Albert J. Arias

Correlates of co-occurring ADHD in drug-dependent subjects: prevalence and features of substance dependence and psychiatric disorders.

UNLABELLED We examined the prevalence and course of psychiatric and substance dependence (SD) disorders in subjects with SD and attention deficit hyperactivity disorder (ADHD). METHOD We interviewed 1761 adults with a lifetime diagnosis of cocaine and/or opioid dependence using the Semi-Structured Assessment for Drug Dependence and Alcoholism. Generalized linear regression with generalized estimating equation analysis was used to examine the associations between a lifetime diagnosis of ADHD and indicators of clinical course, and to identify unique correlates of ADHD. RESULTS Lifetime ADHD prevalence in the SD sample was 5.22% (vs. 0.85% in a group of individuals without SD). ADHD was associated with an earlier age of first substance use, more SD and psychiatric diagnoses, a greater likelihood of attempted suicide, and more hospitalizations. After controlling for conduct disorder, there were unique effects of ADHD on age of first substance use and number of SD diagnoses. CONCLUSION In subjects with cocaine or opioid dependence, ADHD is associated with greater SD and psychiatric comorbidity and a more severe course of illness.

Adverse childhood events as risk factors for substance dependence: Partial mediation by mood and anxiety disorders

AIMS Adverse childhood events (ACEs) are associated with negative health outcomes. We examined ACEs as risk factors for substance dependence (SD) and the mediating effects of mood and anxiety disorders on the relations between ACEs and SD risk. DESIGN We compared early life experiences in 2061 individuals with a lifetime diagnosis of alcohol, cocaine, or opioid dependence and 449 controls. MEASUREMENTS Diagnostic and ACE data were obtained using the Semi-Structured Assessment for Drug Dependence and Alcoholism. FINDINGS Childhood abuse or exposure to violent crime was positively related to the number of lifetime mood and anxiety disorders and to SD risk. Mood and anxiety disorders had their first onset a mean of nearly 3 years before the first SD diagnosis and partially mediated the effect of ACEs on SD risk. CONCLUSION ACEs appear to contribute additively to the risk of SD, with mood and anxiety disorders in the causal path for a portion of this risk. The identification and effective treatment of mood and anxiety disorders associated with ACEs could reduce the risk of developing SD.

Topiramate treatment for heavy drinkers: moderation by a GRIK1 polymorphism.

OBJECTIVE Topiramate has been shown to reduce drinking and heavy drinking in individuals with alcohol dependence whose goal was to stop drinking. The authors evaluated the efficacy and tolerability of topiramate in heavy drinkers whose treatment goal was to reduce drinking to safe levels. METHOD A total of 138 individuals (62.3% men) were randomly assigned to receive 12 weeks of treatment with topiramate (N=67), at a maximal daily dose of 200 mg, or matching placebo (N=71). Both groups received brief counseling to reduce drinking and increase abstinent days. It was hypothesized that topiramate-treated patients would be better able to achieve these goals, and it was predicted that based on prior research, the effects would be moderated by a single nucleotide polymorphism (rs2832407) in GRIK1, encoding the kainate GluK1 receptor subunit. RESULTS The rate of treatment completion was 84.9% and equal by treatment group. Topiramate treatment significantly reduced heavy drinking days and increased abstinent days relative to placebo. Patients receiving topiramate also had lower concentrations of the liver enzyme γ-glutamyl transpeptidase and lower scores on a measure of alcohol-related problems than the placebo group. In a European American subsample (N=122), topiramates effect on heavy drinking days was significantly greater than that for placebo only in rs2832407 C-allele homozygotes. CONCLUSIONS These findings support the use of topiramate at a daily dose of 200 mg to reduce heavy drinking in problem drinkers. The moderator effect of rs2832407, if validated, would facilitate the identification of heavy drinkers who are likely to respond well to topiramate treatment and provide an important personalized treatment option. The pharmacogenetic findings also implicate the kainate receptor in the mechanism of topiramates effects on heavy drinking.

Variation in Nicotinic Acetylcholine Receptor Genes is Associated with Multiple Substance Dependence Phenotypes

There is shared genetic risk for dependence on multiple substances, and the nicotinic receptor gene cluster on chromosome 15 harbors multiple polymorphisms that associate to this risk. Here, we report the results of an association study with 21 SNPs genotyped across the CHRNA5, CHRNA3, and CHRNB4 loci on chromosome 15q25.1. The sample consists of a discovery set (N=1858) of European-American and African-American (AA) families, ascertained on the basis of a sibling pair with cocaine and/or opioid dependence, and a case–control replication sample (N=3388) collected for association studies of alcohol, cocaine, and opioid dependence. We tested the SNPs for association with lifetime cocaine, opioid, nicotine, and alcohol dependence. We replicated several previous findings, including associations between rs16969968 and nicotine dependence (P=0.002) and cocaine dependence (P=0.02), with opposite risk alleles for each substance. We observed these associations in AAs, which is a novel finding. The strongest association signal in either sample was between rs684513 in CHRNA5 and cocaine dependence (OR=1.43, P=0.0004) in the AA replication set. We also observed two SNPs associated with alcohol dependence, that is, rs615470 in CHRNA5 (OR=0.77, P=0.0006) and rs578776 (OR=0.78, P=0.001). The associations between CD and rs684513, AD and rs615470, and AD and rs578776 remained significant after a permutation-based correction for multiple testing. These data reinforce the importance of variation in the chromosome 15 nicotinic receptor subunit gene cluster for risk of dependence on multiple substances, although the direction of the effects may vary across substances.

