An epigenetic candidate-gene association study of parental styles in suicide attempters with substance use disorders.

Suicide attempts (SA) are prevalent in substance use disorders (SUD). Epigenetic mechanisms may play a pivotal role in the molecular mechanisms of environmental effects eliciting suicidal behaviour in this population. Hypothalamic-pituitary-adrenal axis (HPA), oxytocin and neurotrophin pathways have been consistently involved in SA, yet , their interplay with childhood adversity remains unclear, particularly in SUD. In 24 outpatients with SUDs, we examined the relation between three parental dysfunctional styles and history of SA with methylation of 32 genes from these pathways, eventually analysing 823 methylation sites. Extensive phenotypic characterization was obtained using a semi-structured interview. Parental style was patient-reported using the Measure of Parental Style (MOPS) questionnaire, analysed with and without imputation of missing items. Linear regressions were performed to adjust for possible confounders, followed by multiple testing correction. We describe both differentially methylated probes (DMPs) and regions (DMRs) for each set of analyses (with and without imputation of MOPS items). Without imputation, five DMRs in OXTR, CRH and NTF3 significantly interacted with MOPS father abuse to increase the risk for lifetime SA, thus covering the three pathways. After imputation of missing MOPS items, two other DMPs from FKBP5 and SOCS3 significantly interacted with each of the three father styles to increase the risk for SA. Although our findings must be interpreted with caution due to small sample size, they suggest implications of stress reactivity genes in the suicidal risk of SUD patients and highlight the significance of father dysfunction as a potential marker of childhood adversity in SUD patients.

Decreased telomere length in a subgroup of young individuals with bipolar disorders: replication in the FACE-BD cohort and association with the shelterin component POT1.

Bipolar disorder (BD) has been associated with premature cellular aging with shortened telomere length (TL) as compared to the general population. We recently identified a subgroup of young individuals with prematurely shortened TL. The aims of the present study were to replicate this observation in a larger sample and analyze the expression levels of genes associated with age or TL in a subsample of these individuals. TL was measured on peripheral blood DNA using quantitative polymerase chain reaction in a sample of 542 individuals with BD and clustering analyses were performed. Gene expression level of 29 genes, associated with aging or with telomere maintenance, was analyzed in RNA samples from a subsample of 129 individuals. Clustering analyses identified a group of young individuals (mean age 29.64 years), with shorter TL. None of the tested clinical variables were significantly associated with this subgroup. Gene expression level analyses showed significant downregulation of MYC, POT1, and CD27 in the prematurely aged young individuals compared to the young individuals with longer TL. After adjustment only POT1 remained significantly differentially expressed between the two groups of young individuals. This study confirms the existence of a subgroup of young individuals with BD with shortened TL. The observed decrease of POT1 expression level suggests a newly described cellular mechanism in individuals with BD, that may contribute to telomere shortening.

Associations between actigraphy estimates of sleep and circadian rhythmicity and psychotropic medications in bipolar disorders: An exploratory study.

INTRODUCTION: Disturbances in sleep and circadian rhythmicity (CR) are frequent in individuals with bipolar disorders (BD). Very few studies explored the associations between psychotropic medications and these disturbances in euthymic BD. Therefore, we aimed at exploring the associations between several classes of medications (lithium, sedative/non-sedative Atypical Antipsychotics (AAP), anticonvulsants, antidepressants, benzodiazepines) and sleep disturbances and CR dimensions in a sample of euthymic individuals with BD. METHODS: We included euthymic adults with BD type 1 or 2 assessed with 21 days of actimetry. We used a Principal Component Analysis (PCA) of sleep and CR estimates to generate dimensions to be studied in association with the current use of psychotropic medications, with adjustments for potential confounding factors. RESULTS: We included individuals with BD-1 (n = 116) or BD-2 (n = 37). The PCA led to four dimensions of sleep and CR estimates. Benzodiazepines were associated with better sleep quality (pcorrected = 0.032). Aripiprazole was associated with less robust CR (pcorrected = 0.016), but with earlier peak of activity patterns (pcorrected = 0.020). Sedative AAPs were associated with better sleep quality, which was no longer significant after correction. We found no association between lithium or anticonvulsants and CR. LIMITATIONS: The cross-sectional design and the possible non-representativeness of the sample were limitations of our study. CONCLUSIONS: In euthymic individuals with BD, benzodiazepines may have a positive effect on sleep quality, while aripiprazole may have mixed effects on CR (less robust but with earlier peak of activity patterns). No association with lithium or anticonvulsants observed. Further studies are warranted to replicate and extend these results.

