Edna B. Foa - US grants

Two experiments with obsessive-compulsive patients test the efficacy of modalities of treatment by exposure and response prevention. The first study examines the differential effectiveness of exposure alone or response prevention alone or a combination of the two. Exposure and response prevention combined are highly stressful for patients. If either component alone yields similar results, it will constitute a less stressful treatment alternative and consequently a preferable one. Additionally, this study will provide information about theoretical issues basic to the exposure paradigm. The second study tests the effectiveness of exposure in imagination to ruminations of anticipated disasters in patients who are checkers or washers. Here the differential effect of exposure in imagination or exposure in vivo is studied. This investigation bears on the general issue of the relationship between cognitive, physiological and behavioral responses during habituation and treatment outcome. Variables associated with failure to respond to the optimal behavioral treatment are explored, in an attempt to identify such patients before commencement of treatment and to develop procedures that will enable them to improve. This line of research is expected to contribute to the understanding of fear reduction processes in general. In an additional study we are investigating subjective and physiological responses under two conditions of prolonged exposure: distraction and attention-focusing. Results from this study are expected to provide information about the cognitive variables which facilitate anxiety reduction.

The principal aim of the proposed research is to explore the relationship of anxiety to storage, retrieval, and interpretation of information. The effects of anxious mood and physiological arousal on memory and on perception of threat will be studied. The hypotheses to be tested are directed not only at the mechanisms of mood-memory relationships, but also at the apparent involvement of information-processing in the psychopathology of anxiety disorders. Indeed, recall of affective memories and subsequent modification of cognitive representations of threat have been implicated in recent theories of fear and its reduction. Thus, the proposed research is directed at exploring relationships among affect, memory, and perception to understand their mechanisms, especially as they pertain to the psychopathology and treatment of anxiety disorders. A series of five experiments is proposed to address the following issues: Is anxiety-related information more readily remembered in anxiety state than nonanxiety-related information? Does anxious mood provoked by different threats, produce similar effects on memory? How content-specific are mood congruent recall effects? Does state dependent learning occur for anxious mood? Is state dependent learning a necessary mechanism for mood congruent recall? Does elevated autonomic arousal underlie mood/memory effects? Can negative response bias be excluded as a mechanism for mood/memory effects? That is, does anxious mood produce better memory for anxiety-relevant information, or just produce a bias to report such material? Does arousal influence the interpretation of information (e.g., enhance perception of threat)? Do anxiety disordered individuals evaluate threatening events as more probable and more aversive than do normals? Are they more susceptible to effects of arousal? Three experiments will examine the effects of induced states of anxiety, elation and depression on recall of words related to these moods. The remaining two experiments will explore the effects of physiological arousal on memory and on the estimated probabilities and subjective cost of threatening events. The 190 subjects who will participate in this project include agoraphobics, matched normals and student volunteers manifesting speech phobia, high depression, or low depression. In contrast to previous research, convergent physiological and self-report measures will be used to validate mood induction procedures.

Over the past 7 years we have developed and evaluated brief treatments for post-traumatic stress disorder (PTSD) following sexual assault. The proposed study is intended to replicate and extend our treatment studies, and has both practical and theoretical aims. First, Stress Inoculation Training plus Prolonged Exposure (SIT/PE), a successful treatment that we have developed over the last 3 years, will be extended to a community rape crisis center (Women Organized Against Rape [WOAR]). The treatment efficacy at WOAR will be compared with that at our research clinic (Medical College of Pennsylvania), so that its transportability can be ascertained. Second, a new treatment program which is a theoretically and empirically derived refinement of SIT/PE, Cognitive Therapy plus Prolonged Exposure (CT/PE), will also be evaluated in both the research and community settings. Third, the efficacy of 3 additional sessions for partial responders will be examined. The proposed research will also address theoretical issues regarding cognitive processes underlying PTSD and its amelioration by cognitive-behavioral treatment. Specifically, we will examine the relationship of perceptions of the dangerousness of the world, and of one's ability to cope with stress to PTSD and other post- trauma psychopathology. We will also investigate whether the victim's perceptions of aversive events as unpredictable and uncontrollable are associated with PTSD and whether changes in such perceptions via treatment produce improvement. A total of 180 rape victims with PTSD will be randomly assigned to SIT/PE, CT/PE, or a waitlist, half at MCP, and half at WOAR. Assessments will include structured interviews and questionnaires, and will be conducted before treatment, after treatment, and at 3, 6, and 12 months follow-up. Dependent measures will be PTSD symptoms severity and diagnosis, general psychopathology, depression, social function, coping style, cognitive schemas, treatment expectancy, and treatment compliance.

