Association between childhood trauma and bipolar disorders : clinical and molecular correlates

Le trouble bipolaire (TB) est une pathologie fréquente (1 à 3% de la population générale), chronique, récurrente et handicapante. Les patients, même sous traitement, présentent en moyenne un épisode tous les 18 mois. Les traumatismes affectifs dans l'enfance (TE) sont fréquents en population générale et peuvent être évalués par le CTQ (Childhood Trauma Questionnaire) qui recense et cote l'intensité de 5 sous-types : abus émotionnel (EA), physique (PA), et sexuel (SA) ; et négligences émotionnelle (EN) et physique (PN). Les TE sont retrouvés plus fréquemment chez les adultes avec TB, ce qui suggère qu'ils participent au développement du TB, et ils sont également associés à des formes cliniques plus sévères et complexes, et à un pronostic moins favorable. Les TE sont susceptibles de perturber de nombreux systèmes biologiques, dans leur fonctionnement et leur régulation, avec notamment des altérations de leurs niveaux d'expression. Les systèmes potentiellement altérés sont principalement ceux de l'axe HPA (axe hypothalamo-hypophyso-surrénalien) de réponse au stress, la voie des neurotrophines dont le BDNF, les gènes circadiens impliqués dans l'horloge biologique, les systèmes de la neurotransmission et de l'immuno-inflammation. Ce travail a exploré de manière prospective l'association entre les TE et la rechute thymique dans le TB au sein d'une cohorte de 2000 patients avec une durée médiane de suivi de 22.3 mois. Les analyses univariées montrent que les TE, notamment tous les sous-types d'abus (EA, PA et SA), étaient significativement associés à une rechute plus précoce (tous les p<0.001). En incluant les potentiels facteurs confondants, l'association entre l'abus physique et le délai avant la rechute restait significative (HR=1.05 [1.02-1.09] ; p=0.0045). Les facteurs confondants contribuant également à une rechute thymique plus précoce étaient le nombre d'épisodes thymiques antérieurs, les symptômes résiduels dépressifs ou hypomaniaques, un traitement actuel par antidépresseurs ou antipsychotiques atypiques. Nous avons également étudié le lien entre comorbidités psychiatriques et TE dans une cohorte de 3000 patients avec TB. Dans cette cohorte, les 6 comorbidités les plus fréquemment retrouvées étaient les suivantes: tentative de suicide (39%), mésusage d'alcool (25%), de cannabis (19%), troubles du comportement alimentaire (18%), trouble anxieux généralisé (15%) et phobie sociale (14%). La plupart des 11 comorbidités recensées (essentiellement anxieuses et addictives) étaient plus fréquentes et plus actives chez les patients présentant un TE sévère (quartile le plus élevé au CTQ). Sur le plan moléculaire, nous avons étudié, grâce à des analyses de réseau de co-expression, plusieurs gènes candidats impliqués dans les processus biologiques dont le fonctionnement est suggéré comme altéré par les TE. Ces analyses ont montré que l'exposition aux TE modifie significativement l'expression relative des transcrits de 3 voies biologiques d'intérêt : l'axe HPA (EA étant associé à la diminution d'expression de DGKH et NR3C1); les gènes circadiens (l'expression de PPARGC1A était significativement affectée chez les patients avec antécédent de trauma, et en particulier PA), et la voie du BDNF (EA modifiant significativement l'expression relative de NGFR et SA, celles de SORT1 et NGFRAP1). L'ensemble de ces résultats s'inscrit dans la perspective d'une meilleure compréhension des effets à long terme des TE, à la fois sur le plan clinique et moléculaire, chez les patients atteints de TB. Ces résultats pourraient participer au développement d'une médecine personnalisée permettant des stratégies de prise en charge plus intensives et/ou une surveillance accrue de ces patients exposés aux TE, notamment via la prévention d'un risque augmenté de rechute et la prise en charge de leurs comorbidités psychiatriques.Bipolar disorder (BD) is a frequent (1 to 3% of the general population), chronic, recurrent and disabling disease. In individuals with BD, even when treated, mood episodes occur on average every 18 months. Childhood affective traumas (CT) are frequent in the general population, and can be assessed using the CTQ (Childhood Trauma Questionnaire), which identifies and rates the intensity of 5 CT subtypes: emotional abuse (EA), physical abuse (PA) and sexual abuse (SA) ; emotional neglect (EN) and physical neglect (PN). CT are frequently reported in adults with BD and are also associated with more complex and severe clinical forms, and with a poorer prognosis. This suggests that CT participate in the development of the disease. CT are also suggested to alter the functions and regulation of numerous biological systems, notably by affecting expression levels of certain genes. These altered systems are mostly the HPA axis (hypothalamic-pituitary-adrenal axis) involved in stress response; the neurotrophic pathway including BDNF; circadian genes involved in the biological clock; the neurotransmission and the immuno-inflammatory systems. In this work, we prospectively explored the association between CT and mood relapse in BD within a cohort of 2000 adult individuals with a median time of follow-up of 22.3 months. Univariate analyses show that CT, notably all subtypes of abuses (EA, PA and SA), were significantly associated to an earlier relapse (all p-values <0.001). When including potential confounding factors, the association between PA and the time before relapse remained significant (HR=1.05 [1.02-1.09]; p=0.0045). The confounding factors also leading to an earlier relapse were lifetime number of episodes, residual depressive or hypomanic symptoms and current use of antidepressants or second-generation antipsychotics. We have also studied the link between CT and psychiatric comorbidities in a retrospective cohort of 3000 individuals with BD. The six most frequent comorbidities were suicidal attempt (39%), alcohol misuse (25%), cannabis misuse (19%), eating disorders (18%), generalized anxiety disorder (15%) and social phobia (14%). Most of the assessed comorbidities (mainly anxious and addictive) were more frequent and more currently active in the individuals with a severe exposure to CT (highest quartile of CTQ). At the molecular level, we used gene network analyses to study the regulation of expression of candidate genes involved in biological processes whose functioning has been suggested to be altered by CT. These analyses confirmed that CT significantly affects the three tested biological pathways and highlighted the genes of interest in each pathway: HPA axis (with an association between EA and the decreased expression of DGKH and NR3C1); circadian genes (the expression of PPARGC1A was significantly affected in patients with a history of CT, in particular PA); and the neurotrophic pathway of BDNF (with EA affecting significantly the relative expression of NGFR, and SA those of SORT1 and NGFRAP1). Taken together, these findings are part of a better understanding of the long-lasting consequences of CT in individuals with BD, both on clinic and molecular perspectives. This might lead to the development of a personalized medicine offering strategies of care that could be more intensive and/or an increased monitoring of these patients with a history of CT, including carefully treating their psychiatric comorbidities and effectively preventing mood relapses

