Mental Illness Reasearch, Education and Clinical Centers (MIRECC)

Supports MIRECC genetics research and extend expertise in genetics to MIRECC initiatives in comorbidity in mental health disorders. Current MIRECC projects include the identification of a gene on chromosome 18 (human G-protein Golfalpha gene (GNAL)) that appears to be associated with an increased risk of both schizophrenia and bipolar disorder. Available data suggest that further study of this candidate gene may be of value in identifying individuals at risk for psychotic disorders, and for identifying subtypes of these diseases.

Development of the ASI for Patients with Severe Mental Illness, PI: John Cacciola, MD (Philadelphia)

The Addiction Severity Index (ASI) is a widely used multidimensional clinical/research assessment. The VAMC mandates the assessment of alcohol and drug involved patients with the ASI at treatment entry and 6 months later. Because the ASI is undergoing a revision and a number of problems have been identified with its use with patients with mental illness, a mental health version (ASI-MH) will concurrently be developed using expert judgment and patient feedback. Preliminary inter-rater, test-retest, and internal reliability of the new instrument will be evaluated.

A Small Randomized Clinical Trial of an Evidence-Based Cognitive-Behavioral Therapy for Male Veterans with Post-Traumatic Stress Disorder and Substance Use Disorder, PI: Joan M. Cook, Ph.D. (Philadelphia)

The primary aim of this study is to evaluate the feasibility and clinical benefit of implementing an empirically based cognitive-behavioral group treatment, “Seeking Safety,” with veterans diagnosed with Post-Traumatic Stress Disorder (PTSD) co-morbid with one or more substance use disorders (SUD). Seeking Safety is a 25-session psychoeducational and problem-solving intervention designed to help patients learn about PTSD and SUD and why they so frequently co-occur. It teaches coping skills and repeatedly explores the relationship between the two disorders, and may be disseminated readily in community settings without major modification. Fifty new patients with PTSD and SUD will be randomized to either treatment as usual or treatment as usual plus Seeking Safety group. The primary hypotheses are that, relative to those receiving usual care, dual-diagnosed veterans who also receive the Seeking Safety intervention will 1) demonstrate no increase and a greater decrease in substance use; and 2) have a greater decrease in PTSD symptoms.

Supports neuroimaging research, including methods development for image acquisition for fMRI, MRS, and PET, post-imaging data processing, and challenge strategies, and applications related to the comorbidity theme of the MIRECC. The current projects are investigating the neurochemical processes associated with craving for illicit drugs, as well as the structural deficits associated with impairments in decision-making and evaluating the future consequences of behaviors (particularly drug use behaviors). The long-term goal is to develop medications that will assist in “blunt” the craving response that patients with addictions experience that results in the return to drug use.

Coping with Chronic Mental Illness, PI: Marci Gaither, Ph.D. (Pittsburgh)

Research involving the socio-cognitive and phenomenological aspects of schizophrenia is important to the patient’s quality of life and satisfaction with medical treatment (Penn, Corrigan, Bentall, Racenstein, & Newman, 1997). In fact, The Schizophrenia Patient Outcomes Research Team (PORT) has included “individual and group therapies employing well-specified combinations of support, education, and behavioral and cognitive skills training” as a recommended component of treatment for this population (Lehman & Steinwachs, 1998, p. 8). The proposed study seeks to apply a cognitively-oriented individual therapy formulated by Jackson and colleagues (1998) for use with early psychosis to a more chronic population. The four main areas of emphasis within this program are assessment, engagement, adaptation, and secondary morbidity. The therapist will seek to engage the patient in individual therapy and address issues of “psychoeducation, social withdrawal concerns, stigma issues, and secondary morbidity” (Jackson et al., 1998, p. 93).

Subjects will be outpatients, ages 18-65, with a clinical DSM-IV diagnosis of schizophrenia or schizoaffective disorder. Individuals with a diagnosis of dementia or active substance dependence will be excluded. The Structured Clinical Interview for the DSM-IV (SCID) will later be used to confirm the diagnoses. Prior to beginning individual therapy, all patients will complete a battery of measures to assess baseline understanding of illness, adaptation to illness, symptomatology and adjustment, as well as provide demographic information. Participants will be randomly assigned to a therapist and to either the experimental (cognitively-oriented therapy) group or the control (current events) group. Each individual will be asked to complete at least 15 sessions, with 30-minute sessions once per week. Experimental group sessions will follow the guidelines of the COPE protocol developed by Jackson and colleagues (Jackson et al, 1996; Jackson et al., 1998). Control group sessions will involve the discussion of current events from newspaper articles. Midway through the program (i.e., session 8), at the conclusion of the program, and 3 months after completion of the program, participants will receive the same measures they were given prior to beginning therapy.

Processes of Care for Alcohol Detoxification, PI: Adam Gordon, MD, MPH (Pittsburgh)

Background and Aims: Over 10 million Americans, including many veterans, are alcohol dependent. Alcohol dependence is a particular problem among veterans. When alcohol dependent drinkers decrease or stop alcohol consumption, alcohol withdrawal may occur. Health care providers treat alcohol withdrawal through alcohol detoxification, a process of care that prevents adverse withdrawal events, provides supportive therapy, and enables safe patient transition to alcohol rehabilitation services. Detoxification occurs in both inpatient and outpatient settings. Patient, provider, and system factors that influence processes of care and treatment outcomes in each setting are unknown. The long-term goal of this study is to improve the processes of care and treatment outcomes for patients with alcohol problems along the continuum of care from identification through alcohol treatment. The study’s short-term goal is to determine how patient and provider factors influence the processes of care and treatment outcomes of veterans undergoing inpatient and outpatient alcohol detoxification.

