Prevalence and correlates of DSM-5 bipolar and related disorders and hyperthymic personality in the community.

BACKGROUND: To 1) establish the lifetime and 12-month prevalence of DSM-5 bipolar and related disorders including the new algorithmically defined conditions grouped within Other Specified Bipolar and Related Disorders (OSBARD) as well as hyperthymic personality in a randomly selected community sample, and 2) determine the clinical relevance of the OSBARD category in terms of sociodemographic characteristics, course, comorbidity and treatment patterns by comparing the subjects of this category to those with bipolar-I (BP-I), bipolar-II (BP-II), major depressive disorder (MDD), and those with no history of mood disorders. METHODS: The semi-structured Diagnostic Interview for Genetic Studies was administered by masterslevel psychologists to a random sample of an urban area (n=3'719). RESULTS: The lifetime prevalence was 1.0% for BP-I, 0.8% for BP-II, 1.0% for OSBARD and 3% for hyperthymic personality. Subjects with OSBARD were more severely affected than subjects without a history of mood disorders regarding almost all clinical correlates. Compared to those with MDD, they also revealed an elevated risk of suicidal attempts, lower global functioning, more treatment seeking and more lifetime comorbidity including anxiety, substance use and impulse-control disorders. However, they did not differ from subjects with BP-II. LIMITATIONS: Small sample sizes for bipolar and related disorders and potential inaccurate recall of symptoms. CONCLUSIONS: The modifications of diagnostic criteria for manic/hypomanic episodes according to the DSM-5 only marginally affect the prevalence estimates for BP-I and BP-II. The new DSM-5 OSBARD category is associated with significant clinical burden, is hardly distinct from BP-II with respect to clinical correlates and deserves similar clinical attention.

The influence of drinking pattern, at individual and aggregate levels, on alcohol-related negative consequences.

AIM: To determine the extent drinking patterns (at the individual and country level) are associated with alcohol-related consequences over and above the total alcohol the person consumes. METHODS: Hierarchical linear models were estimated based on general population surveys conducted in 18 countries participating in the GENACIS project. RESULTS: In general, the positive association between drinking pattern scores and alcohol-related consequences was found at both the individual and country levels, independent of volume of drinking. In addition, a significant interaction effect indicated that the more detrimental the country's drinking pattern, the less steep the association between the volume of drinking and its consequences. CONCLUSION: Drinking patterns have an independent impact on consequences over and above the relationship between volume and consequences.

Computational analysis of the genetic and environmental contributions to disease-related human phenotypes: From predicting adverse lipid response of HIV patients receiving antiretroviral therapy to genome-wide association studies of cardiovascular and lipid related disorders

Genetic variants influence the risk to develop certain diseases or give rise to differences in drug response. Recent progresses in cost-effective, high-throughput genome-wide techniques, such as microarrays measuring Single Nucleotide Polymorphisms (SNPs), have facilitated genotyping of large clinical and population cohorts. Combining the massive genotypic data with measurements of phenotypic traits allows for the determination of genetic differences that explain, at least in part, the phenotypic variations within a population. So far, models combining the most significant variants can only explain a small fraction of the variance, indicating the limitations of current models. In particular, researchers have only begun to address the possibility of interactions between genotypes and the environment. Elucidating the contributions of such interactions is a difficult task because of the large number of genetic as well as possible environmental factors.In this thesis, I worked on several projects within this context. My first and main project was the identification of possible SNP-environment interactions, where the phenotypes were serum lipid levels of patients from the Swiss HIV Cohort Study (SHCS) treated with antiretroviral therapy. Here the genotypes consisted of a limited set of SNPs in candidate genes relevant for lipid transport and metabolism. The environmental variables were the specific combinations of drugs given to each patient over the treatment period. My work explored bioinformatic and statistical approaches to relate patients' lipid responses to these SNPs, drugs and, importantly, their interactions. The goal of this project was to improve our understanding and to explore the possibility of predicting dyslipidemia, a well-known adverse drug reaction of antiretroviral therapy. Specifically, I quantified how much of the variance in lipid profiles could be explained by the host genetic variants, the administered drugs and SNP-drug interactions and assessed the predictive power of these features on lipid responses. Using cross-validation stratified by patients, we could not validate our hypothesis that models that select a subset of SNP-drug interactions in a principled way have better predictive power than the control models using "random" subsets. Nevertheless, all models tested containing SNP and/or drug terms, exhibited significant predictive power (as compared to a random predictor) and explained a sizable proportion of variance, in the patient stratified cross-validation context. Importantly, the model containing stepwise selected SNP terms showed higher capacity to predict triglyceride levels than a model containing randomly selected SNPs. Dyslipidemia is a complex trait for which many factors remain to be discovered, thus missing from the data, and possibly explaining the limitations of our analysis. In particular, the interactions of drugs with SNPs selected from the set of candidate genes likely have small effect sizes which we were unable to detect in a sample of the present size (<800 patients).In the second part of my thesis, I performed genome-wide association studies within the Cohorte Lausannoise (CoLaus). I have been involved in several international projects to identify SNPs that are associated with various traits, such as serum calcium, body mass index, two-hour glucose levels, as well as metabolic syndrome and its components. These phenotypes are all related to major human health issues, such as cardiovascular disease. I applied statistical methods to detect new variants associated with these phenotypes, contributing to the identification of new genetic loci that may lead to new insights into the genetic basis of these traits. This kind of research will lead to a better understanding of the mechanisms underlying these pathologies, a better evaluation of disease risk, the identification of new therapeutic leads and may ultimately lead to the realization of "personalized" medicine.