The proposed project aims at investigating the reaction of rape victims during the three month period following the assault, in order to elucidate the exact patterns of recovery from the traumatic experience and to identify predictors associated with level of recovery. The project also aims at investigating the relative efficacy of three treatment programs for victims who fail to show substantial reduction of rape related symptoms 3 months to 1 year after the rape. Three treatment programs, prolonged exposure, stress innoculation, training and supportive counseling, will be compared to one another and to a wait-list control condition. Predictors for success and failure following these treatments will be explored. To pursue these aims, two studies which will be conducted in parallel are proposed. The first will include frequent assessment of rape-related behavioral, self-report and physiological responses occurring during the 3 month period post-rape. To this end, 150 victims raped within 10 days of the first interview will be assessed weekly for 12 weeks. An index of distress will be calculated by combining scores on several symptom measures and will be used in the investigation of variables predictive of recovery. The second study will employ a similar broad range of measures to evaluate treatment for persistent rape-related symptoms. Sixty rape victims who show substantial rape-related disturbance will be randomly assigned to one of the three active treatment (14 ninety-minute sessions held biweekly over 7 weeks) or to a wait list control. Assessment of treatment outcome will occur before treatment, at mid and post-treatment and at follow-ups of 3, 6 and 12 months. The mid-treatment assessment is included in order to examine the relative efficiency of the three active treatments.

The proposed study is composed of two stages: 1) investigation of the etiology of PTDSD in recent rape and female non-sexual crime victims during the three months post assault, and 2) an investigation of the relative efficacy of three treatments and a wait-list control for alleviating the three classes of PTSD symptoms (reexperiencing, avoidance, and arousal) for victims who meet diagnostic criteria for this disorder three months or more following the assault. Rape and female non-sexual crime victims (aggravated and simple assault and robbery) who consent to participate in the etiological study will each be assessed weekly for 12 weeks and compared to one another. Subjects in this study will be 160 female rape victims and 160 female crime victims from the ages of 18 to 65. Measurements will include: structured interviews, questionnaires, and electrodermal and cardiac psychophysiological responses to rape-related images and to neutral stimuli (auditory tones) for a subsample. The effects of prolonged exposure (PE), stress inoculation training (SIT), and a combination of PE and SIT, will be compared to each other and to a wait-list condition in rape and crime victims who meet DSM-III- R diagnosis for PTSD at least three months post-assault. Assessments will be conducted before treatment, after treatment (Session 9), and at follow-up of 3 months, 6 months, and one year. Victims will be randomly assigned to one of the 4 conditions. The dependent variables collected in the treatment will be: 1) standardized measures for PTSD symptoms, general anxiety, depression, social and functioning, coping styles, and controllability/predictability, 2) physiological measures and self- ratings taken during the laboratory procedures, 3) treatment expectancy, and 4) compliance with treatment requirements. The short term goals of the proposed project are to examine hypotheses about the etiology of PTSD in crime victims and its treatment within a unified conceptual framework. The long term goals are to develop a predictive model for PTSD and to identify mechanisms of its treatment. Such understanding will help identify individuals at high risk for developing PTSD so that preventive interventions can be devised.

(Adapted from applicant's abstract): This is one half of a proposed multicenter study. The specific goals of this proposed are: a) to compare the effects of chlorimipramine (CMI), behavior therapy (BT), CMI+BT, and pill placebo for symptoms of obsessive-compulsive disorder (OCD); and b) to compare the relapse rates for the different groups after discontinuation of treatment. This proposal is a collaboration between pharmacologically and behaviorally oriented research programs. Each center will enter 76 patients, randomized in a 12-week trial with the following groups: CMI alone, BT alone, CMI + BT, and placebo pill. After week 12, responders will be tapered and/or discontinued from treatments and followed blind to former treatment status for 12 weeks. Medication will be tapered within three weeks.

