Faculty Bibliography

Aims: To determine if specific single-nucleotide polymorphisms (SNPs) in stress-related genes are associated with heroin addiction. Methods: Case-control hypothesis-driven association study of 112 SNPs from 26 stress-related genes. The sample consists of 852 case subjects and 238 controls. The case subjects are former heroin addicts with a history of at least 1 year of daily multiple uses of heroin, treated at a MMTP. European ancestry was verified by ancestry informative markers (AIMs). Association analysis was performed by logistic regression. Results: Nineteen SNPs in 9 genes (AVP, CRHR1, CRHR2, FKBP5, NR3C2, AVPR1A, GAL, GLRA1 and NPY1R) showed nominally significant association (p < 0.05) with heroin addiction. Two tightly linked FKBP5 SNPs, rs1360780 and rs3800373, from intron 2 and the 3' UTR, respectively, remained significant after correction for multiple testing (experiment-wise p = 3.0E-04;OR= 2.35; 95% CI, 1.5-3.7 and p = 1.6E-05; OR= 2.85; 95% CI, 1.8-4.6, respectively). Conclusions: The study provides evidence for the association of FKBP5 SNPs with heroin addiction. These SNPs were previously associated with diverse affective disorders and showed functional differences in gene expression and stress response. The FKBP5 gene encodes a co-chaperone that regulates glucocorticoid sensitivity. The modulation of the stress response by FKBP5 may contribute to the development of opiate dependence and in turn FKBP5 may also mediate the abuse potential of opioids. The study also corroborates our and others previous reports of association of GAL SNP rs694066 and AVPR1A SNPs rs11174811, rs1587097 and rs10784339 with specific general drug addictions and suggests several new associations

BACKGROUND: On October 2012, Hurricane Sandy struck New York City, resulting in unprecedented damages, including the temporary closure of Bellevue Hospital Center and its primary care office-based buprenorphine program. OBJECTIVES: At 6 months, we assessed factors associated with higher rates of substance use in buprenorphine program participants that completed a baseline survey one month post-Sandy (i.e. shorter length of time in treatment, exposure to storm losses, a pre-storm history of positive opiate urine drug screens, and post-disaster psychiatric symptoms). METHODOLOGY: Risk factors of interest extracted from the electronic medical records included pre-disaster diagnosis of Axis I and/or II disorders and length of treatment up to the disaster. Factors collected from the baseline survey conducted approximately one month post-Sandy included self-reported buprenorphine supply disruption, health insurance status, disaster exposure, and post-Sandy screenings for PTSD and depression. Outcome variables reviewed 6 months post-Sandy included missed appointments, urine drug results for opioids, cocaine, and benzodiazepines. RESULTS: 129 (98%) patients remained in treatment at 6 months, and had no sustained increases in opioid-, cocaine-, and benzodiazepine-positive urine drug tests in any sub-groups with elevated substance use in the baseline survey. Contrary to our initial hypothesis, diagnosis of Axis I and/or II disorders pre-Sandy were associated with significantly less opioid-positive urine drug findings in the 6 months following Sandy compared to the rest of the clinic population. CONCLUSION: These findings demonstrate the adaptability of a safety net buprenorphine program to ensure positive treatment outcomes despite disaster-related factors.

BACKGROUND: Drug addiction is influenced by genetic factors. AIM: To determine if genetic variants in the serotonergic and adrenergic pathways are associated with heroin and/or cocaine addiction. SUBJECTS & METHODS: The study examined 140 polymorphisms in 19 genes in 1855 subjects with predominantly European or African ancestries. RESULTS: A total of 38 polymorphisms (13 genes) showed nominal associations, including novel associations in S100A10 (p11) and SLC18A2 (VMAT2). The association of HTR3B SNP rs11606194 with heroin addiction in the European ancestry subgroup remained significant after correction for multiple testing (p corrected = 0.04). CONCLUSION: The study strengthens our previous findings of association of polymorphisms in HTR3A, HTR3B and ADRA1A. The study suggests partial overlap in genetic susceptibility between populations of different ancestry and between heroin and cocaine addiction.

