Faculty Bibliography

BACKGROUND: Drug addiction, a leading health problem, is a chronic brain disease with a significant genetic component. Animal models and clinical studies established the involvement of glutamate and GABA neurotransmission in drug addiction. This study was designed to assess if 258 variants in 27 genes of these systems contribute to the vulnerability to develop drug addiction. METHODS: Four independent analyses were conducted in a sample of 1860 subjects divided according to drug of abuse (heroin or cocaine) and ancestry (African and European). RESULTS: A total of 11 SNPs in eight genes showed nominally significant associations (P<0.01) with heroin and/or cocaine addiction in one or both ancestral groups but the associations did not survive correction for multiple testing. Of these SNPs, the GAD1 upstream SNP rs1978340 is potentially functional as it was shown to affect GABA concentrations in the cingulate cortex. In addition, SNPs GABRB3 rs7165224; DBI rs12613135; GAD1 SNPs rs2058725, rs1978340, rs2241164; and GRIN2A rs1650420 were previously reported in associations with drug addiction or related phenotypes. CONCLUSIONS: The study supports the involvement of genetic variation in the glutamatergic and GABAergic systems in drug addiction with partial overlap in susceptibility loci between cocaine and heroin addiction.

BACKGROUND: Very brief single-item screening questions (SISQs) for alcohol and other drug use can facilitate screening in health care settings, but are not widely used. Self-administered versions of the SISQs could ease barriers to their implementation. OBJECTIVE: We sought to validate SISQs for self-administration in primary care patients. DESIGN: Participants completed SISQs for alcohol and drugs (illicit and prescription misuse) on touchscreen tablet computers. Self-reported reference standard measures of unhealthy use, and more specifically of risky consumption, problem use, and substance use disorders, were then administered by an interviewer, and saliva drug tests were collected. PARTICIPANTS: Adult patients aged 21-65 years were consecutively enrolled from two urban safety-net primary care clinics. MAIN MEASURES: The SISQs were compared against reference standards to determine sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) for alcohol and drug use. KEY RESULTS: Among the 459 participants, 22 % reported unhealthy alcohol use and 25 % reported drug use in the past year. The SISQ-alcohol had sensitivity of 73.3 % (95 % CI 65.3-80.3) and specificity of 84.7 % (95 % CI 80.2-88.5), AUC = 0.79 (95 % CI 0.75-0.83), for detecting unhealthy alcohol use, and sensitivity of 86.7 % (95 % CI 75.4-94.1) and specificity of 74.2 % (95 % CI 69.6-78.4), AUC = 0.80 (95 % CI 0.76-0.85), for alcohol use disorder. The SISQ-drug had sensitivity of 71.3 % (95 % CI 62.4-79.1) and specificity of 94.3 % (95 % CI 91.3-96.6), AUC = 0.83 (95 % CI 0.79-0.87), for detecting unhealthy drug use, and sensitivity of 85.1 (95 % CI 75.0-92.3) and specificity of 88.6 % (95 % CI 85.0-91.6), AUC = 0.87 (95 % CI 0.83-0.91), for drug use disorder. CONCLUSIONS: The self-administered SISQs are a valid approach to detecting unhealthy alcohol and other drug use in primary care patients. Although self-administered SISQs may be less accurate than the previously validated interviewer-administered versions, they are potentially easier to implement and more likely to retain their fidelity in real-world practice settings.