Research Design and Methods: This is a prospective cohort study of veterans identified by a medical provider as needing alcohol detoxification. Inpatient and outpatient alcohol detoxification patients are being recruited over the course of two years. All subjects will complete a baseline assessment during detoxification services. Subsequently, subjects will undergo a brief daily follow-up interview (inpatients) and all subjects will have a 30-day follow-up interview. A chart review is conducted on each subject to determine co-occurring medical conditions, medication and treatments provided during detoxification, and utilization of health care services, including alcohol rehabilitation, from the time of baseline assessment to follow up.

Discharge from Opioid Treatment Program: A Best Practice Review,
PI: Vincent Kane, LSW (Philadelphia)

Burden of Comorbidity Among Veterans with Bipolar Disorder, PI: Amy Kilbourne, Ph.D. (Pittsburgh)

There is a dearth of information on the prevalence and impact of medical and substance use comorbidity among veterans with bipolar disorder. The specific aims of this study are to 1) describe the frequency and burden of medical and substance use comorbidity and 2) determine how medical/substance use comorbidity and treatment-related factors are associated with hospitalizations among veterans with bipolar disorder receiving care at the VA Pittsburgh Healthcare System.

This is a retrospective analysis of data collected from the VA National Patient Care (NPCD) and Pharmacy Benefits Management (PBM v4.0) databases on patients receiving care for bipolar disorder from the VA Pittsburgh Healthcare System in fiscal year (FY) 2000. Data collected from the NPCD including demographics and comorbidities will be linked with follow-up NPCD outpatient and inpatient data and PBM psychopharmacologic prescription data using social security numbers. Data from the NPCD to be collected include demographics and all current and lifetime medical and substance use comorbidities occurring on or prior to the first outpatient or inpatient visit occurring in FY 2000. Longitudinal pharmacotherapy and utilization data will be collected between FY 2000-2002 using the NPCD and PBM databases. All psychopharmacologic prescriptions, outpatient visits, and hospitalizations will be ascertained after the FY 2000 index visit date, and data will be linked using social security numbers. Multiple logistic regression analyses will be performed to determine how race, age, and other independent variables are associated with a current diagnosis of each general medical and substance use disorder. For patients with an index outpatient visit in FY 2000, Cox proportional hazards modeling will be used to determine whether number and type of medical and substance use comorbidities are associated with time to the first inpatient admission, controlling for race and race, age, and mood stabilizer use. Among those with an index inpatient visit in FY 2000, Cox proportional hazards modeling will also be performed to determine the factors associated with time to readmission based on the aforementioned independent variables. The effect of race (nonwhite versus white) will also be added to these analyses.

Findings from this study will be used to generate preliminary data for a Merit Review Application based on an approved Health Services Research and Development Letter of Intent. This initial study is part of a research program to determine the patient, provider, and system factors attributed to differences in quality of care for bipolar disorder, especially among nonwhites, which will inform the development of an intervention to improve the quality of care for bipolar disorder.

The Behavioral Health Laboratory is a MIRECC service provided to primary care (PC) clinicians within the PVAMC wherein patients are assessed by telephone for depression and substance use disorders following screening by PC clinicians. The results of the evaluation consultation are provided to the PC staff, with recommendations for treatment. Includes several projects directed toward evaluating the feasibility and effectiveness of providing behavioral health services.

Use of the Internet and Home Computers to Provide Psychoeducation to VA Patients with Schizophrenia and Their Families, PI: Armando Rotondi, Ph.D. (Pittsburgh)

Objective: The overall goal of this pilot project is to assess the feasibility of using a website and in-home computers to provide patients suffering from schizophrenia or schizoaffective disorder, and their families, with supplemental support services. In addition to standard treatments provided by the VA, we will provide: 1) a multi-family support group, facilitated by mental health professionals, which meets face-to-face once per month, and at other times communicates using a website; 2) a patient support group, facilitated by mental health professionals, which meets face-to-face each week, and at other times communicates using a website; 3) the ability to ask our team of experts questions over the Internet, and receive an answer within 2 days; 4) a library of previously asked and answered questions, and; 4) a list of links to websites with useful information about schizophrenia. The ultimate goals of this approach to providing supplemental mental health services is to improve adherence to treatment, reduce patient relapse, facilitate patient rehabilitation, decrease family distress, and improve patient and family well being.

A working prototype of the Internet website intervention, with initial feasibility data on user acceptance and utilization, will be essential to evaluate the feasibility of this approach, and to assess the appropriateness of developing a clinical trial to evaluate the efficacy of this intervention.

Methods: Subjects will have a clinical diagnosis of schizophrenia or schizoaffective disorder. The following patient data will be collected from the patient and medical chart: all psychiatric and medical diagnoses, sociodemographic information, website utilization (e.g., time of day, each page visited, amount of time spent on a page), and patient self-report evaluation of website. The following family member data will be collected: sociodemographic information, website utilization (e.g., time of day, each page visited, amount of time spent on a page), and self-report evaluation of website.