This competing continuation application is one-half of a jointly proposed multicenter study by Drs. Foa, Franklin, and Kozak, of the Allegheny University of Health Sciences and Drs. Davidson and Keefe of Duke University Medical Center. Who are submitting two separate but similar proposals. We request that the two proposals be reviewed together. The proposed research is a continuation of an ongoing study funded by NIMH for the period of 9/30/94 though 8/31/98. Patient recruitment in the ongoing study has been slower than anticipated, and we are seeking funds to extend the study for an additional 3 years to accrue sufficient sample size to test the original hypotheses. The major goals of the study are: (a) to evaluate the effectiveness of FLU, a comprehensive cognitive behavioral program (CCBT) that includes CT,EX and SST, and a combination of FLU and CCBT in generalized anxiety disorder (GSP); (b) to compare relapse rates associated with different groups after discontinuation of treatment; ~ to examine the transportability of the two treatment approaches; and (d) to examine possible predictors of treatment response. GSP is chronic and debilitating anxiety disorder, affecting over 2% of the population and resulting in significant morbidity and suicide attempts. Recent studies have indicated a number of promising treatments, including fluxetine (FLU), cognitive therapy (CT), exposure therapy (EX) and social skills training (SST). No studies have compared FLU ( or any other serotonergic drug) with cognitive behavior therapy in GSP or examined the effectiveness of a combined treatment group. Moreover, no study has yet evaluated the extent to which different treatments for GSP (e.g., medications, CBT) can be transported/replicated across sites. One hundred and sixty subjects (80 per site) in addition to the 200 to be accrued in the ongoing study, meeting DSM-IV criteria for GSP will be randomly assigned to one of five conditions: FLU, CCBT, FLU+CCBT, CCBT + pill placebo, and placebo alone. Treatment is administered for 14 weeks, followed by a 24 week treatment free follow-up. Outcome is assessed by independent evaluator ratings, self-report scales, and behavioral measures of social skills. Assessments are conducted before, during and after treatment as well as during an extended follow-up phase. Important to this proposal is the collaboration between pharmacologically and cognitive- behaviorally oriented research programs. Long range goals are to establish guidelines for the pharmacological and cognitive behavioral treatment of GSP, to understand the separate and combined effects of pharmacotherapy and cognitive behavioral therapy in this condition, and to integrate pharmacological and psychosocial approaches to the anxiety disorders.

Approximately 90% of female rape victims and 65% of female nonsexual assault victims develop symptoms of post traumatic stress disorder (PTSD) immediately after their assaults, and these symptoms persist three months later in about 50% of victims. The primary goal of the proposed study is to evaluate the efficacy of a low cost, brief program that was developed to prevent chronic PTSD in the large subset of crime victims who exhibit severe acute symptoms, and who are therefore at high risk for developing the disorder. A second goal is to assess cognitive processes hypothesized to underlie PTSD, and to examine whether these processes are reversed by the prevention program. The third aim is to explore the relationship among psychological symptoms, coping styles, and physical health problems in female assault victims. Specifically, we propose to investigate whether providing the Brief Prevention program to victims who are symptomatic immediately after rape or aggravated assault, will protect them from developing chronic PTSD and health problems. Also, we will examine the relationship of PTSD, other psychopathology and health problems to: 1. victims' perceptions of global danger, 2. victims' perception of inability to cope with stress, and 3. victims' perceptions of aversive events as uncontrollable and unpredictable. In addition we will investigate whether the Brief Prevention program influences PTSD by changing such perceptions. Three-hundred-thirty symptomatic female victims of recent rape or nonsexual assault will be randomly assigned to either a Brief Prevention program or an Assessment Control condition, and receive 4 weekly active intervention or control sessions. Evaluations will include structured interviews and questionnaires, and will be conducted before and after the intervention, and at 2, 3, 6, 9, and 12 months after study entry. Dependent measures will be PTSD symptom severity and diagnosis, depression, social functioning, general psychopathology, reported health problems, coping style, cognitive schemas, and expectancy and compliance with the prevention program.

DESCRIPTION (Adapted from applicant's abstract): One in two hundred young suffers from Obsessive-Compulsive Disorder (OCD), yet relatively few receive appropriate treatment. Both cognitive-behavior therapy (CBT) and medication appear beneficial in controlled studies; however, the relative efficacy of CBT and medication, alone and in combination, (COMB), is unknown. Thus well-designed treatment outcome studies are necessary to improve care for youth with OCD. This revised proposal constitutes one half of a (two-center) Multi-Institutional Collaborative Research Project focused on the treatment of pediatric OCD, resubmitted jointly but separately by Drs. Edna Foa at Allegheny University (AU) and John March at Duke University. Using a volunteer sample of 120 (60/site) youth age 8-16 with a DSM-IV diagnosis of OCD, the proposed 5 year treatment outcome study contrasts the degree and durability of improvement obtained across six treatment conditions: 3 active treatments, sertraline alone (SER), OCD-specific behavior therapy (CBT), both SER and CBT (SER+CBT) and 3 control treatments, pill PBO, pill PBO+Educational Support (ES) and SER+ES. The experimental design covers 2 phases. Phase I is a 2 (site) x 2 (sertraline or pill PBO) x 3 (CBT, ES or non psychosocial treatment) x 5 (repeated measures) factorial 12 week comparison of SER, CBT, COMB and the control conditions. In Phase II, responders advance to a 16 week discontinuation study to assess treatment durability. The primary outcome measure is the Yale-Brown Obsessive-Compulsive Scale. Assessments blind to treatment status take place at week 0 (pretreatment); weeks 1, 4, 8, 12 (Phase I treatment); and weeks 16, 20, 24 and 28 (Phase II discontinuation). Besides addressing comparative efficacy and durability of the specified treatments, we also examine time-action effects, differential effects on specific aspects of OCD, including functional impairment, and predictors of response to treatment.