Accelerated aging in bipolar disorders: An exploratory study of six epigenetic clocks.

Bipolar disorder (BD) is a chronic and severe psychiatric disorder associated with significant medical morbidity and reduced life expectancy. In this study, we assessed accelerated epigenetic aging in individuals with BD using various DNA methylation (DNAm)-based markers. For this purpose, we used five epigenetic clocks (Horvath, Hannum, EN, PhenoAge, and GrimAge) and a DNAm-based telomere length clock (DNAmTL). DNAm profiles were obtained using Infinium MethylationEPIC Arrays from whole-blood samples of 184 individuals with BD. We also estimated blood cell counts based on DNAm levels for adjustment. Significant correlations between chronological age and each epigenetic age estimated using the six different clocks were observed. Following adjustment for blood cell counts, we found that the six epigenetic AgeAccels (age accelerations) were significantly associated with the body mass index. GrimAge AgeAccel was significantly associated with male sex, smoking status and childhood maltreatment. DNAmTL AgeAccel was significantly associated with smoking status. Overall, this study showed that distinct epigenetic clocks are sensitive to different aspects of aging process in BD. Further investigations with comprehensive epigenetic clock analyses and large samples are required to confirm our findings of potential determinants of an accelerated epigenetic aging in BD.

Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10-12, R2 = 1.9%) and continuous (P = 6.4 × 10-9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10-4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

Risperidone response in patients with schizophrenia drives DNA methylation changes in immune and neuronal systems.

Background: The choice of efficient antipsychotic therapy for schizophrenia relies on a time-consuming trial-and-error approach, whereas the social and economic burdens of the disease call for faster alternatives. Material & methods: In a search for predictive biomarkers of antipsychotic response, blood methylomes of 28 patients were analyzed before and 4 weeks into risperidone therapy. Results: Several CpGs exhibiting response-specific temporal dynamics were identified in otherwise temporally stable methylomes and noticeable global response-related differences were observed between good and bad responders. These were associated with genes involved in immunity, neurotransmission and neuronal development. Polymorphisms in many of these genes were previously linked with schizophrenia etiology and antipsychotic response. Conclusion: Antipsychotic response seems to be shaped by both stable and medication-induced methylation differences.

The most common way to treat schizophrenia is antipsychotic medication. However, not all antipsychotics work for all patients. The only way to find a suitable antipsychotic is to prescribe one and wait, sometimes for months, to see if it works. Finding an alternative to this trial-and-error method would help reduce patient suffering and costs for healthcare systems. The idea is to look in the DNA of our blood cells for specific marks that can change in response to our lifestyle or health condition. These marks could help us predict how patients will react to the drug. In other words, they can serve as biomarkers of antipsychotic response. The current work examined the blood of schizophrenia patients before and 4 weeks after starting medication. The patients who did not respond well to the drug had different marks on the genes involved in immune defense and nervous system functioning. Some of these genes also play roles in the development of schizophrenia, whereas others can directly affect what happens to the drug in the patient's body. Although marks that predict how patients will react were not identified with certainty, valuable targets for future research were identified.

Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder.

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������.

Telomere length and mitochondrial DNA copy number in bipolar disorder: A sibling study.

