Lori Altshuler - US grants

This proposal outlines a Multi-Institutional Collaborative Research (R-10) Project in which we will evaluate the risk for relapse in pregnancy among women with a history of major depression who either maintain or discontinue antidepressant treatment around the time of conception. The primary aims of this investigation are (1) to establish whether relapse/recurrence rates are lower in women who maintain versus discontinue antidepressant treatment during pregnancy; (2) to identify clinical and psychosocial predictors of relapse during pregnancy in those who maintain or discontinue antidepressants; and (3) to assess perinatal outcome and its relationship to depressive symptomatology in pregnancy. The three participating sites for this investigation include the Perinatal and Reproductive Psychiatry, Clinical Research Program, Massachusetts General Hospital, Harvard Medical School (Dr. Cohen). Women's Life Center and Mood Disorders Research Program, UCLA (Dr. Altshuler), Emory University School of Medicine (Dr. Stowe). Subjects who have been euthymic for at least three months and who have not discontinued antidepressant more than six weeks prior to conception will be accessioned early in their pregnancy and will be followed longitudinally from the first trimester of pregnancy through delivery. Given the prevalence of major depression during the childbearing years and the growing numbers of women who receive treatment with antidepressants, it is crucial to identify those women who may be able to safely discontinue antidepressant treatment during pregnancy as well as those who are particularly vulnerable to relapse. Delineating of these subgroups provides an opportunity to screen for women "at risk" for relapse and allows for thoughtful treatment plan.

This project proposes to study biological and clinical correlates of functional recovery in bipolar subjects after an admission for mania. Specifically, we will explore whether neurocognitive, neuroanatomical or subsyndromal depression variables predict time to functional recovery or persistent functional impairment. We will 1) use a cross-sectional design to test specific hypotheses about factors that may discriminate between bipolar individuals who have concurrent functional recovery with symptomatic recovery versus those whose functional impairment persists after symptomatic recovery; 2) use a prospective design with multiple assessments over time in those patients who are functionally impaired at the time of symptomatic recovery to carefully track the temporal relationship (lag) between symptomatic recovery and functional recovery and test specific hypotheses about predictors of eventual functional recovery, and 3) contrast extreme outcome groups (i.e. those who have rapid functional recovery and those with markedly persistent residual impairment) to explore a hypothesis about brain structure and function in the two groups. An important feature of this study is that it will be done in the context of continuous, competent pharmacotherapy follow-up, thus reducing the potential for functional outcome to be confounded by suboptimal treatment and/or non-compliance. Identifying predictors of functional disability would be a first step toward understanding how and why functional impairment occurs; and would allow for appropriate rehabilitation/intervention strategies to be developed.

[unreadable] DESCRIPTION (provided by applicant): This application is a competitive renewal for a K24 award "fMRI in Bipolar Illness." The applicant proposes to acquire training in functional connectivity analyses of fMRI data and in techniques that map brain functional (fMRI) data to brain structural (sMRI) data. Knowledge in these areas will be critical in further elucidating the functional (neural) circuit abnormalities in bipolar disorder and the anatomic basis, if any, for these neural abnormalities. Learning these techniques will broaden the applicant's expertise in neuroimaging and will allow her to be an even stronger mentor. The applicant proposes to work extensively with the Brain Mapping Division and Laboratory of Neuroimaging (LONI) at UCLA, as well as with offsite collaborators, to learn these cutting edge techniques for image analysis. Additionally, the applicant seeks to develop greater familiarity with neurocognitive tasks that can be adapted for use during fMRI scans, and to obtain basic familiarity with the field of molecular genetics. Greater understanding in these areas will guide her future research endeavors. The applicant proposes to 1) assess whether unmedicated euthymic bipolar subjects early in their course of illness have limbic (amygdala) hyperactivity and orbitofrontal hypoactivity (previously observed in treated patients while manic or euthymic); 2) map functional scans to structural scans to explore the relationship of brain structure to these areas of activation or attenuation seen in fMRI and 3) use functional connectivity analyses to explore whether the normal (inhibitory) modulatory effects of prefrontal regions over the amygdala are dampened in the euthymic bipolar subjects compared to control subjects. Additionally, functional connectivity analyses will be conducted using the fMRI data obtained during the first K24 period, where patients were in the manic and depressed states. Bipolar illness is one of the top ten causes of disability worldwide, and effects 3% of the U.S. population. The neurophysiologic basis of this disorder remains unknown. Elucidating the functional neuroanatomic underpinnings of this disorder is a critical first step in developing targeted treatment. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The postpartum period is a time of heightened risk for the emergence of psychiatric illness, particularly in women who already have a history of mood disorder. Given the prevalence of depressive disorders during the childbearing years, it is crucial to identify women who are at highest risk for new onset or recurrence of depression during the postpartum period. Identification of those women at greatest risk for postpartum depression may allow for interventions that would limit maternal morbidity associated with untreated postpartum depression. This proposal outlines a multi-institutional collaborative research project (R01) in response to PA-00-074, in which risk for postpartum depression will be evaluated in women with histories of major depressive disorder. Subjects who have had at least one episode of DSM-IV major depression will be followed prospectively from late pregnancy (32-36 weeks gestation) up to six months after delivery using a series of standardized instruments. The primary aims of this investigation are (1) to identify clinical and psychosocial predictors of postpartum depression and functional impairment and (2) to determine the extent to which treatment (pharmacologic, nonpharmacologic or a combination) proximate to delivery modulates risk for postpartum relapse. How clinical and psychosocial variables including history of postpartum depression, severity of past depression, number of previous episodes, age at illness onset, depression during pregnancy, and social support affect risk for postpartum depression, as well as psychosocial functioning, will be investigated. The current submission is a natural extension of an ongoing academically productive collaboration in which risk for depressive relapse is evaluated in pregnant women with histories of major depression who either discontinue or maintain antidepressant treatment. This proposal provides an opportunity to study a rigorously followed population into a period of risk -- the postpartum period -- and to investigate the factors that confer or modulate risk for depression at this time. The three participating sites for this investigation include the Perinatal and Reproductive Psychiatry Clinical Research Program at the Massachusetts General Hospital, Harvard Medical School (Drs. Cohen, Nonacs and Otto), the Women's Life Center and Mood Disorders Research Program at UCLA (Dr. AItshuler, Dr. Hendrick), and the Emory Women's Mental Health Program at Emory University School of Medicine (Dr. Stowe).