(Adapted from applicant's abstract): This is one half of a proposed multicenter study. The specific goals of this proposed are: a) to compare the effects of chlorimipramine (CMI), behavior therapy (BT), CMI+BT, and pill placebo for symptoms of obsessive-compulsive disorder (OCD); and b) to compare the relapse rates for the different groups after discontinuation of treatment. This proposal is a collaboration between pharmacologically and behaviorally oriented research programs. Each center will enter 76 patients, randomized in a 12-week trial with the following groups: CMI alone, BT alone, CMI + BT, and placebo pill. After week 12, responders will be tapered and/or discontinued from treatments and followed blind to former treatment status for 12 weeks. Medication will be tapered within three weeks.

DESCRIPTION (Adapted from the Applicant's Abstract): This is one-half of a two-site study proposed jointly by Foa and Franklin at the University of Pennsylvania, and Liebowitz and Simpson at Columbia University, who are submitting separate but similar proposals (collaborative CSMD). Obsessive-compulsive disorder (OCD) is prevalent, chronic, and debilitating. Both cognitive behavior therapy (CBT) by exposure and ritual prevention (EX/RP) and serotonin reuptake inhibitors (SRIs) are recommended for OCD. However, recommended doses of the widely used SRIs leave many patients with substantial residual symptoms and a need for more help. This proposal addresses an important problem in treating OCD: how to augment the limited efficacy of SRIs. This study will examine the immediate and long-term value of adding an established CBT for OCD, i.e., EX/RP, to continuing SRI treatment, for reducing residual symptoms and increasing general functioning. Participants will be 136 individuals (68/site) with clinically significant OCD despite having benefited somewhat from an adequate trial of a SRI. While continuing on an SRI, patients will be randomized to adjunctive EX/RP or another CBT, Stress Management Training (SMT). SMT targets generalized anxiety symptoms, but has not been found effective for OCD. As a credible comparison therapy, SMT will control for time, attention, and other non-specific effects of CBT. Both adjunctive CBT treatments will occur twice a week for 2 months. Responders will enter a 6 month Maintenance Phase, during which they will continue their medication and receive monthly 45 min. maintenance sessions. Those who remain in remission will then enter a 6 month Follow-up Phase, in which they will be allowed to reduce or discontinue medication, and will have no further CBT. Non-responders and relapsers will be treated appropriately and evaluated every 3 months. Assessments will focus on OCD symptoms and on general functioning; they will occur during an Acute Phase (0, 1, 2 mos) and every 3 months thereafter (5, 8, 11, 14 months). The proposed sample will allow sufficient power to test both treatment and site effects. This study has several unique features. 1. It offers a model for pharmacotherapy-psychotherapy studies because experts in each modality will deliver both treatments; this guards against expert biases for either treatment. 2. We wanted the results to be directly applicable to OCD patients seen in routine clinical practice. Accordingly, exclusion criteria are few. 3. The EX/RP protocol was designed to maintain efficacy while maximizing practicality. 4. Patients who are unable to remain in the treatment protocol for any reason will continue to be assessed; this will allow us to describe the long-term outcome of the whole sample. Long-term goals are: a) to provide clinicians with new strategies for treating OCD patients who remain symptomatic despite an adequate trial of a SRI and b) to establish effective treatments that reduces the considerable social costs of unremittant OCD.

