Allison G. Harvey, Ph.D. - US grants

DESCRIPTION (provided by applicant): Bipolar disorder is a severe and chronic disorder, ranked in the top 10 leading causes of disability worldwide. While there have been important advances in treatments, a significant proportion of patients continue to experience disabling symptoms between episodes and the risk of relapse into an episode of depression or mania remains high. Three lines of evidence converge on sleep disturbance as one important mechanism contributing to inter-episode dysfunction and relapse in bipolar disorder: (1) sleep disturbance is a core symptom of bipolar disorder, (2) experimental studies suggest that sleep deprivation can trigger manic relapse and (3) there is evidence that sleep deprivation can undermine emotion regulation the following day. Accordingly, we seek to determine if an intervention to improve sleep can improve treatment outcome for patients with bipolar disorder. Specific Aims: (1) To develop and refine an intervention to improve the sleep of patients with bipolar disorder. (2) To prepare for a larger scale intervention study by conducting a pilot randomized controlled trial which will establish if a Sleep Intervention can produce durable improvements in sleep and improvements in inter-episode quality of life and emotional functioning in bipolar I patients. Research Plan: Phase 1 involves an iterative process of developing and refining the intervention by testing the treatment with patients diagnosed with bipolar I disorder who also suffer from sleep disturbance (n = 12). In Phase 2, a sample of 48 patients with bipolar I disorder, who also suffer from sleep disturbance, will be randomized to one of two groups: (a) Sleep Intervention or (b) Information Only. Outcome measures will be taken at baseline and the end of treatment for both groups. The Sleep Intervention Group will be reassessed at 6 months post treatment. Long-term objective: To develop a novel non-pharmacological adjunctive intervention, or new components to add to existing interventions, that will improve sleep in bipolar patients, enhance inter-episode quality of life and reduce risk of relapse. PUBLIC HEALTH RELEVANCE: Bipolar disorder is a severe and chronic disorder that is difficult to treat. The sleep disturbance commonly suffered by patients with bipolar disorder reduces their quality of life and contributes to relapse. This study seeks to determine if an intervention to improve sleep can improve treatment outcome for patients with bipolar disorder.

DESCRIPTION (provided by applicant): This revised application requests funds to support two years of training to prepare predoctoral students in psychology for scientific careers in the identification of mechanisms underlying severe mental illness and to use this knowledge to develop and test novel interventions. This training program will equip the fellows to establish research careers that genuinely bridge clinical and neuroscience and that solve fundamental problems relating to the development and testing of novel interventions for severe mental illness, in turn reducing the suffering and disability related to mental illness in society. There will be a maximum for four fellows in the program at any one time (two admitted per year). The two-year-long fellowships will fund predoctoral students in their 4th and 5th years of graduate school. We believe there is considerable benefit to providing the proposed training to the most outstanding students, from a very strong pool, at this stage-late in predoctoral education-when the trajectory and interests are clear but the fellows are still far from fully developed. Fellows will engage in a year-long core training seminar and a bimonthly patient case conference, participate in a treatment development clinic, receive training in neuroscience, conduct a research study involving a tool from neuroscience, and participate in career-focused workshops and an annual workshop where trainees' research findings are presented and discussed. In sum, the proposed training program would establish a unique and much needed predoctoral program that will develop scientists who are devoted to the development and testing of novel interventions for severe mental illness. By infusing every aspect of predoctoral training with the principles of clinical science and neuroscience and with the need to integrate multidisciplinary perspectives, we will shape a generation of researchers in ways that could not be achieved in other stages of training.

