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2005 March

Development of an Integrated Treatment for Smoking and Depression

Robert J. Kohlenberg, PhD


Miles McFall, PhD (Co-investigator)

Description: This project proposes to develop and assess the feasibility of a novel cognitive-behavioral therapy for co-morbid smoking and depression. The new treatment (Integrated Treatment for Smoking and Depression; ITSD) integrates empirically validated interventions for smoking cessation and treatment of Major Depressive Disorder (MDD). There are six reasons why this proposal is timely and needed. First, the public health consequences of co-morbid smoking and MDD are significant. Second, depressed smokers are less likely to quit smoking and remain abstinent. Third, demographic data show an increasing trend of co-occurrence of smoking and MDD, suggesting that non-depressed smokers are quitting at a much higher rate than depressed smokers. This phenomenon may partially account for the relative decline in quit rates over the last decade. Fourth, existing independent treatments for smoking and depression have modest efficacy, leaving considerable room for improvement. Fifth, there is a conspicuous absence in the treatment literature of empirically supported treatments or published outcome studies for smokers with concurrent MDD. The rather extensive existing literature on smoking and depression concerns treatments for smokers with a past history of MDD, specifically excluding those with current MDD. Sixth, there is reason to suggest that coordinated treatment aimed at currently depressed smokers holds promise to synergistically improve outcomes for both disorders. Given the current lack of treatments for co-morbid MDD and smoking, we propose an early stage treatment development and feasibility study. Eight smokers with MDD will receive the novel treatment. Dimensions of feasibility to be assessed include (a) ability to recruit and retain subjects, (b) subjects' satisfaction with treatment goals and procedures, (c) absence of adverse effects on psychiatric status, and (d) preliminary assessment of MDD and smoking outcomes through comparison with historical controls.

Buprenorphine Facilitation of Acute Hepatitis C Treatment

Joseph Merrill, MD, MPH
Clinical Assistant Professor of Medicine

Division of General Internal Medicine

Description: Hepatitis C is a major cause of morbidity and mortality among injection drug users. Recent evidence suggests that treatment of acute hepatitis C is far more effective than treatment of chronic infection, underscoring the urgency of treating active drug users, who are at highest risk of exposure. Buprenorphine, a new opioid dependence medication that can be integrated into office-based medical practice, may facilitate successful acute hepatitis C treatment of these patients while promptly engaging them in effective addiction treatment. The objective of this pilot study it to evaluate the feasibility, safety, and potential efficacy of buprenorphine/nalaxone and a brief psychosocial addiction intervention for the treatment of opioid dependence in patients undergoing medical treatment for acute hepatitis C infection. Fifteen subjects with current opioid dependence will be recruited from an ongoing trial of interferon-based acute hepatitis C treatment. Buprenorphine/nalaxone will be provided for up to six months in conjunction with a brief Medical Management psychosocial intervention. Feasibility will be assessed by retention in treatment. Adverse event monitoring will assess preliminary safety. The primary measures of potential efficacy will be a change in opioid use as measured by urine toxicology testing, and change in addiction severity as documented by the Addiction Severity Index. Opioid abstinence at treatment completion will also be compared to a historical control group that received interferon without buprenorphine. Feasibility of the brief psychosocial intervention will be assessed through review of audio taped clinical sessions. The successful treatment of acute hepatitis C has major public health significance for hepatitis C control. The addition of effective opioid dependence treatment has the potential to reduce the injection behavior that spreads hepatitis C infection and to promote early intervention in patients' addiction. Pilot data from this study are crucial to justify larger studies of this promising approach.

Molecular Mechanisms of Endocannabinoid-mediated Long-term Synaptic Plasticity

Jane M. Sullivan, PhD
Assistant Professor

Physiology, Biophysics

Description: Endogenous cannabinoids (endocannabinoids) have recently been identified as key components in a process controlling long-term changes in synaptic strength called long-term depression (LTD). LTD is thought to be required for normal brain development and for compensatory changes in the central nervous system after sensory deprivation (such as blindness or loss of a finger). LTD is also a strong candidate mechanism for storage of memories during learning. The endocannabinoid signaling pathway therefore appears to be critically involved in controlling development and plasticity in the brain, but the underlying molecular mechanisms remain to be identified. These endocannabinoid-mediated processes are likely to be profoundly disrupted by exposure to marijuana-leading to both short-term and long-term deficits in brain function. One of the key questions raised by recent findings is why some parts of the brain that express high levels of cannabinoid receptions-such as neocortex-exhibit endocannabinoid-dependent LTD of excitatory neurotransmission, while other regions -- such as hippocampus -- do not. The goal of this proposal is to develop a neurocortical culture system that will be used to identify the molecular components underlying endocannabinoid-mediated LTD. The long-term goals of this project will aid in the development of therapies targeted at preventing or correcting neurological deficits that are likely to result from cannabis abuse.