Clinical Significance: The traditional approach to mental health care focuses on providing services in a clinic or other provider setting, often as the result of an acute illness or psychiatric episode. Recently, home-based services have been developed that successfully engage patients and families who otherwise might not receive services or continue services. However, sending mental health professionals to consumers’ homes is costly and difficult to administer. The intervention in this proposal is a logical and potentially more economical extension of this approach. It will allow the delivery of a variety of supplemental mental health services to users’ homes, where it is convenient to the patient, often needed, and may be effective at facilitating recovery, preventing relapse, and reducing patient and family morbidity. This approach has the potential to increase the appeal and convenience of mental health services, while improving their outcomes and decreasing their costs.

Combined Pharmacotherapy in Bipolar Alcoholics, PIs: Ihsan Salloum, MD & Jack Cornelius, MD (Pittsburgh)

The aim of this study is to conduct a double-blind, randomized, placebo controlled study, of 12 week duration to evaluate the efficacy of combined pharmacotherapy of valproate + naltrexone and Disease Management Recovery Counseling for Bipolar Alcoholics (DMRC-BA) as compared to valproate + placebo and DMRC-BA. We hypothesize that the combined pharmacotherapy treated group (valproate/naltrexone) will have a higher percentage of alcohol free days, consume less alcohol per drinking day, have fewer relapses to heavy alcohol use, and have greater improvement in their manic/depressive symptoms.

We propose to test the above hypothesize in a double blind, randomized, placebo controlled study of 40 subjects (20 in each group) over 24 months duration. Subjects will be randomized and assessed on a weekly basis for 4 weeks, then every 2 weeks for an additional 8 weeks.

A Double-Blind, Placebo Controlled Study of Citalopram and MET/Case Management for the Prevention of Interferon Associated Side Effects, PI: Robert Weinreib, MD (Philadelphia)

Veterans suffer from high rates of Hepatitis C virus (HCV, for which the only currently available treatment is the administration of Interferon combined with Ribavirin. However, this treatment may result in psychiatric side effects including anhedonia, anxiety, impaired concentration, irritability, insomnia, and even suicidal behavior. Partly out of fear of exacerbating patients’ psychiatric symptoms, physicians undertreat HCV infection in patients with substance use and other psychiatric disorders. This study examines the feasibility of using SSRI medications to prevent the onset of mild depressive and flu-like symptoms associated with the treatment of HCV in patients with substance use disorder. The intervention also includes strong educational and case management components. Other target outcomes include increased patient awareness of HCV status and treatment and management options, and a reduction in behaviors that may exacerbate disease progression or transmit HCV infection to others.

Pharmacogenetics of Naltrexone for Alcohol Dependence, PI: Wade Berrettini, MD (Philadelphia)

Although use of naltrexone in the treatment of alcohol dependence can reduce the risk of relapse, not all alcohol dependent patients are helped. The focus of this project is to examine whether differences in relapse are explained by Mu opioid receptor gene (OPRM1) variants. This hypothesis will be examined by comparing OPRM1 haplotypes in alcohol dependent patients who have not relapsed on naltrexone therapy to those of similar patients who have relapsed while taking naltrexone.

PET Imaging during cue-induced cocaine craving, PI: Anna Rose Childress, Ph.D. (Philadelphia)

The goals of this research are to establish Positron Emission Tomography (PET) methods using the radioactive compound C-11 raclopride to measure release of the neurotransmitter dopamine in specific brain regions, and to apply these methods toward the study of cocaine abuse. Laboratory and clinical evidence suggest that dopaminergic activity and, hence, raclopride displacement, will increase in specific areas of the brain (ventral striatum, amygdala) while participants with cocaine addiction observe the cocaine-related video that induces this craving, and that this effect will be greater under these conditions than when the same subjects view a non-drug video. Similar comparisons are made for dopamine release during the same two videos for carefully age- and sex-matched controls who are not cocaine-dependent, and imaging indicators of dopamine activity for the cocaine-naïve controls are not expected to differ across the two video conditions. Findings from this research will be used to guide the development of treatments to decrease craving and prevent relapse in patients with histories of cocaine abuse, and to explore possible differences in the neurochemical substrate of cocaine addition when it occurs in the face of comorbidity from other disorders, including Attention Deficit Hyperactivity Disorder (ADHD) and Major Depression

Olanzapine vs Haloperidol in Schizophrenia with Cocaine Abuse, PI: Cabrina Campbell, MD (Philadelphia and Pittsburgh)

Cocaine abuse is a substantial problem in schizophrenic patients with a lifetime prevalence in this population that currently exceeds 50%. Schizophrenia patients with comorbid cocaine abuse have a hospitalization rate twice that of those who are cocaine-free and those who abuse substances other than cocaine. Because cocaine affects the same neural systems that underlie the actions of antipsychotic medications, there are theoretical as well as clinical reasons for examining cocaine abuse in connection with the treatment of schizophrenia. It is possible that typical antipsychotic medications such as haloperidol may block the effects of cocaine more effectively than atypical agents such as olanzepine. Cocaine also may decrease the extrapyramidal symptoms (EPS) experienced by patients taking typical medications, suggesting that the use of cocaine may, in part, reflect a patient's efforts to counteract the side effects of antipsychotic drug treatment. Finally, it is possible that schizophrenia patients may abuse cocaine to decrease negative symptoms.

