Schizotypal dimensions are associated with current but not former tobacco consumption.

OBJECTIVES: We aimed to study the relationship between tobacco smoking and attenuated psychosis measures taking into account several aspects of tobacco consumption that to date have not been explored and that could help understand this association, such as age of onset, the influence of former consumption and the duration of abstinence. METHODS: We investigated, in a sample of 580 students, the relationship between schizotypy (using the schizotypal personality questionnaire-brief in a Likert format) and smoking status, nicotine dependence (measured with the Fagerström test for nicotine dependence), age of onset of smoking and in former smokers, duration of smoking abstinence. RESULTS: 35.2% of the students were current smokers and 13.4% were former smokers. We found that current but not former smokers had higher scores of schizotypy (total, positive and disorganized) than non-smokers. We found no association between schizotypy scores and nicotine dependence or earlier age of onset of smoking. The duration of smoking abstinence, in former smokers, was inversely correlated to the score of positive and total schizotypy. CONCLUSIONS: Our results suggest that tobacco has a reversible effect on schizotypy, but more studies with a different design (controlled, longitudinal) and a more thorough exploration of potential confounders (e.g. cannabis) are needed before a firm conclusion can be reached.

Oxidative and nitrosative stress markers in obsessive-compulsive disorder: a systematic review and meta-analysis.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a chronic, prevalent, and highly impairing psychiatric illness. Although the pathophysiology of OCD remains unknown, pathways involved in oxidative and nitrosative stress (O&NS) have been implicated. The present study aims to systematically review the literature for quantitative evidence that patients with OCD have altered measures of blood O&NS markers. METHODS: Independent random-effects meta-analyses using standardized mean differences were conducted to assess each marker separately. Additionally, data from multiple markers were pooled together in a meta-analysis for measures of oxidant activity and another for measures of antioxidant activity. RESULTS: Thirteen studies met inclusion criteria, involving 433 OCD patients and 459 controls. Eleven blood O&NS markers were eligible for independent quantitative analyses. We found that, in OCD patients, the oxidant markers 8-hydroxydeoxyguanosine and malondialdehyde, and the antioxidants glutathione peroxidase and superoxide dismutase, were significantly increased while total antioxidant status, vitamin C, and vitamin E were significantly decreased, when comparing with controls. Regarding pooled meta-analyses, we found a statistically significant increase in oxidant markers, but non-significant results regarding antioxidant markers. CONCLUSIONS: Our meta-analysis suggests that OCD patients have a systemic oxidative imbalance that is not adequately buffered by the antioxidant system. Additional studies are needed in order to support this association.

Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression.

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.

A study of the real-world effectiveness of group psychoeducation for bipolar disorders: Is change in illness perception a key mediator of benefit?

BACKGROUND: Findings from efficacy trials of group psychoeducation (PE) for bipolar disorders (BD) led to its inclusion in evidence-based guidelines as a first-line mandatory treatment. However, pragmatic trials and observational studies are needed to determine its real-world effectiveness, impact on outcomes deemed important to patients and to clarify potential mediators of any benefits. METHODS: Individuals with BD were offered the opportunity to participate in 20h of PE and asked to complete pre- and post-intervention ratings of symptoms, knowledge about BD, medication adherence, and illness perception. A priori, two key patient outcomes were identified (social functioning and self-esteem); sample attrition due to dropout or relapse was recorded. RESULTS: Of 156 individuals who completed the pre-PE assessments, 103 completed the program and post-PE assessments. Only 4 of 53 dropouts were associated with BD relapse. Post-intervention, the PE completers demonstrated a statistically significant improvement in social functioning (p = 0.003, Effect Size (ES) = 0.26) and a trend towards improved self-esteem (ES = 0.14). Whilst there were significant changes in medication adherence (p = 0.002, ES = 0.28), knowledge of BD (p < 0.001, ES = 1.20), and illness perception (p < 0.001, ES = -0.37), mediational analysis demonstrated that only change in illness perception was associated to change in functioning (p=0.03) with no contribution from changes in knowledge of BD or medication adherence. CONCLUSIONS: In real-world settings, over 60% individuals completed 10-session course of PE. After controlling for demography and baseline clinical state, change in illness perception, rather than change in knowledge or medication adherence, emerged as a potential mediator of some benefits of PE.

Childhood trauma, dimensions of psychopathology and the clinical expression of bipolar disorders: A pathway analysis.

