Long and short sleep duration and psychotic symptoms in adolescents: Findings from a cross-sectional survey of 15 786 Japanese students.

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.

Whose depression deteriorates during acute phase antidepressant treatment?

BACKGROUND: Few studies have investigated the proportion of patients with depression who experience worsening of depression symptoms during adequate antidepressant treatment. The current study aimed to investigate the proportion and predictors of worsening depression during antidepressant treatment in a multi-center randomized trial involving patients with major depression. METHODS: We defined the deterioration of depression using depression symptom severity evaluated by total Patient Health Questionnaire (PHQ-9) score increases from week 0 to week 9 during acute phase antidepressant treatment. Patients' baseline demographic and clinical data, change in PHQ-9 scores from week 0 to week 3, and side effects at week 3 were evaluated as potential predictors of subsequent deterioration of depression. RESULTS: Of 1,647 patients, 99 (6.0%) exhibited deterioration of depression, and this proportion was smaller when reliable change index criteria were applied. Logistic regression analysis revealed that the following factors were significantly associated with deterioration of depression: younger age at onset of first episode of major depressive disorder, current older age, and greater increase in PHQ-9 scores between week 0 and week 3. LIMITATIONS: The time of the primary endpoint might not have been sufficiently long. The present study did not include a placebo arm, and potentially relevant predictors might not have been comprehensively investigated. CONCLUSIONS: A small proportion of patients may experience deterioration of depression during acute phase antidepressant treatment. Age at onset at first depressive episode, current age, and early negative response to antidepressants may be useful predictors of subsequent worsening of depression.

Structural variation in the glycogen synthase kinase 3ß and brain-derived neurotrophic factor genes in Japanese patients with bipolar disorders.

BACKGROUND: Lithium is the first-line drug for the treatment of bipolar disorders (BDs); however, not all patients responded. Glycogen synthase kinase (GSK) 3ß 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 GSK3ß 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.

Predicting recurrence of depression using lifelog data: an explanatory feasibility study with a panel VAR approach.

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 association of weight status and weight perception with number of confidants in adolescents.

Weight status and self-weight perception are related to social relationship issues. Studies have suggested links between non-normal weight status or weight perception and youths having fewer confidants, but these relationships are unclear and remain to be studied. This preliminary cross-sectional study examined the effects of weight status and weight perception on the number of confidants in adolescents. Self-report data from 15,279 grade 7-12 students (54.2% boys) were analyzed. The number of confidants (0-3 or ≥ 4) was examined, according to five weight status categories (underweight, low-normal weight, mid-normal weight (reference), high-normal weight, overweight, with Body Mass Index corresponding to ≤ 18.5, ≤ 20.0, ≤ 22.5, ≤ 25.0 and > 25.0 in adults, respectively), and five weight perception categories (too thin, a bit thin, good (reference), a bit fat, too fat). Boys and girls who were overweight and those who perceived themselves to be too fat were significantly more likely to have few confidants. High-normal weight in girls and self-perception of being a bit fat in boys were also associated with having few confidants. In boys, underweight and self-perception of being too thin were additionally associated with having few confidants. Adolescents with non-normal weight status or weight perception may have fewer confidants and require more social support.

Predicting relapse in major depression after successful initial pharmacological treatment.

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.

Optimising first- and second-line treatment strategies for untreated major depressive disorder - the SUN☺D study: a pragmatic, multi-centre, assessor-blinded randomised controlled trial.

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.

Lithium levels in tap water and psychotic experiences in a general population of adolescents.

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.

Behavioral activation: Is it the expectation or achievement, of mastery or pleasure that contributes to improvement in depression?

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.

Decreased serum pyridoxal levels in schizophrenia: meta-analysis and Mendelian randomization analysis.

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.

Retraction: A significant causal association between C-reactive protein levels and schizophrenia.

This retracts the article DOI: 10.1038/srep26105.

Decreased serum pyridoxal levels in schizophrenia: meta-analysis and Mendelian randomization analysis.

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.

Cognitive and Behavioral Skills Exercises Completed by Patients with Major Depression During Smartphone Cognitive Behavioral Therapy: Secondary Analysis of a Randomized Controlled Trial.

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).

De novo non-synonymous TBL1XR1 mutation alters Wnt signaling activity.

Here we report de novo non-synonymous single-nucleotide variants (SNVs) by conducting whole exome sequencing of 18 trios consisting of Japanese patients with sporadic schizophrenia and their parents. Among nine SNVs, we explored the functional impact of the de novo mutation in TBL1XR1 [c.30 C > G (p.Phe10Leu)], a gene previously found to be associated with autism spectrum disorder and epilepsy. Protein structural analysis revealed that Phe10Leu mutation may decrease the structural stability of the TBL1XR1 protein. We demonstrate that Phe10Leu mutation alters the interaction of TBL1XR1 with N-CoR and ß-catenin, which play critical roles in regulation of Wnt-mediated transcriptional activity. Consistently, TBL1XR1-mediated activation of Wnt signaling was up-regulated by Phe10Leu mutation. These results suggest that a de novo TBL1XR1 point mutation could alter Wnt/ß-catenin signaling activity. Further studies are required to clarify the involvement of TBL1XR1 mutations in neuropsychiatric conditions.

Sex differences in auditory verbal hallucinations in early, middle and late adolescence: results from a survey of 17 451 Japanese students aged 12-18 years.

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.

Preference for Solitude, Social Isolation, Suicidal Ideation, and Self-Harm in Adolescents.

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.

Lithium Levels in Tap Water and the Mental Health Problems of Adolescents: An Individual-Level Cross-Sectional Survey.

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.

Effect of Clozapine on DNA Methylation in Peripheral Leukocytes from Patients with Treatment-Resistant Schizophrenia.

Clozapine is an atypical antipsychotic, that is established as the treatment of choice for treatment-resistant schizophrenia (SCZ). To date, no study investigating comprehensive DNA methylation changes in SCZ patients treated with chronic clozapine has been reported. The purpose of the present study is to reveal the effects of clozapine on DNA methylation in treatment-resistant SCZ. We conducted a genome-wide DNA methylation profiling in peripheral leukocytes (485,764 CpG dinucleotides) from treatment-resistant SCZ patients treated with clozapine (n = 21) in a longitudinal study. Significant changes in DNA methylation were observed at 29,134 sites after one year of treatment with clozapine, and these genes were enriched for "cell substrate adhesion" and "cell matrix adhesion" gene ontology (GO) terms. Furthermore, DNA methylation changes in the CREBBP (CREB binding protein) gene were significantly correlated with the clinical improvements. Our findings provide insights into the action of clozapine in treatment-resistant SCZ.

Appetite loss as a potential predictor of suicidal ideation and self-harm in adolescents: A school-based study.

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.