This project is a double-blind, prospective, randomized trial comparing olanzapine and haloperidol in the treatment of schizophrenia patients who abuse cocaine. Olanzapine is expected to produce a greater reduction in cocaine use and a greater attenuation of craving compared to haloperidol. If there is, in fact, greater relative reduction of cocaine use in the olanzapine group, then secondary analyses will examine whether these changes are associated with decreases in EPS, negative or positive symptoms, and depression.

Cognitive Rehabilitation for Schizophrenia with Alcohol Dependence, PI: Gerald Goldstein, Ph.D. (Pittsburgh)

Alcohol abuse associated with medication non-compliance is thought to be a major contributor to relapse in schizophrenia. At the same time, detoxification from alcohol abuse and the subsequent acute recovery phase involves a "cognitive haze," a mild confusional state with impairments of attention, memory, and comprehension that lasts approximately two weeks. These impairments prevent patients from benefiting from early treatment and psychoeducational information about alcohol abuse. A cognitive rehabilitation program developed by the investigators for use with a VA alcoholism rehabilitation program targets memory enhancement and problem-solving, and shows promise for relieving cognitive haze. This, in turn, should permit more effective treatment of alcohol abuse that is expected to aid in schizophrenia relapse prevention. The goals of this study are to test this cognitive rehabilitation program for patients with comorbid schizophrenia and alcohol abuse. An extensive neuropsychological battery will assess 40 patients' functioning following admission and within one week of discharge from the training program. Performance of the patients receiving the training will be compared to that of 40 similar patients in an attention control group.

Telephone Disease Management for Depression and At-Risk Drinking, PIs: Ira R. Katz, MD, Ph.D., David Oslin, MD, Joseph Conigliaro, MD (Philadelphia and Pittsburgh)

The goal of this study is to develop and validate a replicable, efficient, and cost-effective method for delivering first-line treatment for depression and alcohol abuse to veterans within the primary care settings in which these patients receive the rest of their medical care.

Although there are established, effective treatments for depression and alcohol abuse, a number of barriers stand in the way of identifying those in need and delivering care. The challenge has been to develop systems that facilitate efficient care delivery in the context that most patients with these disorders receive ongoing treatment, namely, primary and medical subspecialty care practices. This project tests the effectiveness of telephone-based disease management for these disorders in primary care, as well as cardiology and rheumatology subspecialty care clinics. Patients with depressive disorder and at-risk drinking will be recruited; those identified through screening or referral will be randomized in equal numbers to either the telephone disease management or usual care conditions.

Diabetes Care in Serious Mental Illness, PIs: Joel Streim, MD Jeffrey Whittle, MD (Philadelphia and Pittsburgh)

It is widely recognized that mental illness can complicate the course and treatment of medical illness, but the medical illnesses that occur among the seriously mentally ill (SMI) have rarely been studied. There is evidence that veterans with chronic and severe mental illnesses tend to underutilize medical services. This study is designed to use diabetes as a representative condition to evaluate the quality of medical care of patients with chronic and severe mental illness. It will determine the prevalence of unrecognized diabetes among patients over age 40, targeting those most likely to have this condition. Patients with known diabetes from mental health and general medical clinics then will be compared with respect to whether elements of care recommended in the VHA practice guidelines were ordered and performed and whether appropriate treatments were prescribed and dispensed. Although the target condition in this study is diabetes, the findings will have implications for other medical issues in the care of patients with SMI.

Depression, Diabetes, and Sertraline Treatment, PI: Ripu Jindal, MD (Pittsburgh)

Objective: To study the impact of treatment of depression on insulin resistance in depressed patients.

Research Design: An open label prospective study in which we will measure insulin resistance before and after treatment of depression. In addition, we measure possible confounders (such as activity level and eating choices) and other possible correlates of change (such as cortisol, heart rate variability).

Procedure: Collection of a fasting blood sample, EKG and two questionnaires before and after treatment of depression

Intervention: Treatment of depression with Sertraline (an FDA approved antidepressant). Patients follow up every two weeks for 6 weeks.

Clinical Significance: Depression and diabetes mellitus are both common diseases. Similar neuroendocrine changes have been implicated in the pathogenesis of both these diseases. Depression is more common in diabetics than in the general population. Conversely, individuals with depression have been shown to be at increased risk for diabetes (type 2). Different antidepressant interventions have been studied in the diabetic population. The improvement in glycemic-control observed with the treatment of depression seems to go beyond better compliance with the treatment and dietary regimen of diabetes.

One hypothesis explaining the greater rates of diabetes in patients with depression is that autonomic, metabolic and neuroendocrine dysfunctions associated with depression induce insulin resistance, which has been held as the primary defect in type 2 diabetes mellitus. However, it is not clear if alleviation of depression is associated with reduction in insulin resistance, irrespective of the antidepressant intervention used. We propose to study the impact of treatment of depression (with a commonly used antidepressant agent) on insulin resistance. We also plan to measure heart rate variability, an index of parasympathetic activity, and cortisol (before and after treatment of depression). These pilot data, thus collected, will be used to develop a more definitive study, which will be part of a career development award application to the NIH. Continued research may establish that autonomic dysregulation has a mediating role in the pathophysiological association between depression and diabetes.

