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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. [ABSTRACT FROM AUTHOR]

Bipolar disorders (BD) are chronic, multisystem and multifactorial disorders with significant lifetime morbidity, mortality and socio-economic burden. Understanding the underlying genetic and disease triggering environmental factors should improve diagnosis, prognosis, prevention and therapeutic management of the disease. Since intestinal innate dysimmunity seems to play a significant role in the etiopathogeny of BD, we explored in a sample of French Caucasian BD patients, the genetic polymorphisms of NOD2 (nucleotide-binding oligomerization domain containing 2) gene, a key player in such immunity. We found a Caucasian-specific 'standing' variation to be associated with BD. The significance of this finding is discussed in the context of Crohn's disease as well as the complex function of NOD2 in innate immunity. [ABSTRACT FROM AUTHOR]

Abstract: Background: Toll-like receptor 2 (TLR2) molecules play a pivotal role in innate immune responses by their ability to recognize and sense a wide repertoire of infectious and endogenous cellular structural elements. Here we evaluated whether genetic variants in TLR2 influence the age of the disease onset in bipolar disorder (BD). Methods: DNAs from 571 BD patients 229 early-onset (EO-BD) and 342 late-onset (LO-BD) and 199 healthy controls (HC) were analyzed for the following TLR2 polymorphisms: the 5′-UTR −196 to −174 insertion/deletion (ins/del), the intron 1 rs4696480 A/T, and the exon 3 rs3804099 C/T and rs3804100 C/T. PHASE software was used for haplotype reconstruction. Genetic associations were examined using a chi-square test. Results: We found that the TLR2 rs3804099 TT was significantly more prevalent in EO-BD than in LO-BD patients (corrected p (pc)=0.024). After excluding family history of psychiatric disorders, we also found that the TLR2 rs4696480 TT genotype was significantly more prevalent in EO-BD as compared to LO-BD and controls (pc=0.002 and 0.002). Homozygous state for the insTTT haplotype, carrying the above mentioned risk genotypes, was significantly more frequent in EO-BD than in LO-BD patients (pc=0.007) and in EO-BD without family history of psychiatric disorders as compared to (i) those with positive history (pc=0.03), (ii) with LO-BD without family history (pc=0.001) and (iii) with HC (pc=0.009). Limitations: Confirmation by replication in independent BD cohorts is warranted. Conclusions: Our data suggest the potential role of TLR2 genetic variants in the pathogen-mediated susceptibility to BD. [Copyright &y& Elsevier]

Indicated prevention of mental illness is an important public health concern among youth. The aim of this study was to establish a European school-based professional screening among adolescents, which included variables on both a broad range of risk-behaviours and psychopathology; and to investigate the indicative value of adolescent risk-behaviour and self-reported psychopathology on help-seeking and psychological problems that required subsequent mental healthcare. A two-stage professional screening approach was developed and performed within the multi-centre study 'Saving and Empowering Young Lives in Europe' (SEYLE). The first stage of screening comprised a self-report questionnaire on a representative sample of 3,070 adolescents from 11 European countries. In the second stage, students deemed at-risk for mental health problems were evaluated using a semi-structured clinical interview performed by healthcare professionals. 61 % of participants ( n = 1,865) were identified as being at-risk in stage one. In stage two, 384 participants (12.5 % of the original sample) were found to require subsequent mental healthcare during semi-structured, clinical assessment. Among those, 18.5 % of pupils were identified due to screening for psychopathology alone; 29.4 % due to screening for risk-behaviours alone; and 52.1 % by a combination of both. Young age and peer victimization increased help-seeking, while very low body mass index, depression, suicidal behaviour and substance abuse were the best predictors of referral to mental healthcare. Screening of risk-behaviours significantly increased the number of detected students requiring subsequent mental healthcare. Screening of risk-behaviours added significant value in identifying the significant amount of European pupils with mental health problems. Therefore, attention to adolescent risk-behaviours in addition to psychopathology is critical in facilitating prevention and early intervention. Identifying factors that increase compliance to clinical interviews are crucial in improving screening procedures. [ABSTRACT FROM AUTHOR]