[unreadable] DESCRIPTION (provided by applicant): This proposal is for a three-year extension of a study investigating treatments for patients with comorbid alcohol dependence (AD) and posttraumatic stress disorder (PTSD). AD and PTSD are each associated with profound disruptions of functioning that are compounded in individuals with both disorders. Given the high rate of AD-PTSD comorbidity and the impairment associated with these disorders, it is imperative to identify effective treatments for these patients. The interrelation of AD and PTSD is complex with each disorder exacerbating the other, forming a vicious cycle. Recent years have seen advances in the treatment of each [unreadable] disorder, but no studies have examined the efficacy of treatments for patients presenting with both AD and PTSD. Treatment with naltrexone (NAL) plus counseling has been effective in treating AD, but its efficacy in AD patients with PTSD on AD and PTSD symptoms is unknown. Similarly, prolonged exposure (PE) therapy has proven effective in treating PTSD, but its efficacy in PTSD patients with AD on PTSD and AD symptoms is unknown. The hypothesized vicious cycle between AD and PTSD suggests that treatments targeting only one of the disorders will yield poorer outcomes in comorbid patients than treatment that addresses the two disorders concurrently. To date we have accrued 98 patients and we project entering a total of 105 patients into the study by the end of the current funding. Preliminary results with 70 patients are very promising. However, the projected sample of 105 patients does not afford sufficient power for reaching definitive conclusions about the relative efficacy of PE, AD and their combination. Accordingly, we are proposing to collect data from 75 additional patients with comorbid AD and PTSD to accrue a total of 180 patients into the study. This sample will provide adequate power to test our hypotheses. The study compares four treatment conditions in a 2 (NAL vs. placebo) by 2 (PE vs. no PE) design. The conditions are: 1)100 mg. NAL plus PE; 2) NAL alone; 3) placebo plus PE; 4) placebo alone. A medication management intervention accompanies all [unreadable] treatment conditions. Symptoms will be evaluated before, during, and at the end of a 24-weeks treatment, and at 9 and 12 months following study entry. Our primary study's objective is to compare the short- and long-term effects of the combined treatments to those of each treatment in isolation on symptoms of AD and of PTSD. This research capitalizes on the unique expertise of two internationally renowned centers. One, the Treatment Research Center, known for expertise in pharmacotherapy for AD and the second, the Center for the Treatment and Study of Anxiety, known for cognitive behavioral treatment of PTSD. Therefore the findings from this study will be highly credible and should impact significantly on treatment recommendations for this impaired population. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The grant proposes to employ a longitudinal design to examine alterations in the biology of PTSD in individuals whose symptoms are expected to improve following prolonged exposure therapy (PE). Because a great majority of trauma victims who receive PE show significant improvement in clinical symptoms, examining biological parameters before, during, and after this manipulation provides an opportunity to explore the relationships among biological alterations, changes in PTSD symptom severity, and cognitions related to the disorder. Thus, this study is interested in the relationship between biological alterations and psychological factors (including dysfunctional cognitions about the danger of the world and self- incompetence) that have been implicated in chronic PTSD, particularly as they may change with reduction in PTSD symptoms. Furthermore, the study will assess whether biological alterations associated with chronic PTSD predict, or are altered in relation to, therapeutic outcome. The longitudinal design with multiple measurements will allow us to obtain data that address the temporal relationship between changes in symptom severity with biological and cognitive variables. If biological alterations are principally related to symptom severity and/or cognitive factors that maintain PTSD, then successfully treating the symptoms should alter biological findings in the direction of normality. However, it is possible that changes in symptom severity may occur in the absence of significant shifts in neuroendocrine profile, suggesting a pattern related to underlying risk rather than to symptomatic expression in this disorder. The resolution of these questions has important implications for understanding the pathophysiology of PTSD, and may provide insight into the mechanisms associated with successful psychological treatment for this disorder.

DESCRIPTION (provided by applicant): The disaster of September 11 and the constant threat of imminent terrorist activity have brought into the forefront the need to develop and test efficient interventions for trauma-related psychological disturbances such as PTSD. It is important to remember, however, that terror-attacks constitute only one type of trauma and in fact is much less relevant in the US than other types of trauma such as natural disasters, traffic accidents and assault. Notably, data from large-scale epidemiological studies of children, adolescents, and adults indicate a 10% lifetime prevalence of child sexual abuse (CSA). Moreover, 62% of rapes occur during childhood or adolescence. Given the high prevalence of CSA, a clear association between CSA, PTSD, substance abuse, and sexual re-victimization during adolescence, it is of paramount importance to develop efficient, effective, and readily disseminable treatments for adolescents who suffer PTSD and related emotional difficulties as a result of CSA or sexual assault. Presently, there are effective treatment for adults and for children who suffer from CSA and sexual assault related PTSD, but very little is known about how best to treat traumatized adolescents who suffer from PTSD and associated symptoms, including PTSD related to sexual assault. The proposed research aims to examine the efficacy of a cognitive behavioral treatment developed for PTSD in adolescents exposed to CSA and sexual assault. Most importantly, the treatment will be conducted by counselors at a community clinic that provides services to victims of sexual assault across the developmental spectrum. Primary aims are: 1) To compare the immediate outcome of two active treatments, Prolonged Exposure for Adolescents (PE-A) and supportive counseling (SC), in reducing PTSD symptom severity;and 2) To assess maintenance of PE-A treatment gains at follow-up. Secondary aims are: 1) To compare PE-A and SC's effects in reducing secondary psychopathology symptoms;2) To examine the relationship between change in PTSD symptoms and change in distress-related cognitions and emotions. The proposed research falls squarely within the national health policy and priorities set by the NIH/NIMH Healthy People 2010 by: 1) providing efficacious mental health treatment that promotes the quality and years of healthy life of people suffering from PTSD symptoms;and 2) reducing the mental health access disparity by making specialty mental health resources more accessible to the community at large.