Association entre les traumatismes dans l'enfance et les rechutes thymiques dans les troubles bipolaires : médiateurs cliniques et moléculaires

Bipolar disorder (BD) is a frequent (1 to 3% of the general population), chronic, recurrent and disabling disease. In individuals with BD, even when treated, mood episodes occur on average every 18 months. Childhood affective traumas (CT) are frequent in the general population, and can be assessed using the CTQ (Childhood Trauma Questionnaire), which identifies and rates the intensity of 5 CT subtypes: emotional abuse (EA), physical abuse (PA) and sexual abuse (SA) ; emotional neglect (EN) and physical neglect (PN). CT are frequently reported in adults with BD and are also associated with more complex and severe clinical forms, and with a poorer prognosis. This suggests that CT participate in the development of the disease. CT are also suggested to alter the functions and regulation of numerous biological systems, notably by affecting expression levels of certain genes. These altered systems are mostly the HPA axis (hypothalamic-pituitary-adrenal axis) involved in stress response; the neurotrophic pathway including BDNF; circadian genes involved in the biological clock; the neurotransmission and the immuno-inflammatory systems. In this work, we prospectively explored the association between CT and mood relapse in BD within a cohort of 2000 adult individuals with a median time of follow-up of 22.3 months. Univariate analyses show that CT, notably all subtypes of abuses (EA, PA and SA), were significantly associated to an earlier relapse (all p-values <0.001). When including potential confounding factors, the association between PA and the time before relapse remained significant (HR=1.05 [1.02-1.09]; p=0.0045). The confounding factors also leading to an earlier relapse were lifetime number of episodes, residual depressive or hypomanic symptoms and current use of antidepressants or second-generation antipsychotics. We have also studied the link between CT and psychiatric comorbidities in a retrospective cohort of 3000 individuals with BD. The six most frequent comorbidities were suicidal attempt (39%), alcohol misuse (25%), cannabis misuse (19%), eating disorders (18%), generalized anxiety disorder (15%) and social phobia (14%). Most of the assessed comorbidities (mainly anxious and addictive) were more frequent and more currently active in the individuals with a severe exposure to CT (highest quartile of CTQ). At the molecular level, we used gene network analyses to study the regulation of expression of candidate genes involved in biological processes whose functioning has been suggested to be altered by CT. These analyses confirmed that CT significantly affects the three tested biological pathways and highlighted the genes of interest in each pathway: HPA axis (with an association between EA and the decreased expression of DGKH and NR3C1); circadian genes (the expression of PPARGC1A was significantly affected in patients with a history of CT, in particular PA); and the neurotrophic pathway of BDNF (with EA affecting significantly the relative expression of NGFR, and SA those of SORT1 and NGFRAP1). Taken together, these findings are part of a better understanding of the long-lasting consequences of CT in individuals with BD, both on clinic and molecular perspectives. This might lead to the development of a personalized medicine offering strategies of care that could be more intensive and/or an increased monitoring of these patients with a history of CT, including carefully treating their psychiatric comorbidities and effectively preventing mood relapses.Le trouble bipolaire (TB) est une pathologie fréquente (1 à 3% de la population générale), chronique, récurrente et handicapante. Les patients, même