Objectives To investigate the prevalence and associated psychosocial factors of occasional and repetitive direct self-injurious behavior (D- SIB), such as self-cutting, -burning, -biting, -hitting, and skin damage by other methods, in representative adolescent samples from 11 European countries. Methods Cross-sectional assessment of adolescents was performed within the European Union funded project, Saving and Empowering Young Lives in Europe ( SEYLE), which was conducted in 11 European countries. The representative sample comprised 12,068 adolescents (F/M: 6,717/5,351; mean age: 14.9 ± 0.89) recruited from randomly selected schools. Frequency of D- SIB was assessed by a modified 6-item questionnaire based on previously used versions of the Deliberate Self-Harm Inventory ( DSHI). In addition, a broad range of demographic, social, and psychological factors was assessed. Results Overall lifetime prevalence of D- SIB was 27.6%; 19.7% reported occasional D- SIB and 7.8% repetitive D- SIB. Lifetime prevalence ranged from 17.1% to 38.6% across countries. Estonia, France, Germany, and Israel had the highest lifetime rates of D- SIB, while students from Hungary, Ireland, and Italy reported low rates. Suicidality as well as anxiety and depressive symptoms had the highest odds ratios for both occasional and repetitive D- SIB. There was a strong association of D- SIB with both psychopathology and risk-behaviors, including family related neglect and peer-related rejection/victimization. Associations between psychosocial variables and D- SIB were strongly influenced by both gender and country. Only a minor proportion of the adolescents who reported D- SIB ever received medical treatment. Conclusion These results suggest high lifetime prevalence of D- SIB in European adolescents. Prevalence as well as psychosocial correlates seems to be significantly influenced by both gender and country. These results support the need for a multidimensional approach to better understand the development of SIB and facilitate culturally adapted prevention/intervention. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Background: Bipolar disorder (BD) is considered as a multifactorial disorder involving complex interactions between genetic and environmental factors, where immune dysfunction is thought to play a key etiopathogenic role. In particular, excess of winter births associated with early-life infections raise the possibility of the implication of innate immunity. Given the pivotal role of Toll-like receptor 4 (TLR-4), a major innate immune sensor molecule, we hypothesized that genetic variations of TLR-4 may be associated to BD. Methods: Genomic DNAs from 572 BD patients and 202 healthy controls (HC) were analyzed for the distribution of six single nucleotides polymorphisms (SNPs) scattered along the TLR-4 locus (rs1927914, rs10759932, rs4986790, rs4986791, rs11536889 and rs11536891). Associations between BD and these polymorphisms were examined using the Chi-square test. Results: We found that rs1927914 AA and rs11536891 TT genotype are more frequent in BD patients than in controls (corrected p; pc=.02 and .02 respectively) particularly in early-onset BD patients (pc=.004 and .006) born during the summer season (pc=.02 and .002 respectively). We also found that rs4986790 AG and rs4986791 CT genotypes were significantly associated with presence of autoimmune thyroiditis (pc=.002). Limitations: Our results are to be confirmed by replication in independent BD cohorts. Conclusions: We report for the first time a genetic association between BD and TLR-4 a major player of innate immunity. Possible mechanisms underlying bipolar disorders linking altered TLR-4 expression and increased susceptibility to infections and/or autoimmunity are discussed. [Copyright &y& Elsevier]

Abstract: Background: Poor adherence to medication is frequent in Bipolar Disorder (BD). It is associated with illness severity and increases total medical cost. Several factors are associated with poor adherence but previous studies included heterogeneous cohorts of patients with and without current mood episode, with and without SUD. Methods: We conducted a cross-sectional study, based on the Fondamental Advanced Centers of Expertise in Bipolar Disorders. 382 patients diagnosed with BD (type I, II or NOS) according to DSM-IV, with partial or complete remission and without comorbid SUD, were included. All patients had a large standardized clinical evaluation with structured interview and self reports. Side effects were evaluated with Patient Rated Inventory of Side Effects (PRISE). Adherence behavior was measured by a self reported scale, Medication Adherence Rating Scale (MARS). Univariate analyses and linear regression models were undertaken to determine factors associated with adherence. Results: Residual depressive symptoms (β=−0.155, p=0.004), and side effects (β=−0.142, p=0.008) were the main factors associated with adherence behavior in linear regression model. We found no association with residual manic symptoms, age at assessment, marital status, number of past mood episodes as well as past psychotic symptoms. Limitation: We used no other assessment than self-rating scale for adherence behavior evaluation. We had no information concerning treatment regimen and patient/family knowledge about BD. Conclusions: Adherence behavior in bipolar patients appears to be mainly influenced by the presence of residual depressive symptoms in patients without SUD. Improvement in diagnosis and pharmacotherapy of residual depressive symptoms has to be kept in mind to face low adherence to medication. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Background Executive function ( EF) impairment in alcohol dependence ( AD) has been related to the toxic effects of alcohol on frontal lobes. However, this impairment could be partially present before the onset of the disease and might constitute a vulnerability factor. Although a considerable body of research has investigated executive functioning among AD patients, much less attention has been directed toward high-risk individuals. Most studies were carried out among children or adolescents, and very few were conducted in adults. The aim of this study was to examine EF in a group of adult offspring of AD individuals. Methods One hundred and fifty-five nonalcoholic adults with (family history positive [FHP]) or without (family history negative [FHN]) family history of AD were included in the study. All participants were screened for past and current psychiatric diagnoses, and alcohol, tobacco, and other substance use. They were compared on self-rated impulsiveness using the Barratt Impulsiveness Scale-11 ( BIS-11) and EF using a neuropsychological test battery. Results Group comparison revealed that FHP participants had significantly higher BIS-11 scores than the FHN participants, while neuropsychological examination revealed lower EF scores for FHP participants. Hierarchical regression analysis revealed that the number of AD family members was a predictor of EF results, whereas impulsiveness was not. Conclusions Nonalcoholic adult offspring of AD individuals showed increased impulsiveness and decreased EF, suggesting weakness of 2 distinct neurobehavioral decision systems. Findings support evidence that EF weaknesses may qualify as a suitable endophenotype candidate for AD. [ABSTRACT FROM AUTHOR]