DESCRIPTION (provided by applicant): Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders and a leading cause of disability worldwide. Existing therapies fail to produce complete recovery. Progress toward improving outcome must include innovations that are safe, powerful, inexpensive and simple (for fast and effective dissemination). The proposed research seeks to test one such innovation. We seek to improve outcome by improving memory for the content of cognitive therapy (CT) sessions. CT is one of the most promising approaches to the treatment of MDD, yet there is room for improvement. We believe that adding memory enhancing strategies to CT may improve MDD outcome because: (a) MDD is often characterized by memory impairment, (b) there is evidence that the memory impairment is modifiable, (c) CT typically entails the activation of emotion, (d) emotion can impair or bias memory and (e) there is evidence that memory for the content of therapy sessions is poor. Aim. To evaluate if the addition of a novel strategy, derived from the memory literature and designed to enhance memory for the content of CT sessions, will improve treatment outcome for MDD. Cognitive support involves a series of specific procedures that support the encoding and retrieval stages of an episodic memory. It is hypothesized that CT+Cognitive Support, relative to CT-as-usual, will be associated with improved depression outcome at the end of treatment and 6 months after the completion of treatment. Research Plan. Phase 1 involves an iterative process of developing and refining the cognitive support intervention by testing the treatment with adults with MDD (n = 8). In Phase 2, a small pilot feasibility RCT will be conducted on adults with MDD (n = 48) who will be randomized to either: (a) CT+Cognitive Support (n = 24) or (b) CT-as-usual (n = 24). Outcome measures will be taken at baseline, end of treatment, and 6 months after treatment. Long-term objective. The outcomes, if positive, will have major public health implications because simple, inexpensive memory enhancing strategies can be readily included as a standard feature in all psychosocial treatments for a broad range of mental illness. As a first step toward achieving this goal, this research will provide the pilot data needed to prepare a larger scale intervention study focused on improving outcomes by improving memory for the content of therapy sessions in MDD. PUBLIC HEALTH RELEVANCE: Existing drug and talking therapies for major depressive disorder (MDD) fail to produce complete recovery. This study will determine if substantial improvements to one of the most promising therapies, cognitive therapy (CT), can be achieved by administering a carefully designed procedure to improve memory for the content of CT sessions. This is important because (a) memory deficits are common in MDD patients and (b) each CT therapy session typically covers a complex array of topics and various skills are taught.

DESCRIPTION (provided by applicant): Teens who exhibit a circadian tendency toward eveningness ('night-owls') follow a delayed sleep schedule, increasing activity later in the day and both going to sleep and getting up later, compared to morning-types ('larks'). The circadian tendency toward eveningness during adolescence arises from a confluence of psychosocial, behavioral and biological factors and is an important contributor to, and maybe even cause of, vicious cycles that escalate vulnerability and risk for poor health and major forms of psychopathology. Indeed, an evening circadian tendency has been associated with a wide range of adverse effects including poorer health, poorer academic performance, poorer self-regulation, greater use of substances, greater tendency for impulsivity, more depression and anxiety, greater emotional instability and more aggressive and antisocial behavior. While the biological shift toward eveningness during puberty may be difficult to modify, the psychosocial and behavioral contributors are modifiable. Moreover, modifying these contributors will eliminate key factors that exacerbate the biological shift. The proposed research will advance current knowledge on the role of eveningness as a mechanism contributing to poorer outcomes during adolescence. We aim to reduce eveningness among 10-18 year olds via an innovative intervention; the BRIGHT intervention (Biological Rhythm Intervention for Growing Healthy Teens) which integrates evidence-based treatments derived from basic research on the circadian system. We will randomly allocate adolescents with an evening circadian tendency, and who are 'at risk' in at least one of five health domains (emotional, cognitive, behavioral, social, physical), to either: (a) BRIGHT (n = 86) or (b) Psychoeducation (n = 86). Measures will be taken pre-treatment, post-treatment, and at 6 and 12 months post-treatment. The hypothesis to be tested is that BRIGHT, relative to Psychoeducation, will be associated with improvement in sleep and the five health-relevant domains at the end of treatment and that these gains will be maintained 6 and 12 months later. Planned secondary analyses include an evaluation of the effects of BRIGHT, relative to Psychoeducation, on change to an earlier endogenous circadian phase and change in the timing and intensity of light exposure. Mediation analyses will examine whether improved sleep or a change in the timing of light exposure contributes to reduced risk in the five health domains. Moderation analyses of variation in intervention effect due to baseline demographics (gender, age, pubertal status), baseline sleep and other risk measures will also be evaluated. Multiple methods include self report, ecological momentary assessment, behavioral tasks and biologic measures. Multiple informers include youth, parent/s and teacher. This research is a first step within a longer term plan to accelerate knowledge on the potentially powerful positive effects, for the developing neural system, of simple, disseminable psychosocial interventions specifically designed to target modifiable risk factors across adolescence.

