Jean-Pierre Kahn

Adolescent subthreshold-depression and anxiety: psychopathology, functional impairment and increased suicide risk

BACKGROUND  Subthreshold-depression and anxiety have been associated with significant impairments in adults. This study investigates the characteristics of adolescent subthreshold-depression and anxiety with a focus on suicidality, using both categorical and dimensional diagnostic models. METHODS  Data were drawn from the Saving and Empowering Young Lives in Europe (SEYLE) study, comprising 12,395 adolescents from 11 countries. Based on self-report, including Beck Depression Inventory-II (BDI-II), Zung Self-Rating Anxiety Scale (SAS), Strengths and Difficulties Questionnaire (SDQ) and Paykel Suicide Scale (PSS) were administered to students. Based on BDI-II, adolescents were divided into three groups: nondepressed, subthreshold-depressed and depressed; based on the SAS, they were divided into nonanxiety, subthreshold-anxiety and anxiety groups. Analyses of Covariance were conducted on SDQ scores to explore psychopathology of the defined groups. Logistic regression analyses were conducted to explore the relationships between functional impairments, suicidality and subthreshold and full syndromes. RESULTS  Thirty-two percent of the adolescents were subthreshold-anxious and 5.8% anxious, 29.2% subthreshold-depressed and 10.5% depressed, with high comorbidity. Mean scores of SDQ of subthreshold-depressed/anxious were significantly higher than the mean scores of the nondepressed/nonanxious groups and significantly lower than those of the depressed/anxious groups. Both subthreshold and threshold-anxiety and depression were related to functional impairment and suicidality. CONCLUSIONS Subthreshold-depression and subthreshold-anxiety are associated with an increased burden of disease and suicide risk. These results highlight the importance of early identification of adolescent subthreshold-depression and anxiety to minimize suicide. Incorporating these subthreshold disorders into a diagnosis could provide a bridge between categorical and dimensional diagnostic models.

Childhood trauma is associated with severe clinical characteristics of bipolar disorders.

OBJECTIVE Beyond genetic risk variants, the pathophysiology of bipolar disorders is likely to be partly determined by environmental susceptibility factors. Our study is one of the first to investigate, in a large sample of well-characterized bipolar patients, associations between clinical presentations and childhood trauma subtypes, including neglect and abuse items. METHOD 587 patients with DSM-IV-defined bipolar disorder were recruited from France and Norway between 1996-2008 and 2007-2012, respectively. History of childhood trauma was obtained using the Childhood Trauma Questionnaire. Clinical variables were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders (Norwegian sample) or the Diagnostic Interview for Genetic Studies (French sample). RESULTS Earlier age at onset of bipolar illness, suicide attempts, rapid cycling, and an increased number of depressive episodes each had significant associations (P ≤ .001) with at least 1 subtype of childhood trauma (emotional abuse, sexual abuse, and emotional neglect). Multivariate analyses investigating trauma variables together showed that both emotional and sexual abuse were independent predictors of lower age at onset (P = .002 for each) and history of suicide attempts (OR = 1.60 [95% CI, 1.07 to 2.39], P = .023; OR = 1.80 [95% CI, 1.14 to 2.86], P = .012, respectively), while sexual abuse was the strongest predictor of rapid cycling (OR = 2.04 [95% CI, 1.21 to 3.42], P = .007). Females reported overall higher childhood trauma frequency and greater associations to clinical expressions than males (P values < .05). CONCLUSIONS Our results demonstrate consistent associations between childhood trauma and more severe clinical characteristics in bipolar disorder. Further, they show the importance of including emotional abuse as well as the more frequently investigated sexual abuse when targeting clinical characteristics of bipolar disorder.

Duration of untreated bipolar disorder: missed opportunities on the long road to optimal treatment

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.

Clinical expression of bipolar disorder type I as a function of age and polarity at onset: convergent findings in samples from France and the United States.