Aims To investigate the prevalence of pathological internet use ( PIU) and maladaptive internet use ( MIU) among adolescents in 11 European countries in relation to demographic, social factors and internet accessibility. Design Cross-sectional survey. Setting The 7th Framework European Union ( EU) funded project, Saving and Empowering Young Lives in Europe ( SEYLE), is a randomized controlled trial ( RCT) evaluating interventions for risk behaviours among adolescents in Austria, Estonia, France, Germany, Hungary, Ireland, Israel, Italy, Romania, Slovenia and Spain, with Sweden serving as the coordinating centre. Participants A total of 11 956 adolescents (female/male: 6731/5225; mean age: 14.9 ± 0.89) recruited from randomly selected schools within the 11 study sites. Measurements Internet users were classified by gender into three categories: adaptive, maladaptive and pathological, based on their score in the Young Diagnostic Questionnaire for Internet Addiction ( YDQ). Findings The overall prevalence of PIU was 4.4%; it was higher among males than females (5.2% versus 3.8%) and differed between countries (χ2 = 309.98; d.f. = 20; P < 0.001). PIU correlated significantly with mean hours online and male gender. The highest-ranked online activities were watching videos, frequenting chatrooms and social networking; significantly higher rates of playing single-user games were found in males and social networking in females. Living in metropolitan areas was associated with PIU. Students not living with a biological parent, low parental involvement and parental unemployment showed the highest relative risks of both MIU and PIU. Conclusions Across a range of countries in Europe, using the Young Diagnostic Questionnaire for Internet Addiction yields a prevalence of 'pathological internet use' of 4.4% among adolescents, but varies by country and gender; adolescents lacking emotional and psychological support are at highest risk. [ABSTRACT FROM AUTHOR]

A total of 136 with or without first-degree relatives with alcohol dependence were compared according to lifetime prevalence of psychiatric disorders and personality dimensions. Family history positive women showed significant higher prevalence rates of depression and agoraphobia, and exhibited lower scores on Reward Dependence, Self-Directedness and Cooperativeness dimensions. [ABSTRACT FROM AUTHOR]

Pathological Internet use (but only with respect to gaming) is classified as mental disorder in the ICD-11. However, there is a large group of adolescents showing excessive Internet use, which may rather be considered adolescent risk-behavior. The aim was to test whether pathological and excessive Internet use should be considered as "psychopathology" or "risk-behavior". A representative, cross-sectional sample of 11.110 students from 10 European Union countries was analyzed. Structural equation models, including the factors "risk-behavior" and "psychopathology" and the variables excessive and pathological Internet use, were tested against each other. "Risk-behavior" was operationalized by several risk-behaviors (e.g. drug abuse, truancy, etc). "Psychopathology" included measures of several mental disorders (e.g. depression, hyperactivity, etc). Excessive Internet use was assessed as the duration and frequency of Internet use. Pathological Internet use was assessed with the Young Diagnostic Questionnaire (i.e., presence of addiction criteria). Excessive Internet use loaded on "risk-behavior" (λ = 0.484, p < .001) and on "psychopathology" (λ = 0.071, p < .007). Pathological Internet use loaded on "risk-behavior" (λ = 0.333, p < .001) and on "psychopathology" (λ = 0.852, p < .001). Chi-square tests determined that the loadings of excessive Internet use (χ2 (1) = 81.98, p < .001) were significantly stronger on "risk-behavior" than "psychopathology". Vice versa, pathological Internet use loaded significantly stronger on "psychopathology" (χ2 (1) = 107.10, p < .001). The results indicate that pathological Internet use should rather be considered as psychopathology. Excessive Internet use on the other hand, should be classified as adolescent risk-behavior. [ABSTRACT FROM AUTHOR]

Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II., Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism., Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II., (© 2024. The Author(s).)

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD., (© 2024. The Author(s).)

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 , R 2  = 1.9%) and continuous (P = 6.4 × 10 - 9 , R 2  = 2.6%) outcomes. Compared to bipolar patients in the 1 st decile of the risk distribution, individuals in the 10 th 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 , R 2  = 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., (© 2023. The Author(s).)

