Matt Kushner - US grants

panic disorder; anxiety; alcoholic beverage consumption; ethanol; clinical research; human subject;

DESCRIPTION (provided by applicant): Alcohol use disorders are among the most serious and costly health problems of our time. Studies have been consistent in finding an increased risk of alcohol use disorder among those suffering with the anxiety syndrome, panic disorder "comorbidity". Further, studies suggest that panic disorder can contribute to risk for a new onset of alcohol disorder and to risk for relapse following alcoholism treatment. Both theory and research suggests that relapse in comorbid individuals stems, in part, from the tendency to drink as a means of coping with persistent anxiety and panic symptoms. These findings led us to hypothesize that addressing the panic symptoms of comorbid patients would improve the outcome of comorbid individuals undergoing alcoholism treatment Cognitive behavioral therapy (CBT) for panic disorder would appear to be an ideal intervention for testing this nypothesis; however, the effect of CBT treatment on panic disorder in comorbid individuals remains unknown. Further, conventional CBT treatments do not address the inter-relationship of panic symptoms and pathological alcohol use that is potentially relevant to the persistence of both disorders in comorbid individuals. Therefore, we are proposing an experimental/developmental program (P.21) with a series of research stages aimed at testing the value of CBT for panic among comorbid patients. In stage 1 (conducted in year 1), we will use approximately 4-6 comorbid alcoholism treatment patients as subjects in four separate pilot tests, each focused on one of the four core elements of the panic treatment program, Master your Anxiety and Panic (MAP), along with supplemental material pertinent to comorbidity. Pre- and post-tests along with expert consensus will be used to evaluate whether the material and techniques are working properly, with any problematic materials being modified as needed. In the stage 2 study (year 2 and 3), thirty comorbid patients undergoing a community-based alcoholism treatment will receive either the 10-session MAP program as modified in stage 1 (MMAP) or a 10-session control treatment (progressive muscle relaxation training; PMRT). (Note that PMRT is structured and credible but has been shown to have minimal effects on either alcoholism treatment outcome or panic disorder symptoms.) We hypothesize that those receiving fix MMAP program will demonstrate fewer panic attacks and less intense panic attacks following the study treatments. We also hypothesize that at a 3-month follow-up assessment, subjects in the MMAP group will demonstrate a lower overall rate of several standard alcohol use outcomes as well as time to those outcomes when present. Beyond these directional hypotheses, an important goal of the stage 2 study is to provide effect size parameters indicating the clinical importance of the MMAP intervention. It is expected that the stage 1 and 2 studies proposed here will provide the foundation for an RO1 application to conduct a larger-scale stage 3 study to confirm the value of supplementing standard alcoholism treatment with the MMAP program for comorbid patients.

DESCRIPTION (provided by applicant): In our R21-funded pilot work, we developed and tested a novel Cognitive Behavioral Therapy (CBT) treatment program for individuals with co-occurring alcohol use disorder and anxiety disorder ("co-morbidity"). In stage 1 of the R21, we created the hybrid CBT program by modifying the standard elements and delivery systems of CBT treatment for anxiety disorder to fit the specific problem of co-morbidity among patents undergoing treatment for alcoholism. In stage 2 of the R21, we conducted a clinical trial showing that the hybrid CBT treatment substantially lowered anxiety disorder symptoms and risk for relapse to drinking by 4- month follow-up compared to those patients not receiving the hybrid CBT treatment. We now propose to conduct a controlled clinical trial of the hybrid CBT treatment package (stage 3) in which we will study 60 alcoholism treatment patients (20 each with social phobia, panic disorder and generalized anxiety disorder) in each of two treatment conditions (CBT vs. active placebo control) (N=120). In the CBT condition, three treatment units will each be the focus of two therapy sessions and two "study hall" sessions (12 sessions total). In study halls, subjects are proctored as they review study materials and practice coping skills taught in the therapy sessions. Control subjects undergo relaxation training (RT) on "therapy" days and will read about and practice RT on "study hall" days. (RT is structured and credible but has little effect on anxiety disorder or drinking outcomes.)The study interventions and alcoholism treatment-as-usual will run in parallel;following which, subjects will undergo assessments at post-treatment, four-months, and 12-months. The central prediction is that the$ CBT treatment group will demonstrate less relapse at follow-up than placebo controls and we will also explore whether this effect is mediated by anxiety symptom reduction and whether the CBT treatment effects differ for (i.e., are moderated by) the anxiety disorder subtype. Confirmation of the study's central hypothesis would support the conclusion that the hybrid CBT treatment package could significantly mitigate risk of relapse to drinking among the many alcohol-disordered patients with co-morbid anxiety disorder.

