Sandra A. Brown, Ph.D. - US grants

expectancy; relapse /recurrence; alcoholism /alcohol abuse therapy; adolescence (12-20); alcoholism /alcohol abuse prevention; human therapy evaluation; psychological stressor; coping; longitudinal human study; family structure /dynamics; belief; social support network; questionnaires; human subject;

While knowledge of alcohol use in the general adolescent population is expanding, there is limited empirical data on clinical samples of teen abusers and even less is known about the long term outcome of these teens. Unfortunately, the majority of teens who enter alcohol and drug treatment programs have a history of failure to attend school, suspension or expulsion and consequently, the results of studies from junior and senior high schools cannot be generalized to teens in treatment. Further, there is a plethora of treatment outcome studies involving adult alcoholics, but only recently has the clinical course of alcohol abuse begun to be explored for adolescents following treatment. The present study utilizes findings from adult alcoholism treatment outcome studies, cross-sectional and longitudinal studies of teens in the general population and information on distinctive features of adolescent abusers in treatment to predict the drinking and drug use outcome of adolescents 2 and 4 years following treatment. This study is an extension to 4 years of the current NIAAA 1 year follow-up of 250 abusing teens who have completed treatment. Studying this well characterized sample through periods of late adolescence and young adulthood may provide useful information regarding the degree to which abuse continues into early adulthood and deterrents to chronic abuse. To highlight the specific aims of this proposal, we will: 1) Examine the alcohol and drug treatment outcome for 250 teens at 2 and 4 years following treatment for alcohol and drug abuse, 2) Determine predictors of longer term (2 & 4 year) alcohol and drug use outcome and 3) Determine changes in learned behaviors (e.g., expectancies and coping strategies) which are associated with more successful functioning following treatment as well as neuropsychological status.

APPLICANT'S ABSTRACT: Little is known regarding the process by which teens succeed or fail after treatment for alcohol abuse or their long- term clinical course. In contrast to adult findings, our current research has found that adolescents receiving alcohol treatment demonstrate developmentally related differences in the relapse process, strategies through which they successfully abstain after treatment, and clinical course for up to four years after treatment. Additionally, it has become evident, that psychiatric co-morbidity influences outcome for adolescent alcohol abusers. For example, we have found that alcohol abusing teens with concomitant conduct disorder demonstrate greater relapse rate, briefer periods of sustained abstinence, less forethought regarding relapse risk, and fewer cognitive coping strategies than alcohol abusing teens without conduct disorder. Unfortunately, theory driven research of adolescents with concomitant alcohol/drug and other mental disorders is lacking, and the specific relapse vulnerabilities and strategies for abstinence for teens with comorbid disorders are unknown. The present proposal is designed to address these two information gaps regarding adolescent alcohol abuse. Specifically, we will 1) follow, at six and eight years our sample of 250 adolescent alcohol abusers (already studied for four years) to determine the long term alcohol and drug use outcome, assess psychiatric and other life problems emerging in this sample, and examine the relationship between clinical course and adult functioning; 2) extend our research of adolescent addiction relapse to the critical area of psychiatric comorbidity to test for differences in rate, process, and circumstances of relapse and examine the applicability of current relapse models to comorbid groups of adolescents; and 3) continue our model building analyses of adolescent functioning across the four follow-up time points and replicate these using the new young adult follow-up data. Major advantages of this project are the less costly opportunity to evaluate young adult functioning of a well-described, consistently followed (four years) sample of 250 adolescent alcohol abusers, extensive research experience with the evaluation of adolescent addiction relapse making successful extension to comorbid psychiatric populations more likely, and the opportunity to explore developmentally sensitive models of alcohol abuse clinical course in an already existing data base.

