Varieties of Impulsivity in Opiate and Stimulant Users

The study was conducted in Bulgaria as a collaboration between Virginia Commonwealth University (Richmond, VA, USA), the Bulgarian Addictions Institute (Sofia, Bulgaria), the Molecular Medicine Center/Medical University (Sofia, Bulgaria), and Indiana University (Bloomington, IN, USA). The overall aim of this study is to investigate the role of impulsivity as an endophenotype for drug addiction. Although impulsivity is considered one of the strongest candidate endophenotypes for addiction, progress in the field is hampered by the heterogeneity of impulsivity, characterized by multiple personality, psychiatric, and neurocognitive dimensions, rarely examined concurrently in the same population; and the heterogeneity of addiction phenotypes, due in part to the high rates of polysubstance dependence among substance users. To address these challenges, we have developed a program of addiction research in Bulgaria, a key transit country for heroin trafficking due to its strategic geographical location on the "Balkan Drug Route" and a major European center for production of synthetic amphetamine-type stimulants. This has allowed us to access rare populations of predominantly mono-substance dependent heroin and amphetamine users, many in protracted abstinence. Our preliminary results reveal a complex relationship between trait and neurocognitive (state) dimensions of impulsivity, often manifested in opposite directions in heroin and amphetamine dependent individuals. Pilot computational modeling analyses of decision-making, a central neurocognitive aspect of impulsivity, have proved particularly informative by indicating that different mechanisms may underlie the impaired decision-making of opiate and stimulant users. A different modeling approach, i.e. phenotypic modeling, holds significant promise to address the pervasive "missing heritability" problem in genetic studies. While genetic heterogeneity is often invoked as an explanation, the manner in which complex phenotypic traits are measured and modeled is equally important contributor to the missing heritability problem but has received much less attention in the literature. Despite the multidimensionality of traits measured by psychometric, diagnostic, and neurocognitive instruments, most GWAS studies typically use aggregate sum scores that do not reflect the underlying phenotypic multidimensionality. Therefore, at least part of the missing heritability problem may originate in misspecification of the phenotypic models. Consequently, sample sizes requirements may increase from ~800 subjects in correctly specified models to 6,000-16,000 subjects in incorrectly specified models. The current study aims to increase our understanding of the complex relationship between multiple putative impulsivity endophenotypes to help redefine endophenotypes as multi-level combination of measures that could inform multivariate multilevel models of complex phenotypes. The specific aims of the study are to: (1) Assess the utility of various personality, psychiatric, and neurocognitive indices of impulsivity (either individually or in combination) as candidate endophenotype(s) for drug addiction in general and for opiate and stimulant addictions in particular; (2) Evaluate the viability of computational model parameters modeling various neurocognitive dimensions of impulsivity as novel endophenotype(s) for addiction; and (3) Test the external validity of the optimal endophenotype(s) by evaluating their associations with HIV and other risk behaviors in opiate and stimulant users in protracted abstinence, a question of critical importance for prevention and intervention efforts in this much less-well understood stage of the addiction cycle.

• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 597
• Subject Sample Telemetry Report (SSTR)

• BioProject
• PubMed
• MeSH
• PMC

Inclusion criteria:
(1) age between 18 and 50 years;
(2) estimated IQ > 75 (based on Raven's Progressive Matrices);
(3) minimum of 8th grade education;
(4) ability to read and write in Bulgarian;
(5) no history of neurological illness or injury, closed head injury with loss of consciousness greater than 30 minutes, or open head injury of any type;
(6) presence of psychotic disorders or current use of antipsychotic medication;
(7) HIV seronegative status;
(8) negative breathalyzer test for alcohol;
(9) negative urine toxicology screen for amphetamines, methamphetamines, cocaine, opiates, cannabis, benzodiazepines, barbiturates, and MDMA.

"Pure" (i.e. mono-substance dependent) heroin and amphetamine dependent individuals have a lifetime history of opiate or stimulant dependence by DSM-IV criteria with no current or past dependence on other substances except nicotine, caffeine, or cannabis (if cannabis dependence was met more than five years prior to testing). Polysubstance dependent participants meet criteria for dependence on more than one class of drug (typically opiates or stimulants, with additional abuse/dependence on cannabis and/or alcohol). Control participants have no current or past history of substance abuse or dependence by DSM-IV criteria.

The current study is a 5-year continuation of the parent DA021421 study (2008-2014), which had the following specific aims:
(1) To investigate the associations of different classes of drugs (opiates vs. stimulants) and trait-like personality and psychiatric indices of impulsivity with performance on neurocognitive measures of impulsive choice and impulsive action among opiate dependent individuals, stimulant dependent individuals, and non-substance dependent controls;
(2) Investigate the patterns of associations between individual differences in temporally stable trait-like personality and psychiatric indices of impulsivity with state-dependent performance-based measures of impulsive choice and impulsive action; and
(3) Investigate the associations between different trait and performance-based manifestations of impulsivity with HIV risk behaviors in opiate and stimulant users.

• Primary Phenotype: Impulsive Behavior
• Heroin Dependence
• Amphetamine-Related Disorders

• Principal Investigator
  • Jasmin Vassileva, PhD. Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, USA.
• Co-Investigators
  • Georgi Vasilev, MD, MPH. Bulgarian Addictions Institute, Sofia, Bulgaria.
  • Radka Kaneva, PhD. Molecular Medicine Center/Medical University, Sofia, Bulgaria.
  • Jerome Busemeyer. Indiana University, Bloomington, IN, USA.
• Funding Source
  • R01DA021421. National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA, and Fogarty International Center, National Institutes of Health, Bethesda, MD, USA.