Catherine J. Spellicy

ANKK1 and DRD2 pharmacogenetics of disulfiram treatment for cocaine abuse.

Objective Disulfiram is a potential cocaine addiction pharmacotherapy. Since dopamine deficiency has been found with cocaine addiction, our objective was to examine whether functional variants in the ankyrin repeat and kinase domain-containing 1 (ANKK1) and/or the dopamine receptor D2 (DRD2) genes interact with response to treatment with disulfiram. Materials and methods Cocaine and opioid codependent (DSM-IV) patients were stabilized on methadone and subsequently randomized into treatment groups – disulfiram (250 mg/day, N=31) or placebo (N=37). They were genotyped for ANKK1 (rs1800497) and DRD2 (rs2283265) polymorphisms, and the data were evaluated for an association between a cocaine-free state, as assessed by cocaine-free urine samples, and disulfiram treatment. Data were analyzed using repeated measures analysis of variance corrected for population structure. Results Patients with CT or TT ANKK1 genotypes dropped from 80 to 52% cocaine-positive urines on disulfiram (N=13; P⩽0.0001), whereas those on placebo (N=20) showed no treatment effect. Patients carrying the CC ANKK1 genotype showed no effect on treatment with disulfiram (N=18) or placebo (N=17). The GT/TT DRD2 genotype group showed a significant decrease in the number of cocaine-positive urine samples on disulfiram (N=9; 67–48%; P⩽0.0001), whereas the GG DRD2 genotype group showed only a marginal decrease (N=23; 84–63%; P=0.04). Genotype pattern analysis revealed that individuals carrying at least one minor allele in either gene responded better to disulfiram treatment (N=13; P⩽0.0001) compared with individuals carrying only the major alleles (N=17). Conclusion A patient’s genotype for ANKK1, DRD2, or both, may be used to identify individuals for whom disulfiram may be an effective pharmacotherapy for cocaine dependence.

The MTHFR C677T Variant is Associated with Responsiveness to Disulfiram Treatment for Cocaine Dependency

Objective: Disulfiram is a one of the few pharmacotherapies for cocaine addiction that shows promise. Since disulfiram and cocaine both affect levels of global methylation we hypothesized the MTHFR gene, whose product is involved in supplying methyl groups for DNA and protein methylation, may be associated with responsiveness to disulfiram in cocaine-dependent individuals. Methods: Sixty-seven cocaine-dependent patients were stabilized on methadone for 2 weeks and then randomized into disulfiram (250 mg/day, N = 32) and placebo groups (N = 35) for 10 weeks. Patients were genotyped for the MTHFR (rs1801133, also known as C677T) polymorphism and the data was evaluated for association with cocaine-free urines in the disulfiram or placebo groups. Data from patients that completed all 10 weeks of the study (N = 56) were analyzed using repeated measures analysis of variance (ANOVA), corrected for population structure. Results: The CT or TT MTHFR genotype group (N = 32) dropped from 73 to 52% cocaine-positive urines on disulfiram (p = 0.0001), while the placebo group showed no treatment effect. The CC MTHFR genotype group (N = 24) showed a smaller, but still significant, reduction in cocaine-positive urines on disulfiram compared to placebo; 81–69% (p = 0.007). Conclusion: This study indicates that a patient’s MTHFR genotype may be used to identify individuals who might show improved response to disulfiram treatment for cocaine dependence. Clinical Trial: Pharmacogenetics of Disulfiram for Cocaine, clinicaltrials.gov/ct2/show/NCT00149630, NIDA-18197-2, NCT00149630.

A variant in ANKK1 modulates acute subjective effects of cocaine: a preliminary study.

This study aimed to evaluate whether functional variants in the ankyrin repeat and kinase domain‐containing 1 (ANKK1) gene and/or the dopamine receptor D2 (DRD2) gene modulate the subjective effects (reward or non‐reward response to a stimulus) produced by cocaine administration. Cocaine‐dependent participants (N = 47) were administered 40 mg of cocaine or placebo at time 0, and a subjective effects questionnaire (visual analog scale) was administered 15 min prior to cocaine administration, and at 5, 10, 15 and 20 min following administration. The influence of polymorphisms in the ANKK1 and DRD2 genes on subjective experience of cocaine in the laboratory was tested. Participants with a T allele of ANKK1 rs1800497 experienced greater subjective ‘high’ (P = 0.00006), ‘any drug effect’ (P = 0.0003) and ‘like’ (P = 0.0004) relative to the CC genotype group. Although the variant in the DRD2 gene was shown to be associated with subjective effects, linkage disequilibrium analysis revealed that this association was driven by the ANKK1 rs1800497 variant. A participants ANKK1 genotype may identify individuals who are likely to experience greater positive subjective effects following cocaine exposure, including greater ‘high’ and ‘like’, and these individuals may have increased vulnerability to continue using cocaine or they may be at greater risk to relapse during periods of abstinence. However, these results are preliminary and replication is necessary to confirm these findings.

Serotonin transporter gene promoter polymorphism predicts relationship between years of cocaine use and impulsivity

Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Michael E. DeBakey VA Medical Center, Departments of Pediatrics, Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, Houston, Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas and Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA

Pharmacogenetics of Addiction Therapy

Drug addiction is a serious relapsing disease that has high costs to society and to the individual addicts. Treatment of these addictions is still in its nascency, with only a few examples of successful therapies. Therapeutic response depends upon genetic, biological, social, and environmental components. A role for genetic makeup in the response to treatment has been shown for several addiction pharmacotherapies. For several addiction pharmacotherapies, response to treatment varies based on individual genetic makeup. In this chapter, we discuss the role of genetics in pharmacotherapies, specifically for cocaine, alcohol, and opioid dependences. The elucidation of the role of genetics should aid in the development of new treatments and increase the efficacy of existing treatments.

Apolipoprotein E DNA methylation and posttraumatic stress disorder are associated with plasma ApoE level: A preliminary study

&NA; Mild traumatic brain injury (mTBI) occurred in 15–30% of Veterans returning from Iraq and Afghanistan. We examined whether DNA methylation of the apolipoprotein E (APOE) gene promoter region or plasma ApoE protein levels are altered in mTBI. APOE promoter region DNA methylation, APOE genotype, and plasma ApoE concentration were determined in 87 Veterans with or without mTBI who were recruited from 2010‐2014. Plasma ApoE concentration was found to be associated with Posttraumatic Stress Disorder (PTSD) symptom severity ratings by hierarchical linear regression (p = .013) and ANCOVA (p = .007). Hierarchical linear regression revealed that plasma ApoE concentration was associated with APOE‐&egr;4 genotype status (p=.022). Higher ApoE plasma levels were found in &egr;3/&egr;3 Veterans than in APOE‐&egr;4 carriers (p = .031). Furthermore, plasma ApoE concentration was associated experiment‐wise with DNA methylation at CpG sites ‐877 (p = .021), and ‐775 (p = .014). The interaction between APOE‐&egr;4 genotype and having a PTSD diagnosis was associated with DNA methylation at CpG site ‐675 (p = .009). HighlightsPlasma ApoE was associated with PTSD and APOE‐&egr;4 genotype status.Interaction observed among APOE‐&egr;4 genotype, PTSD diagnosis, and APOE methylation.