BACKGROUND: This study aims at testing for paths from childhood abuse to clinical indicators of complexity in bipolar disorder (BD), through dimensions of affective dysregulation, impulsivity and hostility. METHOD: 485 euthymic patients with BD from the FACE-BD cohort were included from 2009 to 2014. We collect clinical indicators of complexity/severity: age and polarity at onset, suicide attempt, rapid cycling and substance misuse. Patients completed questionnaires to assess childhood emotional, sexual and physical abuses, affective lability, affect intensity, impulsivity, motor and attitudinal hostility. RESULTS: The path-analysis demonstrated significant associations between emotional abuse and all the affective/impulsive dimensions (p < 0.001). Sexual abuse was moderately associated with emotion-related dimensions but not with impulsivity nor motor hostility. In turn, affect intensity and attitudinal hostility were associated with high risk for lifetime presence of suicide attempts (p < 0.001), whereas impulsivity was associated with a higher risk of lifetime presence of substance misuse (p < 0.001). No major additional paths were identified when including Emotional and Physical Neglect in the model. CONCLUSIONS: This study provides refinement of the links between early adversity, dimensions of psychopathology and the complexity/severity of BD. Mainly, dimensions of affective dysregulation, impulsivity/hostility partially mediate the links between childhood emotional to suicide attempts and substance misuse in BD.

Childhood trauma and mixed episodes are associated with poor response to lithium in bipolar disorders.

OBJECTIVES: Reliable predictors of response to lithium are still lacking in bipolar disorders (BDs). However, childhood trauma has been hypothesized to be associated with poor response to lithium. METHODS: We included 148 patients with BD, euthymic when retrospectively and clinically assessed for response to lithium and childhood trauma using reliable scales. RESULTS: According to the 'Alda scale', the sample consisted in 20.3% of excellent responders, 49.3% of partial responders and 30.4% of non-responders to lithium. A higher level of physical abuse significantly correlated with a lower level of response to lithium (P = 0.009). As compared to patients not exposed to any abuse, patients with at least two trauma abuses (emotional, physical or sexual) were more at risk of belonging to the non-responders group (OR = 4.91 95% CI (1.01-27.02)). Among investigated clinical variables, lifetime presence of mixed episodes and alcohol misuse were associated with non-response to lithium. Multivariate analyses demonstrated that physical abuse and mixed episodes were independently associated with poor response to lithium (P = 0.005 and P = 0.013 respectively). CONCLUSIONS: Childhood physical abuse might be involved in a poor future response to lithium prophylaxis, this effect being independent of the association between clinical expression of BD and poor response to lithium.

[Schizotypal Personality Questionnaire-Brief - Likert format: Factor structure analysis in general population in France]. / Analyse de la structure factorielle de la version brève du questionnaire de personnalité schizotypique (SPQ-B) ­ format Likert ­ en population générale en France.

INTRODUCTION: The main objective of the study was to explore the factorial structure of the French version of the Schizotypal Personality Questionnaire-Brief (SPQ-B) in a Likert format, in a representative sample of the general population. In addition, differences in the dimensional scores of schizotypy according to gender and age were analyzed. As the study in the general population of schizotypal traits and its determinants has been recently proposed as a way toward the understanding of aetiology and pathophysiology of schizophrenia, consistent self-report tools are crucial to measure psychometric schizotypy. A shorter version of the widely used Schizotypal Personality Questionnaire (SPQ-Brief) has been extensively investigated in different countries, particularly in samples of students or clinical adolescents, and more recently, a few studies used a Likert-type scale format which allows partial endorsement of items and reduces the risk of defensive answers. METHOD: A sample of 233 subjects representative of the adult population from an urban area near Paris (Créteil) was recruited using the "itinerary method". They completed the French version of the SPQ-B with a 5-point Likert-type response format (1=completely disagree; 5=completely agree). We examined the dimensional structure of the French version of the SPQ-B with a Principal Components Analysis (PCA) followed by a promax rotation. Factor selection was based on Eigenvalues over 1.0 (Kaiser's criterion), Cattell's Scree-plot test, and interpretability of the factors. Items with loadings greater than 0.4 were retained for each dimension. The internal consistency estimate of the dimensions was calculated with Cronbach's α. In order to study the influence of age and gender, we carried out a simple linear regression with the subscales as dependent variables. RESULTS: Our sample was composed of 131 women (mean age=52.5±18.2 years) and 102 men (mean age=53±18.1 years). SPQ-B Likert total scores ranged from 22 to 84 points (mean=43.6±13). Factor analysis resulted in a 3-factor solution that explained 47.7% of the variance. Factor 1 (disorganized; 10 items) included items related to "odd behavior", "odd speech", as well as "social anxiety", one item of "constricted affect" and one item of "ideas of reference". Factor 2 (interpersonal; 7 items) included items related to "no close friends", "constricted affect", and three of the items of "suspiciousness". Factor 3 (cognitive-perceptual; 5 items) included items related to "ideas of reference", "magical thinking", "unusual perceptual experiences" and one item of "suspiciousness". Coefficient α for the three subscales and total scale were respectively 0.81, 0.81, 0.77 and 0.88. We found no differences in total schizotypy and the three dimensions scores according to age and sex. CONCLUSION: Factor analysis of the French version of the SPQ-B in a Likert format confirmed the three-factor structure of schizotypy. We found a pure cognitive perceptual dimension including the most representative positive features. As expected, "Suspiciousness" subscale is included in both positive and negative dimensions, but mainly in the negative dimension. Surprisingly, "social anxiety" subscale is included in the disorganized dimension in our analysis. The SPQ-B in a Likert format demonstrated good internal reliability for both total and subscales scores. Unlike previous published results, we did not find any influence of age or gender on schizotypal dimensions.