AIM: Drug addiction is characterized, in part, by deregulation of synaptic plasticity in circuits involved in reward, stress, cue learning, and memory. This study was designed to assess whether 185 variants in 32 genes central to synaptic plasticity and signal transduction contribute to vulnerability to develop heroin and/or cocaine addiction. METHODS: Analyses were conducted in a sample of 1860 subjects divided according to ancestry (African and European) and drug of abuse (heroin or cocaine). RESULTS: Eighteen SNPs in 11 genes (CDK5R1, EPHA4, EPHA6, FOSL2, MAPK3, MBP, MPDZ, NFKB1, NTRK2, NTSR1, and PRKCE) showed significant associations (P < 0.01), but the signals did not survive correction for multiple testing. SNP rs230530 in the NFKB1 gene, encoding the transcription regulator NF-kappa-B, was the only SNP indicated in both ancestry groups and both addictions. This SNP was previously identified in association with alcohol addiction. SNP rs3915568 in NTSR1, which encodes neurotensin receptor, and SNP rs1389752 in MPDZ, which encodes the multiple PDZ domain protein, were previously associated with heroin addiction or alcohol addiction, respectively. CONCLUSIONS: The study supports the involvement of genetic variation in signal transduction pathways in heroin and cocaine addiction and provides preliminary evidence suggesting several new risk or protective loci that may be relevant for diagnosis and treatment success.

BACKGROUND: Substance use screening is widely encouraged in healthcare settings, but the lack of a screening approach that fits easily into clinical workflows has restricted its broad implementation. The Substance Use Brief Screen (SUBS) was developed as a brief, self-administered instrument to identify unhealthy use of tobacco, alcohol, illicit drugs, and prescription drugs. We evaluated the validity and test-retest reliability of the SUBS in adult primary care patients. METHODS: Adults age 18-65 were enrolled from urban safety net primary care clinics to self-administer the SUBS using touch-screen tablet computers for a test-retest reliability study (n=54) and a two-site validation study (n=586). In the test-retest reliability study, the SUBS was administered twice within a 2-week period. In the validation study, the SUBS was compared to reference standard measures, including self-reported measures and saliva drug tests. We measured test-retest reliability and diagnostic accuracy of the SUBS for detection of unhealthy use and substance use disorder for tobacco, alcohol, and drugs (illicit and prescription drug misuse). RESULTS: Test-retest reliability was good or excellent for each substance class. For detection of unhealthy use, the SUBS had sensitivity and specificity of 97.8% (95% CI 93.7 to 99.5) and 95.7% (95% CI 92.4 to 97.8), respectively, for tobacco; and 85.2% (95% CI 79.3 to 89.9) and 77.0% (95% CI 72.6 to 81.1) for alcohol. For unhealthy use of illicit or prescription drugs, sensitivity was 82.5% (95% CI 75.7 to 88.0) and specificity 91.1% (95% CI 87.9 to 93.6). With respect to identifying a substance use disorder, the SUBS had sensitivity and specificity of 100.0% (95% CI 92.7 to 100.0) and 72.1% (95% CI 67.1 to 76.8) for tobacco; 93.5% (95% CI 85.5 to 97.9) and 64.6% (95% CI 60.2 to 68.7) for alcohol; and 85.7% (95% CI 77.2 to 92.0) and 82.0% (95% CI 78.2 to 85.3) for drugs. Analyses of area under the receiver operating curve (AUC) indicated good discrimination (AUC 0.74-0.97) for all substance classes. Assistance in completing the SUBS was requested by 11% of participants. CONCLUSIONS: The SUBS was feasible for self-administration and generated valid results in a diverse primary care patient population. The 4-item SUBS can be recommended for primary care settings that are seeking to implement substance use screening.

BACKGROUND AND AIMS: Relapse to addiction following incarceration is common. We estimated the feasibility and effectiveness of extended-release naltrexone (XR-NTX) as relapse prevention among opioid-dependent male adults leaving a large urban jail. DESIGN: Eight-week, proof-of-concept, open-label, non-blinded randomized effectiveness trial. SETTING: New York City jails and Bellevue Hospital Center Adult Primary Care clinics, USA. PARTICIPANTS: From January 2010 to July 2013, 34 opioid-dependent adult males with no stated interest in agonist treatments (methadone, buprenorphine) received a counseling and referral intervention and were randomized to XR-NTX (n = 17) versus no medication (n = 17) within one week prior to jail release. INTERVENTION: XR-NTX (Vivitrol((R)) ; Alkermes Inc.), a long-acting injectable mu opioid receptor antagonist. MEASURES: The primary intent-to-treat outcome was post-release opioid relapse at week 4, defined as >/=10 days of opioid misuse by self-report and urine toxicologies. Secondary outcomes were proportion of urine samples negative for opioids and rates of opioid abstinence, intravenous drug use (IVDU), cocaine use, community treatment participation, re-incarceration and overdose. FINDINGS: Acceptance of XR-NTX was high; 15 of 17 initiated treatment. Rates of the primary outcome of week 4 opioid relapse were lower among XR-NTX participants: 38 versus 88% [P<0.004; odds ratio (OR) = 0.08, 95% confidence interval (CI) = 0.01-0.48]; more XR-NTX urine samples were negative for opioids, 59 versus 29% (P<0.009; OR = 3.5, 95% CI = 1.4-8.5). There were no significant differences in the remaining secondary outcomes, including rates of IVDU, cocaine use, re-incarceration and overdose. CONCLUSION: Extended-release naltrexone is associated with significantly lower rates of opioid relapse among men in the United States following release from jail when compared with a no medication treatment-as-usual condition.