BACKGROUND The clinical presentation, course, and comorbidities of bipolar disorder type I are highly heterogeneous, and this variability remains poorly predictable. Certain onset characteristics (eg, age and polarity at onset) may delineate subgroups differing in clinical expression and outcome. METHOD We retrospectively investigated the association between both age and polarity at onset and the clinical characteristics of bipolar I disorder (DSM-IV) in 2 independent adult samples: 480 French patients assessed in 1992-2006 (patients had been recruited from 3 university-affiliated psychiatry departments) and 714 US patients assessed in 1991-2003 (data were extracted from the Bipolar Disorder Phenome Database). RESULTS Polarity at onset correlated with subsequent predominance (P < .001). Most patients experienced a depressive onset (57.9% in France vs 71.0% in the United States; P < .001) associated with a higher density of depressive episodes, suicidal behavior, and alcohol misuse. A manic onset was associated with a higher density of manic episodes. Early onset was frequent in both countries (42% in France vs 68% in the United States; P < .001) and was associated with suicidal behavior and cannabis and cocaine/opiate misuse. Sensitivity for the prediction of clinical characteristics was 1%-35% for age at onset and 26%-47% for polarity at onset. CONCLUSIONS Onset characteristics are associated with subsequent predominant polarity, suicidal behavior, and substance misuse in bipolar I disorder. These findings may facilitate personalized treatment strategies based on type of onset and may also facilitate early focused strategies for preventing comorbidity. Given the relatively low sensitivity and specificity of these onset characteristics for predicting clinical variables, the relevance of age and polarity at onset as specifiers in nosographical classifications will require further studies. However, polarity at onset may be the more relevant specifier, with further investigation required for age at onset.

Hours of sleep in adolescents and its association with anxiety, emotional concerns, and suicidal ideation

OBJECTIVES Anxiety and concerns in daily life may result in sleep problems and consistent evidence suggests that inadequate sleep has several negative consequences on cognitive performance, physical activity, and health. The aim of our study was to evaluate the association between mean hours of sleep per night, psychologic distress, and behavioral concerns. METHODS A cross-sectional analysis of the correlation between the number of hours of sleep per night and the Zung Self-rating Anxiety Scale (Z-SAS), the Paykel Suicidal Scale (PSS), and the Strengths and Difficulties Questionnaire (SDQ), was performed on 11,788 pupils (mean age±standard deviation [SD], 14.9±0.9; 55.8% girls) from 11 different European countries enrolled in the SEYLE (Saving and Empowering Young Lives in Europe) project. RESULTS The mean number of reported hours of sleep per night during school days was 7.7 (SD, ±1.3), with moderate differences across countries (r=0.06; P<.001). A reduced number of sleeping hours (less than the average) was more common in girls (β=0.10 controlling for age) and older pupils (β=0.10 controlling for sex). Reduced sleep was found to be associated with increased scores on SDQ subscales of emotional (β=-0.13) and peer-related problems (β=-0.06), conduct (β=-0.07), total SDQ score (β=-0.07), anxiety (Z-SAS scores, β=-10), and suicidal ideation (PSS, β=-0.16). In a multivariate model including all significant variables, older age, emotional and peer-related problems, and suicidal ideation were the variables most strongly associated with reduced sleep hours, though female gender, conduct problems measured by the SDQ, and anxiety only showed modest effects (β=0.03-0.04). CONCLUSIONS Our study supports evidence that reduced hours of sleep are associated with potentially severe mental health problems in adolescents. Because sleep problems are common among adolescents partly due to maturational processes and changes in sleep patterns, parents, other adults, and adolescents should pay more attention to their sleep patterns and implement interventions, if needed.

Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report

Objective The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the “Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder” scale currently used in the Consortium on Lithium Genetics (ConLiGen) study. Materials and Methods Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling. Results Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders). Conclusions We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.

Pathological Internet use among European adolescents: psychopathology and self-destructive behaviours

Rising global rates of pathological Internet use (PIU) and related psychological impairments have gained considerable attention in recent years. In an effort to acquire evidence-based knowledge of this relationship, the main objective of this study was to investigate the association between PIU, psychopathology and self-destructive behaviours among school-based adolescents in eleven European countries. This cross-sectional study was implemented within the framework of the European Union project: Saving and Empowering Young Lives in Europe. A representative sample of 11,356 school-based adolescents (M/F: 4,856/6,500; mean age: 14.9) was included in the analyses. PIU was assessed using the Young’s Diagnostic Questionnaire. Psychopathology was measured using the Beck Depression Inventory-II, Zung Self-Rating Anxiety Scale and Strengths and Difficulties Questionnaire. Self-destructive behaviours were evaluated by the Deliberate Self-Harm Inventory and Paykel Suicide Scale. Results showed that suicidal behaviours (suicidal ideation and suicide attempts), depression, anxiety, conduct problems and hyperactivity/inattention were significant and independent predictors of PIU. The correlation between PIU, conduct problems and hyperactivity/inattention was stronger among females, while the link between PIU and symptoms of depression, anxiety and peer relationship problems was stronger among males. The association between PIU, psychopathology and self-destructive behaviours was stronger in countries with a higher prevalence of PIU and suicide rates. These findings ascertain that psychopathology and suicidal behaviours are strongly related to PIU. This association is significantly influenced by gender and country suggesting socio-cultural influences. At the clinical and public health levels, targeting PIU among adolescents in the early stages could potentially lead to improvements of psychological well-being and a reduction of suicidal behaviours.