OBJECTIVES: An accelerated cellular ageing has been observed in bipolar disorder (BD) using biomarkers such as telomere length (TL) and mitochondrial DNA copy number (mtDNAcn). Several risk factors might drive premature ageing in individuals with BD, including a familial predisposition. This study compared TL and mtDNAcn between individuals with BD and their (un)-affected siblings, and explored factors that may explain proband-sibling differences. METHODS: Sixty individuals with BD and seventy-four siblings (34 affected with BD or mood disorders and 40 unaffected) were included. Quantitative polymerase chain reaction (qPCR) was used to measure TL and mtDNAcn from peripheral blood genomic DNA. RESULTS: TL and mtDNAcn did not significantly differ between probands and their siblings, whatever these latter were affected or not with mood disorders. However, the correlation plots of TL or mtDNAcn in proband-sibling pairs suggested that some pairs were discordant. The within proband-sibling pairs differences for TL and mtDNAcn were not explained by differences in all tested factors. CONCLUSIONS: This study shows that probands with BD and their siblings are concordant for TL and mtDNAcn suggesting that they may share some environmental or genetic determinants of these two biomarkers of cellular ageing.

Gene expression of circadian genes and CIART in bipolar disorder: A preliminary case-control study.

Based on the observed circadian rhythms disruptions and sleep abnormalities in bipolar disorders (BD), a chronobiological model has been proposed suggesting that core clock genes play a central role in the vulnerability to the disorder. In this context, the analysis of circadian genes expression levels is particularly relevant, however studies focused on the whole set of core clock genes are scarce. We compared the levels of expression of 19 circadian genes (including the recently described circadian repressor (CIART)) in 37 euthymic individuals with BD and 20 healthy controls (HC), using data obtained by RNA sequencing of lymphoblastoid cell lines and validated the results using RT-qPCR. RNA sequencing data showed that CIART gene expression was correlated with those of ARNTL, ARNTL2, DBP, PER2 and TIMELESS. Data from RNA sequencing showed that the level of expression of four circadian genes (ARNTL, ARNTL2, BHLHE41 and CIART) discriminated individuals with BD from HC. We replicated this result using RT-qPCR for ARNTL and CIART. This study suggests that an imbalance between activation/repression of the transcription within the circadian system in individuals with BD as compared to HC and as such opens avenues for further research in larger independent samples combining both expression and epigenetic analyses.

Transcriptomics and miRNomics data integration in lymphoblastoid cells highlights the key role of immune-related functions in lithium treatment response in Bipolar disorder.

BACKGROUND: Bipolar Disorder (BD) is a complex mental disease characterized by recurrent episodes of mania and depression. Lithium (Li) represents the mainstay of BD pharmacotherapy, despite the narrow therapeutic index and the high variability in treatment response. However, although several studies have been conducted, the molecular mechanisms underlying Li therapeutic effects remain unclear. METHODS: In order to identify molecular signatures and biological pathways associated with Li treatment response, we conducted transcriptome and miRNome microarray analyses on lymphoblastoid cell lines (LCLs) from 20 patients diagnosed with BD classified as Li responders (n = 11) or non-responders (n = 9). RESULTS: We found 335 mRNAs and 77 microRNAs (miRNAs) significantly modulated in BD responders versus non-responders. Interestingly, pathway and network analyses on these differentially expressed molecules suggested a modulatory effect of Li on several immune-related functions. Indeed, among the functional molecular nodes, we found NF-κB and TNF. Moreover, networks related to these molecules resulted overall inhibited in BD responder patients, suggesting anti-inflammatory properties of Li. From the integrative analysis between transcriptomics and miRNomics data carried out using miRComb R package on the same samples from patients diagnosed with BD, we found 97 significantly and negatively correlated mRNA-miRNA pairs, mainly involved in inflammatory/immune response. CONCLUSIONS: Our results highlight that Li exerts modulatory effects on immune-related functions and that epigenetic mechanisms, especially miRNAs, can influence the modulation of different genes and pathways involved in Li response. Moreover, our data suggest the potentiality to integrate data coming from different high-throughput approaches as a tool to prioritize genes and pathways.

Plasma tau, NfL, GFAP and UCHL1 as candidate biomarkers of alcohol withdrawal-associated brain damage: A pilot study.

