Tony P. George, M.D - US grants

This section of this Medications Development Unit (MDU) outlines phase ll screening studies for armacotherapy of cocaine use in methadone- maintained subjects with agents that act through GABAergic or lutamatergic mechanisms. These studies would be carried out in two parts, with GABAergic agents being tested in Years l-2, and glutamatergic agents in Years 3-5. Our group has a long history of completing pharmacotherapy trials in cocaine-using methadone subjects, and examples have included desipramine, mazindol, amantadine, bromocriptine and bupropion. Pre- clinical evidence indicates that GABA and glutamate systems can modulate dopamine reward pathways which are thought to underlie the addictive properties of cocaine, and agents which modulate GABA and glutamate systems can reduce the reinforcing properties of cocaine in animal models. The GABAergic agents chosen for these pilot studies are: l) the GABAB agonist baclofen; and 2) the selective GABA reuptake inhibitor tiagabine. The glutamatergic agents chosen for phase I studies are: l) the NMDA receptor antagonist acamprosate and 2) the pre~synaptic glutamate release inhibitor lamotrigine. A total of 60 subjects will be recruited into each study for a total of 120 subjects over the entire five year period. Subjects will be randomized to one of five cells: placebo or two different doses of either baclofen or tiagabine (Study 1) or acamprosate or lamotrigine (Study 2) for a total of 8 or 12 weeks of active treatment for GABAergic and glutamatergic agents respectively. At the end of the active trials, medications would be tapered over a two week period. Primary outcomes will be self-reported cocaine use, three times weekly urine toxicology for the cocaine metabolite benzoylecgonine and treatment retention. It is hoped that we will demonstrate the efficacy and safety one or more of these agents for cocaine use in opiate-maintained subjects, and if encouraging results are obtained, phase ll controlled studies would be planned with promising candidates identified from these phase ll screening trials.

We are proposing a placebo-controlled pilot study of selegiline versus placebo for nicotine dependent smokers (N=30) with depressive symptoms. There is evidence that catecholamines have an important role in the rewarding and withdrawal effects of tobacco smoking, and monoamine oxidase inhibitors (MAOIs) which augment catecholamine (i.e. dopamine, norepinephrine) function may be helpful in attenuating nicotine craving and withdrawal symptoms in nicotine dependent smokers. Thus, the selective MAO-B inhibitor selegiline may be helpful as a pharmacologic adjunct for smoking cessation. The proposed study would be a 6 week trial in nicotine-dependent smokers which will compare selegiline (10 mg daily; n=15) versus placebo (n=15) treatments on smoking cessation outcomes. Subjects would be inducted onto 10 mg/day of selegiline (5 mg po bid) or matching placebo (twice daily) over a two week period prior to the "quit date" at the beginning of Week 1. All subjects would receive brief weekly sessions of smoking cessation counseling consistent with AHCPR smoking cessation guidelines. The primary outcome measures include 1 week post-quit (Week 2) and endpoint (Week 6) smoking abstinence rates, and continuous smoking abstinence during the last four weeks of the trial. Secondary outcomes measures include treatment retention, depressive symptoms, nicotine withdrawal symptoms, weight change, plasma cotinine levels, expired breath carbon monoxide (CO) levels and urinary catecholamine excretion. Data analyses to compare groups will focus of an intention-to-treat sample and will utilize Chi square 2x2 contingency tables for smoking abstinence rates, repeated measures analysis of variance (ANOVA) models for continuous outcome measures (i.e. depression and nicotine withdrawal ratings, CC, plasma cotinine and urinary catecholamines) and Kaplan-Meir survival analysis for treatment retention. Results from this pilot study would be used to calculate an effect size for planning a larger controlled trial if results from this pilot study appear promising. We predict that selegiline will be superior to placebo for smoking cessation in nicotine dependent smokers on both primary and secondary outcome measures.