Genetic and functional abnormalities of the melatonin biosynthesis pathway in patients with bipolar disorder

Patients affected by bipolar disorder (BD) frequently report abnormalities in sleep/wake cycles. In addition, they showed abnormal oscillating melatonin secretion, a key regulator of circadian rhythms and sleep patterns. The acetylserotonin O-methyltransferase (ASMT) is a key enzyme of the melatonin biosynthesis and has recently been associated with psychiatric disorders such as autism spectrum disorders and depression. In this paper, we analysed rare and common variants of ASMT in patients with BD and unaffected control subjects and performed functional analysis of these variants by assaying the ASMT activity in their B-lymphoblastoid cell lines. We sequenced the coding and the regulatory regions of the gene in a discovery sample of 345 patients with BD and 220 controls. We performed an association study on this discovery sample using common variants located in the promoter region and showed that rs4446909 was significantly associated with BD (P= 0.01) and associated with a lower mRNA level (P< 10(-4)) and a lower enzymatic activity (P< 0.05) of ASMT. A replication study and a meta-analysis using 480 independent patients with BD and 672 controls confirmed the significant association between rs4446909 and BD (P= 0.002). These results correlate with the general lower ASMT enzymatic activity observed in patients with BD (P= 0.001) compared with controls. Finally, several deleterious ASMT mutations identified in patients were associated with low ASMT activity (P= 0.01). In this study, we determined how rare and common variations in ASMT might play a role in BD vulnerability and suggest a general role of melatonin as susceptibility factor for BD.

A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain

Bipolar disorder (BD) is one of the most common and persistent psychiatric disorders. Early-onset BD has been shown to be the most severe and familial form. We recently carried out a whole-genome linkage analysis on sibpairs affected by early-onset BD and showed that the 20p12 region was more frequently shared in our families than expected by chance. The synaptosomal-associated protein SNAP25 is a presynaptic plasma membrane protein essential for the triggering of vesicular fusion and neurotransmitter release, and for which abnormal protein levels have been reported in postmortem studies of bipolar patients. We hypothesised that variations in the gene encoding SNAP25, located on chromosome 20p12, might influence the susceptibility to early-onset BD. We screened SNAP25 for mutations and performed a case–control association study in 197 patients with early-onset BD, 202 patients with late-onset BD and 136 unaffected subjects. In addition, we analysed the expression level of the two SNAP25 isoforms in 60 brains. We showed that one variant, located in the promoter region, was associated with early-onset BD but not with the late-onset subgroup. In addition, individuals homozygous for this variant showed a significant higher SNAP25b expression level in prefrontal cortex. These results show that variations in SNAP25, associated with an increased gene expression level in prefrontal cortex, might predispose to early-onset BD. Further analyses of this gene, as well as analysis of genes encoding for the SNAP25 protein partners, are required to understand the impact of such molecular mechanisms in BD.

Age at onset in bipolar I affective disorder in the USA and Europe

Abstract Objective. To test for differences in reported age at onset (AAO) of bipolar I affective disorder in clinical samples drawn from Europe and the USA. Methods. Admixture analysis was used to identify the model best fitting the observed AAO distributions of two large samples of bipolar I patients from Europe and USA (n = 3616 and n = 2275, respectively). Theoretical AAO functions were compared between the two samples. Results. The model best fitting the observed distribution of AAO in both samples was a mixture of three Gaussian distributions. The theoretical AAO functions of bipolar I disorder differed significantly between the European and USA populations, with further analyses indicating that (i) the proportion of patients belonging to the early-onset subgroup was higher in the USA sample (63 vs. 25%) and (ii) mean age at onset (±SD) in the early-onset subgroup was lower for the USA sample (14.5 ± 4.9 vs. 19 ± 2.7 years). Conclusions. The models best describing the reported AAO distributions of European and USA bipolar I patients were remarkably stable. The intermediate- and late-onset subgroups had similar characteristics in the two samples. However, the theoretical AAO function differed significantly between the USA and European samples due to the higher proportion of patients in the early-onset subgroup and the lower mean age-at-onset in the USA sample.