In this translational study, we investigated the plasma tau protein, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCHL1), which are established biomarkers of neurological injury, as predictive biomarkers of alcohol withdrawal-associated brain toxicity. In the clinical study, patients with severe alcohol use disorder (AUD) on D1 of hospitalization for alcohol cessation (AC) (N = 36) were compared to severe AUD patients with at least 3 months of abstinence (N = 16). Overall, patients were 40 men (76.9%), aged 49.8 years [SD ±9.9]. Tau, NfL, GFAP and UCHL1 levels were measured using SIMOA and analysed with a quasipoisson regression model adjusted for age and sex. The NfL level was higher in the AC group (p = 0.013). In the AC group, the tau (p = 0.021) and UCHL1 (p = 0.021) levels were positively associated with the dose of diazepam per weight, and the tau (p = 0.045), NfL (p = 4.9 × 10-3 ) and UCHL1 (p = 0.036) levels were higher in the presence of signs of Wernicke's encephalopathy (n = 9). In the preclinical study, NfL and GFAP levels were assessed in the alcohol deprivation effect (ADE) procedure (N = 17) and control Wistar rats (N = 15). Furthermore, ADE rats were prospectively assessed: after 24 h (T1) and 3 weeks of AC (T2) (paired-samples Wilcoxon and Mann-Whitney tests). The NfL level was higher in the ADE model than in the control rats at both T1 and T2 (p = 0.033 and p = 1.3 × 10-3 ) and higher at T2 than at T1 (p = 0.040). Plasma tau, NfL and UCHL1 are potential biomarkers of brain suffering during alcohol withdrawal.

Individual differences in cocaine-induced conditioned place preference in male rats: Behavioral and transcriptomic evidence.

BACKGROUND: Substance use disorder emerges in a small proportion of drug users and has the characteristics of a chronic relapsing pathology. AIMS: Our study aimed to demonstrate and characterize the variability in the expression of the rewarding effects of cocaine in the conditioned place preference (CPP) paradigm. METHODS: A cocaine-CPP paradigm in male Sprague-Dawley rats with an extinction period of 12 days and reinstatement was conducted. A statistical model was developed to distinguish rats expressing or not a cocaine-induced place preference. RESULTS: Two groups of rats were identified: rats that did express rewarding effects (CPP expression (CPPE), score >102 s) and rats that did not (no CPP expression (nCPPE), score between -85 and 59 s). These two groups did not show significant differences in a battery of behavioral tests. To identify differentially expressed genes in the CPPE and nCPPE groups, a whole-transcriptome ribonucleic acid-sequencing analysis was performed in the nucleus accumbens (NAc) 24 h after the CPP test. Four immediate early genes (Fos, Egr2, Nr4a1, and Zbtb37) were differentially expressed in the NAc of CPPE rats after expression of CPP. Variability in cocaine-induced place preference persisted in the CPPE and nCPPE groups after the extinction and reinstatement phases. Transcriptomic differences observed after reinstatement were distinct from those observed immediately after expression of CPP. CONCLUSION: These new findings provide insights into the identification of mechanisms underlying interindividual variability in the response to cocaine's rewarding effects.

Biomarkers of Relapse in Cocaine Use Disorder: A Narrative Review.

INTRODUCTION: Cocaine use disorder is a chronic disease with severe consequences and a high relapse rate. There is a critical need to explore the factors influencing relapse in order to achieve more efficient treatment outcomes. Furthermore, there is a great need for easy-to-measure, repeatable, and valid biomarkers that can predict treatment response or relapse. METHODS: We reviewed the available literature on the Pubmed database concerning the biomarkers associated with relapse in CUD, including central nervous system-derived, genetic, immune, oxidative stress, and "other" biomarkers. RESULTS: Fifty-one articles were included in our analysis. Twenty-five imaging brain anatomic and function assessment studies, mostly using fMRI, examined the role of several structures such as the striatum activity in abstinence prediction. There were fewer studies assessing the use of neuropsychological factors, neurotrophins, or genetic/genomic factors, immune system, or oxidative stress measures to predict abstinence. CONCLUSION: Several biomarkers have been shown to have predictive value. Prospective studies using combined multimodal assessments are now warranted.

Associations between circadian misalignment and telomere length in BD: an actigraphy study.

