•Sleep and circadian rhythms disturbances are associated to history of suicide attempts.•Suicide attempt is associated with women gender and a familial history of suicide.•Mixed episodes and ...benzodiazepines are associated with history of suicide attempt in BD.•Insomnia, earlier onset of activity, woman gender and vigorous circadian type are independent predictors.•The predictive value of these biomarkers must be confirmed in a prospective study.
The poor prognostic of Bipolar disorders (BD) is closely linked to deaths by suicide. Sleep and circadian abnormalities are observed during all phases of BD and are also associated with suicide attempt (SA). In this context, this study sought to identify specific sleep and circadian rhythms markers associated with suicidal attempt in euthymic patients with BD.
The sample (N = 236) comprised 3 groups: 147 patients with BD including 57 with a history of SA and 90 without (NoSA), and 89 healthy controls (HC). All participants were recorded during 21 days with actigraphy.
SA was associated with women gender (p = 0.03), familial history of SA (p = 0.03), mixed episodes (p = 0.001), and benzodiazepines (p = 0.019). SA, compared to noSA, had a morning phase preference (p = 0.04), and were more vigorous on the circadian type inventory (p = 0.04), and tended to suffer more from insomnia (45% versus 25% respectively, p = 0.10). SA was also associated with an earlier onset of daily activity assessed with actigraphy (M10 onset: p = 0.01). Backward stepwise linear regression indicated that a combination of four variables (Gender, vigour, insomnia, M10onset) significantly differentiated patients with SA from NoSA (p = 0.03).
Cross-sectional design, and no examination of suicidal behaviors’ subgroups such as first attempters or repeaters, or violent suicide attempt.
Woman gender, vigorous circadian type, insomnia and an earlier daily activity appeared independently associated with SA in BD. If these biomarkers are confirmed in prospective studies, they should be screened and used to prevent suicide, with the development of personal and targeted chronobiological treatments.
Abstract Mood spectrum disorders (bipolar disorder, recurrent depressive disorder and seasonal affective disorder) are accompanied by circadian deregulations, which can occur during acute mood ...episodes as well as during euthymic periods, and are particularly common among bipolar patients in remission. This suggests that altered circadian rhythms may be biological markers of these disorders. Rhythm dysfunctions have been observed in mood disorder patients by using actigraphic measures and by assessing social metric rhythms, diurnal preferences and melatonin secretion. Since many of these markers are heritable and therefore driven by clock genes, these genes may represent susceptibility factors for mood spectrum disorders. Indeed, several genetic association studies have suggested that certain circadian gene variants play a role in susceptibility to these disorders. Such connections to circadian genes such as CLOCK, ARNTL1, NPAS2, PER3 and NR1D1 have been repeatedly demonstrated for bipolar disorders, and to a lesser extent for recurrent depressive disorders and seasonal affective disorders. The study of circadian phenotypes and circadian genes in mood spectrum disorders represents a major field of research that may yet reveal the pathophysiological determinants of these disorders.
Objective: Duration of untreated illness represents a potentially modifiable component of any diagnosis‐treatment pathway. In bipolar disorder (BD), this concept has rarely been systematically ...defined or not been applied to large clinically representative samples.
Method: In a well‐characterized sample of 501 patients with BD, we estimated the duration of untreated bipolar disorder (DUB: the interval between the first major mood episode and first treatment with a mood stabilizer). Associations between DUB and clinical onset and the temporal sequence of key clinical milestones were examined.
Results: The mean DUB was 9.6 years (SD 9.7; median 6). The median DUB for those with a hypomanic onset (14.5 years) exceeded that for depressive (13 years) and manic onset (8 years). Early onset BD cases have the longest DUB (P < 0.0001). An extended DUB was associated with more mood episodes (P < 0.0001), more suicidal behaviour (P = 0.0003) and a trend towards greater lifetime mood instability (e.g. rapid cycling, possible antidepressant‐induced mania).
Conclusion: Duration of untreated bipolar disorder (DUB) will only be significantly reduced by more aggressive case finding strategies. Reliable diagnosis (especially for BD‐II) and/or instigation of recommended treatments is currently delayed by insufficient awareness of the early, polymorphous presentations of BD, lack of systematic screening and/or failure to follow established guidelines.
Il existe une variabilité inter-individuelle importante dans la réponse aux traitements antidépresseurs (AD), associée à des taux de non-répondeurs qui restent préoccupant (environ 40 %) et à une ...difficulté à prédire précisément quel patient va répondre à quel traitement. Le développement de biomarqueurs prédictifs de la réponse aux AD constitue donc un enjeu majeur pour l’amélioration de la prise en charge des patients. Ce symposium propose un état des lieux et des illustrations du développement d’une médecine personnalisée dans le domaine des troubles de l’humeur. Le professeur P. Courtet présentera une synthèse des données cliniques et épidémiologiques qui justifient le développement d’une médecine personnalisée dans les troubles de l’humeur et présentera des illustrations. Un premier exemple concerne les idées et conduites suicidaires qui sont fortement associées à la dépression. L’aggravation des idées suicidaires au cours d’une cure d’antidépresseur est un phénomène qui reste mal connu, bien que largement amplifié par les récentes mises en garde et controverses. Si au niveau populationnel, l’utilisation des antidépresseurs est bénéfique pour la prévention du suicide, certains sujets peuvent présenter un risque suicidaire en début de traitement. Il s’agit d’œuvrer pour mieux les identifier et les prendre en charge. Sur une cohorte de 3800 patients déprimés traités par antidépresseur, Nicolas Ramoz présentera les résultats de l’étude des gènes associés, d’une part, à la réponse thérapeutique et d’autre part, à l’apparition ou l’aggravation des idées suicidaires au cours de ce traitement. Enfin, nous disposons maintenant de techniques permettant d’analyser la signature moléculaire dans le sang circulant de patient de différents phénotypes. C’est cette technique qu’a appliqué le Dr Raoul Belzeaux pour rechercher les biomarqueurs associés au phénomène de réponse thérapeutique et d’aggravation des idées suicidaire au cours d’une cure d’antidépresseur.