DESCRIPTION (provided by applicant): This grant proposes to explore the optimal treatment approach to depression in the patient with bipolar II disorder (BDII). BDII represents a critically understudied and important serious mental illness and is characterized by periods of major depression and periods of hypomania. There is now clear recognition of the stability of this diagnostic phenotype of bipolar disorder over time. Further research has revealed that the depressive symptoms in BDII occur frequently and the consequences of this can be severe, as the suicide risk is suggested to be higher than that in patients with BDI. The standard of care in treating depressed BDII patients is to use a mood stabilizer alone or a mood stabilizer and an antidepressant. However, there are virtually no controlled acute treatment trials specifically in patients with BDII to support the validity of these recommendations. Many patients with BDII dislike the idea of taking mood stabilizers and prefer instead to take only an antidepressant. Some open trials suggest good safety and tolerability of antidepressant monotherapy. Yet concerns exist that antidepressant monotherapy could destabilize mood in these patients. Whether taking an antidepressant as monotherapy actually exacerbates the illness (i.e., increases switches into mania or cycling, or intensifies hypomania) has never formally been tested. We propose a randomized, double-blind 16-week acute clinical trial comparing the efficacy and safety of sertraline monotherapy v. lithium monotherapy v. lithium plus sertraline combination in 207 patients with BDII in an acute depressive episode. The application is designed to assess acute treatment response, switch rates into hypomania/mania and side effects in patients with BDII depression undergoing treatment approaches. Primary aims are to compare the 3 treatment strategies in terms of effectiveness, adverse events (e.g., switch rates) and side effects (e.g., tolerability). We hypothesize that all treatment approaches will be equally efficacious in reducing depressive symptoms, but that there will be differences between treatments in regard to switch rates into hypomania/mania. We also hypothesize that the frequency of side effects will be significantly less in patients on SSRI monotherapy. Thus, secondary aims include assessment of patient satisfaction, which may affect compliance in the clinical setting.

[unreadable] DESCRIPTION (provided by applicant): Bipolar disorder is a chronic mental illness affecting up to 3% of the population. It is one of the top ten causes of disability worldwide, yet the neurophysiologic basis of the disorder remains unknown. The use of functional neuroimaging techniques (e.g. fMRI, PET) in combination with neuropsychological (activation) paradigms has served to deepen our understanding of regional brain dysfunction in psychiatric disorders, but the application of such types of functional studies to patients with bipolar disorder has been minimal. This application proposes to combine a neuropsychological paradigm with fMRI data to map functional data to structural MRI data. This has not, to our knowledge, been attempted in the bipolar population. We will use novel computational anatomy techniques to develop average anatomic representations for coregistration with fMRI images in bipolar subjects and compare this to normal controls. This approach will be used to assess the relationship between brain functional deficits seen on fMRI in patients with bipolar disorder and the structural integrity/volume of brain gray and white matter. Using such methods, we hope to clarify whether gray and/or white matter structural deficits are associated with the reduction in neural activity seen in fMRI. This exploration may clarify the neural/biologic underpinnings of bipolar disorder. The discovery of specific anatomic abnormalities that are associated with clear functional consequences may direct the pursuit of targeted neuropharmacologic development and lead to better treatments for bipolar patients. [unreadable] [unreadable] [unreadable]