Background: ED-based SBIRT for alcohol and drug use has the potential to affect public health greatly. Time and resource constraints limit implementation. Objectives: We aimed to determine whether particular chief complaints could be used to identify patients likely to screen positive for unhealthy alcohol or drug use, thus reducing the proportion of patients needing to be screened and increasing the efficiency of SBIRT. Methods: Cross-sectional study using baseline data from NIDA CTN0047: SMART-ED, a multicenter, randomized 3-arm SBIRT trial which screened 14,972 ED patients. Free-text chief complaints were coded using a tested algorithm, then reviewed and further collapsed by multiple team members to ensure agreement. The 454 excluded patients had missing data, complaints related to alcohol or drug use, or complaints stated by <15 subjects. Positive screens were defined as AUDIT-C > 4 for men and >3 for women (alcohol) and DAST >3 (drugs) - to detect the spectrum of unhealthy alcohol or drug use (from at-risk to dependence). We rank-ordered the chief complaints by their (Figure presented) sensitivity and positive predictive value using two strategies: 1) to minimize the number of chief complaints and 2) to assess the fewest number of ED patients. Our goal was to identify 75% of ED patients having positive assessments using these strategies. Results: The screening assessments were positive in 5,805/14,561 (39.9%) for alcohol and 2,454/14,494 (16.9%) for drugs. We collapsed the free-text chief complaints into 50 usable categories. To identify 75% of all ED patients having positive assessments using the first strategy would require including 19 chief complaints for alcohol screening and 20 chief complaints for drug screening. Adapting the second strategy, we would need to screen at least 71% and 68% of all ED patients for alcohol and drugs respectively to identify 75% of those having positive assessments. (See Table 47 and Figure 47.) Conclusion: In this multi-ED study, unhealthy alcohol and drug use was exceptionally prevalent. Using chief complaints did not significantly improve the efficiency of SBIRT for AOD

Drugs of abuse activate the mesolimbic dopaminergic pathway. Genetic variations in the dopaminergic system may contribute to drug addiction. Several processes are shared between cocaine and heroin addictions but some neurobiological mechanisms may be specific. This study examined the association of 98 single nucleotide polymorphisms in 13 dopamine-related genes with heroin addiction (OD) and/or cocaine addiction (CD) in a sample of 801 African Americans (315 subjects with OD +/- CD, 279 subjects with CD, and 207 controls). Single-marker analyses provided nominally significant evidence for associations of 24 SNPs) in DRD1, ANKK1/DRD2, DRD3, DRD5, DBH, DDC, COMT and CSNK1E. A DRD2 7-SNPs haplotype that includes SNPs rs1075650 and rs2283265, which were shown to alter D2S/D2L splicing, was indicated in both addictions. The Met allele of the functional COMT Val158Met was associated with protection from OD. None of the signals remained significant after correction for multiple testing. The study results are in accordance with the results of previous studies, including our report of association of DRD1 SNP rs5326 with OD. The findings suggest the presence of an overlap in genetic susceptibility for OD and CD, as well as shared and distinct susceptibility for OD in subjects of African and European descent.

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