Communication and Barriers to Treatment in Veterans with Hepatitis C and Depression or IV Drug Use, PI: Susan Zickmund, Ph.D. (Pittsburgh)

The Veteran's Health Administration (VHA) has launched initiatives to identify and treat patients with hepatitis C virus (HCV) infection. Despite these efforts, enrollment into and successful completion of treatment protocols remains low, with less than one quarter of HCV infected veterans entering treatment. This has been attributed to a higher prevalence of coexisting diseases, primarily depression and ongoing substance abuse. However, with effective antidepressive therapy and substance abuse rehabilitation programs hepatitis C can be successfully treated in these groups. (1) This has prompted the NIH and VA Centers of Excellence focusing on HCV to modify their recommendations, suggesting an individualized rather than algorithmic approach toward treatment of HCV infection (2). However, data question the successful implementation of these guidelines. In a recent study, we found that one third of non-veteran patients with HCV infection reported problems communicating with their physicians. Such interaction difficulties may be associated with poor satisfaction with overall care. As part of my long term goal of clarifying the relationship between patient satisfaction and interest in HCV therapy and communication problems, this project examines the feasibility of recruiting HCV infected patients not currently in therapy who are in treatment for depression or IV drug use. It also examines the acceptability of the proposed qualitative and quantitative measures for assessing HCV patient attitudes toward provider communication.

Patients with an established diagnosis of hepatitis C and who are in therapy for either depression or IV drug abuse will be recruited at both the Pittsburgh and Philadelphia VA Health Systems. Participants will be asked to complete a telephone interview focusing on interactions with providers charged with managing their HCV infection. In addition, they will complete questionnaires to determine their physical and psychosocial functional status, and their satisfaction with care delivery. Clinical data related to their liver diseases, substance use and coexisting physical and mental illnesses will be abstracted from the medical record.

The pilot study will focus on feasibility of a study generating a complex data set of medical, demographic, questionnaire data and information abstracted from patient interviews. This pilot project will provide critical information about our ability to identify and recruit HCV positive patients, and about the appropriateness of our study instruments for this patient group. This information will provide key elements for the foundation of a larger MERIT project that will address the association of patient reported provider communication problems with treatment enrollment.

Coping with Stress and Voluntary Ethanol Consumption, PI: Francis X. Brennan, Ph.D. (Philadelphia)

Anecdotal as well as experimental reports indicate that exposure to stress is a significant risk factor for the subsequent abuse of ethanol (ETOH). Both correlational and experimental reports in humans, as well as experimental studies in animals, support the notion. The majority of the animal studies have used some inescapable stress procedure (e.g., shock, immobilization), and then measured ETOH consumption. However, anecdotal reports in humans indicate that it is not stress per se that causes increased ETOH consumption, but rather the inability to cope with stress. I will therefore attempt to model this phenomenon in two different rat strains using a leverpress escape/avoidance paradigm. Rats (Sprague-Dawleys and Wistar-Kyotos) will first be exposed to ETOH in their water. Then animals will then be subjected to the escape/avoidance paradigm. I have argued elsewhere that the leverpress procedure is an animal model of behavioral coping with stress (Brennan, Beck, & Servatius, 2003). The leverpress task is difficult for the animals to learn, which leads to different levels of performance or coping. Animals will be given a limited-time ETOH choice following each daily session. The data will indicate whether the animals that are poor behavioral copers consume the most ETOH. This will be an animal model of the anecdotal belief that the inability to cope with stress is what leads to substance abuse, not the stress itself. If this were the case, this would prove to be a valuable model to study both the relationship between coping and ETOH abuse, as well as for treatment options.

Decision-Making Deficits in Co-Morbid ADHD and Cocaine Dependence, PI: Marta MacDougal (Philadelphia)

Problem: Relapse is the most painful and expensive feature of the addictions, with relapse rates as high as 80% at 6 months post-treatment. Our laboratory has focused on two complementary sources of relapse vulnerability: the ability of drug cues to trigger craving, and the compromised ability of frontal lobe structures to help modulate this craving, to help patients resist craving by considering the future consequences of their drug use.

Compromised frontal function is a cardinal feature of Attention Deficit Hyperactivity Disorder (ADHD), potentially explaining why drug-dependent patients with ADHD have an even worse prognosis than those without the comorbid diagnosis. The scope of this problem is significant: in our population of treatment-seeking cocaine patients in Philadelphia, up to 30% met clinical diagnostic criteria for ADHD. Many additional drug dependent patients have symptoms of frontal dysfunction that do not meet full criteria for ADHD, consistent with the view that the traits and symptoms of ADHD are represented on a continuum within the general population, rather than simply representing distinct categories of “ADHD” or “non-ADHD.”

In support of these clinical observations, frontal lobe anomalies have been found both in drug dependence disorders and in ADHD. For both disorders, clear defects (hypoperfusion, hypometabolism, and reduced gray matter concentration) are evident in the brain’s orbitofrontal region (OFC). As this brain region is crucial in the weighing the future consequences (positive and negative) of a decision, OFC defects may explain the poor-decision making, poor planning and impulsivity often observed in patients with addiction and in those with ADHD. We suspect that the poor decision-making associated with orbitofrontal dysfunction may be a critical feature in relapse vulnerability/drug use severity, and that quantitative differences in this defect may account for the worse outcome in patients co-morbid for both cocaine dependence and ADHD.

