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Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder.
Amare, A, Thalamuthu, A, Schubert, KO, Fullerton, J, Ahmed, M, Hartmann, S, Papiol, S, Heilbronner, U, Degenhardt, F, Tekola-Ayele, F, et al
Research square. 2023
Abstract
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<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������.
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Subjects suffering from bipolar disorder taking lithium are less likely to report physical pain: a FACE-BD study.
Risch, N, Dubois, J, Etain, B, Aouizerate, B, Bellivier, F, Belzeaux, R, Dubertret, C, Haffen, E, Januel, D, Leboyer, M, et al
European psychiatry : the journal of the Association of European Psychiatrists. 2023;(1):e8
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Abstract
BACKGROUND Physical pain is a common issue in people with bipolar disorder (BD). It worsens mental health and quality of life, negatively impacts treatment response, and increases the risk of suicide. Lithium, which is prescribed in BD as a mood stabilizer, has shown promising effects on pain. METHODS This naturalistic study included 760 subjects with BD ( FACE-BD cohort) divided in two groups: with and without self-reported pain (evaluated with the EQ-5D-5L questionnaire). In this sample, 176 subjects were treated with lithium salts. The objectives of the study were to determine whether patients receiving lithium reported less pain, and whether this effect was associated with the recommended mood-stabilizing blood concentration of lithium. RESULTS Subjects with lithium intake were less likely to report pain (odds ratio [OR] = 0.59, 95% confidence interval [CI], 0.35-0.95; p = 0.036) after controlling for sociodemographic variables, BD type, lifetime history of psychiatric disorders, suicide attempt, personality traits, current depression and anxiety levels, sleep quality, and psychomotor activity. Subjects taking lithium were even less likely to report pain when lithium concentration in blood was ≥0.5 mmol/l (OR = 0.45, 95% CI, 0.24-0.79; p = 0.008). CONCLUSIONS This is the first naturalistic study to show lithium's promising effect on pain in subjects suffering from BD after controlling for many confounding variables. This analgesic effect seems independent of BD severity and comorbid conditions. Randomized controlled trials are needed to confirm the analgesic effect of lithium salts and to determine whether lithium decreases pain in other vulnerable populations.
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GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
Docherty, AR, Mullins, N, Ashley-Koch, AE, Qin, X, Coleman, JRI, Shabalin, A, Kang, J, Murnyak, B, Wendt, F, Adams, M, et al
The American journal of psychiatry. 2023;(10):723-738
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Abstract
OBJECTIVE Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. METHODS This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. RESULTS Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. CONCLUSIONS This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.
Blokland, GAM, Grove, J, Chen, CY, Cotsapas, C, Tobet, S, Handa, R, , , St Clair, D, Lencz, T, Mowry, BJ, et al
Biological psychiatry. 2022;(1):102-117
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BACKGROUND Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10-8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10-6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10-7; rs73033497, p = 8.8 × 10-7; rs7914279, p = 6.4 × 10-7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.
Mullins, N, Forstner, AJ, O'Connell, KS, Coombes, B, Coleman, JRI, Qiao, Z, Als, TD, Bigdeli, TB, Børte, S, Bryois, J, et al
Nature genetics. 2021;(6):817-829
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Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
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Clinical guidelines for the management of treatment-resistant depression: French recommendations from experts, the French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental.
Bennabi, D, Charpeaud, T, Yrondi, A, Genty, JB, Destouches, S, Lancrenon, S, Alaïli, N, Bellivier, F, Bougerol, T, Camus, V, et al
BMC psychiatry. 2019;(1):262
Abstract
BACKGROUND Clear guidance for successive antidepressant pharmacological treatments for non-responders in major depression is not well established. METHOD Based on the RAND/UCLA Appropriateness Method, the French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental developed expert consensus guidelines for the management of treatment-resistant depression. The expert guidelines combine scientific evidence and expert clinicians' opinions to produce recommendations for treatment-resistant depression. A written survey comprising 118 questions related to highly-detailed clinical presentations was completed on a risk-benefit scale ranging from 0 to 9 by 36 psychiatrist experts in the field of major depression and its treatments. Key-recommendations are provided by the scientific committee after data analysis and interpretation of the results of the survey. RESULTS The scope of these guidelines encompasses the assessment of pharmacological resistance and situations at risk of resistance, as well as the pharmacological and psychological strategies in major depression. CONCLUSION The expert consensus guidelines will contribute to facilitate treatment decisions for clinicians involved in the daily assessment and management of treatment-resistant depression across a number of common and complex clinical situations.
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Clinical guidelines for the management of depression with specific comorbid psychiatric conditions French recommendations from experts (the French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental).
Bennabi, D, Yrondi, A, Charpeaud, T, Genty, JB, Destouches, S, Lancrenon, S, Allaili, N, Bellivier, F, Bougerol, T, Camus, V, et al
BMC psychiatry. 2019;(1):50
Abstract
BACKGROUND Recommendations for pharmacological treatments of major depression with specific comorbid psychiatric conditions are lacking. METHOD The French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental developed expert consensus guidelines for the management of depression based on the RAND/UCLA Appropriatneness Method. Recommendations for lines of treatment are provided by the scientific committee after data analysis and interpretation of the results of a survey of 36 psychiatrist experts in the field of major depression and its treatments. RESULTS The expert guidelines combine scientific evidence and expert clinician's opinion to produce recommendations for major depression with comorbid anxiety disorders, personality disorders or substance use disorders and in geriatric depression. CONCLUSION These guidelines provide direction addressing common clinical dilemmas that arise in the pharmacologic treatment of major depression with comorbid psychiatric conditions.