Childhood adversities as specific contributors to the co-occurrence of posttraumatic stress and alcohol use disorders.

There is much evidence that alcohol use disorders (AUD) often co-occur with posttraumatic stress disorders (PTSD), and that the comorbid condition is associated with a more severe clinical profile than that of PTSD without AUD. However, little is known about the role of childhood adversities as specific risk factors for the development of AUD in individuals presenting with PTSD. The aim of the study was to explore whether specific stressors from the spectrum of trauma and childhood adversities contribute to the development of AUD among subjects with PTSD. From a large community sample, of N=140 individuals with PTSD, N=24 (17.14%) received an additional diagnosis of AUD with an onset after the onset of PTSD. Those with comorbid PTSD/AUD and those with PTSD only were compared regarding type and features of their trauma, childhood adversities and psychiatric comorbidity. Compared to PTSD alone, PTSD/AUD was associated with higher levels of stress in terms of childhood adversities; in particular, sexual abuse below the age of 16, but also with having been brought up in a foster home. PTSD/AUD was also associated with an earlier age of adverse events. Treatment of AUD should include standardized assessments of trauma, especially of trauma experienced during childhood.

Posttraumatic stress avoidance symptoms as mediators in the development of alcohol use disorders after exposure to childhood sexual abuse in a Swiss community sample.

This study examined the role of posttraumatic stress disorder (PTSD) symptoms of re-experience, avoidance, and hyperarousal in the relationship between different types of trauma and alcohol use disorders (AUD). We used data from 731 trauma-exposed individuals who participated in the first wave of the PsyCoLaus-study. Trauma characteristics were assessed relatively to the occurrence of lifetime PTSD symptoms and AUD. The results suggest that lifetime and childhood sexual abuse as well as overall childhood trauma were directly linked to AUD and PTSD symptoms, in particular to avoidance symptoms. From single symptom clusters PTSD avoidance was found to specifically mediate the trauma-AUD pathway. Both childhood and sexual trauma strongly contribute to the comorbidity of PTSD and AUD and avoidance-type symptoms appear to play a central role in maintaining this association. Hence, the alleviation of avoidance symptoms might be an important target for therapeutic intervention among victims of sexual abuse before specific addiction treatment is initiated.

Discrepancies between clinical needs and helpseeking behaviors in co-occurring posttraumatic stress and alcohol use disorders.

OBJECTIVE: The aim of the study was to compare subjects dually diagnosed with posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) to those with only one or none of these conditions regarding helpseeking needs and behaviors. METHOD: Data from a large community sample (N=3694) were used to assess the associations among lifetime PTSD and AUD, other psychiatric disorders, clinical characteristics and lifetime helpseeking behaviors derived from a semi-structured interview. RESULTS: Comorbid individuals had more severe clinical profiles and were more impaired than individuals with either PTSD or AUD alone or those with no/other psychiatric conditions. However, they did not differ in overall helpseeking behavior from any other group. Those with comorbid PTSD/AUD were even less likely than the other groups to seek help for depression and anxiety disorders through specific treatment facilities or the use of prescribed psychotropic drugs. CONCLUSIONS: Despite a greater need for treatment the comorbid group did not seek more help than the others. Their lower use of prescribed drugs supports the self-medication hypothesis, suggesting that those individuals relieve their symptoms through higher alcohol use instead. Our findings underline the need for health care facilities to encourage helpseeking behavior in the aftermath of stressful life events.

Internet-Based Brief Intervention to Prevent Unhealthy Alcohol Use among Young Men: A Randomized Controlled Trial.

Alcohol use is one of the leading modifiable morbidity and mortality risk factors among young adults. 2 parallel-group randomized controlled trial with follow-up at 1 and 6 months. Internet based study in a general population sample of young men with low-risk drinking, recruited between June 2012 and February 2013. Intervention: Internet-based brief alcohol primary prevention intervention (IBI). The IBI aims at preventing an increase in alcohol use: it consists of normative feedback, feedback on consequences, calorific value alcohol, computed blood alcohol concentration, indication that the reported alcohol use is associated with no or limited risks for health. Intervention group participants received the IBI. Control group (CG) participants completed only an assessment. Alcohol use (number of drinks per week), binge drinking prevalence. Analyses were conducted in 2014-2015. Of 4365 men invited to participate, 1633 did so; 896 reported low-risk drinking and were randomized (IBI: n = 451; CG: n = 445). At baseline, 1 and 6 months, the mean (SD) number of drinks/week was 2.4(2.2), 2.3(2.6), 2.5(3.0) for IBI, and 2.4(2.3), 2.8(3.7), 2.7(3.9) for CG. Binge drinking, absent at baseline, was reported by 14.4% (IBI) and 19.0% (CG) at 1 month and by 13.3% (IBI) and 13.0% (CG) at 6 months. At 1 month, beneficial intervention effects were observed on the number of drinks/week (p = 0.05). No significant differences were observed at 6 months. We found protective short term effects of a primary prevention IBI. Controlled-Trials.com ISRCTN55991918.

