However, assessing dependence severity over the past 12 months could have reflected severity over the past 30 days prior to study participation, while average DPDD or CPD in the past 30 days could have also been comparable to average DPDD or CPD over the past year. Given that the sample was comprised of non-treatment seeking participants, it is plausible to hypothesize that past month alcohol and nicotine consumption closely reflect past year consumption of these substances in the current sample. Nevertheless, as patterns of alcohol or nicotine use may vary over a longer time frame, variables that capture quantity of use or frequency of use over a longer period of time would be preferred in future studies. Lastly, given that the average FTND scores of the current participants reflected low-to-moderate nicotine dependence severity, alcohol users with more severe nicotine dependence may be required to detect effects of nicotine use on brain structure. In conclusion, we examined the relationship between gray matter density and quantity of use/dependence severity for both alcohol and nicotine in 39 heavy drinking smokers using VBM. The multiple regression analysis revealed a significant negative relationship between ADS scores and gray matter density in two brains regions, such that higher ADS scores correlated with lower gray matter density in the hypothalamus and right superior frontal gyrus, after controlling for nicotine dependence severity, age, gender, and ICV. The current results may help clarify the contribution of alcohol and nicotine use to gray matter density in heavy drinking smokers,grow racks with lights which could aid in understanding the neurocognitive consequences of co-morbid substance use in heavy drinking smokers. Substance use disorders and addiction represent a global public health problem of substantial socioeconomic implications. In 2010, 147.5 million cases of alcohol and drug abuse were reported , and SUD prevalence is expected to increase over time.
Genetic factors have been implicated in SUD etiology, with genes involved in the regulation of several neurobiological systems found to be important . However, limitations intrinsic to most genetic epidemiological studies support the search for additional risk genes. Attention-deficit/hyperactivity disorder , the most common neurodevelopmental behavioral disorder, is frequently co-morbid with disruptive behaviors such as oppositional defiant disorder , conduct disorder , and SUD. The close association between ADHD and disruptive behaviors is summarized by longitudinal observations in ADHD cohorts. Children diagnosed with ADHD monitored during the transition into adolescence exhibit higher rates of alcohol, tobacco, and psychoactive drug use than control groups of children without ADHD. It has been estimated that the lifetime risk for SUD is ~50% in subjects with childhood ADHD persisting into adulthood. Reciprocally, the prevalence of ADHD is high in adolescents with SUD and the presence of an ADHD diagnosis affects SUD prognosis, with ADHD being associated with both earlier and more frequent alcohol-related relapses and lower likelihood of cannabis-dependence treatment completion. Strong evidence from family, twin, and genome-wide linkage and association studies suggests that genetic factors play a crucial role in shaping the susceptibility to both ADHD and SUD. During the last 15 years, we have collected families clustering individuals affected with ADHD and disruptive behaviors from disparate regions around the world. Although the prevalence of ADHD co-morbid with disruptive behaviors is variable across populations, we found a higher frequency of CD, ODD, and SUD in ADHD individuals than in unaffected relatives.Fine mapping of the 4q13.2 region identified variants in the adhesion G-protein-coupled receptor L3 gene that predispose to ADHD. Characterization of the association between ADHD and ADGRL3 has provided key information to better predict the severity of ADHD, the long-term outcome, the patterns of brain metabolism, and the response to stimulant medication. To the best of our knowledge, ADGRL3 linkage and association results represent some of the most robustly replicated genetic and pharmacogenetic findings in ADHD genetic research. While ADGRL3 has also shown association with disruptive behaviors in the context of ADHD, a direct link to SUD has not been systematically investigated.
In this manuscript we tested the hypothesis that ADHD risk variants harbored at the ADGRL3 locus interact with clinical, demographic, and environmental variables associated with SUD.This population isolate is unique in that it was used to identify ADHD susceptibility genes by linkage and association strategies. Detailed clinical and demographic information on this sample has been published elsewhere. The sample consists of 1176 people , mean age 28 ± 17 years, ascertained from 18 extended multigenerational and 136 nuclear Paisa families inhabiting the Medellin metropolitan area in the State of Antioquia, Colombia. Initial coded pedigrees were obtained through a fixed sampling scheme from a parent or grandparent of an index proband after having collected written informed consent from all subjects or their parent/guardian, as approved by the University of Antioquia and the NIH Ethics Committees, and in accordance with the Helsinki Declaration. Patients were recruited under NHGRI protocol 00-HG-0058 . Exclusion criteria for ADHD participants were IQ < 80, or any autistic or psychotic disorders. Parents underwent a full psychiatric structured interview regarding their offspring . All adult participants were assessed using the Composite International Diagnostic Interview , as well as the Disruptive Behavior Disorders module from the DICA-IV-P modified for retrospective use. The interview was conducted by a “blind” rater at the Neurosciences Clinic of the University of Antioquia, or during home visits. ADHD status was defined by the best estimate method. Specific information regarding clinical diagnoses and co-morbid disruptive disorders, affective disorders, anxiety, and substance use has been published elsewhere.The ADHD sample consisted of 670 adult ADHD patients, mean age 33 ± 10 years, 69% males , recruited and evaluated at the Psychiatry Department of the Hospital Universitari Vall d’Hebron according to DSM-IV TR criteria. ADHD diagnosis was based on the Spanish version of the Conners Adult ADHD Diagnostic Interview for DSM-IV. Comorbidity was assessed by Structured Clinical Interview for DSM-IV Axis I and Axis II Disorders . ODD during childhood and adolescence was retrospectively evaluated with the Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present and Lifetime Version .
