Jennifer W. Tidey - US grants

DESCRIPTION: (provided by applicant) There is a high prevalence (60-88 percent) of cigarette smoking among people with schizophrenia, but few smoking cessation interventions have been developed for these patients. Little is known about factors that control smoking in this population or whether interventions that reduce cigarette smoking among the general population are effective in smokers with schizophrenia. Two pharmacotherapies that reduce smoking in the general population are transdermal nicotine and sustained release bupropion. Because of neurochemical dysfunction associated with schizophrenia, these pharmacotherapies may be less effective in smokers with schizophrenia. Clinical and experimental studies on the effects of nicotine replacement in smokers with schizophrenia have yielded equivocal results. Preliminary results from a single treatment study with sustained release bupropion appear promising. The studies in the present proposal are designed to examine under controlled laboratory conditions the effects of transdermal nicotine (0, 21, 42 mg/day) and sustained release bupropion (0, 150, 300 mg/day) on smoking in people with schizophrenia and non-schizophrenic controls. The effects of transdermal nicotine and sustained release bupropion on smoking topography measures, smoking urges, nicotine withdrawal symptoms and affect will be determined. These studies use within-subjects, repeated measures, placebo controlled designs. Together, they will provide much-needed information on the biological, behavioral and subjective effects of transdermal nicotine and sustained release bupropion on smoking in people with schizophrenia. In turn, this information could contribute to the development of effective smoking cessation treatments for smokers with schizophrenia.

[unreadable] DESCRIPTION (provided by applicant): There is a high prevalence of cigarette smoking among people with schizophrenia, but few smoking treatments have been developed for these patients. Laboratory and clinical studies have begun to delineate environmental and biological factors that affect smoking in schizophrenics. Recent laboratory feasibility studies have shown promising results with contingent monetary reinforcement for smoking reductions. Similarly, several smoking treatment studies in schizophrenics have shown promising results with bupropion- SR. Our long-term goal is to develop an effective, feasible, research-based smoking cessation program for smokers with schizophrenia. In this laboratory-based feasibility study, we will evaluate 128 male and female smokers with schizophrenia who are interested in quitting smoking in the future, using a 2 x 2 between groups factorial design. The primary aims are: (1) to evaluate the efficacy of a novel contingency management procedure for shaping smoking abstinence by reinforcing salivary cotinine reductions, compared to non-contingent reinforcement; (2) to evaluate the efficacy of 300 mg/day bupropion-SR, compared to placebo; (3) to evaluate the efficacy of combining contingent reinforcement for smoking reductions with bupropion, versus either intervention alone. Secondary aims are (1) to evaluate whether gender or individual differences in nicotine dependence and motivation moderate responsivity to each intervention; (2) to evaluate whether abstinence is related to changes in psychiatric symptoms, extrapyramidal symptoms or cognitive functioning. This study will provide significant information regarding the efficacy and feasibility of using a combination of contingency management and smoking pharmacotherapy to treat smoking in schizophrenics. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): [unreadable] Although rates of cigarette smoking are declining in the general population, rates of smoking among people with schizophrenia remain markedly high. Quit rates in these smokers are virtually zero. Few studies have systematically examined biological and behavioral factors that affect smoking in this population. The long-term objectives of this research program are to learn how biological and behavioral variables contribute to smoking addiction in these patients, and to use this information to develop strategies of reducing smoking in people with schizophrenia. This study will investigate, under laboratory conditions, the separate and combined effects of nicotine replacement (42 mg versus placebo) and sensorimotor replacement (access to denicotinized cigarettes versus no access) on smoking behavior in smokers with schizophrenia. We will also investigate effects in smokers who are matched on age, gender distribution, daily smoking rate and nicotine dependence, but do not have current psychiatric illness. We will also investigate effects of these interventions on urges to smoke, nicotine withdrawal symptoms, psychiatric symptoms, and cognitive task performance, and examine whether effects on these variables mediate effects on smoking. Relevance: We anticipate that this project will expand existing knowledge concerning factors that affect smoking in people with schizophrenia and heavy smokers without current mental illness. In turn, this information could be used to develop novel treatment strategies for these smokers. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Schizophrenia is associated with an unusually high rate of cigarette smoking. Smokers with schizophrenia have low quit rates, even when they are motivated to quit and enroll in highly-supportive treatments. The overall aim of this research program is to learn how biological and environmental factors control smoking in smokers with schizophrenia and to use this knowledge to design more effective smoking treatments for these patients. The specific objectives of this R21 Exploratory/ Developmental project are to test two hypotheses concerning the low cessation rates in smokers with schizophrenia: (1) that these smokers experience more severe and sustained levels of negative affect during abstinence than equally-heavy smokers without psychiatric illness, and (2) that smokers with schizophrenia experience stronger reinforcing effects of smoking and specifically of nicotine during a smoking lapse than smokers without psychiatric illness. These hypotheses have solid theoretical and preclinical support, but have not been tested in humans. In this exploratory/ developmental study, we will use high-value contingent monetary reinforcement to engender 3 days of continuous abstinence in smokers with schizophrenia and equally-heavy smokers without psychiatric illness. During the abstinence period, negative affect and smoking urge will be measured twice-daily. Laboratory assessments of nicotine preference and hedonic response to smoking will be conducted at baseline and after the abstinence period. After the second nicotine preference task, participants will receive a small-value reinforcer if they continue to abstain for another day. We will then compare latency to the second lapse in these groups and examine predictors of the second lapse. Smokers with schizophrenia are expected to have stronger levels of negative affect and craving during abstinence and stronger reinforcing effects of nicotine and smoking during the programmed lapse. These factors are expected to predict time to second lapse in both groups. This project will expand existing knowledge concerning factors that affect smoking in people with schizophrenia, which is necessary for the development of effective treatments for these smokers. PUBLIC HEALTH RELEVANCE: There is an unusually high rate of cigarette smoking among people with schizophrenia and correspondingly high rates of smoking-related morbidity and mortality in these patients. The aim of this project is to compare, in smokers with schizophrenia and heavy smokers without psychiatric illness, negative affect and craving during a practice quit attempt and positive reinforcing effects of a smoking lapse. This project will expand existing knowledge concerning factors that affect smoking in people with schizophrenia, which is necessary for the development of effective treatments for these smokers.