APPLICANT'S ABSTRACT: Despite the high rate of alcohol related problems among adolescents, only a limited number of interventions have been demonstrated to have efficacy for youth. While there are notable exceptions (e.g., multi systemic intervention and family-based therapy), a major problem involves the enlisting and engaging youth, particularly minority youth, in intervention efforts. The present project seeks to capitalize on the naturally occurring self-change efforts that adolescents normally make to resolve their alcohol problems in order to refine and test a set of change options for adolescents in the high school context. Specifically, in four high schools (approximately 9,000 students), we will test the effectiveness of a package of self-change options based on cognitive social learning theory formulations of alcohol involvement and grounded in both social and developmental psychology theory. The package of self-change options (i.e., Brief Intervention, Guided Self-Change, and Peer Group Counseling) have been selected based on our pilot studies of: 1) prevalence of self-change efforts for alcohol problems among high school students (approximately 25%); 2) types and characteristics of self-change efforts adolescents perceive as helpful; and 3) types of self-change efforts engaged in by adolescents who successfully (for at least a one year period) reduce their alcohol involvement to non-problematic levels or cease drinking (Wagner, Brown, et al., in press). These low cost, low threshold strategies are thus developmentally sensitive, acceptable to youth, and offer an opportunity to evaluate the effectiveness of this new self-selection intervention paradigm to successfully engage youth in reducing alcohol problems. The proposed five-year study will be conducted in two phases: 1) manualize/systematize the change facilitation options and gather baseline data at all schools and 2) sequentially implement the intervention options package across sites with up to two year follow-up for outcome evaluation. In addition to specific alcohol use and problem outcomes, we will evaluate the generalizability of the intervention for other related or problem behaviors (e.g., cigarette and other drug use, affective distress). Finally, using a three-tiered analytic approach, we will analyze data to determine: 1) effectiveness of the intervention package, 2) preference and effectiveness of various intervention options, 3) utilization rates across genders, age, and ethnic groups and in relation to both types of alcohol problems experienced and risk factors exhibited by adolescents.

DESCRIPTION (provided by applicant): The competitive renewal seeks four years of funding to conduct a multi-site clinical trial of a promising and innovative secondary intervention to facilitate youth efforts to stop hazardous drinking. Recent studies demonstrate the critical role o progression to heavy episodic drinking in the developmental process of alcohol use disorders, and important associations between certain cognitive factors and recent and planned alcohol change attempts for teens. This voluntary, school-based brief intervention (BI), which targets such hazardous drinking, will be tested in three cities (Miami, Florida; Minneapolis, Minnesota; and Portland, Oregon) at 6 socioculturally and ethnically diverse schools (approximately 1440 students). We will test a conceptual model of purposeful drinking change efforts of youth and determine the 4 and 12 week effectiveness of the BI to increase quit efforts and reduce progression of alcohol involvement (frequency of binge drinking, maximum drinks per occasion, and alcohol-related problems) compared to an Education (ED) comparison condition. The proposed block randomized clinical trial will serve the critical step of replicating initial intervention effectiveness findings in diverse communities and test important treatment factors in facilitating behavior change of adolescents. The intervention design, methods and analyses are specifically linked to the conceptual model of purposeful alcohol change efforts of youth. Based on prior research by our group, we hypothesize that three cognitive factors (e.g. use and non-use expectancies, motivation, perceived peer norms) partially mediate purposeful alcohol self-change efforts of adolescents. The intervention targets these potentially malleable cognitions using Motivational Interviewing in an adolescent-friendly group format. The proposed study also examines the therapy process measure of therapeutic alliance and a new Motivational Interviewing specific construct of group level change talk, hypothesized to influence adolescent efforts to reduce hazardous drinking and alcohol related problems. Using longitudinal modeling procedures we will test impact of the intervention and proposed cognitive and therapeutic process mediators on quit attempts and severity of alcohol involvement at 1 month and 3 months following initiation of treatment. Should results of this model prove fruitful, t would open a new direction to interventions for hazardous drinking among adolescents, and lead to greater understanding of mechanisms of behavior change for youth and processes of therapy effective in promoting self-regulation of drinking behavior at this stage of life.