This study of a cohort of 1-year treatment-compliant survivors of a suicide attempt examined for the first time whether a high CYP2D6-CYP2C19 metabolic capacity (pharmacogenes related to psychopathology, suicide, and attempt severity) and/or polypharmacy treatments predicted repeat suicide attempts, adjusting for sociodemographic and clinical factors as confounders. Of the 461 (63% women) consecutively hospitalized patients who attempted suicide and were evaluated and treated after an index attempt, 191 (67.5% women) attended their 6- and 12-month follow-up sessions. Clinicians were blinded to the activity scores (AS) of their genotypes, which were calculated as the sum of the values assigned to each allele (CYP2C19 *2, *17; CYP2D6 *3, *4, *4xN, *5, *6, *10, wtxN). No differences were found in polypharmacy prescription patterns and the variability of CYP2D6 and CYP2C19 genotypes between adherents and dropouts, but the formers were older, with a higher frequency of anxiety and bipolar disorders and fewer alcohol and substance use disorders. The risk of reattempts was higher for CYP2D6 ultrarapid (AS > 2) metabolizers (β = 0.561, p = 0.005) and violent suicide survivors (β = -0.219, p = 0.042) if the attempt occurred during the first 6-month period, individuals with an increased number of MINI DSM-IV Axis I mental disorders (β = 0.092, p = 0.032) during the second 6-month period and individuals with a combined high CYP2D6-CYP2C19 metabolic capacity (AS > 4) (β = 0.345, p = 0.024) and an increased use of drugs other than antidepressants, anxiolytics-depressants and antipsychotics-lithium (β = 0.088, p = 0.005) in multiple repeaters during both periods. CYP2D6 and CYP2C19 rapid metabolism and polypharmacy treatment for somatic comorbidities must be considered to prevent the severe side effects of short-term multiple suicide reattempts after a previous attempt., (© 2022. The Author(s).)

Objective: The potential role of sub-optimal pharmacological treatment in the poorer outcomes observed in bipolar disorder (BD) with vs. without comorbid substance use disorders (SUDs) is not known. Thus, we investigated whether patients with BD and comorbid SUD had different medication regimens than those with BD alone, in samples from France and Norway, focusing on compliance to international guidelines., Methods: Seven hundred and seventy patients from France and Norway with reliably ascertained BD I or II (68% BD-I) were included. Medication information was obtained from patients and hospital records, and preventive treatment was categorized according to compliance to guidelines. We used Bayesian and regression analyses to investigate associations between SUD comorbidity and medication. In the Norwegian subsample, we also investigated association with lack of medication., Results: Comorbid SUDs were as follows: current tobacco smoking, 26%, alcohol use disorder (AUD), 16%; cannabis use disorder (CUD), 10%; other SUDs, 5%. Compliance to guidelines for preventive medication was lacking in 8%, partial in 44%, and complete in 48% of the sample. Compliance to guidelines was not different in BD with and without SUD comorbidity, as was supported by Bayesian analyses (highest Bayes Factor = 0.16). Cross national differences in treatment regimens led us to conduct country-specific adjusted regression analyses, showing that (1) CUD was associated with increased antipsychotics use in France (OR = 2.4, 95% CI = 1.4-3.9, p = 0.001), (2) current tobacco smoking was associated with increased anti-epileptics use in Norway (OR = 4.4, 95% CI = 1.9-11, p < 0.001), and (3) AUD was associated with decreased likelihood of being medicated in Norway (OR = 1.2, 95% CI = 1.04-1.3, p = 0.038)., Conclusion: SUD comorbidity in BD was overall not associated with different pharmacological treatment in our sample, and not related to the level of compliance to guidelines. We found country-specific associations between comorbid SUDs and specific medications that warrant further studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Icick, Melle, Etain, Høegh, Gard, Aminoff, Leboyer, Andreassen, Belzeaux, Henry, Bjella, Kahn, Steen, Bellivier and Lagerberg.)