DESCRIPTION (provided by applicant): Adolescent substance use is prevalent and associated with a broad range of adverse outcomes such as poorer academic performance, risky sexual behavior, mental health problems and increased risk of developing a substance use disorder. The aim of the proposed research is to pilot test a universal intervention to prevent substance use in youth by improving sleep. This indirect approach to substance use prevention is predicated on several lines of evidence: a) few programs directly targeting prevention of substance use in high school populations have been found to be effective, b) multiple cross-sectional and prospective studies have reported that insufficient sleep in youth predates and predicts substance use, c) multiple modifiable factors contribute to the current epidemic of insufficient sleep among youth (e.g., use of technology late into the night, irregular sleep-wake schedules from weekdays to weekends) and d) previous sleep interventions for youth have yielded promising results for improving sleep. We will pilot the 'Sleep Fitness' (SF) intervention. SF is an 8 session, scale-able, school-based prevention program for urban adolescents attending 9th grade (ages 14 to 16; n=300). The SF intervention draws on empirically- supported interventions for sleep problems, adapted to be effective in promoting healthful sleep patterns. The study uses a cluster-randomized experimental design (randomized at classroom level) in schools to test our hypotheses that the SF intervention will be more effective than a Psycho-education (PE) control condition in achieving improvements in sleep, substance use, and selected mental health outcomes (anxiety, depression). Outcome measures will be assessed at baseline, post-intervention, and 6 and 12 months later. We will further examine if reductions in substance use are mediated by improvements in sleep and mental health. All outcome analyses will control for perceived stress. The research conducted as part of this R34 application is intended to inform future large-scale testing of the intervention via: a) Establishig the feasibility of the intervention, study design, and measures in diverse high school settings; b) Generating initial effect size estimates for outcomes and potential moderators; and c) Further adaptation of the intervention for maximal effectiveness, including involvement of students at each school to clarify motivational levers for behavior change. The proposed program of research is the first to test a universal intervention to promote sleep as a means of reducing substance initiation and use. If positive, the findings will have major public health implications or adolescent health promotion as well as for the interactive relationships among sleep, substance use, and mental health among urban teenagers.

? DESCRIPTION (provided by applicant): Despite advances in treatment, severe mental illness (SMI) remains common, chronic and difficult to treat. SMI is defined as having at least one mental disorder that lasts for 12-months and leads to substantial life interference. Sleep and circadian dysfunctions are among the most prominent correlates of SMI, yet have been minimally studied in ways that reflect the complexity of the sleep problems experienced by people with SMI. In SMI, sleep and circadian dysfunction undermines affect regulation, cognitive function and physical health, predicts onset and worsening of symptoms and is often chronic even with evidence-based SMI treatment. Prior treatment studies have been disorder-focused-they have treated a specific sleep problem (e.g., insomnia) in a specific diagnostic group (e.g., depression). However, real life sleep and circadian problems are not so neatly categorized, particularly in SMI where features of insomnia overlap with hypersomnia, delayed sleep phase and irregular sleep-wake schedules. Accordingly, we aim to test the hypothesis that a Trans diagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) will improve functional impairment, disorder- focused symptoms and sleep and circadian functioning. We will recruit participants across DSM diagnoses and across common sleep and circadian problems. The elements of TranS-C are efficacious across SMI in research settings with research-based providers. The next step is to test TranS-C in community settings with community-based providers. Accordingly, we propose to conduct an 'efficacy in the real world' randomized controlled trial within Alameda County Behavioral Health Care Services (ACBHCS), the CMHC for Alameda County. Alameda County is the most ethnically diverse county in the Bay Area. We will recruit 120 adults diagnosed with SMI and sleep and circadian dysfunction within ACBHCS. Individuals will be randomly allocated to TranS-C (n = 60) or 6-months of Usual Care followed by Delayed Treatment with TranS-C (UC- DT; n = 60). TranS-C is modularized and delivered across eight 50-minute, weekly, individual sessions. All participants will be assessed before, immediately following treatment and again 6 months later. Mediation analyses will examine whether improved sleep and circadian rhythm functioning mediate improvements in primary outcomes. Moderation analyses will examine if intervention efficacy is related to previously reported risk factors including demographics, symptom severity, medications, site, and season of treatment as well as psychiatric and medical comorbidity. This application is responsive to NIMH priorities focusing on implementing effective services in the community as well as treatments that are personalized, generalizable and not constrained by diagnostic criteria. RDoC is addressed by recruiting participants across diagnoses and defining sleep and circadian dysfunction broadly. The 'sleep-wake' and 'biological rhythms' constructs from the Arousal and Modulatory Systems domain are intervention targets and outcome measures. Our long-term objective is to establish the potential for widespread dissemination of TranS-C.