Affective lability mediates the association between childhood trauma and suicide attempts, mixed episodes and co-morbid anxiety disorders in bipolar disorders.

BACKGROUND: Many studies have shown associations between a history of childhood trauma and more severe or complex clinical features of bipolar disorders (BD), including suicide attempts and earlier illness onset. However, the psychopathological mechanisms underlying these associations are still unknown. Here, we investigated whether affective lability mediates the relationship between childhood trauma and the severe clinical features of BD. METHOD: A total of 342 participants with BD were recruited from France and Norway. Diagnosis and clinical characteristics were assessed using the Diagnostic Interview for Genetic Studies (DIGS) or the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I). Affective lability was measured using the short form of the Affective Lability Scale (ALS-SF). A history of childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Mediation analyses were performed using the SPSS process macro. RESULTS: Using the mediation model and covariation for the lifetime number of major mood episodes, affective lability was found to statistically mediate the relationship between childhood trauma experiences and several clinical variables, including suicide attempts, mixed episodes and anxiety disorders. No significant mediation effects were found for rapid cycling or age at onset. CONCLUSIONS: Our data suggest that affective lability may represent a psychological dimension that mediates the association between childhood traumatic experiences and the risk of a more severe or complex clinical expression of BD.

Revisiting the association between childhood trauma and psychosis in bipolar disorder: A quasi-dimensional path-analysis.

BACKGROUND: Childhood trauma has been associated with a more severe clinical expression of bipolar disorder (BD). However, the results that specifically associated traumatic events and psychotic features in BD have been inconsistent, possibly due to the low resolution of the phenotypes being used. METHODS: 270 normothymic patients with BD completed the Childhood Trauma Questionnaire (CTQ) and the Peters Delusion Inventory (PDI) that assessed 21 delusional beliefs. Patients were characterized for the lifetime presence of psychotic features during episodes and cannabis misuse in accordance with DSM-IV. We performed a series of path analyses to investigate the links from three types of childhood abuse (physical, sexual and emotional) directly to delusional beliefs and psychotic features, and indirectly through cannabis misuse. RESULTS: A first path analysis showed no link between any of the childhood abuse types and psychotic features when only a categorical definition of psychosis was used. When incorporating the quasi-dimensional measure of delusional beliefs in a second path analysis, we found that emotional and physical abuse and cannabis misuse were each directly associated with PDI score. PDI score and psychotic features were strongly correlated. Childhood abuse did not operate through cannabis misuse to increase delusional beliefs. Including type of BD in the model did not alter the results. CONCLUSION: Emotional and physical abuse, but also cannabis misuse, increased delusional beliefs in patients with BD. Using a quasi-dimensional measure of psychotic symptoms in BD provided higher resolution of the psychosis phenotype and helped reconcile ambiguous findings from previous studies.

Association between childhood dimensions of attention deficit hyperactivity disorder and adulthood clinical severity of bipolar disorders.