Background: Suicidal behaviors are known to be increased in people with epilepsy compared to the general population. However, few studies have explored the frequency of epilepsy in a large sample of suicide attempters, and scarce data exist about differences and similarities between epileptic attempters (EA) and nonepileptic attempters (NEA). The aim of this study was to explore the frequency of epilepsy as well as psychopathological and somatic factors among suicide attempters., Methods: In this multicenter cross-sectional study, 1,229 adults hospitalized for attempted suicide were included during the period between July 2001 and December 2015. They were assessed with the Mini-International Neuropsychiatric Interview for DSM-IV Axis I mental disorders. Data concerning sociodemographic and somatic diseases, including epilepsy, were collected., Results: Sixty-five patients (5.3%) had epilepsy. EA had significantly fewer mean ± SD years of education compared with NEA (11.2 ± 3.2 vs 12.1 ± 2.9; P  = .011) as well as increased rates of head trauma (29.2% for EA vs 16.2% for NEA; P  = .007), antiepileptic use (35.4% for EA vs 23.8% for NEA; P  = .036), and lifetime substance abuse and/or dependance (49.2% for EA vs 36.1% for NEA; P  = .034). Multivariate analyses showed that years of education, head trauma, and panic disorder with agoraphobia predicted belonging to the EA group., Conclusions: These results suggest that epilepsy is overrepresented among suicide attempters. Few psychopathological differences as well as differences in somatic comorbidities except head trauma were observed between EA and NEA in this sample. These results contribute to draw a clinical profile of people with epilepsy in the population of suicide attempters., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients ( N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = -0.14; 95% confidence interval [CI]: -0.24 to -0.03; p value = 0.010) and MDD (β = -0.16; 95% CI: -0.27 to -0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34-1.93; p value = 2e-7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD., Competing Interests: Eduard Vieta has received grants and served as consultant, advisor, or CME speaker for the following entities: AB-Biotics, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, GlaxoSmithKline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), and the Stanley Medical Research Institute. Michael Bauer has received grants from the Deutsche Forschungsgemeinschaft and Bundesministeriums für Bildung und Forschung and served as consultant, advisor, or CME speaker for the following entities: Allergan, Aristo, Janssen, Lilly, Lundbeck, neuraxpharm, Otsuka, Sandoz, Servier, and Sunovion outside the submitted work. Sarah Kittel-Schneider has received grants and served as consultant, advisor, or speaker for the following entities: Medice Arzneimittel Pütter GmbH and Shire. Bernhard Baune has received grants and served as consultant, advisor, or CME speaker for the following entities: AstraZeneca, Bristol-Myers Squibb, Janssen, Lundbeck, Otsuka, Servier, the National Health and Medical Research Council, the Fay Fuller Foundation, and the James and Diana Ramsay Foundation. Tadafumi Kato received honoraria for lectures, manuscripts, and/or consultancy, from Kyowa Hakko Kirin Co., Ltd., Eli Lilly Japan K.K., Otsuka Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., Taisho Toyama Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Meiji Seika Pharma Co., Ltd., Pfizer Japan Inc., Mochida Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Janssen Pharmaceutical K.K., Janssen Asia Pacific, Yoshitomiyakuhin, Astellas Pharma Inc., Wako Pure Chemical Industries, Ltd., Wiley Publishing Japan, Nippon Boehringer Ingelheim Co. Ltd., Kanae Foundation for the Promotion of Medical Science, MSD K.K., Kyowa Pharmaceutical Industry Co., Ltd., and Takeda Pharmaceutical Co., Ltd. T.K. also received a research grant from Takeda Pharmaceutical Co., Ltd. Peter Falkai has received grants and served as consultant, advisor, or CME speaker for the following entities Abbott, GlaxoSmithKline, Janssen, Essex, Lundbeck, Otsuka, Gedeon Richter, Servier, and Takeda as well as the German Ministry of Science and the German Ministry of Health. Eva Reininghaus has received grants and served as consultant, advisor, or CME speaker for the following entities: Janssen and Institut Allergosan. Mikael Landén declares that, over the past 36 months, he has received lecture honoraria from Lundbeck and served as scientific consultant for EPID Research Oy; no other equity ownership, profit-sharing agreements, royalties, or patent. Kazufumi Akiyama has received consulting honoraria from Taisho Toyama Pharmaceutical Co., Ltd. The other authors have no other conflict of interest to disclose., (Copyright © 2021 by S. Karger AG, Basel.)

Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium's therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi + Gen; www.ConLiGen.org ). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD., (© 2021. The Author(s).)

Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10 -3 ; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response., (© 2021. The Author(s).)

Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi + Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

The school-based mental health promotion and suicide prevention universal program Youth Aware of Mental Health (YAM) significantly reduces incident suicide attempts and severe suicidal ideation. This paper aims at elucidating psychological mechanisms underlying YAM's efficacy. Our hypothesis is that YAM operates through interactions with coping strategies (CS) on the reduction of suicidal ideation (SI). In the Saving and Empowering Young Lives in Europe (SEYLE) study, five coping strategies were assessed at baseline (T0) and 12-month follow-up (T12): "learning", "help-seeking", "arts", "sports" and "fight". We analyzed interactions between the YAM intervention, coping strategies and SI in the YAM group (N = 1693) and the minimal intervention group (N = 1909), after excluding prevalent cases with SI and previous suicide attempts from our total sample (N = 5654). General Linear Mixed Model regressions were performed. The present study confirms that coping strategies play an influential role on suicidal ideation. Our results showed that YAM acts whatever the prevailing coping strategies used. It is particularly efficient for pupils insufficiently using adaptive coping strategies such as LEARN and HELP-SEEKING or using maladaptive coping strategies, such as ARTS and FIGHT. The socialization induced by the YAM intervention seems to be a strong component of its efficiency.