Abstract of Research Supplement For an intervention to be effective, patients must adhere to its prescribed behavioral or cognitive changes. One factor that may impact such adherence is memory for treatment. Unfortunately, memory for treatment is often poor, particularly for health behavior change advice. We cannot act on advice we cannot remember, and so the proposed research supplement seeks to investigate the impact of The Memory Support Intervention, designed by the parent R01, on behavioral and cognitive change. By designing a mixed-methods interview, called The Cognitive Behavior Change Interview, and administering it to participants of the parent R01, the proposed research supplement examines the relationship between memory support and targets of behavior change outlined in the Theoretical Domains Framework. These targets, referred to as domains, are taken from 33 theories of behavior and are the building blocks of behavior change. Over a 2-year period, 60 adults with Major Depressive Disorder who successfully completed Cognitive Behavioral Therapy (CBT) in the parent R01 will be interviewed. We will compare the effects of CBT-as-usual to CBT+Memory Support to determine if The Memory Support Intervention better engages behavior change domains compared to CBT-as-usual. This research will contribute to the science of behavior change by identifying how we might better facilitate change in mental health interventions, and by bringing a stronger focus to the interplay between behavior and memory. !

Abstract Responding to RFA-RM-17-028, this R21 seeks to examine a novel interpersonal target; namely, parent-teen conversations about teen health behavior change. The scientific premise is that parents have profound impacts on teen risk and vulnerability. Yet parents receive minimal training in the elements of conversations that optimally inspire their children toward engaging in healthy behaviors. A theoretically grounded and reliable taxonomy of behavior change techniques (BCTs) will be used to scientifically derive the conversational elements, or micro-mechanisms, that reduce parent-teen coercion and conflict and facilitate upward spirals of healthy behavior change. We build on a recently completed NICHD-funded R01, in which a behavioral medical regimen to promote engagement in healthy sleep behaviors improved sleep and reduced risk on selected outcomes among 10-18 year olds. This behavioral medical regimen is delivered via 6 individually administered 50 minute sessions, known as the Transdiagnostic Intervention for Sleep and Circadian Rhythms (TranS-C). During the conduct of this research a significant impediment to youth behavior change was coercion and conflict with one or more parent/s. We will recruit parent-teen dyads in which the teen exhibits sleep problems and code two parent-teen conversations: (1) the last 10 minutes of each treatment session, referred to as the `End of Treatment Conversation' and (2) the discussion of a topic of frequent disagreement involving teen behavior change, referred to as the `Hot Topics Task'. Aim 1 involves an iterative process of developing and refining a method to experimentally manipulate parent use of BCTs (n = 8). The product will be referred to as the Parent Behavior Change Intervention (PBC-I). Aim 2 involves a small open trial of the PBC-I (n = 36) to verify target engagement and test if target engagement produces behavior change. Aim 3 examines potential mediators of the relationship between BCT frequency and engagement in sleep promoting behavior and address potential moderators of parent use of BCTs (age/sex of teen, parent/caregiver sex, one or two parent households). Assays from the SOBC repository feature in the methods (e.g., the `Hot Topics Task' is an adaptation of the Couples Conflict Task) and outcomes (i.e., Parent-Child Coercion Scale). Also, the measures are selected to represent various levels of explanation including self-report, behavioral tasks and actigraphy. In terms of the experimental medicine approach, the target is improved interpersonal process between parent and teen. Increased use of BCTs by parents in parent-teen conversations about youth behavior change is a manipulation check. The assays to verify target engagement include the Parent-Child Coercion Scale. The target will be engaged via the development of an experimental manipulation of the target in the form of a novel intervention (i.e., the PBC-I). This 2-year R21 will provide pilot data to prepare for larger scale research that harnesses a novel interpersonal target?the important role of parents in promoting sustainable health behaviors among their teenage children.