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Primary Aims: 1. To determine the switch rate into hypomania or mania when treating patients with BD II depression with SSRI antidepressant (sertraline) monotherapy, mood stabilizer (lithium) monotherapy or the combination (lithium plus sertraline). 2. To assess the relative tolerability (side effects rate) of sertraline monotherapy vs. lithium monotherapy or the combination. 3. To determine good outcome rates defined as good antidepressant response without manic switch or unacceptable side effects.

DESCRIPTION (provided by applicant): The use of functional neuroimaging techniques (e.g. functional magnetic resonance imaging-- fMRI) in combination with neuropsychological activation paradigms has served to deepen our understanding of regional brain dysfunction in psychiatric disorders, but the application of such types of functional studies to patients with bipolar disorder has been minimal. Bipolar disorder is one of the top ten causes of disability worldwide, yet the neurophysiologic basis of the disorder remains unknown. In this proposal, we will use novel computational anatomy techniques to develop average anatomic representations for coregistration with fMRI images in bipolar subjects and compare this to normal controls. Using such methods, we hope to clarify whether orbitofrontal gray and/or white matter structural deficits are primarily associated with the reduction in neural activity seen in fMRI. Specifically, we will 1) assess disease-specific alterations in neural function in the orbitofrontal cortex using fMRI tasks that activate this region;2) explore the underlying structural etiology of orbitofrontal hypofunction using novel techniques to measure gray and white matter;and 3) determine the relationship between alteration in gray matter (cortical thickness) or white matter volume and neural function. This has not, to our knowledge, been attempted in the bipolar population. This exploration may clarify the neural/biologic underpinnings of bipolar disorder. The discovery of specific anatomic abnormalities that are associated with clear functional consequences may direct the pursuit of targeted neuropharmacologic development and lead to better treatments for patients with bipolar disorder. PUBLIC HEALTH RELEVANCE: The neurophysiologic basis of bipolar disorder remains unknown. This application proposes to compare the brain functional deficits in persons with bipolar disorder (observed during the performance of neuropsychological tasks during functional MRI) to gray and white matter volume data obtained from structural MRI. We hope to clarify whether gray and/or white matter structural deficits are associated with the reduction in neural activity seen in fMRI and in turn clarify the neural/biologic underpinnings of bipolar disorder.

DESCRIPTION (provided by applicant): Bipolar disorder affects up to 3% of the population and is one of the top 10 causes of disability worldwide, yet the underlying neurophysiologic causes of the disorder remain elusive. The fluctuation of emotion that is the disorder's hallmark suggests a dysfunction of brain networks that normally maintain emotional homeostasis. Recent neuroimaging studies that have combined fMRI with neuropsychological paradigms known to activate limbic structures have revealed limbic hyperarousal and orbitofrontal hypoactivation in bipolar subjects, when manic and even when euthymic. Whether this persistent limbic hyperreactivity represents an abnormality in local neuronal function or an abnormality in an inhibitory connection to limbic structures remains to be fully elucidated. In this application we propose to use novel techniques to assess the relationship between white matter integrity and neuronal function. Using DTI-tractography we will examine white matter connections between brain regions (anatomical connectivity) in the same persons for which we simultaneously collect functional (fMRI) data. We will specifically look for abnormalities in structural white matter connections between the amygdala and orbitofrontal cortex that may explain increased amygdala function and reduced OFC-amygdala functional connectivity seen in prior studies. Collection of white matter tract data and functional neuroimaging data at the same time in the same subjects has never before been reported in the bipolar population. The results of this exploratory analysis could significantly advance our knowledge about the etiology of functional abnormalities of the brain seen in bipolar disorder. Results from these exploratory data could lay the groundwork for a future R01 application. PUBLIC HEALTH RELEVANCE: Bipolar illness is one of the top 10 causes of disability worldwide, yet the underlying neurophysiologic causes of the disorder remain unknown. In the proposed study we will use novel research tools to concomitantly obtain "structural" neuroimaging data of the white matter tracts that interconnect neurons and "functional" neuroimaging data that indicates level of neuron activity in different brain regions to determine the relationship, if any, between abnormal brain structure and abnormal brain function. This has the potential to markedly advance our understanding of underlying neurophysiologic causes of brain abnormalities in bipolar illness.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. N/A