Resulting articles & projects:

  • ADAI Small Grant funding allowed Dr. Sullivan to set up a new model system using cultured neurons derived from the visual cortex of rodents. This system was used to collect preliminary data on cannabinoid receptor-mediated changes in the strength of synaptic transmission. These results were used for an R03 proposal to NIH; unfortunately, that NIH grant was not funded on its first submission.

2005 October

Regulation of Cannabinoid Receptor Signaling by RGS Proteins

Chris Hague, PhD
Assistant Professor


Description: The endocannabinoid signaling system represents a major pharmacological target to treat a variety of disorders, including obesity, drug dependence and analgesia. This family of lipid messengers includes anandamide and 2-arachidonoylglycerol (2-AG), which are synthesized in neurons and stimulate cannabinoid (CB) receptors upon release. CB receptors are G-protein coupled receptors (GPCRs) and comprise two subtypes, CB1 and CB2. Upon agonist stimulation both subtypes couple to G i/o and inhibit adenylyl cyclase, decrease Ca2+ channel opening and increase K+ channel conductance. Through stimulation of these pathways, cannabinoids cause significant alterations in behavior, memory and feeding. However, chronic administration of cannabinoids results in rapid tolerance in part through B-arrestin/GRK3 dependent mechanisms. However, other factors are most likely involved in the initial termination of signaling.

The regulators of G-protein signaling (RGS) comprise a family of cytosolic proteins with >30 members which terminate G-protein signaling by binding to and enhancing the GTPase activity of G?-subunits. The small B/R4 subfamily of RGS proteins represents the most well characterized RGS members. Recent reports suggest B/R4 RGS form stable GPCR-RGS protein complexes to terminate signaling. For example, RGS2 binds directly to the third intracellular loops of M1 muscarinic receptors and ?1A-adrenergic receptors and terminate receptor signaling. Based on these findings, we hypothesize that RGS proteins directly associate with CB receptors and terminate agonist responses. We will address this hypothesis with the following specific aims:
  • Specific Aim #1: B/R4 RGS proteins form direct complexes with specific domains of CB1 receptors.
  • Specific Aim #2: B/R4 RGS proteins terminate CB1 receptor signaling upon complex formation.
This study will identify novel mechanisms involved in the regulation of CB receptor signaling. These findings will increase our understanding of the mechanisms involved in drug tolerance and provide novel drug targets for use in CB signaling pathways.

21st Birthday Card Intervention Project

Clayton Neighbors, PhD
Assistant Professor

Psychiatry & Behavioral Sciences

Christine Lee, PhD, Psychiatry & Behavioral Sciences (Co-investigator)

Description: Empirically supported brief interventions utilizing personalized feedback have consistently focused on non-specific drinking and consequences. No empirically supported interventions have been developed to target drinking associated with specific events despite the fact that serious consequences are often associated with specific events (e.g. 21st birthday celebrations). The development of an event-specific prevention (ESP) paradigm would represent a novel and important contribution to the prevention field. Many students consume extreme amounts of alcohol on their 21st birthdays putting them at risk for experiencing serious consequences. This practice has resulted in the deaths and other serious consequences of several students across the county. The proposed research is designed to evaluate a brief intervention aimed at reducing excessive drinking and associated consequences related to 21st birthday celebrations. Participants will include 300 UW students turning 21 who will be randomly assigned to intervention or assessment only control. One week before turning 21, participants will complete an online baseline assessment The day before their birthdays, participants in the intervention condition will receive an electronic birthday card signed by Dr. Mark A. Emmert (University of Washington President) and Eric Godfrey (UW Acting Vice President of Student Affairs). These students will also receive personalized feedback based on their baseline responses. Personalized feedback will be modified from existing empirically supported feedback interventions but will be tailored to specifically address 21st birthday drinking. Follow-up assessments will take place online one week after participants' 21st birthdays. The goals of this project are to 1) evaluate the prevalence of excessive 21st birthday drinking and negative consequences among UW students, and 2) assess the effectiveness of a birthday card/personalized feedback intervention, and 3) obtain preliminary data for an NIH grant proposal outlining a larger study evaluating event specific prevention.