6. Project Summary/Abstract Little is known about the rate and pattern of change in Neurocognitive skills among abstaining youth with histories of heavy drinking. Decades of research on adult alcohol dependence has shown that substantial improvements in neuropsychological (NP) functioning unfold during the early weeks of abstinence and may extend for years. Since adolescent alcohol use may more adversely affect neurocognitive processes than adult exposure, examination of improvement in NP skills and the neuroanatomical underpinnings and behavioral correlates of such changes is merited. The present study seeks to: 1) develop and refine methodology critical to examination abstention related changes in NP skills and neuroanatomical functioning among adolescents, and 2) conduct a pilot study of such changes comparing abstaining, former heavy drinking 16-18 year olds (>100 lifetime alcohol episodes, recent high dose drinking and withdrawal symptoms) to matched nondrinking peers over 6 weeks of monitored abstention. The methods development and refinement stage (Phase I) uses new technology to continuously assess abstinence (via transdermal alcohol monitor) and remotely conduct experience sampling (text messaging and activity logs) of potential moderators of NP change (affect, sleep, activities), and evaluates feasibility of repeated NP/Behavioral testing at 2,4, and 6 wks. Phase II pilots the full NP, behavioral and neuroimaging (MRI, fMRI, DTI) protocol on a sample of 55 heavy drinking adolescents who are abstaining over a 6 week time period and 20 matched nondrinking peers. Changes in NP skills, and neuroanatomical structure and functioning will be examined along with proposed moderators of such change and potential behavioral correlates of NP improvement (driving skills, risk taking, cue reactivity, and school participation). Linear mixed[unreadable]effects models will be used to: 1) examine hypotheses regarding greater NP improvement and neuroanatomical changes among abstaining heavy drinkers relative to controls, 2) ascertain predictive power of proposed moderators of NP change, and 3)explore relations between NP skills and developmentally relevant behavioral functioning. Results will serve as a foundation for RO1 to more fully evaluate abstinence-related NP recovery of youth. 7. Project Narrative Relevence, Alcohol consumption during adolescence is becoming an increasing problem in the U.S. with 78% of youth drinking before they even finish high school and the majority of high school seniors who drink exhibiting one or more alcohol problems. Research now indicates that adolescent brains may be more vulnerable to the effects of alcohol than adults and little is known about improvement in cognitive functioning when teens become abstinent. The present study examines the extent to which thinking abilities of adolescents with heavy drinking histories improve in the first six weeks of abstinence. The study also examines underlying brain changes and predictors and correlates of cognitive improvement.

DESCRIPTION (provided by applicant): This application continues a multisite collaboration, initiated under DA 012845, to address critical issues in the genetic epidemiology of adolescent onset antisocial drug dependence. Addressing these issues requires sample sizes greater than a single site can reasonably attain, as well as the multidisciplinary expertise of psychiatrists, psychologists, and behavioral and molecular geneticists, that is difficult to provide at a single site. This collaboration includes longitudinal assessment of previously studied probands and siblings, and adds community controls. It will yield a total of ~800 clinical probands, together with their siblings, to assess differing developmental trajectories and clinical courses, and the role of comorbidity, early onset, and familial loading. After allowing for desistance, we anticipate a final sample of ~600 persistent cases, together with their siblings, and a matched sample of ~600 control subjects, for genetic association analyses of persistent, adolescent onset, antisocial substance dependence. The current application will use dense SNP association mapping to identify genetic loci predisposing to this pattern of behavior. The specific aims of the project are as follows: 1) We will complete the five year follow-up assessment of ~800 clinical probands, aged 19 though 23 years at follow-up, and their siblings, and ascertain a sample of matched control subjects from our existing databases together with 300 newly ascertained control subjects. The new assessments will be conducted at the San Diego and Denver sites. 2) We will assess differing developmental trajectories and clinical courses, and the role of comorbidity, early onset, and familial loading on these. The data set we are collecting would, even in the absence of a single DMA sample, represent a unique, and unsurpassed, research resource for studying the development and familial influences on adolescent antisocial drug dependence. 3) We will use Affymetrix SNP chip technology to genotype an average of 25 SNPs in each of 200 candidate genes for drug dependence vulnerability and/or conduct disorder. 4) We will conduct association analyses using the -600 persistent cases and their ~600 matched controls, and then conduct confirmatory tests of the best signals using a within-family association analysis (Laird and Lange, 2006). These analyses will confirm the significance and robustness of genetic associations with adolescent onset persistent antisocial drug dependence. 5) Through a continuation of our NIDA Genetics Consortium data sharing agreement, we will share all the core substance dependence and psychopathology phenotypic data, and DNA from lymphoblastoid cell lines established for the multisite samples. Our Affymetrix SNP chip will be made available, at cost, to any qualified researcher.