Thirty-nine percent of ADHD patients fulfilled diagnostic criteria for SUD, 21% for disruptive behavior disorders , 21% for depression , 13% for anxiety , and 8% for phobias . The level of impairment was measured with the Clinical Global Impression included in the CAADID Part II and the Sheehan Disability Inventory. Exclusion criteria for ADHD patients were IQ < 80; pervasive developmental disorders; schizophrenia or other psychotic disorders; presence of mood, anxiety or personality disorders that might explain ADHD symptoms; birth weight ≤ 1.5 kg; and other neurological or systemic disorders that might explain ADHD symptoms. The SUD sample consisted of 494 adults recruited and evaluated at the Addiction and Dual Diagnosis Unit of the Psychiatry Department at the Hospital Universitari Vall d’Hebron with the Structured Clinical Interview for DSMIV Axis I Disorders . None were evaluated for ADHD. The control sample consisted of 483 blood donors in which DSM-IV lifetime ADHD symptomatology was excluded under the following criteria: not having been diagnosed with ADHD and answering negatively to the lifetime presence of the following DSM-IV ADHD symptoms: often has trouble keeping attention on tasks,layout commercial grow room design plans often loses things needed for tasks, often fidgets with hands or feet or squirms in seat, and often gets up from seat when remaining in seat is expected. Individuals affected with SUD were excluded from this sample. None of them had self-administered drugs intravenously. It is important to mention that the exposure criterion was not applied; therefore, this set cannot be classified as “pure” controls. All patients and controls were Spanish of Caucasian descent. This study was approved by the ethics committee of the Hospital Universitari Vall d’Hebron and informed consent was obtained from all subjects in accordance with the Helsinki Declaration.The Multimodal Treatment Study of Children with ADHD was designed to evaluate the relative efficacy of treatments for childhood ADHD, combined sub-type, in a 14-month randomized controlled trial of 579 children assigned to four treatment groups: medication management, behavior modification, their combination, and treatment as usual in community care. After the 14- month treatment-by-protocol phase, the MTA continued as a naturalistic follow-up in which self-selected use of psychoactive medication was monitored. A local normative comparison group of 289 randomly selected classmates group-matched for grade and sex was added when the ADHD participants were between 9–12 years of age. The outcomes in childhood , and adolescence and into adulthood have been reported. Substance use was assessed with a child/adolescent-reported questionnaire adapted for the MTA. The measure included items for lifetime and current use of alcohol, cigarettes, tobacco, cannabis, and other recreational drugs. Also included were items for non-prescribed use or misuse of psychoactive medications, including stimulants. The measure was modeled after similar substance use measures in longitudinal or national survey studies of alcohol and other drug use that also rely on confidential youth self-report as the best source of data. A National Institutes of Health Certificate of Confidentiality further strengthened the assurance of privacy.
Substance use was coded positive if any of the following behaviors, selected after examining distributions, were endorsed as occurring in the participant’s lifetime up to 8 years post-baseline: alcohol consumption more than five times or drunk at least once; cigarette smoking or tobacco chewing more than a few times; cannabis use more than once; or use of inhalants, hallucinogens, cocaine, or any of amphetamines/stimulants, barbiturates/sedatives, and opioids/narcotics without a prescription or misused a prescription . Each of the four types of substances, as well as daily use of tobacco and the number of substance use classes endorsed , were explored in secondary analyses. DSM-IV abuse or dependence was based on a positive parent or child report with the Diagnostic Interview Schedule for Children version 2.3/3.0 at the 6- and 8-year follow-up assessments. The DISC includes both lifetime and past year diagnoses. The Diagnostic Interview Schedule-IV was used at the 8-year follow-up for 18 + year-olds . SUD was defined as the lifetime presence of any abuse or dependence . Additional analyses explored SUD for alcohol, tobacco, and cannabis/other drugs separately. All patients in this study provided informed written consent as approved by the NIH Ethics Committee.A sample of 560 inpatients and outpatients with severe SUD from Central Kentucky psychiatric facilities was collected during a pharmacogenetics investigation. Patient interviews and medical record information DNA was extracted from whole blood or buccal swabs using standard protocols. The Paisa sample was genotyped using the service provided by Illumina . The Spanish, MTA, and Kentucky samples were genotyped for select variants using pre-designed TaqMan® SNP genotyping assays . Allelic discrimination real-time PCR reactions were performed in a 384-well plate format for each individual sample according to the manufacturer’s instructions. Briefly, 20 ng of genomic DNA were mixed with 2.5 μL of 2X TaqMan Universal PCR Master Mix and 0.25 μL of 20X SNP Genotyping Assay in a total volume of 5 μL per reaction. Assays were run in an ABI 7900HT Fast Real-Time PCR System . Allele calling was made by end-point fluorescent signal analysis using the ABI’s SDS2.3 software. In addition, we had previously collected exome genotype data from the MTA sample using the Infinium® HumanExome-12 v1.2 BeadChip kit , which covers putative functional exonic variants selected from over 12,000 individual exome and whole-genome sequences. Processed and raw intensity signals for the array data can be accessed at GEO . SNP markers harbored at the ADGRL3 gene were filtered in from this dataset and added to those genotyped using TaqMan® assays.Association studies of ADGRL3 variants with ADHD, ODD, CD, response to stimulant treatment and severity outcome have been published elsewhere for the Paisa and Spanish populations. We used ARPA to build a predictive framework to forecast the behavioral outcome of children with ADHD, suitable for translational applications. Our goal was to test the hypothesis that ADGRL3 variants predisposing to ADHD also increase the risk of co-morbid disruptive symptoms, including SUD. ARPA is a tree-based method widely used in predictive analyses because it accounts for non-linear and interaction effects, offers fast solutions to reveal hidden complex substructures and provides truly non-biased statistically significant analyses of high-dimension, seemingly unrelated data. In a visionary manuscript, D.C. Rao suggested that recursive-partitioning techniques could be useful for genetic dissection of complex traits.