A Double-blind, Randomized Trial of Sertraline for Alcohol Dependence: Moderation by Age of Onset and 5-HTTLPR Genotype

Late-onset/low-vulnerability alcoholics (LOAs) appear to drink less when treated with a selective serotonin reuptake inhibitor than placebo, whereas early-onset/high-vulnerability alcoholics (EOAs) show the opposite effect. We conducted a 12-week, parallel-group, placebo-controlled trial of the efficacy of sertraline in alcohol dependence (AD). We compared the effects in LOAs versus EOAs and examined the moderating effects of a functional polymorphism in the serotonin transporter gene. Patients (N = 134, 80.6% male, 34.3% EOAs) with Diagnostic and Statistical Manual of Mental Disorders-IV AD received up to 200 mg of sertraline (n = 63) or placebo (n = 71) daily. We used urn randomization, and patients were genotyped for the tri-allelic 5-hydroxytryptamine transporter protein linked promoter region polymorphism. Planned analyses included main and interaction effects of medication group, age of onset (≤25 years vs >25 years), and genotype (L&vprime;/L&vprime; vs S&vprime; carriers) on drinking outcomes. Results showed that the moderating effect of age of onset on the response to sertraline was conditional on genotype. There were no main or interaction effects among S&vprime; allele carriers. However, in L&vprime; homozygotes, the effects of medication group varied by age of onset (P = 0.002). At the end of treatment, LOAs reported fewer drinking and heavy drinking days when treated with sertraline (P = 0.011), whereas EOAs had fewer drinking and heavy drinking days when treated with placebo (P < 0.001). The small cell sizes and high rate of attrition, particularly for L&vprime; homozygotes, render these findings preliminary and their replication in larger samples necessary. Because AD is common, particularly in medical settings, and selective serotonin reuptake inhibitors are widely prescribed by practitioners, these findings have potential public health significance and warrant further evaluation.

Targeted Naltrexone for Problem Drinkers

This study aimed to replicate and extend prior research showing that the targeted use of naltrexone is a useful strategy to reduce heavy drinking. We compared the effects of naltrexone with those of placebo in a sample of 163 individuals (58.3% male) whose goal was to reduce their drinking to safe limits. Patients received study medication (ie, naltrexone 50 mg or placebo) and were instructed to use it daily or targeted to situations identified by them as being high risk for heavy drinking. An interactive voice response system was used to obtain daily reports of drinking and medication use during the 12-week trial. Analyses were conducted using hierarchical linear modeling, with sex as a potential moderator variable. On the primary outcome measure, mean drinks per day, at week 12, men in the targeted naltrexone group drank significantly less than patients in the other groups did. On a secondary outcome measure, drinks per drinking day, during week 12, the targeted naltrexone group drank significantly less than the other groups did, with no moderating effect of sex. These results support the use of a targeted approach to reduce drinking among heavy drinkers, particularly men, but argue for the use of additional strategies or more efficacious medications than naltrexone to increase the effects of such an intervention.

Effects of opioid receptor gene variation on targeted nalmefene treatment in heavy drinkers.

BACKGROUND Recent studies examining the moderating effects of polymorphic variation in opioid receptor genes have yielded conflicting results. We examined opioid receptor gene polymorphisms as moderators of the therapeutic effects of the opioid antagonist nalmefene. METHODS Participants (n = 272) were subjects who consented to the pharmacogenetic analysis of a multi-site, randomized, placebo-controlled trial of targeted nalmefene for the reduction of heavy drinking. We genotyped two single nucleotide polymorphisms (SNPs) in OPRM1 (including A118G, a commonly studied SNP that encodes an Asn40Asp amino acid substitution), two SNPs in OPRD1, and one SNP in OPRK1, which encode the mu-, delta-, and kappa-opioid receptors, respectively. Regression analysis served to examine the moderating effects of these SNPs on medication response. RESULTS As previously described by Karhuvaara et al. (2007), nalmefene significantly reduced the number of heavy drinking and very heavy drinking days per week, compared with placebo. There were no main or moderating effects of the genotypes examined on these outcomes. CONCLUSIONS Our finding that the therapeutic effects of targeted nalmefene were not moderated by polymorphic variation in opioid receptor genes is consistent with two recent reports showing that variation in opioid receptor genes does not moderate the response to naltrexone. However, these findings contrast with those from two other studies, in which the Asn40Asp polymorphism in OPRM1 moderated the naltrexone treatment response. Additional research is needed to clarify the role of variation in opioid receptor genes on the response to opioid antagonist treatment of alcoholism.

