Rachel Manber - US grants

This project concentrates on algorithmic aspects of problems in combinatorics, emphasizing the interplay between combinatorics and qualitative matrix theory. Qualitative matrix problems arise in situations where data is imprecise, for example, where knowledge is limited to qualitative information. One problem is to derive more qualitative information from qualitative data, such as determining the sign pattern of the solution to a linear system of equations from that of its coefficients. Graph theoretic problems relating to such signsolvability will be studied. In many real life situations, the data available is not in the form of numbers, but rather the information may be only that each number of interest is positive or negative. Mathematical methods to extract further information from such data are being developed, and have bearing on such areas as ecology, chemistry, mechanics, and energy planning.

DESCRIPTION (provided by applicant): Context: The purpose of the proposed Exploratory/Developmental R21 Grant is to pilot test a combined treatment of an antidepressant medication and cognitive-behavioral therapy for insomnia (CBTi) in patients with depressive disorders who have concomitant difficulty initiating and/or maintaining sleep. The proposed combined approach targets the patients' insomnia, because this common depression symptom is often associated with less favorable outcome of standard treatment and with increased risk of relapse. Specific aims: 1) To test whether the proposed intervention improves response to acute treatment (12 weeks) for depression, as measured the percent of patients who remit and the time course to remission, relative to the control treatment; 2) To test whether the proposed citalopram + CBTI intervention enhances longer-term outcome by reducing the proportion of participants who relapse during a 6-months follow-up phase, relative to the control treatment. Research Design and Method: In this prospective, randomized, controlled study, participants will be randomized to receive 12 weeks of acute treatment with the SSRI citalopram plus either CBTI or a validated, placebo psychotherapy for insomnia. Participants will be followed-up for 6 months after the end of acute treatment phase. Participants will be transitioned to community care during the first follow-up month. Participants: Participants will be 58 men and women ages 18 to 65 who 1) meet DSM-IV criteria for Major Depressive Disorder; 2) have a score greater than or equal to14 on the first 17 items of the 24-item Hamilton Depression Rating Scale (HRSD); 3) have difficulty initiating sleep (sleep onset latency > 30 minutes) and/or maintaining sleep (wake after sleep onset > 30 minutes per night at least 3 nights per week), to be confirmed by one week of sleep diary recording. Participants will also have to meet all study exclusion criteria. The ethnic distribution of the sample will be representative of the ethnic distribution in the San Francisco Bay Area. Women-to-men ratio is expected to be 2:1 as it is the case for depression. Main Outcome Measure(s): The primary outcome measures are the HRSD and the depression portion of the SCIDIV, to be administered at baseline, at the end of weeks 1, 2, 4, 8, and 12 of the acute phase, and at the end of 1, 2, 3, and 6 months of the follow-up phase. Other important measures include the Beck Depression Inventory (weekly), measures of sleep (diaries and wrist activity monitors, weekly) and measures of provider and patient expectations, adherence, and compliance. Expected Outcomes: We hypothesize that the group of patients who receive the combination of citalopram and CBTI will have higher remission and partial response rates following acute treatment and lower relapse rates during follow-up as compared to the group that receive citalopram and placebo psychotherapy for insomnia. The study will assess the feasibility and acceptability of the combination of the two treatments and will provide estimates of effect sizes, and attrition rate. The findings from the proposed pilot study will inform the design of a subsequent full-scale randomized controlled trial.