DESCRIPTION (provided by applicant): Obsessive-compulsive disorder (OCD) is a chronic and debilitating illness affecting up to 2-3% of the population. The only medications proven effective for OCD are serotonin reuptake inhibitors (SRIs), but even with SRI treatment, most patients continue to experience significant OCD symptoms, impaired functioning, and diminished quality of life. With the goal of maximizing treatment outcome, the primary aim of this competing continuation/collaborative R01 application is to compare the two SRI augmentation strategies in OCD proven effective in randomized controlled trials: the addition of the antipsychotic medication risperidone (RIS) and the addition of cognitive-behavioral therapy consisting of exposure and ritual prevention (EX/RP). Because prior studies found that even with 6-8 weeks of antipsychotic or EX/RP augmentation, most patients have significant residual OCD symptoms, the second aim is to examine whether patients who benefit from 8 weeks of augmentation will maintain their gains or improve further with continued treatment. Accordingly, during the Acute Augmentation Phase, 100 patients with OCD (50 per site) who have received an adequate SRI trial but still experience clinically significant symptoms will remain on their SRI and be randomized to 8 weeks of one of three adjunctive treatments: 1) twice-weekly EX/RP;2) RIS;or 3) pill placebo. Patients who benefit from the Acute Augmentation Phase will enter the Continuation Phase, and receive the same adjunctive treatment for an additional 24 weeks. This study will be the first to compare the only SRI augmentation strategies for OCD with strong empirical support and to determine whether OCD patients can achieve and maintain an excellent treatment outcome if provided up to 32 weeks of adjunctive treatment. Relevance: Given that most patients who take SRIs for OCD continue to experience significant OCD symptoms, determining how best to augment SRI response and help OCD patients achieve an excellent treatment outcome is an important public health challenge. The long-term goal of the proposed study is to provide clinicians with specific guidelines for how to maximize treatment outcome and help people with OCD lead productive and high quality lives.

DESCRIPTION (provided by applicant): This study will evaluate an innovative program for smokers with Post-Traumatic Stress Disorder (PTSD) that integrates the most effective medication for smoking cessation (varenicline) with prolonged exposure (PE), a highly efficacious cognitive behavioral therapy for PTSD. The development of specifically tailored and more efficacious smoking cessation treatments for smokers with psychiatric disorders, whose cigarette smoking is disproportionately high, has been identified as a high priority in public health policy. PTSD is a common mental disorder with a lifetime prevalence of 6.8%. The prevalence of smoking in people with current PTSD is 44.6% -- double the rate of those with no history of a psychological disorder (22.5%). Smokers with PTSD are more likely to be nicotine dependent, smoke heavily, experience more severe withdrawal symptoms, and relapse after a quit attempt. In fact, the quit rate for smokers with PTSD is among the lowest compared to other mental disorders. Factors that may contribute to smokers'progression to nicotine dependence and relapse include negative affect, fear, anxiety sensitivity, increased arousal, irritability, and anger. Therefore, the integration of treatment for smoking cessation with treatment for PTSD that reduces these factors is hypothesized to improve success of smoking cessation about smokers with PTSD. To test this hypothesis, we will randomly assign smokers with PTSD to either the "best practice" pharmacotherapy for smoking cessation (varenicline) alone or to a treatment that integrates varenicline with PE. The primary outcome measure will be biochemically confirmed abstinence rates at the end of treatment and at follow-up 6-months post quit date. Secondary outcome measures will be continuous abstinence, prolonged abstinence, and time to relapse. We will also obtain measures of PTSD and associated psychopathology (e.g. depression and anxiety) and risk factors (e.g. anxiety sensitivity). Collectively, our research group has expertise in the development of efficacious treatments for PTSD, including PE (Foa, Cahill, Hembree), the epidemiology of smoking and psychiatric disorders (Breslau), and smoking cessation (Lerman, O'Brian, Gariti). The proposed research affords a unique opportunity to combine experts from diverse areas with the aim of developing an innovative, integrated approach to the treatment of people who are likely to fail using existing treatments. PUBLIC HEALTH RELEVANCE: Cigarette smoking is the single most preventable cause of premature death in the US;approximately 50% of long-term smokers die of a disease caused by their dependence, shortening lives by an average of 13-14 years. Smokers with Post Traumatic Stress Disorder (PTSD) are more likely to be nicotine dependent, to smoke heavily (25 cigarettes per day or more), experience more severe withdrawal symptoms, and relapse following a quit attempt than smokers without PTSD. In this grant application, we propose to evaluate an innovative treatment program for smokers with PTSD that integrates varenicline, the most effective medication for smoking cessation, with prolonged exposure therapy, a highly effective form of psychotherapy for PTSD.