Objectives: Interestingly, though poor decision-making is a clinical feature of both ADHD and drug-dependence, this dimension is not explicitly captured by the current DSM-IV nosology for either disorder, or by the usual symptom scales for ADHD (inattention, hyperactivity). Bechara, et al. (1994) developed the Gambling Task (GT) to quantify the poor decision-making associated with orbitofrontal dysfunction.

The proposed study will assess (Aim 1) the relationship between decision-making (assessed by the GT) and severity of prior clinical course (drug use history) in drug dependent patients with a range of ADHD symptoms. This study is unique in its use of the GT to capture a dimension of vulnerability -- poor decision-making – that may help explain the poor outcome of ADHD substance users. The GT may be a sensitive and specific measure of this vulnerability.

In addition to Aim 1, the study will also determine if continuous measures of ADHD symptoms predict severity of drug use history, and whether ADHD composite scores predict performance on the GT. As the proposed neuropsychological aims will be interlinked with ongoing neuroimaging studies at our Center, including those supported by the MIRECC Neuroimaging Core, future studies will be able to directly address brain substrates, to find whether patients with poorer GT scores indeed have poorer orbitofrontal structure and function.

Research Design and Methods: 60 treatment-seeking cocaine and/or opioid dependent patients will be recruited from the Addiction Recovery Unit and Building 7 at the Philadelphia VA Medical Center, and from the adjunctive site at 3900 Chestnut Street. Five to seven days following the last use of cocaine, participants who meet study inclusion criteria will be administered standard clinical and diagnostic measures, and a neuropsychological battery: IQ, working memory, three continuous measures of ADHD symptoms, and four measures which may be sensitive to frontal defects (a Go-NoGo Task, the Bechara Gambling task, the Balloon Analog Risk Task, and the Delay Discounting task). Drug use history will be obtained by ASI and by detailed structured interviews (years of cocaine/other drug use, amount of drug-free time proportionate to years of opportunity, longest successive abstinence, etc.) Correlational analyses will be used to test the relationships suggested (e.g., whether poorer neuropsychological performance on frontal tasks indeed predicts more severe drug use history, etc.).

Significance: The proposed research has both clinical and theoretical significance. If poor decision-making is demonstrated to be a critical link in ADHD-SUD vulnerability, behavioral or medication treatments could target this dimension to improve clinical outcomes in drug-dependent veterans with ADHD symptoms. Theoretically, linking poor decision-making to relapse will encourage a focus on the frontal brain circuits as critical for the “top-down” modulation of downstream limbic activity, e.g., drug craving states which occur in response to drug-related cues. In this role, defective frontal circuits may play a role not only in the vulnerability to relapse, but to addiction itself.

Antibiotic Resistance as a Risk for Functional Decline in Nursing Homes, PI: Joel Maslow, M.D., Ph.D. (Philadelphia)

Nursing home residents are at great risk for functional decline. Infections, and in particular infections with antibiotic-resistant bacteria, represent a known risk for functional impairment. Infections represent a unique category of comorbid illness that result in a multitude of secondary complications all of which may produce functional derangement. Long-term care facilities present an ideal setting for the emergence of antibiotic resistance. Abnormal clearance mechanisms, caused by indwelling catheters or prostatic hypertrophy, and decreased host immunity increase the risk of infections among NH residents. Antibiotic choices in LTCFs are generally limited to a restricted oral formulary. Once resistant organisms emerge, spread is likely to be amplified within the relatively closed and constant population of LTCFs. Compounding the problem is the impracticality of imposing strict hospital-based Infection Control practices in an interactive, ambulatory population. For NHs, limitations and delays accessing laboratory studies and laboratory results represents a further impediment to the initiation of effective therapy.

Motivational Interviewing to Enhance Behavioral Health Outcomes in Primary Care Patients, PI: Belinda E. Barnett, Ph.D. (Pittsburgh)

The tremendous patient care burden carried by primary care practitioners (PCPs) is increasingly compounded by the number of patients who visit PCPs for psychiatric symptoms, particularly symptoms of depression. While PCPs frequently refer such patients to specialized behavioral health services, less than half will follow up with the referral.

Motivational interviewing (MI) is a technique that has been recognized for its effectiveness in promoting treatment readiness and enhancing treatment adherence. This approach promotes patient engagement in therapy by facilitating the uncovering of the patient’s own desires and intrinsic motivations to change.

The purpose of this study is to assess the effectiveness of MI in promoting follow-up with behavioral health for individuals referred from primary care clinics with symptoms of depression. Subjects in the MI group will receive a one-session motivational interview along with a referral to Behavioral Health Services, while those in the Treatment as Usual group will receive a referral only. Appointment records will be tracked over six months through the patients’ electronic medical records.

This study will allow us to examine the effectiveness of MI in increasing treatment adherence in patients who screen positive for depression in primary care settings. If effective, MI may provide a low-cost, useful means for increasing transfer of behavioral health care from primary care to behavioral health settings, thus decreasing the burden on PCPs and increasing the quality of patient care.