Nearly half of the tobacco consumed in the United States is smoked by people with psychiatric illness. In particular, smokers with schizophrenia (SWS) infrequently attempt and attain sustained smoking abstinence and have a 25-year shorter lifespan due to smoking-related illness. SWS are in dire need of effective smoking treatment and are not benefiting from treatments that are currently available. Reducing the nicotine content of cigarettes to non-addicting levels is an innovative strategy that has the potential to significantly reduce tobacco-related morbidity and mortality in this population. In evaluating the potential impact of this strategy, one critical knowledge gap that was identified is whether this strategy would be effective in smokers with serious mental illness, who are more nicotine-dependent than other smokers and who may smoke for self-medication purposes. We are currently studying the acute effects of VLNC cigarettes in SWS, with promising results showing that use of these cigarettes reverses abstinence-induced cigarette craving, withdrawal-related negative mood and usual-brand smoking. Furthermore, SWS rate the subjective effects VLNC cigarettes highly, indicating that such an approach may be acceptable to SWS. However, the effects of prolonged use of VLNC cigarettes on smoking tiehavior, psychiatric symptoms and cognitive functioning in SWS are unknown. This study would be the first to examine whether a regulatory approach of reducing the nicotine content of cigarettes to non-addicting levels is a viable method of reducing smoking in this population. Smokers will be randomized to one of two experimental conditions: 1) very low nicotine content (VLNC) cigarettes with a 0.06 mg nicotine yield (actual dose to be determined by Project 1; n = 40), or 2) normal nicotine content cigarettes (n = 40). Over the 2-week baseline and 6-week treatment phases, subjects will be assessed for patterns of tobacco use, biomarkers of exposure, subjective responses (e.g., satisfaction, craving, withdrawal symptoms), psychiatric symptoms, cognitive performance, smoking cue reactivity and smoking topography. At the end of the 6-week treatment period, subjective and behavioral responses to smoking abstinence will be assessed. The results from this study will describe the possible risks and benefits to smokers with schizophrenia of dramatically reducing the nicotine content of cigarettes. This project will complement and use similar measures as Projects 1 and 2. RELEVANCE (See instructions); There is an unusually high rate of cigarette smoking and correspondingly high rates of smoking-related morbidity and mortality in smokers with schizophrenia. This project will investigate the effects of 6-week use of very low nicotine content cigarettes on smoking, mood, psychiatric symptoms, cognitive functioning and other measures in smokers with schizophrenia. This information will help to determine whether a public health policy of limiting the nicotine content of cigarettes to very low levels would be effective and safe for these smokers

