Polygenic contributions to performance on the Balloon Analogue Risk Task.

Risky decision-making is a common, heritable endophenotype seen across many psychiatric disorders. Its underlying genetic architecture is incompletely explored. We examined behavior in the Balloon Analogue Risk Task (BART), which tests risky decision-making, in two independent samples of European ancestry. One sample (n = 1138) comprised healthy participants and some psychiatric patients (53 schizophrenia, 42 bipolar disorder, 47 ADHD); the other (n = 911) excluded for recent treatment of various psychiatric disorders but not ADHD. Participants provided DNA and performed the BART, indexed by mean adjusted pumps. We constructed a polygenic risk score (PRS) for discovery in each dataset and tested it in the other as replication. Subsequently, a genome-wide MEGA-analysis, combining both samples, tested genetic correlation with risk-taking self-report in the UK Biobank sample and psychiatric phenotypes characterized by risk-taking (ADHD, Bipolar Disorder, Alcohol Use Disorder, prior cannabis use) in the Psychiatric Genomics Consortium. The PRS for BART performance in one dataset predicted task performance in the replication sample (r = 0.13, p = 0.000012, pFDR = 0.000052), as did the reciprocal analysis (r = 0.09, p = 0.0083, pFDR=0.04). Excluding participants with psychiatric diagnoses produced similar results. The MEGA-GWAS identified a single SNP (rs12023073; p = 3.24 × 10-8) near IGSF21, a protein involved in inhibitory brain synapses; replication samples are needed to validate this result. A PRS for self-reported cannabis use (p = 0.00047, pFDR = 0.0053), but not self-reported risk-taking or psychiatric disorder status, predicted behavior on the BART in our MEGA-GWAS sample. The findings reveal polygenic architecture of risky decision-making as measured by the BART and highlight its overlap with cannabis use.

Evaluation of delay discounting as a transdiagnostic research domain criteria indicator in 1388 general community adults.

BACKGROUND: The Research Domain Criteria (RDoC) approach proposes a novel psychiatric nosology using transdiagnostic dimensional mechanistic constructs. One candidate RDoC indicator is delay discounting (DD), a behavioral economic measure of impulsivity, based predominantly on studies examining DD and individual conditions. The current study sought to evaluate the transdiagnostic significance of DD in relation to several psychiatric conditions concurrently. METHODS: Participants were 1388 community adults (18-65) who completed an in-person assessment, including measures of DD, substance use, depression, anxiety, posttraumatic stress disorder, and attention-deficit hyperactivity disorder (ADHD). Relations between DD and psychopathology were examined with three strategies: first, examining differences by individual condition using clinical cut-offs; second, examining DD in relation to latent psychopathology variables via principal components analysis (PCA); and third, examining DD and all psychopathology simultaneously via structural equation modeling (SEM). RESULTS: Individual analyses revealed elevations in DD were present in participants screening positive for multiple substance use disorders (tobacco, cannabis, and drug use disorder), ADHD, major depressive disorder (MDD), and an anxiety disorder (ps < 0.05-0.001). The PCA produced two latent components (substance involvement v. the other mental health indicators) and DD was significantly associated with both (ps < 0.001). In the SEM, unique significant positive associations were observed between the DD latent variable and tobacco, cannabis, and MDD (ps < 0.05-0.001). CONCLUSIONS: These results provide some support for DD as a transdiagnostic indicator, but also suggest that studies of individual syndromes may include confounding via comorbidities. Further systematic investigation of DD as an RDoC indicator is warranted.

Steep discounting of delayed monetary and food rewards in obesity: a meta-analysis.