Objectives: The aim of this study was to evaluate the French use, misuse and abuse/dependence of non-injectable forms of fentanyl (transdermal and transmucosal fentanyl formulations)., Methods: Problematic use of transdermal and transmucosal fentanyl formulations was evaluated using an approach combining multiple sources of information: (1) spontaneous notifications recorded during 6 years (2010-2015) for transdermal fentanyl form and 3 years for transmucosal fentanyl forms and (2) data from annual epidemiological systematic surveys conducted by the French Addictovigilance Network during 6 years (2010-2015)., Results: In all, 147 cases were notified for transdermal fentanyl formulation and 109 cases for transmucosal fentanyl formulations. According to the galenic formulation, analysis of these cases emphasizes different profiles: for transdermal fentanyl formulation, two consumption profiles: 1/mainly for analgesic effects (74 %): women (61 %), 47 years, with addictive and/or psychiatric history (46 %), treated for chronic non-cancer related pain (93 %), 2/seeking positive psychic effects other than analgesia (26 %): men (82 %), 32 years, with addictive and/or psychiatric history (87 %) and having obtained the fentanyl patch illegally (60 %) for non-medical use. For transmucosal fentanyl formulations, only one consumption profile was observed: women (52 %), 48 years, with addictive (24 %) and/or psychiatric history (28 %), off label indication (72 %) (indications for non-cancer pain and/or no or insufficient opioid background treatment). The misuse of transmucosal fentanyl formulations implies a high risk of adverse effects: those already known of opioid-based drugs, sometimes lethal (withdrawal syndrome, respiratory and central nervous system depression…) but also serious reactions at the application site (buccal or nasal). For the transdermal fentanyl formulation, 27 cases (18 %) of involuntary intoxication were observed, of which 25 were serious. Nineteen deaths involving both forms of fentanyl have been reported (2 for the transmucosal formulations and 17 for the transdermal formulation)., Conclusion: Our results report significant and worrying misuse of transmucosal fentanyl formulations with wide off-label use and also primary dependence on fentanyl, regardless of galenic formulation, in patients treated for chronic non cancer pain. Given the significant risks of fentanyl, it is necessary to continue the monitoring of misuse, in particular, thanks to the activities of the French Addictovigilance network allowing a multisource approach and who provides information concerning cases of abuse, misuse and dependence., (Copyright © 2019 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Genome-wide association studies on bipolar disorders (BD) have revealed an additive polygenic contribution of common single-nucleotide polymorphisms (SNPs). However, these SNPs explain only 25% of the overall genetic variance and suggest a role of rare variants in BD vulnerability. Here, we combined high-throughput genotyping data and whole-exome sequencing in cohorts of individuals with BD as well as in multiplex families with a high density of affected individuals in order to determine the contribution of both common and rare variants to BD genetic vulnerability. Using polygenic risk scores (PRS), we showed a strong contribution of common polymorphisms previously associated with BD and schizophrenia (SZ) and noticed that those specifically associated with SZ contributed more in familial forms of BD than in non-familial ones. The analysis of rare damaging variants shared by affected individuals in multiplex families with BD revealed a single interaction network enriched in neuronal and developmental biological pathways, as well as in the regulation of gene expression. We identified four genes with a higher mutation rate in individuals with BD than in the general population and showed that mutations in two of them were associated with specific clinical manifestations. In addition, we showed a significant negative correlation between PRS and the number of rare damaging variants specifically in unaffected individuals of multiplex families. Altogether, our results suggest that common and rare genetic variants both contribute to the familial aggregation of BD and this genetic architecture may explain the heterogeneity of clinical manifestations in multiplex families.

Purpose: Self-injurious behavior is a frequent phenomenon in adolescence. The present study prospectively examined life events as risk factors for the first onset of direct self-injurious behavior (D-SIB) in the Saving and Empowering Young Lives in Europe school-based multicenter sample., Methods: Longitudinal assessments with an interval of 1 year were performed within a sample of 1,933 adolescents (51.47% females; mean age 14.84 ± .9 years) from 10 European countries and Israel., Results: The number of life events during the past 6 months predicted the first onset of D-SIB in the following year. Gender neither predicted the onset of D-SIB nor moderated the association with life events. Moreover, analyses of individual events identified a range of mainly interpersonal events within both family and peer group as proximal risk factors for first episode D-SIB., Conclusions: The results support the critical role of interpersonal life events in the development of D-SIB for both genders and refine the conceptualization of proximal risk factors in terms of accumulated stressors and interpersonal events., (Copyright © 2019 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Impulsivity is commonly assessed using the Barratt Impulsiveness Scale (BIS-11). Some studies challenged the reliability of its three dimensional structure and proposed a bi-dimensional structure., Methods: The psychometric reliability of the BIS-11 scale was studied in a sample of 580 euthymic bipolar patients. An alternative structure of the scale was conceived, using confirmatory factorial analysis (CFA) in the first half (N = 290) and cross-validated in the second half of our sample. Associations between the newly defined shortened scale and predefined clinical variables were computed., Results: The original three dimensional structure did not fit in our sample according to statistical criteria in CFA. A 12 items Impulsivity Scale (IS-12) was designed with strong indices of fitting in the first half of our sample and replicated in the second half of our sample. The IS-12 evidences two dimensions: "behavioral impulsivity" and "cognitive impulsivity". Associations between "behavioral impulsivity" and both presence of past suicide attempts and number of suicide attempts were observed. Substance misuse was strongly associated with both subscores of the new scale., Limitations: The rating of the items assessing the two dimensions of the IS-12 is reversed. The population is restricted to euthymic bipolar patients., Conclusions: The Impulsivity Scale assesses two distinct dimensions named behavioral and cognitive impulsivity. It was reliable and valid in our sample and associated with the existence of suicidal behavior and with substance misuse (alcohol and cannabis). Further studies are needed to demonstrate its predictive validity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: France is the only European country with a dedicated addictovigilance network (French addictovigilance network [FAN]). However, the reporting of cases of abuse/dependence is insufficient. In an attempt to overcome this under-reporting, data from the medical information systems program (PMSI) is regularly used to identify cases. Since addictions are frequently associated with psychiatric comorbidities, a pilot study was conducted for the first time in a psychiatric hospital. It aims, through a PMSI request, to identify the sociodemographic characteristics and psychiatric diagnoses of patients consuming psychoactive substances (PAS) and the PAS types consumed., Methods: This is a retrospective observational study conducted over a nine-month period at the psychotherapeutic center of Nancy (CPN). The codes used for the PMSI request are those of the international classification of diseases, tenth revision (ICD-10), codes F10 to F19 that characterize mental and behavioral disorders associated with the use of PAS. Cases presenting the four criteria necessary for an addictovigilance notification: (1) identified notifier, (2) identified patient, (3) known consumed product (s) and (4) presence of an effect related to the abuse/dependence of PAS; were retained and analyzed., Results: On an initial number of 252 cases, 82 cases of abuse/dependence were retained. The selected sample is predominantly male (67%). Cannabis (29%) and heroin (15%) are the most common illicit PAS. Regarding drugs, the consumption of benzodiazepines, a predominantly female phenomenon, is observed in 34% of subjects. Sixty-four per cent of the subjects were diagnosed "disorders related to the use of PAS", 14% as neurotic disorders, 9% as schizophrenia and 5% as of the mood disorders., Conclusion: This study identified a significant number of potentially reportable cases to the French Addictovigilance Network and demonstrated the interest of investigating cases of abuse/dependence in a psychiatric hospital., (Copyright © 2018 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients., Methods: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models., Results: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment., Conclusions: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype., (© 2018 The Authors. Bipolar Disorders Published by John Wiley & Sons Ltd.)