DESCRIPTION(provided by applicant): Schizophrenics have high prevalence rates of cigarette smoking (58-88 percent) compared to the general population (-25 percent), and are often nicotine-dependent smokers who have considerable difficulty quitting smoking. Several factors may predispose these patients to cigarette smoking including alleviation of dysphoric mood states, improvements in extrapyramidal symptoms and deficits in information processing and neuropsychological function, as well as genetic factors that determine a vulnerability to both nicotine dependence and schizophrenia. Schizophrenic patients have deficits in cognitive function, including executive function (Wisconsin Card Sorting Test; WCST), verbal and spatial working memory Visuospatial Working Memory (VSWM)], response inhibition (Stroop Color-Word Test; SCWT), attention and concentration (Continuous Performance Test; CPT) and information processing {prepulse inhibition (PPI) of the startle response}. Preliminary evidence suggests that cigarette smoking can improve, and abstinence can worsen, cognitive function in schizophrenic patients. Nicotine withdrawal has been associated with reductions in central dopamine (DA) function in animal and human studies, and several of the above tasks are dependent, in part, on prefrontal cortical DA function. Our preliminary results suggest that smoking abstinence impairs visuospatial working memory (VSWM) in schizophrenic smokers, but improves VSWM in healthy smokers. However, the effects of cigarette smoking and abstinence on cognitive function in schizophrenic vs. healthy smokers have not been carefully evaluated. In the present studies, we will evaluate the effects of cigarette smoking and abstinence on cognitive tests known to be deficient in schizophrenic patients, including neuropsychological tests (WCST, SCWT, CPT, WSPT, VSWM) and PPI. After baseline testing, schizophrenic (n=25) and healthy control (n=25) smokers will undergo overnight smoking abstinence, followed by repeat testing, and then subsequent testing after resuming smoking. A group of schizophrenic (n=25) and healthy (n=25) non-smokers will serve as controls and complete the same sequence of testing. We will also assess the role of high-affinity nicotinic acetylcholine receptors (nAChRs), using pre-treatment with the nAChR antagonist mecamylamine (0.0, 5.0 and 10.0 mg/day), in mediating the effect of cigarette smoking on these cognitive assessments. Accordingly, these studies may provide data on the mechanisms by which cigarette smoking alters cognitive function in schizophrenic vs. control smokers, and suggest novel treatment approaches for both nicotine dependence and cognitive dysfunction in schizophrenic disorders.

DESCRIPTION: (provided by applicant) Schizophrenic patients have high co-morbid rates of cigarette smoking (up to 90 percent), and are typically nicotine dependent smokers who have great difficulty quitting smoking. This may relate to improvement of extrapyramidal side effects, cognitive dysfunction and information processing deficits by cigarette smoking, as well as shared genetic factors between the two disorders. Over the past three years, our research program has studied the effects of cigarette smoking on clinical and cognitive function in schizophrenic smokers, and the development of pharmacological and behavioral treatment approaches. These studies have suggested that: 1) the atypical antipsychotic clozapine may reduce smoking consumption in schizophrenic outpatients; 2) atypical antipsychotic drugs are superior to typical antipsychotic drugs in combination with the nicotine patch for smoking cessation in treatment-motivated schizophrenic smokers; 3) cigarette smoking may enhance some aspects of cognitive function in schizophrenic patients, and; 4) the anti-smoking agent bupropion (Zyban) appears to be safe and effective for treatment of nicotine dependence in schizophrenia. These findings could have important health benefits for schizophrenic patients, as many often die prematurely from smoking-related medical illness. Furthermore, our findings also suggest that nicotinic receptor mechanisms may be important in the biology of schizophrenia. In this randomized, double-blind trial, we propose to study optimal strategies for smoking cessation in n=100 nicotine dependent outpatient schizophrenic smokers. We will compare bupropion (n=50) to placebo (n=50), in combination with nicotine patch and a specialized group therapy program, for smoking cessation in these patients. The effects of antipsychotic medication class (atypical versus typical antipsychotic) on treatment responses will also be evaluated. Our predictions are that: 1) Bupropion will be superior to placebo for smoking cessation in schizophrenia; 2) atypical versus typical antipsychotic treatment status will enhance smoking cessation outcomes in these patients. The results of this study could provide valuable information on effective medication treatments for cigarette smoking in schizophrenic patients.