BACKGROUND: An increasing number of studies have investigated delay discounting (DD) in relation to obesity, but with mixed findings. This meta-analysis synthesized the literature on the relationship between monetary and food DD and obesity, with three objectives: (1) to characterize the relationship between DD and obesity in both case-control comparisons and continuous designs; (2) to examine potential moderators, including case-control v. continuous design, money v. food rewards, sample sex distribution, and sample age (18 years); and (3) to evaluate publication bias. METHOD: From 134 candidate articles, 39 independent investigations yielded 29 case-control and 30 continuous comparisons (total n = 10 278). Random-effects meta-analysis was conducted using Cohen's d as the effect size. Publication bias was evaluated using fail-safe N, Begg-Mazumdar and Egger tests, meta-regression of publication year and effect size, and imputation of missing studies. RESULTS: The primary analysis revealed a medium effect size across studies that was highly statistically significant (d = 0.43, p < 10-14). None of the moderators examined yielded statistically significant differences, although notably larger effect sizes were found for studies with case-control designs, food rewards and child/adolescent samples. Limited evidence of publication bias was present, although the Begg-Mazumdar test and meta-regression suggested a slightly diminishing effect size over time. CONCLUSIONS: Steep DD of food and money appears to be a robust feature of obesity that is relatively consistent across the DD assessment methodologies and study designs examined. These findings are discussed in the context of research on DD in drug addiction, the neural bases of DD in obesity, and potential clinical applications.

Getting high to cope with COVID-19: Modelling the associations between cannabis demand, coping motives, and cannabis use and problems.

During the COVID-19 pandemic, people may use substances like cannabis for enhancement or coping purposes. Behavioral economic demand for a substance is a key determinant of its use and misuse and can be measured via hypothetical purchase tasks. Previous research suggests that motivations to use a substance play a mediational role between elevated substance demand and problems, but comparable mechanistic research has yet to be done in the COVID-19 context and on the effects of cannabis demand on cannabis use patterns. Participants (n = 137) were recruited via the online crowdsourcing platform Prolific. Participants completed measures of cannabis use and problems, motivations for cannabis use, and the Marijuana Purchase Task. Two indices of demand, Persistence (i.e., sensitivity to increasing cost of cannabis) and Amplitude (i.e., consumption of cannabis at unrestricted cost), were related to increased cannabis problems via the use motive of coping during the COVID-19 pandemic. This model did not support the mediational role of enhancement motives. Those with increased cannabis demand who tend to use cannabis to cope are at increased risk of experiencing negative cannabis-related consequences during the COVID-19 pandemic.

Vapers exhibit similar subjective nicotine dependence but lower nicotine reinforcing value compared to smokers.

INTRODUCTION: E-cigarette use has increased rapidly over the last 10 years, mostly among smokers and ex-smokers. Although there may be some degree of dependency on nicotine via e-cigarette use, the nature of this dependency is poorly understood. The aim of this paper is to use tasks from behavioural economics to compare the value that smokers place on tobacco cigarettes to the value that vapers place on e-cigarettes. METHOD: Exclusive current smokers (n = 25) and vapers (n = 20) attended one session where they completed the Cigarette/e-cigarette Dependence Scale, the Cigarette/e-cigarette Purchasing Task (CPT) and the Concurrent Choice Task (CCT). The CPT requires participants to indicate how many puffs of their chosen product they would purchase at increasing price points. The CCT requires participants to choose between earning a money point or a point towards a cigarette/e-cigarette after being presented with a neutral, money or cigarette/e-cigarette cue. RESULTS: Overall scores on the self-report scales suggest a comparable level of dependency between smokers and vapers. The CPT revealed that vapers are more sensitive than smokers to escalating costs as consumption declined as costs increased. On the CCT, when primed with money, vapers showed a decrease in choosing e-cigarettes. CONCLUSION: These findings suggest that, on behavioural economic tasks, tobacco cigarettes have a higher relative value than e-cigarettes. Vapers appear to place a lower limit on what they will spend to access e-cigarettes and more readily choose money over e-cigarette puffs when primed by money cues.

Consistent evidence of indirect effects of impulsive delay discounting and negative urgency between childhood adversity and adult substance use in two samples.