DESCRIPTION (provided by applicant): The objective of this K02 application is to allow the candidate to increase the time he has allocated to research and related career development activities from a projected annual average of between 25-45% without the K02 to between 75-80% with the K02. The application overviews the candidate's 15-year history of NI/\AA-supported alcohol research and provides a career development plan aimed at acquiring and deploying sophisticated data analytic and methodological strategies that fall under the broad heading of latent variable-structural equation modeling (LV-SEM) (e.g., factor analysis, path analysis, latent class and trait modeling, growth mixture modeling, item response theory). This would be accomplished via specific career development objectives involving: 1) interactions with mentors and collaborators (15%);2) hypotheses testing (25%);3) formal courses/training (25%);4) scholarly production (25%);and, 5) teaching/ service (10%). The "parent R01" ("CBT Treatment of Anxiety Disorders in Comorbid Alcoholics" /\A0105069) targets a sample of 400 patients undergoing a standard community-based alcoholism treatment program who are also diagnosed with at least one of several common comorbid anxiety and affective ("internalizing") disorders. In addition to the alcohol treatment, patients receive one of two psychosocial treatments for internalizing disorder. LV-SEM would allow the candidate to empirically partition highly inter- correlated internalizing disorders/symptoms in the parent R01 dataset into distinct vs. common components that could then be related in causal models to the alcohol and internalizing treatment outcomes. Next, the candidate would replicate these models in community, student and psychiatric-based datasets that are either publicly available (e.g., NESARC) or available via his collaborators (e.g., Drs. Ken Sher and Carrie Randall). These efforts would provide an empirically parsimonious characterization of the internalizing problems experienced by individuals with alcohol use disorders and how these relate to alcoholism and psychiatric treatments across a number of populations and treatment modalities. The longer-term goal would be to develop more effective treatments for alcohol disorders with comorbid internalizing disorders. RELEVANCE: By further clarifying the best clinical strategies for and conceptualization of internalizing disorders occurring in alcoholism treatment patients, the proposed work will improve our ability to effectively treat alcohol dependence.

DESCRIPTION (provided by applicant): This is a competitive renewal application for the recently completed parent R01 (AA015069: CBT Treatment for Anxiety Disorder in Comorbid Alcoholics). Up to half of patients in treatment for an alcohol use disorder (AUD) have a co-occurring anxiety disorder and these patients relapse to drinking at twice the rate of other patients. To address this, the parent R01 evaluated a CBT-based program that combined three sessions of trans-diagnostic anxiety reduction therapy with three sessions designed to de-couple the cognitive and behavioral bonds linking anxiety to alcohol use (e.g., expectancies, coping drinking motives, conditioned associations). In a randomized trial with over 300 cases, the parent R01 showed that adding this CBT to a residential community-based AUD treatment significantly improved four-month alcohol outcomes (e.g., 41% relapsed) compared to adding a stress reduction control treatment (53% relapsed) and compared to a matched, non-randomized cohort undergoing the AUD treatment alone (61% relapsed). While this confirmed the primary study hypotheses in the parent R01, it must be acknowledged that the effects were not large and that the CBT alleviated only about half of the increased relapse risk associated with co- occurring anxiety disorders. Fortunately, the results of the parent R01 also point the way to modifications that are likely to significantly increase the therapeutic effect of the CBT. Specifically, the pattern of findings in the parent R01 indicates that the de-coupling therapy, rather than the anxiety reduction therapy, caused the improved alcohol outcomes. This suggests that further emphasizing the de-coupling therapy elements would increase the CBT's overall effectiveness; however, the importance of anxiety reduction for improving alcohol outcomes in these patients remains ambiguous. For example, the three sessions devoted to anxiety reduction may have been insufficient to affect alcohol outcomes in the parent R01. Alternatively, anxiety reduction therapy may be needed to work synergistically with de-coupling therapy to improve alcohol outcomes. The renewal work would use a dismantling approach to isolate the separate and interactive effects of these therapy components at two dose levels toward the goal of increasing the effectiveness of the validated but still sub-optimally performing parent R01 version of the CBT. 350 AUD patients with an anxiety disorder would be randomized to groups receiving either: 1) six sessions of CBT for anxiety reduction (CBT- AR); 2) six sessions of CBT for anxiety-alcohol de-coupling (CBT-DC); or, 3) the original CBT with its three anxiety reduction sessions and three de-coupling sessions (CBT-O). Based on the parent R01 findings indicating that the de-coupling components are the active ingredients of the CBT therapy, we predict that the best alcohol outcomes will be obtained in the CBT-DC group (six DC sessions) followed by the CBT-O (three DC sessions) further followed by the CBT-AR (zero DC sessions). This design would also indicate synergy effects between the AR and DC CBT components if the CBT-O out-performs the other two groups.

