Larry W. Hawk - US grants

DESCRIPTION (provided by applicant): Although there is a long history of research on basic cognitive and motivational processes in ADHD and a long history of research on effective treatments for ADHD, there is almost a total absence of research relating basic processes to the impact of clinical interventions. Contemporary theories of ADHD emphasize a range of basic cognitive processes, including inhibitory control, working memory, and sustained attention, and basic motivational processes such as delay-related impulsivity (a tendency to choose small, immediate rewards over larger, delayed rewards). An important, yet untested, corollary of these models is that the primary treatments for ADHD - stimulants such as methylphenidate (MPH), behavioral treatment, and their combination - exert their effects by improving these basic processes. Thus, there are important gaps in our understanding of the extent to which the basic processes are sensitive to each of these treatments, and there are almost no data to address whether changes in basic cognitive and motivational processes actually account for treatment effects in clinical settings. The proposed research fills these gaps. First, it is the first study to concurrently examine the effects of both MPH and performance-based motivational incentives (i.e., monetary rewards, an analogue of behavioral treatment) on laboratory measures of inhibitory control, working memory, sustained attention, and delay-related impulsivity in children with ADHD (n=108). A group of age- and gender-matched controls (n=108) is included for comparison but not given MPH. We hypothesize that children with ADHD will exhibit impaired performance in the absence of motivational incentives, but that this pattern will be ameliorated in the presence of incentives for good performance. Second, among the children with ADHD, incentive will be crossed with doses of extended-release MPH (placebo, O.3., and 0.6 mg/kg) on a within-subjects basis to provide an initial examination of the separate and interactive effects of these analogue treatments on neurocognitive processing. Third, the proposed research will be the first to test the extent to which MPH effects on basic processes assessed in the lab actually mediate, or account for, individual differences in clinical response to MPH. To accomplish this aim, the participants with ADHD will undergo a 3-week, double blind school-based medication assessment to examine MPH effects on ADHD children's functioning in a natural setting. Thus, the proposed research will bridge basic and clinical research in ADHD and will provide critical initial tests of the hypothesis that changes in basic cognitive and motivational processes are the mechanisms by which treatments for ADHD work. This work will pave the way for a new generation of translational research and theory in ADHD.

[unreadable] DESCRIPTION (provided by applicant): In clinical trials bupropion has been shown to double long-term smoking cessation rates. Nevertheless, most smokers using bupropion relapse back to smoking within the first few weeks of cessation. Bupropion has been hypothesized to help smokers to quit in part by reducing the reinforcing effects of smoking during the typical 1-week pre-quitting treatment phase. Learning theory and previous basic human and animal research support the hypothesis that a longer duration of bupropion treatment prior to the target quit date (TQD) will yield greater decreases in smoking satisfaction and the number of cigarettes smoked per day before quitting, and higher rates of continuous cessation after quitting. The proposed research is the first study of which we are aware to systematically vary the pre-quitting duration of bupropion treatment in smokers to test these predictions. A two group randomized experimental design will be used. One hundred male and female smokers who are motivated to quit smoking will be randomized to a brief run-in group (3 weeks of placebo, followed by the typical 1 week of pre-TQD bupropion) and an extended run-in group (4 weeks of pre-TQD bupropion). Both groups will receive 7 weeks of post-TQD bupropion, as well as group behavioral counseling for smoking cessation. During the pre-quitting treatment phase we predict that bupropion will reduce the number of cigarettes smoked daily and smoking satisfaction, relative to placebo. During a 3-month post-quitting phase, we predict that relapse will be lower in those who experience the greatest pre-quit reductions in smoking rate and satisfaction. We will conduct exploratory analyses of whether cessation is greater for subjects in the extended run-in group compared to the brief run-in group, and whether this effect is mediated by differences in the pre-quit effects of bupropion. This theory-based research may lead to enhanced treatment with bupropion and more broadly stimulate programmatic basic and clinical studies that improve cancer control through a better understanding of learning and behavioral processes implicated in pharmacotherapy for tobacco cessation. [unreadable] [unreadable]

PROJECT SUMMARY/ABSTRACT Varenicline is the most effective smoking cessation therapy available. Nevertheless, most smokers using varenicline relapse within the first few months after quitting. Varenicline is hypothesized to help smokers to quit in part by reducing the reinforcing effects of smoking during the standard 1-week pre-quitting treatment phase. Learning theory and previous human and animal research support the hypothesis that a longer duration of varenicline treatment prior to the target quit date (TQD) will yield greater decreases in the number of cigarettes smoked per day before quitting, and higher long-term cessation rates, compared to standard varenicline treatment. Building on our promising preliminary clinical data, we propose to test these hypotheses with a full-scale randomized clinical trial (RCT). Four hundred treatment-seeking smokers (200 female) will be randomized to a standard run-in group (3 weeks of placebo, followed by the standard 1 week of pre-TQD varenicline) or an extended run-in group (4 weeks of pre-TQD varenicline). Both groups will receive brief individual cessation counseling and 11 weeks of post-TQD varenicline. The primary outcome measure will be bio-verified continuous abstinence at end-of-treatment (weeks 8-11 post-quit) and at long-term follow-up (weeks 8-26 and 8-52 post-quit). Hypothesized mediating mechanisms (e.g., smoking reinforcement) will be evaluated by converging behavioral, physiological, and subjective measures assessed both in the lab and using real-world, real-time electronic momentary assessments (EMA). We predict that long-term, bio-verified smoking cessation will be improved among the extended run-in group compared to the standard run-in group. We further predict the improved clinical outcomes with extended run-in varenicline will be explained (or mediated) by greater pre-quit reductions in smoking reinforcement among the extended run-in group compared to the standard run-in group. The significance of this work is clear: We aim to make best available treatment for smoking cessation even better, using a method that is ripe for dissemination and an approach that will elucidate critical mechanisms to target in the next generation of treatment enhancement.