RATIONALE: Exposure to adverse life experiences (ACEs) is robustly associated with problematic alcohol and other drug use. In addition, both ACEs and substance use have been independently associated with impulsivity. OBJECTIVE: To examine whether impulsivity is implicated in the link between ACE and adult substance use in two samples. METHODS: The primary sample was a cohort of community adults (N = 1431) who completed a one-time in-person assessment. A second sample was crowdsourced using Amazon Mechanical Turk (N = 3021). All participants were assessed for ACEs using the Adverse Childhood Experience Questionnaire and for current alcohol and other drug use. Given its multidimensional nature, impulsivity was assessed using the UPPS-P measure of impulsive personality traits, Go/NoGo (GNG) task (in-person community adult sample only), and delay discounting (Monetary Choice Questionnaire [MCQ] in the community adults and Effective Delay-50 [ED50] in the crowdsourced sample. Structural equation modeling was used to examine the hypothesized indirect effects for the measures of impulsivity between ACEs and substance use. RESULTS: In the community adults, significant indirect effects were observed from ACEs to substance use via UPPS-Negative Urgency (ß = 0.07, SE = 0.02, 95% CI [0.04, 0.10]), and the MCQ (ß = 0.02 SE = .01, 95% CI [0.01, 0.03]). In the crowdsourced sample, significant indirect effects were observed from ACEs to substance use via UPPS-Negative Urgency (ß = 0.05, SE = .01, 95% CI [0.04, 0.07]), UPPS-Premeditation (ß = 0.04, SE = .01, 95% CI [0.02, 0.05), and the ED50 (ß = 0.02, SE = .01; 95% CI [0.01, 0.03]). CONCLUSION: These findings provide consistent evidence that decrements in regulation of negative emotions and overvaluation of immediate rewards indirectly link ACE and substance use. These robust cross-sectional findings support the need for elucidating the underlying neural substrates implicated and for longitudinal evaluations.

Optimizing screening for depression, anxiety disorders, and post-traumatic stress disorder in inpatient addiction treatment: A preliminary investigation.

OBJECTIVE: Substance use disorders (SUD) are frequently comorbid with other psychiatric conditions, but a comprehensive diagnostic assessment is often not feasible clinically. Efficient psychometrically-validated screening tools exist for commonly comorbid conditions, but cutoff accuracies have typically not been evaluated in addiction treatment settings. This study examined the performance of several widely-used screening measures in relation to diagnostic status from a clinical interview to identify and validate cutoff scores in an inpatient SUD treatment setting. METHOD: Participants were 99 patients in a large residential SUD treatment program in Ontario, Canada. Participants completed a screening battery, including the Patient Health Questionnaire - 9 (PHQ-9), Generalized Anxiety Disorder - 7 (GAD-7), and Post-Traumatic Stress Disorder Checklist-5 (PCL-5), and underwent a semi-structured diagnostic clinical interview. Receiver operating characteristic curves were used to determine optimal cutoff scores on the screening tool against the interview-based diagnosis. RESULTS: Area under the curve (AUC) was statistically significant for all screens and were as follows: PHQ-9 = 0.70 (95% CI = 0.59-0.80), GAD-7 = 0.74 (95% CI = 0.63-0.84), and PCL-5 = 0.79 (95% CI = 0.66-0.91). The optimal accuracy cutoff scores based on sensitivity and specificity were: PHQ-9 ≥ 16, GAD-7 ≥ 9, the PCL-5 ≥ 42. CONCLUSIONS: In general, the candidate screeners performed acceptably in this population. However, the optimal cutoff scores were notably higher than existing guidelines for depression and PTSD, potentially due to the general elevations in negative affectivity among individuals initiating SUD treatment. Further validation of these cutoff values is warranted. PUBLIC HEALTH SIGNIFICANCE: This study provides modified screening cutoff scores for major depression, anxiety disorders, and post-traumatic stress disorder in addiction treatment settings.