Importance: Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ)., Objectives: To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association., Design, Setting, and Participants: A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017., Main Outcomes and Measures: Treatment response to lithium was defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained., Results: Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 × 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines., Conclusions and Relevance: This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.

Background The relationship between residual depressive symptoms, cognition and functioning in patients with euthymic bipolar disorder is a subject of debate. Aims To assess whether cognition mediates the association between residual depressive symptoms and functioning in patients with bipolar disorder who were euthymic. Method We included 241 adults with euthymic bipolar disorder in a multicentre cross-sectional study. We used a battery of tests to assess six cognition domains. A path analysis was then used to perform a mediation analysis of the relationship between residual depressive symptoms, cognitive components and functioning. Results Only verbal and working memory were significantly associated with better functioning. Residual depressive symptoms were associated with poorer functioning. No significant relationship was found between residual depressive symptoms and any cognitive component. Conclusions Cognition and residual depressive symptoms appear to be two independent sources of variation in the functioning of people with euthymic bipolar disorder., Competing Interests: Declaration of interestNone., (© The Royal College of Psychiatrists 2017.)

Genome-wide analysis (GWA) is an effective strategy to discover extreme effects surpassing genome-wide significant levels in studying complex disorders; however, when sample size is limited, the true effects may fail to achieve genome-wide significance. In such case, there may be authentic results among the pools of nominal candidates, and an alternative approach is to consider nominal candidates but are replicable across different samples. Here, we found that mRNA expression of the choline dehydrogenase gene (CHDH) was uniformly upregulated in the brains of bipolar disorder (BPD) patients compared with healthy controls across different studies. Follow-up genetic analyses of CHDH variants in multiple independent clinical datasets (including 11,564 cases and 17,686 controls) identified a risk SNP rs9836592 showing consistent associations with BPD (P meta  = 5.72 × 10 -4 ), and the risk allele indicated an increased CHDH expression in multiple neuronal tissues (lowest P = 6.70 × 10 -16 ). These converging results may identify a nominal but true BPD susceptibility gene CHDH. Further exploratory analysis revealed suggestive associations of rs9836592 with childhood intelligence (P = 0.044) and educational attainment (P = 0.0039), a "proxy phenotype" of general cognitive abilities. Intriguingly, the CHDH gene is located at chromosome 3p21.1, a risk region implicated in previous BPD genome-wide association studies (GWAS), but CHDH is lying outside of the core GWAS linkage disequilibrium (LD) region, and our studied SNP rs9836592 is ∼1.2 Mb 3' downstream of the previous GWAS loci (e.g., rs2251219) with no LD between them; thus, the association observed here is unlikely a reflection of previous GWAS signals. In summary, our results imply that CHDH may play a previously unknown role in the etiology of BPD and also highlight the informative value of integrating gene expression and genetic code in advancing our understanding of its biological basis.