BACKGROUND: Clinical features of attention deficit hyperactivity disorder can be frequently observed in cases with bipolar disorders and associated with greater severity of bipolar disorders. Although designed as a screening tool for attention deficit hyperactivity disorder, the Wender Utah Rating Scale could, given its factorial structure, be useful in investigating the early history of impulsive, inattentive or mood-related symptoms among patients with bipolar disorders. METHODS: We rated the Wender Utah Rating Scale in 276 adult bipolar disorder cases and 228 healthy controls and tested its factorial structure and any associations with bipolar disorder phenomenology. RESULTS: We confirmed a three-factor structure for the Wender Utah Rating Scale (' impulsivity/temper', ' inattentiveness' and ' mood/self-esteem'). Cases and controls differed significantly on Wender Utah Rating Scale total score and sub-scale scores ( p-values < 10-5). About 23% of bipolar disorder cases versus 5% of controls were classified as ' WURS positive' (odds ratio = 5.21 [2.73-9.95]). In bipolar disorders, higher Wender Utah Rating Scale score was associated with earlier age at onset, severity of suicidal behaviors and polysubstance misuse; multivariate analyses, controlling for age and gender, confirmed the associations with age at onset ( p = 0.001) and alcohol and substance misuse ( p = 0.001). CONCLUSION: Adults with bipolar disorders who reported higher levels of childhood symptoms on the Wender Utah Rating Scale presented a more severe expression of bipolar disorders in terms of age at onset and comorbidity. The Wender Utah Rating Scale could be employed to screen for attention deficit hyperactivity disorder but also for ' at-risk behaviors' in adult bipolar disorder cases and possibly for prodromal signs of early onset in high-risk subjects.

Circadian genes and lithium response in bipolar disorders: associations with PPARGC1A (PGC-1α) and RORA.

Preliminary studies suggest that lithium (Li) response might be associated with some circadian gene polymorphisms, we therefore performed a pharmacogenetic study on the core clock genes in two independent samples suffering from bipolar disorder (BD) and thoroughly characterized for their Li response. Two independent Caucasian samples (165 and 58 bipolar patients) treated with Li were selected from samples recruited in a French multicenter study and assessed for their Li response using the Alda scale. The two samples were genotyped using the Human660 (H660) and OmniExpress (OE) BeadChips and gene-based association analyses of 22 core clock genes were conducted. In the first sample (H660 chip), the RAR-related orphan receptor-a gene (RORA) and the Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Alpha gene (PPARGC1A or PGC-1α) were significantly associated with the Li response (empirical P-value = 0.0015 and 0.04, respectively), and remained significant only for RORA after Bonferroni correction. In the second sample (OE chip), PPARGC1A was significantly associated with the Li response (empirical P-value = 0.04), and did not remain significant after Bonferroni correction. PPARGC1A is a master regulator of mitochondrial function and a key component of the endogenous clock that stimulates the expression of Bmal1 and Rev-erb-alpha through coactivation of RORA. Although the observed associations deserve further replication and investigation, our results suggest genetic associations between Li response and these two close biological partners: PPARGC1A and RORA involved in circadian rhythms and bioenergetics processes in Li response.

Differential effects of childhood trauma and cannabis use disorders in patients suffering from schizophrenia.

BACKGROUND: Childhood trauma (CT) and cannabis use are both environmental and modifier risk factors for schizophrenia. However, little is known about how they interact in schizophrenia. We examined the main effect of each of these two environmental factors on the clinical expression of the disease using a large set of variables, and we tested whether and how cannabis and CT interact to influence the course and the presentation of the illness. METHODS: A sample of 366 patients who met the DSM-IV-TR criteria for schizophrenia was recruited through the FACE-SCZ (Fondamental Advanced Centre of Expertise - Schizophrenia) network. Patients completed a large standardized clinical evaluation including Structured Clinical Interview for DSM Disorders-I (SCID-I), Positive and Negative Symptoms Scale (PANSS), Columbia-Suicide Severity Rating Scale (C-SSRS), Global Assessment of Functioning (GAF), Short-Quality of Life-18 (S-QoL-18), and Medication Adherence Rating Scale (MARS). We assessed CT with the Childhood Trauma Questionnaire and cannabis status with SCID-I. RESULTS: CT significantly predicted the number of hospitalizations, GAF, and S-QoL-18 scores, as well as the PANSS total, positive, excitement, and emotional distress scores. Cannabis use disorders significantly predicted age of onset, and MARS. There was no significant interaction between CT and cannabis use disorders. However, we found evidence of a correlation between these two risk factors. CONCLUSIONS: CT and cannabis both have differential deleterious effects on clinical and functional outcomes in patients with schizophrenia. Our results highlight the need to systematically assess the presence of these risk factors and adopt suitable therapeutic interventions.