Treating Comorbid PTSD and Substance Use Disorders: Applicability of the Seeking Safety Approach, PI: Joan M. Cook, Ph.D. (Philadelphia)

Treatment of veterans with substance use and other psychiatric disorders is traditionally delivered using one of three paradigms: parallel, sequential, and integrated. Most VA programs deliver parallel services where veterans receive treatment for substance use disorders in one setting and treatment for other psychiatric disorders, such as PTSD, in another. This structure tends to fragment care and promote barriers to treatment. Fewer programs use the sequential model that focuses on first stabilizing the most acute disorder and then addressing the others. Because PTSD and substance use often overlap, it is sometimes not easy to distinguish which is the primary disorder. Further, becoming abstinent from substances may, in some cases, exacerbate PTSD symptoms. These problems can be minimized in an integrated model. This model is the one used the least in VA settings, however it is generally viewed as the most effective because it is staffed so that the same treatment team can address both disorders.

Seeking Safety is a cognitive-behavioral integrated approach that was recently developed to treat concurrent PTSD and substance dependence and serves as an integrated model for patients with these disorders. It is a 25-session psychoeducational, motivationally enhancing and problem-solving treatment designed to help patients learn about the two disorders and why they so frequently co-occur. It teaches safe coping skills that apply to both PTSD and substance abuse to decrease current symptoms of both disorders, repeatedly explores the relationship between the two disorders, and helps patients understand that healing from both disorders requires attention to each one.

The Behavioral Health service at the Philadelphia VAMC has implemented Seeking Safety as a treatment modality for veterans afflicted with PTSD and substance use disorders. This project will examine the outcomes of this intervention.

Racial Differences in Bipolar Disorder Management Among Veterans, PI: Amy Kilbourne, Ph.D. (Pittsburgh)

A report by the U.S. Surgeon General revealed that people of color experience disparities in depression care. Yet there has been little empirical research on whether the continuity of depression care (pharmacotherapy, outpatient treatment), varies by race in the VA. The specific aims of this research are 1) to compare the use and adequacy (dose and duration) of depression pharmacotherapy between white veterans and veterans of color (African-Americans, Latinos, Asian-Americans, and Native Americans), and 2) to compare the adequacy of outpatient visits for depression between white veterans and veterans of color. The long-term study objectives are to identify racial and ethnic groups that are most vulnerable to disparities in depression care, ultimately to inform intervention and translational research to improve depression management among people of color. All patients with any inpatient or outpatient ICD-9 depression diagnosis in FY 2000 will be identified. Data on race/ethnicity will be available from the VA National Patient Care Database (NPCD). We will collect data on antidepressant medication use from the VA national Pharmacy Benefits Management (PBM) database, and outpatient mental health treatment will be ascertained using clinic stop codes for both primary care and mental health clinic visits from the NPCD. This research will inform a large demonstration trial in the VA to improve depression management.

Insight and Neurocognitive Functioning in Bipolar Subjects, P.I. Mujeeb Shad, MD (Pittsburgh)

This study examines the relationship between deficits in insight and neurocognition in bipolar subjects and will study the impact of alcohol on their insight and neurocognition. Poor insight has become an important clinical outcome measure in psychiatric disorders due to its association with treatment non-adherence. However, the data on insight is scant, and most studies are performed on subjects with schizophrenia. A few studies available in bipolar subjects have reported the same degree of deficits in insight and executive functioning as those observed in subjects with schizophrenia. Similarly, no study has investigated the impact of alcohol on insight, even though alcohol dependence is reported to be common in bipolar subjects. It is predicted that bipolar subjects with alcohol dependence will have more insight deficits than bipolar subjects without alcohol dependence and there will be an association between poor insight and neurocognitive deficits. Thus, in addition to increasing our understanding of the neuropsychology of insight, the findings from this study may also help understand the impact of alcohol on insight in bipolar subjects.

Depression in Parkinson's Disease: Prevalence and
Correlates, PI: Dan Weintraub, MD (Philadelphia)

This study uses a convenience sample of patients from the Parkinson's Disease Research, Education, and Clinical Center (PADRECC) with a diagnosis of idiopathic Parkinson's disease (PD). The aims of the study are to estimate frequency of depression in this population and to test for correlates of depression, including demographic characteristics, clinical features of PD, cognitive function, and comorbid psychiatric symptoms. We also are looking at frequency and characteristics of antidepressant use and the impact of non-motor symptoms of function in PD.

Non-reactive cognitive measure of nicotine dependence in depressed and non-depressed smokers, PI: Ronald Ehrman, Ph.D. (Philadelphia)

This study will use non-reactive performance measures to characterize depressed and non-depressed smokers’ relapse vulnerability in three realms: attentional bias, emotional bias, and attitudinal bias. The goal is to determine whether these attentional/attitudinal processes mediate the increased relapse vulnerability of depressed smokers.

Comparisons of outcomes of veteran and community housing programs for vulnerable homeless populations, PI: Adam Gordon, MD (Pittsburgh)

This study will compare the medical, psychiatric, and social outcomes of veterans enrolled in community versus veteran sponsored subsidized housing programs. The attitudes of veterans in community housing programs toward veteran programs and facilities also will be explored.

Excess zeros in the analysis of ordinal healthcare outcomes, PI: Mary Kelley, MD (Pittsburgh)

This research will develop a statistical technique for the analysis of ordinal data with an unusually high number of observations in the lowest category. MIRECC data sets from three ongoing studies will be used to demonstrate the benefits of this type of analysis.