Childhood adversities as specific contributors to the co-occurrence of posttraumatic stress and alcohol use disorders.

There is much evidence that alcohol use disorders (AUD) often co-occur with posttraumatic stress disorders (PTSD), and that the comorbid condition is associated with a more severe clinical profile than that of PTSD without AUD. However, little is known about the role of childhood adversities as specific risk factors for the development of AUD in individuals presenting with PTSD. The aim of the study was to explore whether specific stressors from the spectrum of trauma and childhood adversities contribute to the development of AUD among subjects with PTSD. From a large community sample, of N=140 individuals with PTSD, N=24 (17.14%) received an additional diagnosis of AUD with an onset after the onset of PTSD. Those with comorbid PTSD/AUD and those with PTSD only were compared regarding type and features of their trauma, childhood adversities and psychiatric comorbidity. Compared to PTSD alone, PTSD/AUD was associated with higher levels of stress in terms of childhood adversities; in particular, sexual abuse below the age of 16, but also with having been brought up in a foster home. PTSD/AUD was also associated with an earlier age of adverse events. Treatment of AUD should include standardized assessments of trauma, especially of trauma experienced during childhood.

A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis.

Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world. We performed a genome-wide association study for alcohol-related cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 (P = 1.03 × 10(-9)) and TM6SF2 (P = 7.89 × 10(-10)) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis (P = 1.54 × 10(-48)) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.

Temporal Patterns of Alcohol Consumption and Alcohol-Related Road Accidents in Young Swiss Men: Seasonal, Weekday and Public Holiday Effects.

AIMS: To assess seasonal, weekday, and public holiday effects on alcohol-related road accidents and drinking diaries among young Swiss men. METHODS: Federal road accident data (35,485 accidents) from Switzerland and drinking diary data from a large cohort of young Swiss men (11,930 subjects) were analysed for temporal effects by calendar week, weekday and public holiday (Christmas, New Years, National Day). Alcohol-related accidents were analysed using rate ratios for observed versus expected numbers of accidents and proportions of alcohol-related accidents relative to the total number. Drinking diaries were analysed for the proportion of drinkers, median number of drinks consumed, and the 90th percentile's number of drinks consumed. RESULTS: Several parallel peaks were identified in alcohol-related accidents and drinking diaries. These included increases on Fridays and Saturdays, with Saturday drinking extending until early Sunday morning, an increase during the summer on workdays but not weekends, an increase at the end of the year, and increases on public holidays and the evening before. CONCLUSIONS: Our results suggest specific time-windows that are associated with increases in drinking and alcohol-related harm. Established prevention measures should be enforced during these time-windows to reduce associated peaks.

Are alcohol outlet densities strongly associated with alcohol-related outcomes? A critical review of recent evidence.

ISSUES: There have been reviews on the association between density of alcohol outlets and harm including studies published up to December 2008. Since then the number of publications has increased dramatically. The study reviews the more recent studies with regard to their utility to inform policy. APPROACH: A systematic review found more than 160 relevant studies (published between January 2009 and October 2014). The review focused on: (i) outlet density and assaultive or intimate partner violence; (ii) studies including individual level data; or (iii) 'natural experiments'. KEY FINDINGS: Despite overall evidence for an association between density and harm, there is little evidence on causal direction (i.e. whether demand leads to more supply or increased availability increases alcohol use and harm). When outlet types (e.g. bars, supermarkets) are analysed separately, studies are too methodologically diverse and partly contradictory to permit firm conclusions besides those pertaining to high outlet densities in areas such as entertainment districts. Outlet density commonly had little effect on individual-level alcohol use, and the few 'natural experiments' on restricting densities showed little or no effects. IMPLICATIONS AND CONCLUSIONS: Although outlet densities are likely to be positively related to alcohol use and harm, few policy recommendations can be given as effects vary across study areas, outlet types and outlet cluster size. Future studies should examine in detail outlet types, compare different outcomes associated with different strengths of association with alcohol, analyse non-linear effects and compare different methodologies. Purely aggregate-level studies examining total outlet density only should be abandoned. [Gmel G, Holmes J, Studer J. Are alcohol outlet densities strongly associated with alcohol-related outcomes? A critical review of recent evidence. Drug Alcohol Rev 2015].