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 (β = 0.22; P = 0.03) and non‐significantly lower levels of residual depressive symptoms in BD cases (β = −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.
•Genetic and environmental factors play a role in lithium response variability.•Epigenetic mechanisms mediate the interplay between genetic and environmental factors.•Pre-existing or Li-induced ...epigenetic marks may play a role in Li response.•Epigenetic measures could shorten the time to identify lithium response status.
Lithium (Li) remains the first line long-term treatment of bipolar disorders notwithstanding a high inter-individual variability of response. Significant research effort has been undertaken to understand the molecular mechanisms underlying Li cellular and clinical effects in order to identify predictive biomarkers of response. Li response has been shown to be partly heritable, however mechanisms that do not rely on DNA variants could also be involved. In recent years, modulation of epigenetic marks in relation with the level of Li response has appeared increasingly plausible. Recent results in this field of research have provided new insights into the molecular processes involved in Li effects. In this review, we examined the literature investigating the involvement of three epigenetic mechanisms (DNA methylation, noncoding RNAs and histone modifications) in Li clinical efficacy in bipolar disorder.
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.
Clear guidance for successive antidepressant pharmacological treatments for non-responders in major depression is not well established.
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.
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.
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.
Summary
Background
Epidermal necrolysis is a rare and severe cutaneous adverse reaction to drugs with long‐term somatic consequences and potentially underrecognized psychological complications.
...Objectives
To assess the prevalence and risk factors of post‐traumatic stress disorder (PTSD) in Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in a population of adults undergoing psychiatric evaluation.
Methods
In this prospective study, we included adult patients admitted at the acute phase of SJS/TEN to our dermatology department from June 2009 to February 2013. The main objective was to assess the prevalence of PTSD at 6 months after the acute disease phase, defined by a PTSD Checklist score > 44. Secondary objectives were to investigate risk factors of PTSD in the medical history of patients and characteristics of the disease at the acute phase by the Peritraumatic Dissociative Experience Questionnaire (PDEQ) and Peritraumatic Distress Inventory (PDI) and the degree of impairment on the Sheehan Disability Scale.
Results
We initially included 32 of 80 patients admitted during the study period. At 6 months, seven of 30 still followed up had a PTSD Checklist score > 44, suggesting a PTSD prevalence of 23%; 23 (77%) patients had a hydroxyzine prescription at the acute phase. The main risk factors associated with PTSD at 6 months were psychological results at the acute phase.
Conclusions
Despite frequent prescription of hydroxyzine at the acute phase, almost one‐quarter of patients with SJS/TEN had PTSD at 6 months. A systematic psychiatric evaluation should be offered regularly for at least 1 year after the acute disease phase.
What's already known about this topic?
Epidermal necrolysis, comprising Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), is a rare and severe cutaneous adverse reaction with long‐term somatic consequences and still underrecognized psychological complications.
What does this study add?
We conducted a prospective study including 31 (32 initially) adults with SJS/TEN and found a 23% prevalence of post‐traumatic stress disorder at 6 months after the acute disease phase.
Risk factors were high scores of peritraumatic emotional reaction and dissociation at the acute phase but not age, sex or initial severity of the disease.
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The 10-15-years decrease in life expectancy observed in individuals with bipolar disorder (BD) has been linked to the concept of accelerated cellular aging. Telomere length (TL) and mitochondrial DNA ...copy number (mtDNAcn) have been proposed as markers of cellular aging and comparisons between individuals with BD and healthy controls (HC) sometimes led to conflicting results. Previous studies had moderate sample sizes and studies combining these two markers into a single analysis are scarce. Using quantitative polymerase chain reaction, we measured both TL and mtDNAcn in DNA (peripheral blood) in a sample of 130 individuals with BD and 78 HC. Regression analyses, receiver operating characteristic (ROC), and clustering analyses were performed. We observed significantly lower TL and mtDNAcn in individuals with BD as compared to HC (respective decrease of 26.5 and 35.8%). ROC analyses showed that TL and mtDNAcn highly discriminated groups (AUC = 0.904 for TL and AUC = 0.931 for mtDNAcn). In the whole population, clustering analyses identified a group of young individuals (age around 36 years), with accelerated cellular aging (both shorter TL and lower mtDNAcn), which consisted mostly of individuals with BD (85.5%). The subgroup of patients with young age but accelerated aging was not characterized by specific clinical variables related to the course of BD or childhood maltreatment. However, patients in this subgroup were more frequently treated with anticonvulsants. Further characterization of this subgroup is required to better understand the molecular mechanisms and the risk factors of accelerated cellular aging in BD.
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