Interaction between SLC6A4 promoter variants and childhood trauma on the age at onset of bipolar disorders.

Age at onset (AAO) of bipolar disorders (BD) could be influenced both by a repeat length polymorphism (5HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4) and exposure to childhood trauma. We assessed 308 euthymic patients with BD for the AAO of their first mood episode and childhood trauma. Patients were genotyped for the 5HTTLPR (long/short variant) and the rs25531. Genotypes were classified on functional significance (LL, LS, SS). A sample of 126 Brazilian euthymic patients with BD was used for replication. In the French sample, the correlation between AAO and trauma score was observed only among 'SS' homozygotes (p = 0.002) but not among 'L' allele carriers. A history of at least one trauma decreased the AAO only in 'SS' homozygotes (p = 0.001). These results remained significant after correction using FDR. Regression models suggested an interaction between emotional neglect and 'SS' genotype on the AAO (p = 0.009) and no further interaction with other trauma subtypes. Partial replication was obtained in the Brazilian sample, showing an interaction between emotional abuse and 'LS' genotype on the AAO (p = 0.02). In conclusion, an effect of childhood trauma on AAO of BD was observed only in patients who carry a specific stress responsiveness-related SLC6A4 promoter genotype.

Genetics of emotional reactivity in bipolar disorders.

BACKGROUND: Emotional reactivity has been proposed as a relevant intermediate phenotype of bipolar disorder (BD). Our goal was to identify genetic factors underlying emotional reactivity in a sample of bipolar patients. METHODS: Affect intensity (a proxy measure of emotional reactivity) was measured in a sample of 281 euthymic patients meeting DSM-IV criteria for BD. We use a validated dimensional tool, the 40-item self-report Affect Intensity Measure scale developed by Larsen and Diener. Patients with BD were genotyped for 475. 740 SNPs (using Illumina HumanHap550 Beadchips or HumanHap610 Quad chip). Association was investigated with a general mixed regression model of the continuous trait against genotypes, including gender as covariate. RESULTS: Four regions (1p31.3, 3q13.11, 11p15.1 and 11q14.4) with a p-value lower or equal to 5×10(-6) were identified. In these regions, the joint effect of the four variants accounted for 24.5% of the variance of AIM score. Epistasis analysis did not detect interaction between these variants. In the 11p15.1 region, the rs10766743 located in the intron of the NELL1 gene remained significant after correction for multiple testing (p=2×10(-7)). CONCLUSIONS: These findings illustrate that focusing on quantitative intermediate phenotypes can facilitate the identification of genetic susceptibility variants in BD.

Violent suicidal behaviour in bipolar disorder is associated with nitric oxide synthase 3 gene polymorphism.

OBJECTIVE: Given the importance of nitric oxide system in oxidative stress, inflammation, neurotransmission and cerebrovascular tone regulation, we postulated its potential dysfunction in bipolar disorder (BD) and suicide. By simultaneously analysing variants of three isoforms of nitric oxide synthase (NOS) genes, we explored interindividual genetic liability to suicidal behaviour in BD. METHOD: A total of 536 patients with BD (DSM-IV) and 160 healthy controls were genotyped for functionally relevant NOS1, NOS2 and NOS3 polymorphisms. History of suicidal behaviour and violent suicide attempt was documented for 511 patients with BD. Chi-squared test was used to perform genetic association analyses and logistic regression to test for gene-gene interactions. RESULTS: NOS3 rs1799983 T homozygous state was associated with violent suicide attempts (26.4% vs. 10.8%, in patients and controls, P = 0.002, corrected P (Pc) = 0.004, OR: 2.96, 95% CI = 1.33-6.34), and this association was restricted to the early-onset BD subgroup (37.9% vs. 10.8%, in early-onset BD and controls, P = 0.0003, Pc = 0.0006 OR: 5.05, 95% CI: 1.95-12.45), while we found no association with BD per se and no gene-gene interactions. CONCLUSION: Our results bring further evidence for the potential involvement of endothelial NOS gene variants in susceptibility to suicidal behaviour. Future exploration of this pathway on larger cohort of suicidal behaviour is warranted.