DESCRIPTION (provided by applicant): This proposal Attaining and Maintaining Wellness in OCD is a competing continuation of our prior collaborative R01 project, Cognitive Behavior Therapy Augmentation of Serotonin Reuptake Inhibitor Pharmacotherapy for Obsessive-Compulsive Disorder, and is one-half of a two-site study proposed by Dr. Edna Foa at the University of Pennsylvania and Dr. Helen Blair Simpson at the New York State Psychiatric Institute/Columbia University. Most OCD patients in clinical practice are on serotonin reuptake inhibitors (SRIs) for many years, but continue to have clinically significant residual symptoms. Our prior research showed that adding cognitive- behavioral therapy consisting of exposure and response prevention (EX/RP) is the best current strategy to help OCD patients on SRIs attain wellness. However, it is not known whether patients who attain wellness following EX/RP augmentation can then safely discontinue their SRI. OCD patients often remain on SRIs because of fear of relapse despite side effects that over time can compromise their quality of life and health (e.g., sexual dysfunction, sleep disturbance, weight gain). Hence, determining whether EX/RP can help OCD patients not only attain but also maintain wellness after discontinuing their SRI is an extremely important public health question. The primary aim of the proposed study is to examine whether adults with OCD (age 18-75) on SRIs who attain wellness after EX/RP augmentation can discontinue their SRI and maintain wellness over 6-month follow-up. We hypothesize that patients switched to pill placebo compared to those maintained on SRIs will have noninferior outcomes for OCD severity (Hypothesis #1), depressive symptoms (Hypothesis #2), and quality-of-life (Hypothesis #3) at 6-month follow-up. A secondary aim is to explore specific psychological (e.g., metacognitions) and biological factors (i.e., genetic polymorphisms) that have been theoretically or empirically linked to EX/RP outcomes and to test whether these factors help identify who will (or will not) benefit from this treatment strategy. We will recruit 150 OCD patients who have received an adequate SRI trial but still have clinically significant OCD symptoms. During the Preparatory Phase, they will receive up to 25 sessions of twice-weekly EX/RP. During the Study Phase (Weeks 0 to 24), patients (expected n=100) who attain wellness (using a Yale-Brown Obsessive Compulsive Scale score d 14 as a proxy) will be randomized to continue their SRI or switch to pill placebo and followed for 24 weeks. This study will fill an important gap in our knowledge: can EX/RP augmentation help OCD patients discontinue from SRIs? By exploring what moderates and mediates the effects of SRI discontinuation, we will also investigate who is likely to benefit from this treatment strategy and how it works. Our long-term goals are to provide clinicians with effective treatment strategies to help people with OCD live full and productive lives and to advance knowledge about the psychological, biological, and behavioral factors associated with attaining wellness with EX/RP augmentation and maintaining wellness without SRIs.