DESCRIPTION (provided by applicant): The purpose of the proposed study is to improve depression outcome for individuals with major depressive disorder and co-morbid insomnia by combining state-of-the-art antidepressant algorithm (MED) and empirically supported cognitive-behavioral therapy for insomnia (CBTI). Insomnia is an important aspect of depression and is only incompletely addressed by existing treatments. As persistent insomnia is both a risk factor for depressive relapse and a more general indicator of disease severity and poor prognosis, identification of more effective therapies for depressed patients with insomnia has public health significance. Therefore, we propose a prospective, randomized controlled study that will test the efficacy of the proposed strategy in individuals with major depressive disorder and comorbid insomnia. The primary aim is to test whether the proposed intervention increases rates of remission from depression following 16 weeks of treatment compared with a control intervention. A secondary aim is to test whether the proposed intervention enhances longer-term outcome by reducing the proportion of participants who relapse during a 6-months follow-up phase, relative to the control treatment. Participants will be 300 men and women, drawn from 3 study sites, so that the sample is diverse with respect to race and ethnicity. Participants will meet DSM-IV criteria for Major Depressive Disorder, score 18 or higher on the 17-item Hamilton Depression Rating Scale (HRSD) and have difficulty initiating or maintaining sleep that is clinically significant (DSM-IV criteria for insomnia). After the end of the acute treatment phase, participants will be transitioned to community care and will be followed-up for 6 months. The primary outcome measures are the HRSD and the depression portion of the SCID-IV, to be administered by masked raters at baseline, biweekly during the acute phase, and monthly during the follow-up phase. Secondary measures include measures of sleep and functional outcome. Relevance: Achieving and maintaining remission is the desired clinical goal for MDD. By evaluating the efficacy of a treatment strategy that combines a standardized antidepressant pharmacotherapy with a non- pharmacological therapy that targets insomnia (CBTI), the proposed study, could lead to clinically meaningful improvement in the lives of many patients with MDD and insomnia. Insomnia is a common problem in patients with major depression, and is associated with poor response to depression treatment, recurrence of depression, and increased risk for suicide. This study will examine whether a specific psychological-behavioral treatment for insomnia, in conjunction with state-of-the-art antidepressant medication treatment, improves the outcomes of patients with major depression and insomnia. The results of this study may offer a method for improving the treatment of major depression without the use of additional medication.

DESCRIPTION (provided by applicant): Consistent with the NINR strategic plan to identify strategies that will reduce the long-term adverse consequences of poor maternal and reproductive health in minorities and underserved populations, this proposal aims to evaluate a primary care based intervention for maternal insomnia disorder (MID) among economically, educationally, racially, and ethnically diverse samples of pregnant women. MID, which encompasses insomnia during pregnancy and postpartum, is associated with adverse consequences to the mother and her family. These include increased risk for preterm birth, births of infants small for gestational age, cesarean birth, poor maternal infant attachment, worsening of the marital relationship, and increased risk for perinatal depression. Cognitive Behavioral Therapy for Insomnia (CBTI) is an effective treatment for insomnia even when factors outside of an individual's control interfere with sleep. CBTI is effective for postpartum insomnia, despite sleep disruption caused by the need to attend to an infant at night. TIPS (Tips for Infant and Parent Sleep) is a two- session, nurse-administered educational intervention aimed at optimizing infant sleep. We propose to evaluate the efficacy and effectiveness of an integrated CBTI+TIPS treatment. To maximize the public health impact, improve access, and reduce treatment barriers (stigma and transportation issues), treatment will be delivered by nurses in community obstetrical clinics, where women receive care during their pregnancy until six weeks postpartum. This will be the first study to test the efficacy of CBTI for the treatment o MID. Primary outcomes, for which the study is optimally designed and sufficiently powered, are maternal sleep and infant sleep. Secondary outcomes, for which we are either unable to estimate power or expect to be under powered, are pregnancy outcomes (proportion of infants who are small for gestational age), maternal-infant attachment and its biological marker, oxytocin, and maternal wellbeing (depressive symptom severity and quality of life). The Aims of this research are to: (1) evaluate the efficacy of CBTI+TIPS in terms of a) maternal sleep during pregnancy and b) maternal and infant sleep during the postpartum; (2) evaluate the effectiveness of CBTI+TIPS on measures beyond sleep, including number of infants born small for gestational age, b) maternal-infant attachment (based on observations of a parent-child interactions with the NCAST), c) oxytocin levels, d) maternal depressive symptom severity, and (e) maternal quality of life.