5-HTTLPR as a Potential Moderator of the Effects of Adverse Childhood Experiences on Risk of Antisocial Personality Disorder

Introduction Antisocial personality disorder (ASPD) frequently co-occurs with substance dependence (SD). A functional polymorphism (5-HTTLPR) in the serotonin transporter gene has been widely studied as a risk factor for a variety of psychopathologic conditions including aggressive/violent behavior. Childhood abuse is an important predictor of ASPD. We examined 5-HTTLPR genotype and adverse childhood events (ACEs) as risk factors for ASPD in a SD sample. Materials and methods Study participants [602 European–Americans (EAs) and 779 African–Americans (AAs)] were interviewed to obtain lifetime diagnoses of ASPD and SD and information on ACEs. Triallelic genotypes for 5-HTTLPR were obtained using standard methods. We used logistic generalized estimating equations regression to examine ACEs and 5-HTTLPR genotype and their interaction as predictors of ASPD, separately by population group. Results There were 203 (14.7%) participants diagnosed with ASPD. The frequency of the low-activity 5-HTTLPR S′ allele did not differ by ASPD diagnosis, and there was no overall 5-HTTLPR×ACE interaction. However, among European–Americans, male sex (odds ratio=3.36; P<0.001) and ACE history (odds ratio=1.47; P=0.002) were significant predictors of ASPD. Among AAs, there was a significant interaction of sex×5-HTTLPR genotype×ACEs (&khgr;2=13.92, P<0.001). Among AA men, each additional ACE significantly increased the odds of ASPD irrespective of genotype, whereas among AA women, the effect of ACEs on ASPD was significant only among S′ homozygotes. However, these results are limited by the small sample size in each subgroup, (particularly AA women with S′S′ genotype; N=7) and require replication. Conclusions Childhood maltreatment contributes to the risk of ASPD, an effect for which there is preliminary evidence of moderation by 5-HTTLPR genotype in AA women.

Effects of Aripiprazole on Subjective and Physiological Responses to Alcohol

BACKGROUND Aripiprazole is an atypical antipsychotic with partial agonist activity at D(2) receptors, which could reduce the reinforcing effects of alcohol. The present study examined whether aripiprazole modifies the behavioral and physiological effects of a moderate dose of alcohol in a group of social drinkers. METHODS Eighteen healthy subjects (9 men; mean age = 27.6 years) completed a double-blind, within-subject study with 3 experimental sessions in a randomized sequence, during which they received no medication, aripiprazole 2.5 mg, or aripiprazole 10 mg on the day prior to the laboratory session. During the session, subjects consumed alcohol that was served as three standardized drinks (i.e., a total of 0.8 g/kg for men and 0.7 g/kg for women). Breath alcohol concentration (BrAC), heart rate, blood pressure, static ataxia, and subjective effects were measured regularly throughout the laboratory sessions. RESULTS Alcohol consumption produced physiological and subjective responses that were consistent with the literature on its effects. Pre-treatment with aripiprazole was generally well tolerated, with tiredness being the most commonly reported adverse event. The medication was associated with modest physiological effects. It also significantly and dose-dependently increased the sedative effects of alcohol and, to a lesser degree, decreased the euphoric effects of alcohol. CONCLUSIONS These findings require replication in a larger subject sample that includes heavy drinkers and in a study that employs a placebo session. Based on its capacity to increase the sedative effects and decrease the euphoric effects of alcohol, aripiprazole could be of value in the treatment of heavy drinking.

Placebo-controlled trial of zonisamide for the treatment of alcohol dependence.

Introduction: Zonisamide is an anticonvulsant medication with GABAergic, glutamatergic, and monoaminergic effects. Zonisamide has also been shown to reduce alcohol intake in rodents and in risky drinkers in the context of a laboratory study. This pilot clinical trial evaluated the safety, tolerability, and efficacy of zonisamide for the treatment of alcohol dependence. Methods: Forty alcohol-dependent subjects (23 men) were randomly assigned to receive treatment with either placebo or zonisamide in a 12-week double-blind trial. Zonisamide was initiated at a dosage of 100 mg/d, which was increased by 100 mg/d every 2 weeks for 8 weeks to a maximum dosage of 500 mg/d. The medication was continued for 4 weeks at the target dosage and then tapered and discontinued. The primary outcomes were drinks per week, heavy drinking days per week, and abstinent days per week, which were measured using the Timeline Follow-Back method. Results: There was a significant medication by treatment week interaction effect favoring the zonisamide group for heavy drinking days (HDD; P = 0.012), drinks per week (P = 0.004), and alcohol urge scores (P = 0.006). There was not a significant effect on the number or rate of increase in abstinent days. There were no serious adverse events reported and zonisamide treatment was well tolerated. Conclusion: The findings provide preliminary support for the use of zonisamide to treat alcohol dependence. Efforts to replicate and extend these findings are warranted.