DESCRIPTION (provided by applicant): People with schizophrenia have two- to three-times the mortality risk of the general population. This is primarily due to their unusually high rates o cigarette smoking, as well as other cardiovascular risk factors such as physical inactivity, obesity, high blood cholesterol and diabetes. Effective smoking treatments are needed to reduce morbidity and mortality in this population. Over a dozen experimental studies indicate that walking and other forms of exercise acutely reduce cigarette craving, nicotine withdrawal symptoms and smoking behavior in non-psychiatric smokers. However, the effects of acute exercise on smoking measures have not been studied in smokers with schizophrenia. The primary aim of this NIH Exploratory/Developmental (R21) Research Grant application is to investigate the acute effects of exercise, compared to a passive control condition, on subjective and behavioral smoking measures in smokers with schizophrenia. As episodic craving following exposure to smoking cues is associated with relapse during quit attempts, the secondary aim is to investigate whether exposure to smoking cues alters the ability of exercise to reduce cigarette craving and other smoking measures. The tertiary aim is to investigate whether factors known to moderate responses to smoking cessation medications (gender, antipsychotic medication type, intention to quit smoking) moderate the effects of exercise on smoking measures. This study will use a within-subjects, repeated-measures design, in which participants will undergo 1 practice session followed by 4 experimental sessions: (1) smoking cues followed by exercise, (2) smoking cues followed by passive activity, (3) neutral cues followed by exercise, (4) neutral cues followed by passive activity. Outcome measures include cigarette craving, nicotine withdrawal symptoms, mood and smoking behavior. If the results of this study indicate that walking acutely reduces craving and smoking in smokers with schizophrenia, the next step in this research would be to test the effectiveness of a smoking cessation intervention that incorporates exercise bouts as a behavioral strategy for improving smoking cessation rates in this population. PUBLIC HEALTH RELEVANCE: There is an unusually high rate of cigarette smoking among people with schizophrenia and correspondingly high rates of smoking-related morbidity and mortality in these patients. The aim of this project is to examine, under laboratory conditions, whether exercise reduces cigarette craving, nicotine withdrawal symptoms and smoking behavior in smokers with schizophrenia. If so, the next step in this research would be to examine the effectiveness of a smoking cessation intervention that incorporates exercise bouts as a behavioral strategy for reducing cigarette craving and smoking in smokers with schizophrenia.

Project Summary/Abstract The prevalence of cigarette smoking among people with schizophrenia in the United States is two- to three- times that of the general population. Smokers with schizophrenia have very low rates of smoking cessation, resulting in a disproportionate burden of tobacco-related morbidity and mortality. The overall objective of this project is to develop a novel, theory-driven intervention for smoking cessation for this population. Based on our experimental research, we hypothesize that the primary targets that need to be changed in order to improve cessation outcomes in smokers with schizophrenia are negative affect and smoking urges during abstinence. In smokers without psychiatric illness, varenicline decreases negative affect and smoking urges during abstinence, as well as smoking reward and satisfaction during a smoking lapse. However, the effects of varenicline on these specific target mechanisms in smokers with schizophrenia are unknown. In the R21 phase of this research, we will use an efficient experimental model to conduct a randomized, placebo-controlled investigation of the effects of varenicline on these target mechanisms. If varenicline is found to be effective, we will proceed to an R33 phase, in which we will conduct a randomized, placebo-controlled study to examine whether varenicline, in combination with a novel mobile contingency management (CM) intervention, reduces smoking rates in this population. We will also examine whether the intervention affects smoking through effects on the proposed target mechanisms. This project will provide new and urgently-needed information about factors that contribute to smoking relapse in people with schizophrenia, and information on the feasibility and initial efficacy of a novel intervention for smoking, to indicate whether a larger clinical trial of this intervention is warranted.

ABSTRACT Cigarette smoking is more prevalent (50-70%) in persons living with HIV (PLWH) in the U.S. when compared with the general population and is linked to increased morbidity and mortality in this population. Furthermore, HIV-infected smokers have increased rates of cardiovascular disease, pulmonary diseases and infections, and lung cancers. Because of their high levels of nicotine dependence, low quit rates, and familiarity with harm reduction, PLWH may view use of alternative nicotine delivery products, such as electronic cigarettes (EC), an attractive option for reducing and eventually stopping combustible cigarette (CC) use. However, little is known about the health effects of EC use in PLWH. Some studies have shown that EC use was associated with increased readiness and confidence to quit smoking in the general population. However, because of their high severity of nicotine dependence, PLWH may be more likely to use both EC and CC and experience lower reduction and cessation rates. The primary objectives of this project are to examine the acceptability of EC in PLWH who are unmotivated to quit smoking, to assess the effect of EC use on smoking-related behaviors, and to assess change in cardiac and pulmonary biomarkers in PLWH who transition from CC to EC use. We propose to enroll 72 HIV-infected smokers, who decline a smoking cessation treatment referral at the time of study screening, into a randomized trial consisting of a baseline (BL) assessment visit, followed by randomization to a 6-week period of free EC distribution or usual care (control group). At weekly visits, we will assess EC and CC use, cardiac and respiratory symptoms, and perceived safety and/or harm of EC use. At BL and week 6 visits, we will measure inflammatory biomarkers and markers of tobacco toxicant exposure. At week 6, all participants will receive a smoking cessation counseling intervention and a referral to treatment. At week 12, we will assess changes in EC or CC use, quit line contact, and quit attempts. This study will be the first to examine the health effects of EC on smoking in PLWH. Given the high prevalence of smoking and the significant morbidity associated with it in PLWH, the development of effective strategies to reduce the risks related to CC smoking is critical in this group. EC may be an option for PLWH who have tried to quit and failed, and for those who are unmotivated to quit but would like to reduce the risks related to smoking while continuing to satisfy the urge to smoke. Prospective clinical studies are needed to understand whether EC have value in harm reduction by leading to a complete switch from CC to EC, reducing CC use, or by aiding in smoking cessation. Our study will provide key information on the potential benefits and harms of EC in a population that is highly dependent on nicotine and highly vulnerable to smoking-related morbidity and mortality.

