Genome-wide association study of stimulant dependence

Stimulant dependence is heritable, but specific genetic factors underlying the trait have not been identified. A genome-wide association study for stimulant dependence was performed in a discovery cohort of African- (AA) and European-ancestry (EA) subjects ascertained for genetic studies of alcohol, opioid, and cocaine use disorders. The sample comprised individuals with DSM-IV stimulant dependence (393 EA cases, 5288 EA controls; 155 AA cases, 5603 AA controls). An independent cohort from the family-based Collaborative Study on the Genetics of Alcoholism (532 EA cases, 7635 EA controls; 53 AA cases, AA 3352 controls) was used for replication. One variant in SLC25A16 (rs2394476, p = 3.42 × 10−10, odds ratio [OR] = 3.70) was GWS in AAs. Four other loci showed suggestive evidence, including KCNA4 in AAs (rs11500237, p = 2.99 × 10−7, OR = 2.31) which encodes one of the potassium voltage-gated channel protein that has been linked to several other substance use disorders, and CPVL in the combined population groups (rs1176440, p = 3.05 × 10−7, OR = 1.35), whose expression was previously shown to be upregulated in the prefrontal cortex from users of cocaine, cannabis, and phencyclidine. Analysis of the top GWAS signals revealed a significant enrichment with nicotinic acetylcholine receptor genes (adjusted p = 0.04) and significant pleiotropy between stimulant dependence and alcohol dependence in EAs (padj = 3.6 × 10−3), an anxiety disorder in EAs (padj = 2.1 × 10−4), and ADHD in both AAs (padj = 3.0 × 10−33) and EAs (padj = 6.7 × 10−35). Our results implicate novel genes and pathways as having roles in the etiology of stimulant dependence.

Pharmacotherapy for Comorbid Adult Attention-Deficit Hyperactivity Disorder and Stimulant Dependence: A Systematic Review

Comorbid adult attention-deficit hyperactivity disorder (ADHD) and stimulant dependence is widely recognized, but efficacy of pharmacotherapy in this patient population is not well established. We aimed to review whether pharmacotherapy is efficacious in reducing ADHD symptoms and stimulant use in comorbid adult ADHD and stimulant use disorder. English articles until June 2017 were systematically searched in electronic databases (MEDLINE and PsycINFO), an online clinical trials register (ClinicalTrial.gov), and through hand-search of article references. Randomized, double-blind, placebo-controlled trials that studied efficacy of pharmacotherapy in adults with comorbid ADHD and stimulant dependence were included. Two reviewers assessed studies for inclusion and extracted data; disagreements were resolved by consensus. Study outcomes included were changes in ADHD symptom severity, substance abstinence, treatment retention rates and safety. From the 1394 records identified, five trials (n=358) were included. Four studies involved methylphenidate; in another study extended-release mixed amphetamine were used. The comorbid stimulant was cocaine in three studies, and amphetamines in the rest. All were short-term studies involving predominantly young male adults conducted in outpatient settings. There is early promising but mixed evidence for therapeutic efficacy in improving ADHD symptoms. Stimulant medications did not worsen stimulant dependence or adverse effects of stimulant medications. Side effects were mild and tolerable. High attrition rates and small sample size limited the generalizability of findings. Current limited evidence suggests that stimulant treatment for comorbid adult ADHD and stimulant dependence is feasible. Welldesigned trials with adequate power are needed for more robust evidence on ADHD and stimulant use outcomes.

Neurocognitive and psychiatric markers for addiction: Common vs. specific (endo)phenotypes for opiate and stimulant dependence

BACKGROUNDThe differential utility of neurocognitive impulsivity and externalizing/internalizing traits as putative addiction endophenotypes among individuals dependent on opiates vs. stimulants is unclear. The present study aims to determine: (1) whether neurocognitive impulsivity dimensions and externalizing/internalizing traits are correlated between siblings discordant for opiate and stimulant dependence; and (2) which of these associations are common across substances and which are substance-specific.METHODPearson correlations between individuals with ‘pure’ heroin and ‘pure’ amphetamine dependence and their unaffected biological siblings (n = 37 heroin sibling pairs; n = 30 amphetamine sibling pairs) were run on 10 neurocognitive measures, 6 externalizing measures, and 5 internalizing measures. Sibling pair effects were further examined using regression.RESULTSSiblings discordant for heroin dependence were significantly correlated on delay aversion on the Cambridge Gambling Task, risk-taking on the Balloon Analogue Risk Task, sensation seeking, and hopelessness. Siblings discordant for amphetamine dependence were significantly correlated on quality of decision-making on the Cambridge Gambling Task, discriminability on the Immediate Memory Task, commission errors on the Go/No-Go Task, trait impulsivity, ADHD, and anxiety sensitivity.CONCLUSIONSDimensions of impulsivity and externalizing/internalizing traits appear to aggregate among siblings discordant for substance dependence. Risk-taking propensity, sensation seeking, and hopelessness were specific for heroin sibling pairs. Motor/action impulsivity and trait impulsivity were specific to amphetamine sibling pairs. Decisional/choice impulsivity was common across both heroin and amphetamine sibling pairs. These findings provide preliminary evidence for the utility of neurocognitive impulsivity and externalizing/internalizing traits as candidate endophenotypes for substance dependence in general and for substance-specific dependencies.

dACC Response to Presentation of Negative Feedback Identifies Stimulant Dependence Diagnoses and Stimulant Use Severity

Error-monitoring abnormalities in stimulant-dependent individuals (SDIs) may be due to reduced awareness of committed errors, or to reduced sensitivity upon such awareness. The distinction between these alternatives remains largely undifferentiated, but may have substantial clinical relevance. We sought to better characterize the nature, and clinical relevance, of SDIs’ error-monitoring processes by comparing carefully isolated neural responses during the presentation of negative feedback to a) stimulant dependence status and b) lifetime stimulant use. Forty-eight SDIs and twenty-three non-SDIs performed an fMRI-based time-estimation task specifically designed to isolate neural responses associated with the presentation (versus expectation) of contingent negative feedback. SDIs showed reduced dACC response compared to non-SDIs following the presentation of negative feedback, but only when error expectancies were controlled. Moreover, lifetime stimulant use correlated negatively with magnitude of dACC attenuation. While this findings was minimized after controlling for age, these results suggest that SDIs may be characterized by a core reduction in neural activity following error feedback, in the context of intact feedback expectancies. Correlations with lifetime stimulant use suggest that this neural attenuation may hold clinical significance.