ABSTRACT Up to one-half of those in treatment for alcohol use disorder (AUD) has a co-occurring anxiety disorder (?comorbidity?), a condition that marks a high degree of treatment resistance, severity and relapse risk in AUD treatment patients. We conceptualize comorbidity as a feed-forward system (?vicious cycle?, [VC]) of interacting negative affect/stress, drinking motives/behavior, coping skills deficits, environmental circumstances, and neurobiological adaptations. Based on this model, we developed and validated the VC cognitive-behavioral therapy (VC-CBT) to disrupt this system at several key linkage points. In a recently completed randomized controlled trial (RCT), we found that adding the VC-CBT to standard AUD inpatient treatment resulted in better alcohol outcomes 4 months following treatment than did adding an anxiety treatment or standard AUD treatment alone. With a number needed to treat (NNT) index of 8 (relative to standard AUD treatment alone), the VC-CBT could, if broadly disseminated, have a large positive impact on AUD treatment. Unfortunately, several significant barriers related to the resource- and expertise-intensive delivery of the VC-CBT limit its dissemination potential and, hence, the impact of this otherwise effective treatment. Therefore, to maximize the public health and scientific potential of our work, we propose to adapt the therapist-delivered VC-CBT to a computer-delivered format to facilitate reliable and economical dissemination of the VC-CBT while maintaining its established efficacy. The first phase of the work (Year 1) will be to adapt the 6-session therapist-delivered VC-CBT for delivery on an internet-based computer platform. This work will be done using a standard iterative process for developing e-content in partnership with local technology experts experienced in producing engaging and effective e-learning products. Approximately 24 patients (6 to test and supply feedback on each of three 2-session therapy modules and 6 to test and supply feedback on all 3 modules given together) will be employed in this phase. The second phase (Years 2 and 3) will be devoted to conducting an RCT to test the efficacy of the refined computer-delivered VC-CBT. We will randomize AUD treatment patients with co- occurring anxiety disorder to receive either the computer-delivered VC-CBT or standard AUD treatment alone (50 patients in each group) to establish significance and effect size estimates of clinical effect for the adapted e-therapy. In addition to analyzing the RCT data, we will perform quasi-experimental contrasts of the process and outcome measures from the computer-delivered VC-CBT group in the RCT with parallel data from the therapist-delivered VC-CBT obtained in an earlier clinical trial. These contrasts will provide a reasonable estimate of how well the computer format compares to the therapist format of the VC-CBT. The proposed work aims to provide an easy and inexpensive computer-delivered version of the VC-CBT that has comparable efficacy to the validated but resource-intensive therapist-delivered version. Achieving this will enable the VC- CBT therapy to benefit more AUD treatment patients and to be more easily studied by other investigators.  