BACKGROUND: Life expectancy is significantly decreased in bipolar disorder (BD). This is associated with accelerated cellular aging which can be estimated by telomere length (TL). However, specific determinants of shorter TL in BD are under-explored. This study examines whether circadian misalignment (i.e. mismatch between preferred and actual phase of circadian activity rhythms) is associated with shorter TL in BD. METHODS: Euthymic individuals with BD (n = 101) undertook 21 consecutive days of actigraphy recording and completed the Composite Scale of Morningness (CSM) to assess phase preference for activities (chronotype). Polymerase chain reaction was used to measure TL in blood. Cluster analysis identified circadian aligned/misaligned subgroups as defined by preferred (CSM score) and actual phases of activity (actigraphically determined onset of active and inactive periods). We tested for any associations between TL and clusters, with adjustments for between-cluster differences in socio-demographic and illness factors. RESULTS: We identified three clusters: an "Aligned Morning" cluster (n = 31) with preferred and actual timing of activity in the morning, an "Aligned Evening" cluster (n = 37) with preferred and actual timing of activity in the evening and a "Misaligned" cluster (n = 32) with an evening chronotype, but an earlier objective onset of active periods. After adjustment for confounders, we found that TL was significantly associated with circadian misalignment and older age. CONCLUSIONS: Circadian misalignment may partly explain shorter TL in BD and could contribute to accelerated aging in these individuals.

Occurrence and severity of cocaine-induced hallucinations: Two distinct phenotypes with shared clinical factors but specific genetic risk factors.

Cocaine-induced transient hallucinations (CIH) are a frequent complication following cocaine intake that is associated with addiction severity. METHODS: Two hundred and forty-two non-psychotic and Caucasian lifetime cocaine users were included in a French multicentric study. Clinical variables and dopamine pathway genotype data were extracted and tested with CIH scores using a zero-inflated binomial model, which allows for the exploration of factors associated with occurrence and severity separately. RESULTS: Cocaine dependence (poccurrence= 6.18 × 10-5, pseverity= 9.25 × 10-8), number of cocaine dependence DSM IV-Tr criteria (poccurrence= 1.22 × 10-7, pseverity= 5.09 × 10-6), and frequency of intake during the worst period of misuse (poccurrence= 8.51 × 10-04, pseverity= 0.04) were associated with greater occurrence and higher severity of CIH. The genetic associations did not yield significant results after correction for multiple tests. However, some nominal associations of SNPs mapped to the VMAT2, DBH, DRD1, and DRD2 genes were significant. In the multivariate model, the significant variables were the number of cocaine dependence criteria, lifetime alcohol dependence, and the nominally associated SNPs. CONCLUSION: Our study shows that CIH occurrence and severity are two distinct phenotypes, with shared clinical risk factors; however, they likely do not share the same genetic background.

The molecular pathophysiology of mood disorders: From the analysis of single molecular layers to multi-omic integration.

Next-generation sequencing now enables the rapid and affordable production of reliable biological data at multiple molecular levels, collectively referred to as "omics". To maximize the potential for discovery, computational biologists have created and adapted integrative multi-omic analytical methods. When applied to diseases with traceable pathophysiology such as cancer, these new algorithms and statistical approaches have enabled the discovery of clinically relevant molecular mechanisms and biomarkers. In contrast, these methods have been much less applied to the field of molecular psychiatry, although diagnostic and prognostic biomarkers are similarly needed. In the present review, we first briefly summarize main findings from two decades of studies that investigated single molecular processes in relation to mood disorders. Then, we conduct a systematic review of multi-omic strategies that have been proposed and used more recently. We also list databases and types of data available to researchers for future work. Finally, we present the newest methodologies that have been employed for multi-omics integration in other medical fields, and discuss their potential for molecular psychiatry studies.

Methylomic Biomarkers of Lithium Response in Bipolar Disorder: A Proof of Transferability Study.