OBJECTIVE: The goal of the study was to evaluate whether enhanced normative feedback recovery curves are needed for treatment of substance use problems. METHOD: Patient predictors of outcome were examined using data from four substance abuse treatment clinics. RESULTS: Baseline severity of symptoms/functioning, employment, and craving were found to be associated with rate of change in symptoms/functioning. Several other variables were associated with rate of change in alcohol use, although in the opposite direction than found in efficacy trials. CONCLUSIONS: The results point to the complexity of designing feedback systems using normative recovery curves for those with substance use problems and highlight the important differences between real-world treatment of those with substance use problems compared to data from efficacy trials.

BACKGROUND & AIM: The dopaminergic pathways have been implicated in the etiology of drug addictions. The aim of this study was to determine if variants in dopaminergic genes are associated with heroin addiction. MATERIALS & METHODS: The study includes 828 former heroin addicts and 232 healthy controls, of predominantly European ancestry. Ninety seven SNPs (13 genes) were analyzed. RESULTS: Nine nominally significant associations were observed at CSNK1E, ANKK1, DRD2 and DRD3. CONCLUSION: The results support our previous report of association of CSNK1E SNP rs1534891 with protection from heroin addiction. CSNK1E interacts with circadian rhythms and DARPP-32 and has been implicated in negative regulation of sensitivity to opioids in rodents. It may be a target for drug addiction treatment. Original submitted 8 August 2014; Revision submitted 8 October 2014.

Hurricane Sandy led to the closing of many major New York City public hospitals including their substance abuse clinics and methadone programs, and the displacement or relocation of thousands of opioid-dependent patients from treatment. The disaster provided a natural experiment that revealed the relative strengths and weaknesses of methadone treatment in comparison to physician office-based buprenorphine treatment for opioid dependence, two modalities of opioid maintenance with markedly different regulatory requirements and institutional procedures. To assess these two modalities of treatment under emergency conditions, semi-structured interviews about barriers to and facilitators of continuity of care for methadone and buprenorphine patients were conducted with 50 providers of opioid maintenance treatment. Major findings included that methadone programs presented more regulatory barriers for providers, difficulty with dose verification due to impaired communication, and an over reliance on emergency room dosing leading to unsafe or suboptimal dosing. Buprenorphine treatment presented fewer regulatory barriers, but buprenorphine providers had little to no cross-coverage options compared to methadone providers, who could refer to alternate methadone programs. The findings point to the need for well-defined emergency procedures with flexibility around regulations, the need for a central registry with patient dose information, as well as stronger professional networks and cross-coverage procedures. These interventions would improve day-to-day services for opioid-maintained patients as well as services under emergency conditions.

AIMS: We evaluated the immunogenicity, efficacy, and safety of succinylnorcocaine conjugated to cholera toxin B protein as a vaccine for cocaine dependence. METHODS: This 6-site, 24 week Phase III randomized double-blind placebo-controlled trial assessed efficacy during weeks 8 to 16. We measured urine cocaine metabolites thrice weekly as the main outcome. RESULTS: The 300 subjects (76% male, 72% African-American, mean age 46 years) had smoked cocaine on average for 13 days monthly at baseline. We hypothesized that retention might be better and positive urines lower for subjects with anti-cocaine IgG levels of >/=42 mug/mL (high IgG), which was attained by 67% of the 130 vaccine subjects receiving five vaccinations. Almost 3-times fewer high than low IgG subjects dropped out (7% vs 20%). Although for the full 16 weeks cocaine positive urine rates showed no significant difference between the three groups (placebo, high, low IgG), after week 8, more vaccinated than placebo subjects attained abstinence for at least two weeks of the trial (24% vs 18%), and the high IgG group had the most cocaine-free urines for the last 2 weeks of treatment (OR=3.02), but neither were significant. Injection site reactions of induration and tenderness differed between placebo and active vaccine, and the 29 serious adverse events did not lead to treatment related withdrawals, or deaths. CONCLUSIONS: The vaccine was safe, but it only partially replicated the efficacy found in the previous study based on retention and attaining abstinence.