Abstract Introduction: This is a renewal application for T32 institutional training grant application ? Comorbidity: Substance Use Disorders and Other Psychiatric Conditions (NIDA DA037183) -- following the completion of its first five-year funding cycle. Among the current portfolio of NIDA funded training grants, only one program other than ours (Dartmouth) has comorbidity as a primary focus. This is striking given co-occurrence prevalence of Substance Use Disorders (SUD) with other psychiatric conditions and health conditions (e.g. diabetes), and the extent to which either SUD or the comorbid disorder can go under- or untreated in conventional treatment settings. The goals, elements and resources of the renewal program retains critical and effective elements of the initial funding period while incorporating important lessons learned. Long term goals: The proposed program will develop a cadre of scientists with research expertise in comorbidity mechanisms, antecedents and correlates, diagnostics, and psychosocial and pharmacological interventions. Component objectives are to provide each trainee with a working knowledge of comorbidity research including: (a) translational science from Early Phase Clinical Trials to Community Based Participatory Research perspectives; (b) effective research strategies for comorbid conditions across populations and ethnic and cultural groups (e.g. American Indian, Hmong, Somali). Accomplishing programmatic features will capitalize on (a) the spectrum of faculty expertise providing mentoring across multiple areas, and (b) integration across training programs and departments. Key Elements: (1) Involvement of scientists and clinicians with diverse expertise and a core internal advisory group. Primary sites (4 postdoctoral trainees, 2 yrs each) are the Departments of Psychiatry and Psychology (UMN Twin Cities) and Family Medicine and Biobehavioral Health (UMN Duluth); (2) Recruitment, including under represented group outreach, of rigorously screened PhD and MD candidates with SUD and comorbidity as primary career focus; (3) Training with an interdisciplinary mentoring team (primary & 2 secondary mentors) with complementary expertise; (4) Formal training plans with clear milestones including trainee development of an NIH application initiated in Year 1; (5) Active research, seminars, didactic course work, workshops, and development of management, ethics, and regulatory expertise; (6) Dynamic program administration entailing monitoring with enhancements and problem resolution along with continued contact with trainees after completion and; (7) Annually convened external advisory group. Resources: Mentor funding sources include NIH Institutes, NSF, Minnesota Medical Foundation, and pharmaceutical industry. Key Personnel and Primary Mentors are directors of clinics, centers, or departments with significant resources.

Project Summary The broad goal of the proposed work is to conduct a randomized controlled trial of a specialized computer- delivered cognitive-behavioral therapy (CBT) to supplement standard alcohol use disorder (AUD) treatment in patients with a co-occurring anxiety disorder (?comorbidity?). Comorbidity is both common in AUD treatment patients (up to 50%) and confers a substantial increase in the risk of a return to drinking in the months following treatment. Because research shows that simply adding a standard psychiatric treatment does not substantially improve the AUD outcomes of comorbid individuals, we developed a CBT-based intervention aimed at disrupting the positive-feedback loop (?vicious cycle?; VC) of mutually aggravating negative affect and drinking behavior/urges (the ?VC-CBT?). In an RCT, AUD treatment patients who received the therapist- delivered VC-CBT demonstrated significantly improved alcohol use outcomes as compared to those who received a standard anxiety treatment. Unfortunately, most community-based AUD treatment programs do not have clinical staff with the specialized training and technical expertise needed to deliver the VC-CBT. To help bridge this ?research-to-practice? gap, we went on to develop a fully autonomous and interactive computer- delivered version of the VC-CBT and have demonstrated its functionality in AUD patients. Now, we propose to test the clinical efficacy of the computer-delivered VC-CBT, as well as the mechanisms and processes by which it is hypothesized to work. Aim I is a randomized controlled trial comparing the computer-delivered VC- CBT to an intensity-matched computer-delivered active control intervention that focuses on healthy lifestyles. 256 individuals in residential AUD treatment who have a comorbid anxiety disorder will receive either the VC- CBT or the active control intervention to obtain 200 cases that complete a 1-, 4- and 8-month follow-up. We predict the VC-CBT group will demonstrate superior alcohol-related outcomes at follow-up relative to the control group. Aim II evaluates the extent to which the computer-delivered VC-CBT selectively imparts the skills and knowledge targeted and whether they convey (mediate) the interventions therapeutic effect. This entails a formal series of ?causal steps? analyses of the associations of: treatment?skills/knowledge; skills/knowledge ?outcomes; and, treatment?outcomes with vs. without statistically controlling the effect of skills/knowledge. Aim III will test the theoretically-derived prediction that the computer-delivered VC-CBT moderates (i.e., weakens) the association between levels of real-time negative affect and drinking behavior/ urge. This will be accomplished by analyzing a series of twice-daily ecological momentary assessments (EMAs) that participants record in their natural environment for the 7 days prior to each of the three follow-up assessments. The impact of this work would be to provide a scalable and inexpensive means of improving the otherwise poor AUD treatment outcomes of comorbid AUD treatment patients. The work will also provide new scientific knowledge about the mechanisms and processes of change in comorbidity treatment.