! Abstract An obstacle to the roll-out of evidence-based treatments (EBTs) for severe mental illness (SMI) is that the context for the implementation typically differs from the original testing context causing a lack of ?fit? between the setting and the EBT. We propose to evaluate if adapting a specific treatment to improve the contextual fit improves outcomes in a setting that typifies this challenge?community mental health centers (CMHCs). Following the Experimental Therapeutics Approach, the target is sleep and circadian dysfunction. In SMI, sleep and circadian dysfunction undermines affect regulation, cognitive function and physical health, predicts the onset and worsening of symptoms and is often chronic even with evidence-based SMI treatment. Prior treatment studies have been disorder-focused?they have treated a specific sleep problem (e.g., insomnia) in a specific diagnostic group (e.g., depression). However, real life sleep and circadian problems are not so neatly categorized, particularly in SMI. Hence, we developed the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) to treat a wide range of sleep and circadian problems experienced in SMI. With NIMH support, including a study in CMHCs, we established that TranS-C engages the target. Yet gaps remain: 1) Thus far, the TranS-C providers have been employed, trained and supervised by the university. We will determine if TranS-C can be effectively delivered by providers within CMHCs. 2) We will test a version of TranS-C that has been adapted to improve the fit and to address potential barriers to scaling TranS-C. The rigorous adaptation process used theory, data and stakeholder inputs. 3) We will study ad hoc adaptations made by providers to TranS-C. 4) We include two stages; namely, the Implementation Phase (2 years) and the Sustainment Phase (1 year). The latter responds to urgent calls to study the sustainability of EBTs. Guided by the Replicating Effective Programs (REP) framework, in this Hybrid Type 1, 4-year study, 8 CMHC clinic sites will be cluster randomized to either Standard or Adapted TranS-C. Then, within each CMHC site, patients will be randomized to immediate TranS-C or to Usual Care followed by Delayed Treatment (UC-DT). A total of 96 providers and 576 patients will participate. Patients will be assessed pre, mid and post-treatment and at 6 months follow-up. UC Berkeley will co-ordinate the research, facilitate implementation, collect data etc. Providers within an established network of CMHCs will implement TranS-C. SA1 is to confirm that both Standard vs. Adapted TranS-C, compared to UC-DT, improve sleep and circadian functioning and reduce functional impairment and disorder-focused psychiatric symptoms. SA2 is to evaluate the fit, to the CMHC context, of Standard vs. Adapted TranS-C. SA3 will examine if better fit mediates the relationship between treatment condition and patient outcome. This research will determine if sleep and circadian problems can be effectively addressed in SMI in CMHC settings, test two variations of TranS-C that each have unique advantages and focus on community providers and typical community patients.

Project Summary/Abstract Youth who exhibit an evening circadian chronotype (?night-owls?) follow a delayed sleep schedule, increasing activity later in the day and both going to sleep and getting up later, compared to morning types (?larks?). Eveningness arises from a confluence of psychosocial, behavioral and biological factors and is an important contributor to vicious cycles that escalate vulnerability and risk among youth. While the basic biological shift toward eveningness?initially triggered around the onset of puberty?may be difficult to modify, the psychosocial and behavioral contributors are modifiable. Supported by R01HD071065, we have conducted a ?treatment experiment? in which we delivered the Transdiagnostic Sleep and Circadian Intervention for Youth (TranS-C) to reduce eveningness among 10-18 year olds. We randomly allocated youth with an evening chronotype, and who were ?at risk? in at least one of five health-relevant domains (emotional, cognitive, behavioral, social, physical), to either: (a) TranS-C (n = 89) or (b) Psychoeducation (n = 87). While the results were promising, some drop off in treatment gains were observed. This is consistent with prior research documenting that a drop-off in the years following treatment is too commonly observed. Indeed, there have been calls to study if and how behavioral interventions are maintained (NOT-OD-19-040). Hence, in this revised renewal application, we propose to study the maintenance of behavior change by conducting a 6-year follow-up of the unique cohort of youth recruited for R01HD071065. The youth will be 16 to 26 years old. They will be assessed for sleep and circadian functioning and functioning in five health-relevant domains (emotional, cognitive, behavioral, social, physical) (SA1) and for their utilization of sleep health behavior (SA2). As a next step in this research program, we propose to evaluate if a Habit-based Sleep Health Intervention (?HABITs?)?a novel low-cost approach derived by leveraging the science of habit formation?improves the utilization of sleep health behavior and improves sleep and circadian outcomes and functioning in the five health-relevant domain outcomes in the short and longer term (SA3). An independent sample of youth who exhibit a high level of eveningness and are ?at risk? in at least one of the five health-relevant domains will be randomly allocated to HABITs alone or HABITs plus Text Messaging (?HABITs+Texts?) (n = 160). The text messaging portion is derived from learning theory, the Behavior Change Wheel and focus groups. We will also examine if sleep health behavior that has become habitual mediates the effects of treatment on improvement in sleep, circadian and health outcomes. Moderation analyses will examine if intervention effectiveness is related to age/developmental stage, sex, SES, racial/ethnic minority group and season of participation. This research will advance knowledge on longer-term outcomes, the role of eveningness as a mechanism contributing to poorer youth outcome and the value of leveraging of learning theory and the science of habit formation in health promotion.