Resulting articles & projects:

  • This ADAI small grant formed the basis and provided invaluable pilot work for a grant from NIAAA to Christine Lee: "Event Specific Prevention (ESP)." R01AA016099.
  • Neighbors C, Lee CM, Lewis MA, Fossos N, Walter T. Internet-based personalized feedback to reduce 21st-birthday drinking: a randomized controlled trial of an event-specific prevention intervention. J Consult Clin Psychol 2009;77(1):51-63. [PubMed abstract | Free online]
  • Neighbors C, Walters ST, Lee CM, Vader AM, Vehige T, Szigethy T, Dejong W. (2007). Event-specific prevention: Addressing college student drinking during known windows of risk. Addictive Behaviors, 32, 2667-2680. [PubMed abstract | Free online]
  • Neighbors C, Lee CM, Lewis MA, Fossos N, Mittmann A (2008). Mechanisms of change in a brief intervention targeting 21st birthday drinking. Paper to be presented at the annual meeting of the Research Society on Alcoholism, Washington, DC.
  • Lee CM, Patrick ME, Neighbors C, Fossos N. (2008) The influences of men's and women's beliefs about 21st birthdays on intended and actual 21st birthday drinking. Poster to be presented at the annual meeting of the Research Society on Alcoholism, Washington, DC.
  • Funasaki, K, Fossos N, Neighbors C, Lee CM (2007). Sensation seeking and 21 st birthday alcohol use. Poster presented at the annual University of Washington Mary Gates Undergraduate Research Symposium, Seattle, WA.
  • Neighbors C, Lee CM, Lewis MA, Fossos N, Mittmann A (2008). Evaluating and extending an event specific intervention for 21st birthdays. Paper presented at the annual meeting of the American Psychological Association, Boston, MA.
  • Neighbors C. (2007). Event Specific Prevention (ESP) of Heavy Drinking among College Students. Invited keynote address presented at the annual meeting of the Oregon Campus and Community Coalition on Alcohol Issues, Corvallis, OR.
  • Neighbors C. (2007). Extensions of personalized normative feedback in two domains: 21st birthdays and intimate partner violence. Invited paper presented at the annual meeting of the National Conference on the Social Norms Approach, Cambridge, MA.

Computer Assisted Rapid HIV Counseling and Testing: New Options To Expand HIV Counseling and Testing in Drug Treatment Settings

Freya Spielberg, MD, MPH
Assistant Professor

Family Medicine

Description: Widely expanded access to HIV testing is now being promoted, yet many people who are chemically dependent may not seek care in clinics where HIV counseling and testing is offered. Providing rapid HIV counseling and testing in drug treatment settings would be ideal, but half of these settings are unable to provide staffing even for expedited HIV consent, testing, and counseling procedures. In this study we set out to pilot our existing computerized HIV/STD counseling tool, (the Computer-Assisted Risk assessment & Education: 'CARE' CD-ROM), for use with rapid HIV testing among chemically dependent patients in drug treatment settings. The CARE CD-ROM is based on one of the only empirically-validated brief counseling models shown to reduce incident STD and HIV (Project RESPECT, Kamb et al., NEJM 1998). We will determine the acceptability and usability [Aim 1] and potential impact on risk behaviors [Aim 2] of the CARE computerized HIV counseling and consent tool, among n = 60 clients from three different types of treatment settings (detox, out-patient and in-patient) in the National Drug Abuse Treatment Clinical Trials Network. Participants will have an opportunity to use the CARE tool with rapid HIV testing and to give feedback. We will compare pre- and post-computer-session measures of intent to reduce risk behavior, to assess the potential for the computerized counseling to reduce HIV/STD acquisition and transmission. And we will gather participant recommendations to adapt the CARE tool for substance using populations [Aim 3]. This study will demonstrate the feasibility, and potential impact of computerized HIV testing and counseling in drug treatment settings serving at-risk populations, and will provide pilot data for an R01 to determine the effectiveness of computer assisted rapid testing for HIV in these settings.