Brain Substrates of PTSD-induced heroin craving in opiate dependent veterans co-morbid for PTSD, PI: Daniel Langleben, MD (Philadelphia)

This study seeks to identify the brain correlates of heroin “craving” in methadone-maintained patients co-morbid for Post-Traumatic Stress Disorder (PTSD) using functional magnetic resonance imaging (fMRI). This research will test the hypothesis that combat-related cues in methadone-maintained subjects co-morbid for combat-related PTSD will induce heroin craving and increased MRI signal in the amygdala and the cingulate, inferior, and middle frontal gyri.

Sequence Variations in the Mu Opioid Receptor Gene and Functional Responsivity to Naloxone Challenge in Alcoholics, PI: Howard Moss, MD (Philadelphia)

This study will investigate both the functional responsivity of the endogenous opioid system and the genetic variability in the loci encoding this receptor in alcoholic veterans with and without familial alcohol dependence. The goal is to determine whether this polymorphism in the OPRM1 gene could account for variations in the physiological state of the endogenous opioid system in patients at familial risk. This information could allow drug treatment to be individualized and therapeutic responses optimized.

Integrated comorbidity model of congestive heart failure, PI: Steven Sayers, Ph.D. (Philadelphia)

This will be a short-term longitudinal study to obtain preliminary data regarding a comorbidity model for mortality in CHF that integrates the effects of family environment and patient depression on adherence to diet restrictions, medications, and other requirements of CHF treatment. The study also will demonstrate the feasibility, reliability, and validity of the assessment of adherence and family environment in CHF patients.

PET studies of depression in diabetes- focus on 5HT-1a receptors, PI: Julie C. Price, Ph.D. (Pittsburgh)

Evidence shows that depression that co-occurs with diabetes is more than an emotional reaction to disease diagnosis. This pilot project will test the hypothesis that late-life depression in patients with diabetes may be due to diabetes-related alterations in serotonergic systems in specific areas of the brain.

In this study, PET measures of cerebral blood flow and serotonin 5-HT1A receptor binding will be obtained in 40-60 year-old subjects with Type 2 diabetes. The specific hypothesis is that patients with diabetes and depression lack the capacity to fully express the diabetes-related 5-HT1A upregulation, and that they, in fact, show reduced binding in midline brainstem, mesial temporal cortex, hippocampus, and other cortical areas.

Specificity of Antidepressant Prescribing in Primary Care, PI: Catherine Datto, MD (Philadelphia)

The goal of this study is to evaluate current utilization practices for newer antidepressant medications, as prescribed in primary care settings. Newer antidepressant medications may have significant advantages over traditional medications for depression (e.g., fewer side effects, greater safety) that make them ideal for use in primary care practice, but questions have been raised about the extent to which established guidelines for prescribing practices are followed in this setting. Studying their use in primary care practices will provide information about the specificity of prescribing and the quality of care. Findings will be used to develop models for improving care and for estimating the costs of inappropriate use of these agents.

Naltrexone augmentation of valproate treatment of patients with bipolar/alcohol comorbidity, PI: Ishan M. Salloum, MD, MPH (Pittsburgh)

Large epidemiological surveys have shown that bipolar disorder with co-occurring alcohol dependence is highly prevalent; however very little research has been conducted on effective treatments of this clinical problem. The presence of comorbidity has a significant negative impact on treatment compliance, treatment response, and the course of illness with increased risk for suicide, recurrence of bipolar illness, and increased rates of psychiatric hospitalization.

The aim of this pilot study is to examine the utility of valproate plus naltrexone versus valproate alone in the context of supportive Dual Disorders Recovery Counseling, in decreasing the quantity and frequency of alcohol consumption, decreasing the rate of alcohol relapse, and improving mood related symptoms in patients with comorbid bipolar disorder and alcohol dependence. These hypotheses will be tested in a small scale, open-label, randomized, pilot study over a period of 12 months. Findings will be used to estimate effect sizes for combined treatment to evaluate the feasibility and guide the design of a more definitive clinical trial.

SSRI pretreatment and tolerability of interferon treatment for hepatitis C, PI: Robert Weinrieb, MD (Philadelphia)

Nearly 20% of US Veterans are thought to be infected with the hepatitis C virus, and the majority of these cases are due to intravenous drug use. The best treatment available is interferon alpha-2B plus ribavirin. However, this therapy is known to cause a syndrome characterized by irritability, insomnia, anxiety, and depression. Patients with histories of drug abuse may be at the greatest risk for contracting hepatitis C, but treatment is rarely offered to them because of concerns that they are highly vulnerable to these neuropsychiatric side effects. According to case reports, the addition of a serotonin re-uptake inhibitor (SSRI) after the emergence of side effects appears to improve the tolerability of interferon and adherence to recommended treatment, but there have been no controlled studies of this approach. Furthermore, the benefits of SSRI's may take up to two weeks to become manifest, so there are potential benefits of instituting an antidepressant as a preventive intervention 10 to 14 days prior to starting interferon/ribavirin therapy.

This study is a small scale, randomized, open-label pilot comparison of two treatment conditions: 1) interferon/ribavirin alone, and 2) SSRI teatment initiated 10 - 14 days prior to starting the interferon/ribavirin. Subjects will be treated for up to 48 weeks and assessed at regular intervals. The primary analyses will estimate effect sizes that compare adherence, liver function, and psychiatric status of the patients on interferon/ribavirin supplemented by SSRI treatment with the patients who have not received the SSRI.