DESCRIPTION (provided by applicant): This proposal Attaining and Maintaining Wellness in OCD is a competing continuation of our prior collaborative R01 project, Cognitive Behavior Therapy Augmentation of Serotonin Reuptake Inhibitor Pharmacotherapy for Obsessive-Compulsive Disorder, and is one-half of a two-site study proposed by Dr. Edna Foa at the University of Pennsylvania and Dr. Helen Blair Simpson at the New York State Psychiatric Institute/Columbia University. Most OCD patients in clinical practice are on serotonin reuptake inhibitors (SRIs) for many years, but continue to have clinically significant residual symptoms. Our prior research showed that adding cognitive- behavioral therapy consisting of exposure and response prevention (EX/RP) is the best current strategy to help OCD patients on SRIs attain wellness. However, it is not known whether patients who attain wellness following EX/RP augmentation can then safely discontinue their SRI. OCD patients often remain on SRIs because of fear of relapse despite side effects that over time can compromise their quality of life and health (e.g., sexual dysfunction, sleep disturbance, weight gain). Hence, determining whether EX/RP can help OCD patients not only attain but also maintain wellness after discontinuing their SRI is an extremely important public health question. The primary aim of the proposed study is to examine whether adults with OCD (age 18-75) on SRIs who attain wellness after EX/RP augmentation can discontinue their SRI and maintain wellness over 6-month follow-up. We hypothesize that patients switched to pill placebo compared to those maintained on SRIs will have noninferior outcomes for OCD severity (Hypothesis #1), depressive symptoms (Hypothesis #2), and quality-of-life (Hypothesis #3) at 6-month follow-up. A secondary aim is to explore specific psychological (e.g., metacognitions) and biological factors (i.e., genetic polymorphisms) that have been theoretically or empirically linked to EX/RP outcomes and to test whether these factors help identify who will (or will not) benefit from this treatment strategy. We will recruit 150 OCD patients who have received an adequate SRI trial but still have clinically significant OCD symptoms. During the Preparatory Phase, they will receive up to 25 sessions of twice-weekly EX/RP. During the Study Phase (Weeks 0 to 24), patients (expected n=100) who attain wellness (using a Yale-Brown Obsessive Compulsive Scale score d 14 as a proxy) will be randomized to continue their SRI or switch to pill placebo and followed for 24 weeks. This study will fill an important gap in our knowledge: can EX/RP augmentation help OCD patients discontinue from SRIs? By exploring what moderates and mediates the effects of SRI discontinuation, we will also investigate who is likely to benefit from this treatment strategy and how it works. Our long-term goals are to provide clinicians with effective treatment strategies to help people with OCD live full and productive lives and to advance knowledge about the psychological, biological, and behavioral factors associated with attaining wellness with EX/RP augmentation and maintaining wellness without SRIs.

Cognitive behavioral therapy involving exposure and ritual prevention (EX/RP) is a first-line treatment for obsessive compulsive disorder (OCD). Despite its efficacy, it remains unclear how EX/RP influences the neural mechanisms of the fear and anxiety brain networks to yield clinical improvement. Moreover, data indicate that EX/RP outcomes may be more variable in women. Studies in rodents and healthy humans show that estrogen (E) affects the brain regions involved in fear learning, extinction, and extinction retention (the fear extinction network); E also has been shown to enhance extinction memory retention. In addition, the structure and connectivity of these same brain regions predict OCD treatment outcomes, including EX/RP. These and other data lead to the hypothesis that this Collaborative R01 will begin to test: that delivering EX/RP to women with OCD during high E states improves extinction memory retention via enhanced engagement of the fear extinction brain network, resulting in better clinical outcomes. We will also explore whether EX/RP-induced extinction processes differ between women and men. Our specific aims are to examine: 1) the impact of menstrual-cycle phase and sex on extinction-induced neural responses pre and post EX/RP; 2) the impact of menstrual-cycle phase and sex on EX/RP outcome; and 3) the relationship between OCD symptom change and EX/RP-induced neuronal changes. Our long-term goal is to understand how sex as a biological variable affects specific neural processes and hence EX/RP treatment outcomes. To achieve our aims, 120 adults with OCD ? 80 natural cycling women and 40 men--will be recruited across two sites: The University of Pennsylvania (UPenn) and the New York State Psychiatric Institute/Columbia University (NYSPI). Through a subcontract, New York University (NYU) will provide expertise in the fMRI imaging paradigm that will be used as an experimental tool to probe the fear extinction brain network. Study participants will complete fMRI scanning before and after receiving manualized EX/RP. The EX/RP protocol will consist of 8 (90 minute) daily sessions comprised of two introductory and six exposure sessions. Women will be randomly assigned to complete EX/RP during either: a) the first 10 days after the start of menstruation (early follicular phase), when E levels are low; or b) days 12-22 of the menstrual cycle (late follicular, early luteal phase), when E levels are elevated. OCD symptoms and E levels will be measured at multiple time points. This design will allow us to study the effects of hormonal variation during the menstrual cycle and sex on the fear extinction network and on EX/RP outcome. The results will elucidate treatment mechanisms and could lead to personalized treatment recommendations for women with OCD.