, JOURNAL OF NERVOUS AND MENTAL DISEASE. 200(4):305-309 (2012)

Aims: We examined the duration of untreated psychosis (DUP) and its social and clinical correlates in patients with schizophrenia in a rural/suburban region of Japan. Methods: We conducted a retrospective cohort study of patients with first-episode psychosis from 11 hospitals in Kochi Prefecture. There were 108 patients who met the eligibility criteria, and data regarding their DUP and social/clinical variables were collected. Results: The median (mean) DUP of our cohort was 10.5 (34.6) months. Longer DUP was associated with younger age at onset, older age at first consultation, less educational attainment, insidious mode of onset and not being accompanied by another person at first consultation. After adjusting for confounding factors, age at onset, age at first consultation and mode of onset remained significantly and independently associated with DUP. In terms of treatment and response, longer DUP was associated with less antipsychotics prescribed upon first visit, and worse Clinical Global Impression Severity and Improvement scores after 1 year. Conclusion: The patients treated in a rural/suburban region of Japan had a long DUP, and shortening their DUP through promoting family involvement could improve their outcomes.

The relationships between expressed emotion (EE) of the families and the course of bipolar disorder have been examined only in a limited number of cohort studies. No study has yet been reported from Asia. The subjects were 12 patients that had been diagnosed with bipolar I disorder according to DSM-IV and their 12 key family members. The families of the patients were interviewed using the Camberwell Family Interview (CFI) within 2 weeks of the admission of the patients, and their EE were evaluated. The patients were then followed up for 9 months after their discharge from the hospital. The patients were divided into a high-EE group and a low-EE group using the cut-off based on the number of critical comments (CC) and emotional overinvolvement (EOI), and the 9-month relapse risk was compared. When the subjects with 3 or more CC or an EOI score of 3 or more were regarded as the high-EE group, and the others as the low-EE group, the 9-month relapse risk was 100% (3/3) for the high EE group and 0% (0/9) for the low EE group. (Fisher’s exact test p = 0.005) EE based on the CFI appear to be correlated with relapse in bipolar I disorder in Japan.