Sleep in patients with remitted bipolar disorders: a meta-analysis of actigraphy studies.

OBJECTIVE: Sleep dysregulation is highly prevalent in bipolar disorders (BDs), with previous actigraphic studies demonstrating sleep abnormalities during depressive, manic, and interepisode periods. We undertook a meta-analysis of published actigraphy studies to identify whether any abnormalities in the reported sleep profiles of remitted BD cases differ from controls. METHOD: A systematic review identified independent studies that were eligible for inclusion in a random effects meta-analysis. Effect sizes for actigraphy parameters were expressed as standardized mean differences (SMD) with 95% confidence intervals (95% CI). RESULTS: Nine of 248 identified studies met eligibility criteria. Compared with controls (N=210), remitted BD cases (N=202) showed significant differences in SMD for sleep latency (0.51 [0.28-0.73]), sleep duration (0.57 [0.30-0.84]), wake after sleep onset (WASO) (0.28 [0.06-0.50]) and sleep efficiency (-0.38 [-0.70-0.07]). Moderate heterogeneity was identified for sleep duration (I2=44%) and sleep efficiency (I2=44%). Post hoc meta-regression analyses demonstrated that larger SMD for sleep duration were identified for studies with a greater age difference between BD cases and controls (ß=0.22; P=0.03) and non-significantly lower levels of residual depressive symptoms in BD cases (ß=-0.13; P=0.07). CONCLUSION: This meta-analysis of sleep in remitted bipolar disorder highlights disturbances in several sleep parameters. Future actigraphy studies should pay attention to age matching and levels of residual depressive symptoms.

Links between sleep and body mass index in bipolar disorders: an exploratory study.

STUDY OBJECTIVES: Obesity and excess bodyweight are highly prevalent in individuals with bipolar disorders (BD) and are associated with adverse consequences. Multiple factors may explain increased bodyweight in BD including side effects of psychotropic medications, and reduced physical activity. Research in the general population demonstrates that sleep disturbances may also contribute to metabolic burden. We present a cross-sectional study of the associations between body mass index (BMI) and sleep parameters in patients with BD as compared with healthy controls (HC). METHODS: Twenty-six French outpatients with remitted BD and 29 HC with a similar BMI completed a 21-day study of sleep parameters using objective (actigraphy) and subjective (PSQI: Pittsburgh Sleep Quality Index) assessments. RESULTS: In BD cases, but not in HC, higher BMI was significantly correlated with lower sleep efficiency (P=0.009) and with several other sleep parameters: shorter total sleep time (P=0.01), longer sleep onset latency (P=0.05), higher fragmentation index (P=0.008), higher inter-day variability (P=0.05) and higher PSQI total score (P=0.004). CONCLUSIONS: The findings suggest a link between a high BMI and several sleep disturbances in BD, including lower sleep efficiency. Physiological mechanisms in BD cases may include an exaggeration of phenomena observed in non-clinical populations. However, larger scale studies are required to clarify the links between metabolic and sleep-wake cycle disturbances in BD.

Association between circadian genes, bipolar disorders and chronotypes.

Abnormalities in circadian rhythms play an important role in the pathogenesis of bipolar disorders (BD). Previous genetic studies have reported discrepant results regarding associations between circadian genes and susceptibility to BD. Furthermore, plausible behavioral consequences of at-risk variants remain unclear since there is a paucity of correlates with phenotypic biomarkers such as chronotypes. Here, we combined association studies with a genotype/phenotype correlation in order to determine which circadian genes variants may be associated with the circadian phenotypes observed in patients with BD. First, we compared the allele frequencies of 353 single nucleotide polymorphisms spanning 21 circadian genes in two independent samples of patients with BD and controls. The meta-analysis combining both samples showed a significant association between rs774045 in TIMELESS (OR = 1.49 95%CI[1.18-1.88]; p = 0.0008) and rs782931 in RORA (OR = 1.31 95%CI[1.12-1.54]; p = 0.0006) and BD. Then we used a "reverse phenotyping approach" to look for association between these two polymorphisms and circadian phenotypes in a subsample of patients and controls. We found that rs774045 was associated with eveningness (p = 0.04) and languid circadian type (p = 0.01), whereas rs782931 was associated with rigid circadian type (p = 0.01). Altogether, these findings suggest that these variants in the TIMELESS and RORA genes may confer susceptibility to BD and impact on circadian phenotypes in carriers who thus had lower ability to properly adapt to external cues.