DESCRIPTION (provided by applicant): In response to RFA-AA-12-006, this application proposes the Administrative Component of the National Consortium on Alcohol and Neurodevelopment in Adolescence (N-CANDA), located at UCSD, to determine the effects of alcohol use on the developing adolescent brain. This consortium was designed to provide a nationally representative sample of adolescents and to integrate the diverse scientific expertise and research experience with youth represented by researchers at each site. As such, the following applications should be considered jointly: N-CANDA: Administrative Component, UCSD (PI: Sandra Brown PhD (Contact), Susan Tapert PhD) N-CANDA: Data Component, SRI (PI: Adolf Pfefferbaum, M.D.) N-CANDA: Duke (PI: Michael DeBellis, M.D.) N-CANDA: Pittsburgh (PI: Duncan Clark, Ph.D., M.D.) N-CANDA: SRI (PIs: Ian Colrain, Ph.D. (Contact) and Fiona Baker, Ph.D.) N-CANDA: UCSD (PI: Susan Tapert, Ph.D.) Recruited at ages 12 through 21, a high-risk enhanced community sample of 680 subjects will complete a baseline assessment then undergo three annual follow-up assessments in an accelerated longitudinal design. At each visit, a multimodal MRI protocol, comprehensive neuropsychological battery, and assessment of alcohol use and related problems, along with other substance involvement, mental health symptoms, and other risk factors, will be measured. Brain imaging uses state-of-the-art high-resolution structural MRI (sMRI), diffusion tensor imaging (DTI), resting state MRI (rsMRI), and an anti-saccade or Stroop functional MRI task to capitalize on local expertise. The examination of alcohol consequences will focus on structural and functional maturation of brain areas that are actively developing during adolescence, involved in psychological regulation, responsive to rewards, and thought to be vulnerable to toxic alcohol effects. Five aims specified in the RFA will be systematically tested with a focus on adolescent substance use and neuromaturational trajectories. Each of the four Research Components will collaborate with another site on two additional aims. Examined in the context of risks and baseline brain characteristics, we will determine both the effects of alcohol exposure on the developmental trajectory of the adolescent human brain, and identify preexisting psychobiological vulnerabilities that may put an adolescent at greater risk for an alcohol use disorder. PUBLIC HEALTH RELEVANCE: Successful completion of the above aims will demonstrate that adolescent alcohol involvement disrupts brain development. This project represents a critical step in understanding neurobiological risks for accelerated alcohol use and alcohol effects on brain development in adolescence.

? DESCRIPTION (provided by applicant): The ABCD-USA Consortium proposes a study designed to permit our investigators and the scientific community to answer important questions about the effects of substance use (SU) on behavioral and brain development of adolescents. We have assembled a team of investigators with unparalleled research experience with youth, and specific expertise in adolescent SU, child and adolescent development, developmental psychopathology, longitudinal multi-site imaging, developmental neuroimaging and cognitive neuroscience, genetics and imaging genetics, bioassays, epidemiology, survey research, bioinformatics, and mobile assessment technologies. We propose a nationwide study of 10,000 9-10 year olds conducted at 21 sites organized into 11 hubs (29% of the US population lives within 50 miles of our geographically spread sites), that, uniquely, can provide a nationally representative sample and a large twin sample that together can help distinguish environmental, sociocultural, and genetic factors relevant to SU and brain development. We ensure cohesion and standardization with a recruitment strategy designed by a professional survey company (experience with Monitoring the Future); standardized environmental, neurocognitive and mental health assessments, MRI assessments with scanners using harmonized Human Connectome Project procedures, and computerized data collection with real-time quality control. Developmentally tailored assessments will have stable sensitivity and construct validity across childhood and adolescence, minimize participant burden, capture even subtle changes in SU, mental health, neurocognition, development, and environment, and employ novel bioassays and passive data collection from mobile devices. The retention plan builds on the experience of our investigators to ensure success. This application describes the ABCD-USA Coordinating Center (CC) which will: provide overall administrative and logistical support and scientific integration fr the consortium; establish and implement procedures for core protocols, participant recruitment and retention, and data quality control; provide initial and ongoing training of personnel for standardization; monitor cohort attributes, recruiting and retention practices, data quality, and consortium-wide consistency in real time, and monitor progress toward benchmarks and timelines. CC will ensure adherence to ethical standards and cultural sensitivity of research, and establish and implement policies for dispute resolution, internal and external data sharing, and publication. CC organizes and provides logistical support for meetings and teleconferences of the consortium, steering committee, scientific advisory board and workgroups as well as for educational, scientific, outreach, and dissemination events. By design, CC processes are flexible for problem resolution and incorporation of emerging scientific opportunities. We provide transparent study updates to the public via the web, and a well-managed and fully annotated repository of data for timely sharing. Importantly, we provide training and mentoring to developing scientists in the drug abuse area.