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Binge eating behaviours in bipolar disorders.
Boulanger, H, Tebeka, S, Girod, C, Lloret-Linares, C, Meheust, J, Scott, J, Guillaume, S, Courtet, P, Bellivier, F, Delavest, M
Journal of affective disorders. 2018;225:482-488
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Plain language summary
Bipolar disorder (BD) is a mental health condition that is often found alongside other health conditions including eating disorders such as anorexia nervosa and bulimia nervosa. More recently, it has been also associated with binge eating disorder (BED) which is characterised by frequent episodes of binge eating (BE), often involving a lot of food in a short space of time and a loss of control. It is estimated that 15-17% of people with BD binge eat, compared to 2-5% of the general population. The added burden of binge eating for those with BD includes increased mood instability, anxiety, additions, episodes of psychosis, obesity, suicide, and cardiovascular disease. This study aimed to explore the prevalence and characteristics of binge eating behaviour in those with BD attending BD clinics in France. Individuals with BD with and without binge eating behaviour were compared on factors including demographics and behavioural elements like eating habits. 145 outpatients with BD were included and assessed for binge eating using the Binge Eating Scale. 19% of BD patients were found to binge eat and was more likely in those with a shorter duration of BD, being emotional reactive and having higher levels of anxiety. However, the small sample meant it was hard to assess any differences in personality characteristics like impulsivity.
Abstract
BACKGROUND Recent research, especially from the USA, suggests that comorbid binge eating (BE) behaviour and BE disorder are frequent in individuals with Bipolar Disorder (BD). Although basic clinical associations between BD and BE have been investigated, less is known about psychological or temperamental dimensions and qualitative aspects of eating habits. In a French cohort of patients with BD, we investigated the prevalence of BE behaviour and any associations with illness characteristics, anxiety, impulsivity, emotional regulation and eating habits. METHODS 145 outpatients with BD (I and II) were assessed for the presence of BE behaviour using the Binge Eating Scale (BES). Characteristics identified in univariate analyses as differentiating BD cases with and without BE behaviour were then included in a backward stepwise logistic regression (BSLR) model. RESULTS In this sample, 18.6% of BD patients met criteria for BE behaviour. Multivariate analysis (BSLR) indicated that shorter duration of BD, and higher levels of anxiety and emotional reactivity were observed in BD with compared to BD without BE behaviour. LIMITATIONS Relatively small sample referred to specialist BD clinics and cross-sectional evaluation meant that it was not possible to differentiate between state and trait levels of impulsivity, emotional instability and disinhibition. These dimensions may also overlap with mood symptoms. CONCLUSION BE behaviour is common in females and males with BD. Emotional dysregulation and anxiety may represent important shared vulnerability factors for worse outcome of BD and increased likelihood of BE behaviour.
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Can the response to mood stabilizers be predicted in bipolar disorder?
Geoffroy, PA, Bellivier, F, Leboyer, M, Etain, B
Frontiers in bioscience (Elite edition). 2014;(1):120-38
Abstract
Bipolar disorder (BD) is a severe chronic multifactorial disease that requires maintenance therapy with mood stabilizers (MS). Even with medications, the rate of response among patients with BD is low and the risk of relapse is high. Therefore, in this context of the urgent need for reliable and reproducible predictors of individual responses to MS, pharmacogenetics research is expected to provide helpful progress. Most pharmacogenetic studies of MS have focused on the response to lithium with several good putative candidate genes but informative results are sparse. There have been few studies on valproate, lamotrigine or atypical antipsychotics. Overall, the results of pharmacogenomics studies have not provided sufficient data to change daily practices in BD significantly and further investigation is warranted to identify highly relevant genetic predictors of response their roles. Although progress still remains to be made, the clinical assessment of a subject including the identification of specific individual phenotypic and pharmacogenetic characteristics is likely to become a powerful instrument for the development of personalized therapies.
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Beyond genetics: childhood affective trauma in bipolar disorder.
Etain, B, Henry, C, Bellivier, F, Mathieu, F, Leboyer, M
Bipolar disorders. 2008;(8):867-76
Abstract
OBJECTIVES Despite the demonstrated high heritability of bipolar disorder, few susceptibility genes have been identified and linkage and/or association studies have produced conflicting results. This search for susceptibility genes is hampered by several methodological limitations, and environmental risk factors for the disease (requiring incorporation into analyses) remain misunderstood. Among them, childhood trauma is probably the most promising environmental factor for further investigation. The objectives are to review the arguments in favor of an association between childhood trauma and bipolar disorder and to discuss the interpretations of such an observation. METHODS We computed a literature search using PubMed to identify relevant publications concerning childhood trauma and bipolar disorder. We also present some personal data in this field. RESULTS Growing evidence suggests that incidences of childhood trauma are frequent and severe in bipolar disorder, probably affect the clinical expression of the disease in terms of suicidal behavior and age at onset, and also have an insidious influence on the affective functioning of patients between episodes. The relationships between childhood trauma and bipolar disorder suggest several interpretations, mainly a causal link, a neurodevelopmental consequence, or the intergenerational transmission of traumatic experiences. The neurobiological consequences of childhood trauma on a maturing brain remain unclear, although such stressors may alter the organization of brain development, leading to inadequate affective regulation. CONCLUSIONS Childhood trauma is associated with bipolar disorder and its clinical expression and may interact with genetic susceptibility factors. Although not completely understood, the relationships between childhood trauma and bipolar disorder require further attention. Several suggestions for further exploration of this environmental factor and of its interaction with susceptibility genes are proposed.