DESCRIPTION (provided by applicant): Despite the utility of nicotine replacement therapies and sustained-release bupropion for the treatment of nicotine dependence, there is still a significant proportion of cigarette smokers who are unable to quit smoking, and thus new and effective pharmacotherapies for smoking cessation are needed. Dopamine plays a critical role in nicotine reinforcement, and monoamine oxidase B (MAO-B) inhibitors, which preferentially inhibit dopamine metabolism, may have utility for smoking cessation. In support of this hypothesis, in preliminary studies, we have shown that the selective MAO-B inhibitor selegiline hydrochloride (10 mg/day) significantly increases smoking abstinence rates compared to placebo. This R01 re-submission proposes to study n=200 nicotine dependent cigarette smokers in a randomized, double-blind, placebo-controlled trial to determine the efficacy of selegiline for smoking cessation. Subjects would be inducted onto 10 mg/day of selegiline (5 mg po bid) or placebo (twice daily) over a two-week period prior to the target quit date on trial Day 15. All smokers would receive manualized brief weekly individual smoking cessation counseling. The primary smoking cessation outcome measure will be 7-day point prevalence smoking abstinence at the 6-month follow-up, and secondary cessation outcome measures will include continuous smoking abstinence during the last four weeks of the trial (Days 29-56) and 7-day point prevalence abstinence at the end of the 8-week trial (Days 49-56). Other secondary treatment outcome measures will include retention in the trial, nicotine withdrawal and craving, body weight, depressive symptoms, and selegiline study medication adherence using MEMS technology and detection of urinary selegiline metabolites. Data analysis will focus on an intention-to-treat sample and will utilize Odds Ratios and logistic regression analyses to determine the effects of selegiline on cessation outcomes, and hierarchical linear models (HLM) for continuous outcomes (e.g., craving and withdrawal, weight, depressive symptoms). We predict that selegiline will be superior to placebo, and will lead to greater suppression of tobacco craving and withdrawal. Positive results from this trial would add further support for the safety and efficacy of selegiline for the treatment of nicotine dependence.

This is a resubmission of a NIDA K02 Independent Investigator Award. The application proposes to provide the candidate, Tony P. George, M.D., with salary support over the next five years (2004-2009). Dr. George is currently an Assistant Professor in his sixth year on the psychiatry faculty at Yale University School of Medicine. Since joining the Yale faculty in 1998, Dr. George has developed a unique research program with a focus on understanding the effects of nicotine and tobacco use on cognitive and clinical function in patients with major psychiatric disorders, including schizophrenia. He has established an early record of significant publications, national recognition, and independent funding support in the area of nicotine and mental illness, including two NARSAD Young Investigator Awards, pilot studies in the Yale-VA MIRECC and the NIDA-funded Yale Transdisciplinary Tobacco Use Research Center, a Donaghue Medical Research Foundation grant, and two R01 grants from NIDA. The R01 grants have defined his translational focus on smoking and mental illness, and include a human laboratory study of smoking and cognitive function in schizophrenia (DA-14039, 20% effort with salary), and the development of a pharmacological treatment optimizing strategy for smoking cessation in schizophrenic patients using nicotine patch, bupropion and atypical antipsychotic drugs (DA-13672; 20% effort with salary). Accordingly, the receipt of a K02 award would allow him to: 1) continue to develop his independent research program at Yale and relieve the commitment of R01 funds from these projects to support his salary, and; 2) acquire knowledge and expertise in novel techniques from senior colleagues at Yale and elsewhere that are unfamiliar to him, including assessment of novel neuropsychological and psychophysiological endophenotypes, human molecular genetic and biochemical pharmacology techniques, and advanced biostatistical methods for smoking cessation clinical trials. To achieve these goals, he will organize a formal training program consisting of didactic instruction, guidance from senior colleagues and brief training experiences in the laboratories of collaborators working in these areas of interest. Ultimately, this K02 would support two new and integrated projects that will correlate neurocognitive, genetic and biochemical assessments with smoking cessation treatment response in schizophrenic patients.