sous traitement, présentent en moyenne un épisode tous les 18 mois. Les traumatismes affectifs dans l'enfance (TE) sont fréquents en population générale et peuvent être évalués par le CTQ (Childhood Trauma Questionnaire) qui recense et cote l'intensité de 5 sous-types : abus émotionnel (EA), physique (PA), et sexuel (SA) ; et négligences émotionnelle (EN) et physique (PN). Les TE sont retrouvés plus fréquemment chez les adultes avec TB, ce qui suggère qu'ils participent au développement du TB, et ils sont également associés à des formes cliniques plus sévères et complexes, et à un pronostic moins favorable. Les TE sont susceptibles de perturber de nombreux systèmes biologiques, dans leur fonctionnement et leur régulation, avec notamment des altérations de leurs niveaux d'expression. Les systèmes potentiellement altérés sont principalement ceux de l'axe HPA (axe hypothalamo-hypophyso-surrénalien) de réponse au stress, la voie des neurotrophines dont le BDNF, les gènes circadiens impliqués dans l'horloge biologique, les systèmes de la neurotransmission et de l'immuno-inflammation. Ce travail a exploré de manière prospective l'association entre les TE et la rechute thymique dans le TB au sein d'une cohorte de 2000 patients avec une durée médiane de suivi de 22.3 mois. Les analyses univariées montrent que les TE, notamment tous les sous-types d'abus (EA, PA et SA), étaient significativement associés à une rechute plus précoce (tous les p<0.001). En incluant les potentiels facteurs confondants, l'association entre l'abus physique et le délai avant la rechute restait significative (HR=1.05 [1.02-1.09] ; p=0.0045). Les facteurs confondants contribuant également à une rechute thymique plus précoce étaient le nombre d'épisodes thymiques antérieurs, les symptômes résiduels dépressifs ou hypomaniaques, un traitement actuel par antidépresseurs ou antipsychotiques atypiques. Nous avons également étudié le lien entre comorbidités psychiatriques et TE dans une cohorte de 3000 patients avec TB. Dans cette cohorte, les 6 comorbidités les plus fréquemment retrouvées étaient les suivantes: tentative de suicide (39%), mésusage d'alcool (25%), de cannabis (19%), troubles du comportement alimentaire (18%), trouble anxieux généralisé (15%) et phobie sociale (14%). La plupart des 11 comorbidités recensées (essentiellement anxieuses et addictives) étaient plus fréquentes et plus actives chez les patients présentant un TE sévère (quartile le plus élevé au CTQ). Sur le plan moléculaire, nous avons étudié, grâce à des analyses de réseau de co-expression, plusieurs gènes candidats impliqués dans les processus biologiques dont le fonctionnement est suggéré comme altéré par les TE. Ces analyses ont montré que l'exposition aux TE modifie significativement l'expression relative des transcrits de 3 voies biologiques d'intérêt : l'axe HPA (EA étant associé à la diminution d'expression de DGKH et NR3C1); les gènes circadiens (l'expression de PPARGC1A était significativement affectée chez les patients avec antécédent de trauma, et en particulier PA), et la voie du BDNF (EA modifiant significativement l'expression relative de NGFR et SA, celles de SORT1 et NGFRAP1). L'ensemble de ces résultats s'inscrit dans la perspective d'une meilleure compréhension des effets à long terme des TE, à la fois sur le plan clinique et moléculaire, chez les patients atteints de TB. Ces résultats pourraient participer au développement d'une médecine personnalisée permettant des stratégies de prise en charge plus intensives et/ou une surveillance accrue de ces patients exposés aux TE, notamment via la prévention d'un risque augmenté de rechute et la prise en charge de leurs comorbidités psychiatriques

Childhood maltreatment and HPA axis gene expression in bipolar disorders: A gene network analysis.