Response to lithium (Li) is highly variable in bipolar disorders (BD) and no clinical or biological predictors of long-term response have been validated to date. Using a genome-wide methylomic approach (SeqCapEpi), we previously identified seven differentially methylated regions (DMRs) that discriminated good from non-responders (prophylactic response phenotype defined using the "Alda" scale). This study is a proof of transferability from bench to bedside of this epigenetic signature. For this purpose, we used Methylation Specific High-Resolution Melting (MS-HRM), a PCR based method that can be implemented in any medical laboratory at low cost and with minimal equipment. In 23 individuals with BD, MS-HRM measures of three out of seven DMRs were technically feasible and consistencies between SeqCapEpi and MS-HRM-measures were moderate to high. In an extended sample of individuals with BD (n = 70), the three MS-HRM-measured DMRs mainly predicted nonresponse, with AUC between 0.70-0.80 according to different definitions of the phenotype (Alda- or machine-learning-based definitions). Classification tree analyses further suggested that the MS-HRM-measured DMRs correctly classified up to 84% of individuals as good or non-responders. This study suggested that epigenetic biomarkers, identified in a retrospective sample, accurately discriminate non-responders from responders to Li and may be transferrable to routine practice.

Association between childhood maltreatment and the clinical course of bipolar disorders: A survival analysis of mood recurrences.

OBJECTIVES: Childhood maltreatment, also referred as childhood trauma, increases the severity of bipolar disorders (BD). Childhood maltreatment has been associated with more frequent mood recurrences, however, mostly in retrospective studies. Since scarce, further prospective studies are required to identify whether childhood maltreatment may be associated with the time to recurrence in BD. METHODS: Individuals with BD (N = 2008) were assessed clinically and for childhood maltreatment at baseline, and followed up for two years. The cumulative probability of mood recurrence over time was estimated with the Turnbull's extension of the Kaplan-Meier analysis for interval-censored data, including childhood maltreatment as a whole, and then maltreatment subtypes as predictors. Analyses were adjusted for potential confounding factors. RESULTS: The median duration of follow-up was 22.3 months (IQR:12.0-24.8). Univariable analyses showed associations between childhood maltreatment, in particular all types of abuses (emotional, physical, and sexual) or emotional neglect, and a shorter time to recurrence (all p < 0.001). When including potential confounders into the multivariable models, the time to mood recurrence was associated with multiple/severe childhood maltreatment (i.e., total score above the 75th percentile) (HR = 1.32 95%CI (1.11-1.57), p = 0.002), and more specifically with moderate/severe physical abuse (HR = 1.44 95%CI(1.21-1.73), p < 0.0001). Living alone, lifetime anxiety disorders, lifetime number of mood episodes, baseline depressive and (hypo)manic symptoms, and baseline use of atypical antipsychotics were also associated with the time to recurrence. CONCLUSIONS: In addition to typical predictors of mood recurrences, an exposure to multiple/severe forms of childhood maltreatment, and more specifically to moderate to severe physical abuse, may increase the risk for a mood recurrence in BD. This leads to the recommendations of more scrutiny and denser follow-up of the individuals having been exposed to such early-life stressors.

Neurobiological and behavioral mechanisms of circadian rhythm disruption in bipolar disorder: A critical multi-disciplinary literature review and agenda for future research from the ISBD task force on chronobiology.

AIM: Symptoms of bipolar disorder (BD) include changes in mood, activity, energy, sleep, and appetite. Since many of these processes are regulated by circadian function, circadian rhythm disturbance has been examined as a biological feature underlying BD. The International Society for Bipolar Disorders Chronobiology Task Force (CTF) was commissioned to review evidence for neurobiological and behavioral mechanisms pertinent to BD. METHOD: Drawing upon expertise in animal models, biomarkers, physiology, and behavior, CTF analyzed the relevant cross-disciplinary literature to precisely frame the discussion around circadian rhythm disruption in BD, highlight key findings, and for the first time integrate findings across levels of analysis to develop an internally consistent, coherent theoretical framework. RESULTS: Evidence from multiple sources implicates the circadian system in mood regulation, with corresponding associations with BD diagnoses and mood-related traits reported across genetic, cellular, physiological, and behavioral domains. However, circadian disruption does not appear to be specific to BD and is present across a variety of high-risk, prodromal, and syndromic psychiatric disorders. Substantial variability and ambiguity among the definitions, concepts and assumptions underlying the research have limited replication and the emergence of consensus findings. CONCLUSIONS: Future research in circadian rhythms and its role in BD is warranted. Well-powered studies that carefully define associations between BD-related and chronobiologically-related constructs, and integrate across levels of analysis will be most illuminating.