Patterns of substance use among adolescents: A systematic review.

PURPOSE: This review characterizes empirically derived patterns of multiple (multi-) substance use among adolescents. A secondary objective was to examine the extent to which mental health symptomatology was included in the empirical analyses examining substance use patterns. METHODS: Eligible studies included those that used cluster-based approaches, included the assessment of at least two different substances, and were based on study samples with mean ages between 11 and 18 years. 4665 records were screened including 461 studies for full-text screening. RESULTS: 70 studies were included with common clusters being: low use, single or dual substance use, moderate general multi-use, and high multi-use. The most common patterns of single or multi-substance use were: alcohol only, alcohol with cannabis and/or tobacco, and use of alcohol, tobacco, and cannabis with and without other drugs. Lower socioeconomic status, older age, and male gender were consistent predictors of multi-use clusters. Only 37 % of studies compared differences in levels of mental health across clusters with symptoms consistently associated with a greater likelihood of multi-use. Only 29 % of studies included mental health indicators in cluster-based analyses, with over half identifying distinct mental health and substance use clusters. Fit indices in cluster analyses and measurement properties of substance use were heterogeneous and inconsistently reported across studies. CONCLUSIONS: Distinct patterns of substance use were derived but methodological differences prevented direct comparison and reduced capacity to generalize across studies. There is a need to establish standardized methodological approaches to identify robust patterns of substance use to enhance etiological, prognostic, and intervention research.

The genetics of human personality.

Personality traits are the relatively enduring patterns of thoughts, feelings and behaviors that reflect the tendency to respond in certain ways under certain circumstances. Twin and family studies have showed that personality traits are moderately heritable, and can predict various lifetime outcomes, including psychopathology. The Research Domain Criteria characterizes psychiatric diseases as extremes of normal tendencies, including specific personality traits. This implies that heritable variation in personality traits, such as neuroticism, would share a common genetic basis with psychiatric diseases, such as major depressive disorder. Despite considerable efforts over the past several decades, the genetic variants that influence personality are only beginning to be identified. We review these recent and increasingly rapid developments, which focus on the assessment of personality via several commonly used personality questionnaires in healthy human subjects. Study designs covered include twin, linkage, candidate gene association studies, genome-wide association studies and polygenic analyses. Findings from genetic studies of personality have furthered our understanding about the genetic etiology of personality, which, like neuropsychiatric diseases themselves, is highly polygenic. Polygenic analyses have showed genetic correlations between personality and psychopathology, confirming that genetic studies of personality can help to elucidate the etiology of several neuropsychiatric diseases.

An initial investigation of associations between dopamine-linked genetic variation and smoking motives in African Americans.

Nicotine dependence (ND) is a heterogeneous phenotype with complex genetic influences that may vary across ethnicities. The use of intermediate phenotypes may clarify genetic influences and reveal specific etiological pathways. Prior work in European Americans has found that the four Primary Dependence Motives (PDM) subscales (Automaticity, Craving, Loss of Control, and Tolerance) of the Wisconsin Inventory of Smoking Motives represent core features of nicotine dependence and are promising intermediate phenotypes for understanding genetic pathways to ND. However, no studies have examined PDM as an intermediate phenotype in African American smokers, an ethnic population that displays unique patterns of smoking and genetic variation. In the current study, 268 African American daily smokers completed a phenotypic assessment and provided a sample of DNA. Associations among haplotypes in the NCAM1-TTC12-ANKK1-DRD2 gene cluster, a dopamine-related gene region associated with ND, PDM intermediate phenotypes, and ND were examined. Dopamine-related genetic variation in the DBH and COMT genes was also considered on an exploratory basis. Mediational analysis was used to test the indirect pathway from genetic variation to smoking motives to nicotine dependence. NCAM1-TTC12-ANKK1-DRD2 region variation was significantly associated with the Automaticity subscale and, further, Automaticity significantly mediated associations among NCAM1-TTC12-ANKK1-DRD2 cluster variants and ND. DBH was also significantly associated with Automaticity, Craving, and Tolerance; Automaticity and Tolerance also served as mediators of the DBH-ND relationship. These results suggest that PDM, Automaticity in particular, may be a viable intermediate phenotype for understanding dopamine-related genetic influences on ND in African American smokers. Findings support a model in which putatively dopaminergic variants exert influence on ND through an effect on patterns of automatic routinized smoking.