International audienceIntroduction: Bipolar disorder (BD) is highly associated with childhood maltreatment (CM), the exposure to such early adversity being suggested to disrupt the expression of several biological pathways. This study aims at exploring associations between the mRNA levels of 9 HPA axis genes in lymphoblastoid cell lines from patients with BD according to their self-reported exposure to CM.Methods: The sample consisted of 33 Caucasian patients with a diagnosis of BD type 1, assessed for the exposure to CM with the Childhood Trauma Questionnaire (CTQ). Quantitative RT-PCR was performed on 9 transcripts of the HPA axis genes: DGKH, FKBP5, NR3C1, SGK1, SGK2, SGK3, SKA2, STAT5A and UCN. RT-qPCR data were analyzed using the method of disjoint gene networks with SARP.compo package for R.Results: We found no associations between CTQ total score and the amount of HPA axis transcripts neither in univariate analyses, nor with network analyses. Emotional abuse (EA) was associated with a significant decreased expression of two transcripts, DGKH (p = 0.009) and NR3C1 (p = 0.04). This was confirmed by the disjoint network analysis, which showed that NR3C1 and DGKH were expressed differently from the rest of the HPA axis network in presence of emotional abuse.Discussion: This study described the expression levels of a comprehensive set of HPA axis genes according to childhood maltreatment in a sample of patients with BD type 1 and suggested that emotional abuse decreased the expression of NR3C1 and DGKH. Our results require further replication in independent larger samples

Selecting reference genes in RT-qPCR based on equivalence tests: a network based approach

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Childhood maltreatment contributes to the medical morbidity of individuals with bipolar disorders

International audienceBackground: Individuals with bipolar disorders (BD) are at risk of premature death, mainly due to medical comorbidities. Childhood maltreatment might contribute to this medical morbidity, which remains underexplored in the literature.Methods: We assessed 2891 outpatients with BD (according to DSM-IV criteria). Childhood maltreatment was assessed using the Childhood Trauma Questionnaire. Lifetime diagnoses for medical disorders were retrospectively assessed using a systematic interview and checked against medical notes. Medical morbidity was defined by the sum of medical disorders. We investigated associations between childhood maltreatment (neglect and abuse) and medical morbidity while adjusting for potential confounders.Results: One quarter of individuals had no medical comorbidities, while almost half of them had at least two. Multivariable regression showed that childhood maltreatment (mainly abuse, but also sexual abuse) was associated with a higher medical morbidity. Medical morbidity was also associated with sex, age, body mass index, sleep disturbances, lifetime anxiety disorders and lifetime density of mood episodes. Childhood maltreatment was associated with an increased prevalence of four (i.e. migraine/headache, drug eruption, duodenal ulcer, and thyroid diseases) of the fifteen most frequent medical disorders, however with no difference in terms of age at onset.Conclusions: This large cross-sectional study confirmed a high medical morbidity in BD and its association with childhood maltreatment. The assessment of childhood maltreatment in individuals with BD should be systematically included in routine care and the potential impact on physical health of psycho-social interventions targeting childhood maltreatment and its consequences should be evaluated

Influence of childhood maltreatment on prevalence, onset, and persistence of psychiatric comorbidities and suicide attempts in bipolar disorders

International audienceAbstract Background Psychiatric comorbidities and suicide attempts are highly prevalent in Bipolar Disorders (BD). We examined the associations between childhood maltreatment, psychiatric comorbidities, and suicide attempts, in terms of lifetime prevalence, sequence of onset, and current symptoms. Methods We assessed 3,047 individuals with BD for suicide attempts, anxiety disorders, substance use disorders, and eating disorders. Participants completed a self-report for the assessment of childhood maltreatment. Associations between childhood maltreatment and characteristics of comorbidities (lifetime prevalence, current symptoms, and age at onset) were examined using logistic regressions and network analyses. Results Psychiatric comorbidities were frequent with a mean number per individual of 1.23 (SD = 1.4). Most comorbidities occurred prior to the onset of BD. Participants who reported higher levels of childhood maltreatment had more frequent and multiple comorbidities, which were also more currently active at inclusion. Childhood maltreatment did not decrease the age of onset of comorbidities, but was associated with a faster accumulation of comorbidities prior to the onset of BD. Logistic regression and network analyses showed that emotional abuse and sexual abuse might play a prominent role in the lifetime prevalence of psychiatric comorbidities and suicide attempts. Conclusions Childhood maltreatment was associated with suicide attempts, and with frequent, multiple, and persistent psychiatric comorbidities that accumulated more rapidly prior to the onset of BD. Hence, childhood maltreatment should be systematically assessed in individuals with BD, in particular when the course of the disorder is characterized by a high comorbid profile or by a high suicidality

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

International audienceObjectives: 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 month (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 values <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