Insomnia and use of sleep medications increase around age 50 and affect approximately one in three middle aged and older adults. Untreated insomnia is associated with a range of negative sequelae, including several, such as visual impairment, cognitive impairment, imbalance, and greater risk for falls that are specific to this older age group. In primary care, insomnia is treated with hypnotics; but even the newer and safer hypnotics are associated with cognitive impairment and risk of falls. Cognitive behavioral therapy for insomnia (CBTi) offers a viable alternative to hypnotic medications and could reduce their use, as recommended by the American Geriatric Society Beers Criteria. CBTi is a brief insomnia-focused psychotherapy that is as efficacious as a variety of hypnotic medications in the short-term and superior over the long-term. Although it is the recommended first line treatment for insomnia by the American College of Physicians, access to this safe and effective treatment is limited by current models of therapist-led delivery. Broad long term objectives: This proposal aims to fill in the science-to-service gap between proven efficacy of CBTi and future large scale implementation. We have developed and propose to test a primary-care-friendly stepped-care CBTi model (STEPPED CARE) that offers an easy to use Decision Checklist for matching delivery of CBTi to individual patient characteristics so that patients will begin treatment with the appropriate delivery mode. Specific aims: We propose to compare STEPPED CARE to an ONLINE ONLY program. We will focus on comparative effectiveness (Aims 1) and testing the Decision Checklist (Aim 2), as well as evaluating other aspects of the two-steps STEPPED CARE program, including the specific Checklist Criteria and the added benefit of the second step for those with insufficient response to the first step (Aim 3). We will perform a rigorous mixed-methods formative evaluation to guide future implementation and dissemination potential (Aim 4). Results will yield a simple and effective way for primary care providers to prescribe CBTi to middle aged and older adults. Methods: Participants will be randomized to receive ONLINE ONLY or STEPPED CARE CBTi. Primary outcomes are insomnia severity and the amount of hypnotic medications used, assessed over a 12 month period. A mix of quantitative and qualitative methods will be used to collect data from multiple steak-holders about the potential for reach, adoption, implementation, and maintenance of the two approaches. Impact: The proposed STEPPED CARE model for delivering CBTi has the potential to improve sleep, reduce use of hypnotic medication, and promote safety and wellbeing of middle aged and older adults. Importantly, it offers convenient access to treatment for patients, while using resources efficiently. Efficient use of resources will result from provision of the less expensive online CBTi as a first line of treatment to those who are likely to benefit from it so that the limited therapist-led treatment resources can be focused on patients who are less likely to benefit from online CBTi and to those for whom online treatment was unsuccessful.

Project Abstract: This is an application for competitive renewal of an institutional training grant. The intent of this program is to prepare clinically trained MDs, MD/PhDs, and PhDs for a career in preclinical, clinical and translational research in mood, eating, or anxiety disorders. Physician trainees are eligible if they have completed the PGY 3 year of psychiatry training or PGY 4 year of neurology; psychology trainees are eligible if they have completed an APA approved clinical internship. The program is centered on mood, anxiety, and eating disorders, reflecting the ongoing and long-standing research interests of the core faculty involved in the program. Fellows work with a mentor who is a member of the Stanford University faculty for a period of two years on projects related to the phenomenology, clinical biology (including brain imaging), basic neuroscience (including optogenetics), and translational treatment outcomes in the three major classes of disorders. The Program includes formal seminars in research methodology, clinical research design and statistical analysis. Additionally, all fellows are required to take a course focused on ethics in medical research. Trainees also have access to a wide array of more specialized course work. Mentorship emphasizes development of an independent career and fellows are expected to design and conduct their own research projects and apply for their own funding to support their research post fellowship. An Executive Committee, representing the principal areas of research, provides program oversight including continual review of both the program and trainees' progress towards their individual goals. The program also offers summer stipends for medical students interested in psychiatric research. The Program is now in its 25th year. Fifty postgraduate trainees (12 MDs, 10 MD/PhDs and 28 PhDs) and 28 pre-doctoral summer medical students have been in the program in the past 15 years. Graduating fellows have been successful in obtaining faculty positions around the US and Canada, as well as in obtaining their own research funding?NIH Career Development Awards, R01s; NIMH Director Awards (e.g., Pioneer Awards), NARSAD Young Investigator Awards, Klingenstein Foundation Awards, etc. Six fellows left before completing the full 2 years: four accepted tenure line faculty positions and two segued into full-time clinical positions at community-based programs, such as the PAVA. Building on the success of our program in attaining its goals, we aim to continue to train promising clinically trained fellows to become independent mental health researchers.