Purpose: To examine risk and protective factors moderating the associations between three types of bullying victimization (physical, verbal, and relational bullying) with suicide ideation/attempts in a large representative sample of European adolescents., Methods: We analyzed cross-sectional data on 11,110 students (mean age = 14.9, standard deviation = .89) recruited from 168 schools in 10 European Union countries involved in the Saving and Empowering Young Lives in Europe study. A self-report questionnaire was used to measure victimization types, depression, anxiety, parental and peer support, and suicide ideation and attempts. For each outcome, we applied hierarchical nonlinear models controlling for sociodemographics., Results: Prevalence of victimization was 9.4% physical, 36.1% verbal, and 33.0% relational. Boys were more likely to be physically and verbally victimized, whereas girls were more prone to relational victimization. Physical victimization was associated with suicide ideation, and relational victimization was associated with suicide attempts. Other associations between victimization and suicidality (ideation/attempts) were identified through analysis of interactions with additional risk and protective factors. Specifically, verbal victimization was associated with suicide ideation among adolescents with depression who perceived low parental support. Similarly, low peer support increased the associations between verbal victimization and suicide ideation. Verbal victimization was associated with suicide attempts among adolescents with anxiety who perceived low parental support., Conclusions: Findings support the development of prevention strategies for adolescent victims of bullying who may be at elevated risk for suicide ideation/behavior, by taking into account gender, the type of bullying, symptomatology, and availability of interpersonal support., (Copyright © 2017. Published by Elsevier Inc.)

On average, in one year in France, six in every thirty teenagers have suicidal thoughts and two attempt suicide. At this age, suicidal behaviour is structured around psychopathological, developmental and relational dimensions. Talking about suicide helps to avoid it but educating teenagers in mental health is the best way of preventing this definitive act., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Reelin (RELN) is identified as a risk gene for major psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BPD). However, the role of its downstream signaling molecule, the low-density lipoprotein receptor-related protein 8 (LRP8) in these illnesses is still unclear. To detect whether LRP8 is a susceptibility gene for SCZ and BPD, we analyzed the associations of single nucleotide polymorphisms (SNPs) in LRP8 in a total of 47,187 subjects (including 9379 SCZ patients; 6990 BPD patients; and 12,556 controls in a screening sample, and 1397 SCZ families, 3947 BPD patients, and 8387 controls in independent replications), and identified a non-synonymous SNP rs5174 in LRP8 significantly associated with SCZ and BPD as well as the combined psychosis phenotype (P meta  = 1.99 × 10 -5 , odds ratio (OR) = 1.066, 95 % confidence interval (CI) = 1.035-1.098). The risk SNP rs5174 was also associated with LRP8 messenger RNA (mRNA) expression in multiple brain tissues across independent samples (lowest P = 0.00005). Further exploratory analysis revealed that LRP8 was preferentially expressed in fetal brain tissues. Protein-protein interaction (PPI) analysis demonstrated that LRP8 significantly participated in a highly interconnected PPI network build by top risk genes for SCZ and BPD (P = 7.0 × 10 -4 ). Collectively, we confirmed that LRP8 is a risk gene for psychosis, and our results provide useful information toward a better understanding of genetic mechanism involving LRP8 underlying risk of complex psychiatric disorders.

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P =  5.87 × 10  -   9 ; odds ratio (OR) = 1.12) and markers within ERBB2 (rs2517959, P =  4.53 × 10  -   9 ; OR = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS., (Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the United States.)

Background: Many countries are developing suicide prevention strategies for which up-to-date, high-quality evidence is required. We present updated evidence for the effectiveness of suicide prevention interventions since 2005., Methods: We searched PubMed and the Cochrane Library using multiple terms related to suicide prevention for studies published between Jan 1, 2005, and Dec 31, 2014. We assessed seven interventions: public and physician education, media strategies, screening, restricting access to suicide means, treatments, and internet or hotline support. Data were extracted on primary outcomes of interest, namely suicidal behaviour (suicide, attempt, or ideation), and intermediate or secondary outcomes (treatment-seeking, identification of at-risk individuals, antidepressant prescription or use rates, or referrals). 18 suicide prevention experts from 13 European countries reviewed all articles and rated the strength of evidence using the Oxford criteria. Because the heterogeneity of populations and methodology did not permit formal meta-analysis, we present a narrative analysis., Findings: We identified 1797 studies, including 23 systematic reviews, 12 meta-analyses, 40 randomised controlled trials (RCTs), 67 cohort trials, and 22 ecological or population-based investigations. Evidence for restricting access to lethal means in prevention of suicide has strengthened since 2005, especially with regard to control of analgesics (overall decrease of 43% since 2005) and hot-spots for suicide by jumping (reduction of 86% since 2005, 79% to 91%). School-based awareness programmes have been shown to reduce suicide attempts (odds ratio [OR] 0·45, 95% CI 0·24-0·85; p=0·014) and suicidal ideation (0·5, 0·27-0·92; p=0·025). The anti-suicidal effects of clozapine and lithium have been substantiated, but might be less specific than previously thought. Effective pharmacological and psychological treatments of depression are important in prevention. Insufficient evidence exists to assess the possible benefits for suicide prevention of screening in primary care, in general public education and media guidelines. Other approaches that need further investigation include gatekeeper training, education of physicians, and internet and helpline support. The paucity of RCTs is a major limitation in the evaluation of preventive interventions., Interpretation: In the quest for effective suicide prevention initiatives, no single strategy clearly stands above the others. Combinations of evidence-based strategies at the individual level and the population level should be assessed with robust research designs., Funding: The Expert Platform on Mental Health, Focus on Depression, and the European College of Neuropsychopharmacology., (Copyright © 2016 Elsevier Ltd. All rights reserved.)