Abstract We propose to establish a COBRE Center for Addiction and Disease Risk Exacerbation (CADRE) at Brown University to study mechanisms by which substance use increases risk for, and progression of, chronic disease. The CADRE Research Projects (RPs) will investigate these mechanisms using experimental studies that investigate the subjective, behavioral and physiological effects of opioids, cannabis, tobacco, and alcohol, in a variety of patient populations i.e., people living with HIV infection (PLWH), patients with opioid use disorder (OUD), and patients with rheumatoid arthritis (RA). The CADRE's Clinical Laboratory Core (CLC) will provide these and the future CADRE research and pilot project investigators with the scientific expertise, technical capability, space, equipment and supplies necessary to meet the needs of their current and future projects. Provision of these resources via the CLC will optimize efficiency consistency across projects. The physical space requirements of the CADRE projects include laboratory space where biological samples (urine, saliva, blood) can be processed and stored. The available laboratory suite contains a 533 sq ft workroom in which biological samples can be biobanked prior to analysis. However, currently this room is not appropriately ventilated for processing (i.e., centrifuging and aliquoting) blood samples. In order to accomplish the aims of the CADRE projects, we are therefore requesting support to replace the CADRE workroom's current ventilation system with a system that delivers single-pass air that meets the specifications of the NIH Lab Design Guidelines. In addition, we are requesting support for several minor necessary renovations to this space in order to meet NIH Lab Design Guidelines: to install an emergency eyewash, to change the direction of the swing of the workroom door so that it swings in the direction of exit travel, and to paint the walls of the workroom in latex wall finish. Successful completion of these renovations will enable the CLC to process blood samples for the CADRE projects within the laboratory suite workroom, where they will be biobanked for future analysis.

Abstract Substance use is associated with increased risk of, progression to, and negative outcomes from chronic disease. Although associations between substance use disorders (SUDs) and chronic disease are well documented, specific mechanisms underlying these associations are poorly understood and underappreciated. Experimental studies that use placebo-controlled, randomized designs are essential for understanding physiological mechanisms that link SUDs and chronic disease. The research and pilot projects in the Center for Addiction and Disease Risk Exacerbation (CADRE) COBRE at Brown University will investigate physiological mechanisms underlying the effects of opioids, cannabis, tobacco, and alcohol on risks for and progression of SUD-related disease. Mechanisms to be studied in the initial four CADRE research projects include systemic inflammation, immune system dysregulation, high blood pressure, pulmonary effects and carcinogen exposure. The CADRE's Clinical Laboratory Core (CLC) will provide the current and future CADRE research and pilot project investigators with the space, supplies, equipment, technical capability, scientific expertise and data management/analysis expertise necessary to meet the needs of their projects. These resources are not otherwise available at Brown, and are essential for achieving the Specific Aims of the CADRE projects. Provision of these resources via the CLC will improve efficiency, consistency and economy of scale across projects. Specific Aim 1 of the CLC Core is to provide resources necessary for developing and sustaining a multi-disciplinary center focused on SUDs and chronic disease. Specific Aim 2 is to facilitate and coordinate assay and other services provided to the CADRE investigators through neighboring COBREs. Specific Aim 3, an exploratory aim, is to build a center-wide biobank and database of biological, behavioral and environmental risk factors associated with the development and progression of SUDs and chronic disease. Resources provided by the CLC will build on and complement, but not overlap, resources currently available at Brown. The successful achievement of these aims will be a thematically- and technically-linked center that supports the initial and future projects, enhances the competitiveness of the project leaders for independent external funding, becomes a national leader in understanding biobehavioral mechanisms linking SUDs and chronic disease, and serves as a resource for training and research within Brown, regionally, and nationally.