Stress is a significant risk factor in the development of drug addictions and in addiction relapse susceptibility. This hypothesis-driven study was designed to determine if specific SNPs in genes related to stress response are associated with heroin and/or cocaine addiction in African Americans. The analysis included 27 genes (124 SNPs) and was performed independently for each addiction. The sample consisted of former heroin addicts in methadone maintenance treatment (n = 314), cocaine addicts (n = 281), and controls (n = 208). Fourteen SNPs showed nominally significant association with heroin addiction (p < 0.05), including the African-specific, missense SNP rs5376 (Asn334Ser) in the galanin receptor type 1 gene (GALR1) and the functional FKBP5 intronic SNP rs1360780. Thirteen SNPs showed association with cocaine addiction, including the synonymous SNPs rs237902, in the oxytocin receptor gene (OXTR), and rs5374 in GALR1. No signal remained significant after correction for multiple testing. Four additional SNPs (GALR1 rs2717162, AVP rs2282018, CRHBP rs1875999, and NR3C2 rs1040288) were associated with both addictions and may indicate common liability. The study provides preliminary evidence for novel association of variants in several stress-related genes with heroin and/or cocaine addictions and may enhance the understanding of the interaction between stress and addictions.

The time required to conduct drug and alcohol screening has been a major barrier to its implementation in mainstream healthcare settings. Because patient self-administered tools are potentially more efficient, we translated the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) into an audio guided computer assisted self interview (ACASI) format. This study reports on the test-retest reliability of the ACASI ASSIST in an adult primary care population. Adult primary care patients completed the ACASI ASSIST, in English or Spanish, twice within a 1-4week period. Among the 101 participants, there were no significant differences between test administrations in detecting moderate to high risk use for tobacco, alcohol, or any other drug class. Substance risk scores from the two administrations had excellent concordance (90-98%) and high correlation (ICC 0.90-0.97) for tobacco, alcohol, and drugs. The ACASI ASSIST has good test-retest reliability, and warrants additional study to evaluate its validity for detecting unhealthy substance use.

BACKGROUND: Stress is a critical risk factor affecting both the development of and the relapse to drug addictions. Drug addictions are caused by genetic, environmental and drug-induced factors. The objective of this hypothesis-driven association study was to determine if genetic variants in stress-related genes are associated with heroin addiction. METHODS: 112 selected genetic variants in 26 stress-related genes were genotyped in 852 case subjects and 238 controls of predominantly European ancestry. The case subjects are former heroin addicts with a history of at least one year of daily multiple uses of heroin, treated at a methadone maintenance treatment program (MMTP). The two most promising SNPs were subsequently tested in an African-American sample comprising of 314 cases and 208 control individuals. RESULTS: Nineteen single nucleotide polymorphisms (SNPs) in 9 genes (AVP, AVPR1A, CRHR1, CRHR2, FKBP5, GAL, GLRA1, NPY1R and NR3C2) showed nominally significant association with heroin addiction. The associations of two FKBP5 SNPs that are part of one haplotype block, rs1360780 (intron 2) and rs3800373 (the 3' untranslated region), remained significant after correction for multiple testing (Pcorrected=0.03; OR=2.35, Pcorrected=0.0018; OR=2.85, respectively). The two SNPs also showed nominally significant association (P<0.05) with heroin addiction in an independent African-American cohort. FKBP5 is a co-chaperone that regulates glucocorticoid sensitivity. These FKBP5 SNPs were previously associated with diverse affective disorders and showed functional differences in gene expression and stress response. This study also supports our and others' previous reports of association of the GAL SNP rs694066 and the AVPR1A SNPs rs11174811, rs1587097 and rs10784339 with heroin and general drug addiction, respectively. CONCLUSIONS: This study suggests that variations in the FKBP5 gene contribute to the development of opiate addiction by modulating the stress response. These findings may enhance the understanding of the interaction between stress and heroin addiction.