NCAM1-TTC12-ANKK1-DRD2 variants and smoking motives as intermediate phenotypes for nicotine dependence.

RATIONALE: Nicotine dependence (ND) is a heterogeneous phenotype with complex genetic influences. The use of intermediate ND phenotypes may clarify genetic influences and reveal specific etiological pathways. Prior work has found that the four Primary Dependence Motives (PDM) subscales (Automaticity, Craving, Loss of Control, and Tolerance) of the Wisconsin Inventory of Smoking Motives (WISDM) represent heavy, pervasive smoking, which is a core feature of nicotine dependence, making these motives strong candidates as intermediate phenotypes. OBJECTIVE: This study examines the WISDM PDM as a novel intermediate phenotype of nicotine dependence. METHODS: The study used data from 734 European Americans who smoked at least 5 cigs/day [M = 16.2 (SD = 9.5) cigs/day], completed a phenotypic assessment, and provided a sample of DNA. Based on prior evidence of the role of genetic variation in the NCAM1-TTC12-ANKK1-DRD2 region on chromosome 11q23 in smoking behavior, associations among 12 region loci with nicotine dependence and PDM phenotypes were examined using haplotype and individual loci approaches. In addition, mediational analysis tested the indirect pathway from genetic variation to smoking motives to nicotine dependence. RESULTS: NCAM1-TTC12-ANKK1-DRD2 region loci and haplotypes were significantly associated with the motive of Automaticity and, further, Automaticity significantly mediated associations among NCAM1-TTC12-ANKK1-DRD2 cluster variants and nicotine dependence. CONCLUSIONS: These results suggest that motives related to automaticity are a viable intermediate phenotype for understanding genetic contributions to nicotine dependence. Further, NCAM1-TTC12-ANKK1-DRD2 variants may increase the likelihood that a person will become dependent via a highly automatic smoking ritual that can be elicited with little awareness.

D-cycloserine to enhance extinction of cue-elicited craving for alcohol: a translational approach.

Cue-elicited craving for alcohol is well established but extinction-based treatment to extinguish this response has generated only modest positive outcomes in clinical trials. Basic and clinical research suggests that D-cycloserine (DCS) enhances extinction to fear cues under certain conditions. However, it remains unclear whether DCS would also accelerate extinction of cue-elicited craving for alcohol. The goal of the current study was to examine whether, compared with placebo (PBO), DCS enhanced extinction of cue-elicited craving among treatment-seeking individuals with alcohol use disorders (AUDs). Participants were administered DCS (50 mg) or PBO 1 h before an alcohol extinction paradigm in a simulated bar environment on two occasions. The extinction procedures occurred 1 week apart and were fully integrated into outpatient treatment. Subjective craving for alcohol was the primary variable of interest. Follow-up cue reactivity sessions were conducted 1 week and 3 weeks later to ascertain persisting DCS effects. Drinking outcomes and tolerability were also examined. DCS was associated with augmented reductions in alcohol craving to alcohol cues during the first extinction session and these effects persisted through all subsequent sessions, suggesting facilitation of extinction. Participants in the DCS condition reported significant short-term reductions in drinking, although these did not persist to follow-up, and found the medication highly tolerable. These findings provide evidence that DCS enhances extinction of cue-elicited craving for alcohol in individuals with AUDs in the context of outpatient treatment. The potential clinical utility of DCS is discussed, including methodological considerations and context-dependent learning.