Fetal Antecedents to Sex Differences in Depression: Implications for Comorbidity with Cardiovascular Risk. Jill M. Goldstein, Ph.D.

Transcription

1 Fetal Antecedents to Sex Differences in Depression: Implications for Comorbidity with Cardiovascular Risk Jill M. Goldstein, Ph.D. Departments of Psychiatry & Medicine, Harvard Medical School Brigham & Women s Hospital, Connors Center for Women s Health & Gender Biology 03/08/10

2 Fetal Origins of Sex Differences in Depression & Comorbidity with General Medicine ~ 2:1 female : male sex ratio in incidence of major depressive disorder (MDD) MDD and comorbidity with general medical disorders, e.g. cardiovascular disease (CVD), are the 4 th leading causes of morbidity & mortality worldwide We are testing hypothesis of shared etiologies to understanding sex differences in MDD and CVD Initiated during the sexual differentiation of the brain Involve disruption of fetal hormonal programming & consequent endocrine disruptions throughout lifecycle and sex differences in adulthood.

3 Fetal Origins Explaining Sex Differences Across the Lifespan Premorbid History Illness Onset Illness Course Fetal Development Birth Childhood / Puberty Young Adult Adulthood, Peri-menopauseincl. pregnancy Menopause Older Aging 3 Trimesters Day 1 ~10-13 ~21-24 ~25-40 ~47-50 s > 60 Age Age

4 Developmental Risk Factors for Depression Risk Factors Relative Risks Small for Gestational Age 2.0 Low Birthweight 3.5 Obstetric Complications nd Trimester Influenza nd -3 rd trimester Famine 1.6 (Kinney, 1998; Sacker, 1995; Preti, 2000; Bellingham-Young, 2003; van Os, 1997 Machon, 1997 Brown, 2000; Costello et a.,2007)

5 Developmental Risk Factors for Cardiovascular Disease (Hypertension) Risk Factors Relative Risks Small for Gestational Age 1.3 Low Birthweight 3.9 Pre-eclampsia 1.2 Maternal Prenatal Famine 1.4 Exposure ~Disruption of HPA circuitry in development (Barker, D, 1992; Johansson et al., 2005; Mogren et al., 2001; Stein et al., 2006)

6 1 st Trimester Sex Effects in Timing of Fetal Risk Factors for Depression Males -Malnutrition; Influenza 2 nd & 3 rd Trimesters -Hypoxia -Maternal Diabetes -- Females -Pre-eclampsia -- -Influenza -Maternal Cortisol = significant = trend

7 Organizational Effects of Gonadal Steroids on Fetal Brain Development Mid-gestation: Active period of sexual differentiation; e.g., testes begin to secrete T Testosterone: Direct effects and indirect effects through aromatization into estrogen Estrogen & Testosterone: Major impact on neuronal growth and development

8 Organizational Effects of Gonadal Steroids on Brain Development (cont.) Region-Specific Effects on: Hypothalamus, amygdala Hippocampus, MD thalamus Dorsolateral, orbital & medial prefrontal Basal forebrain, cingulate, insula Posterior parietal & primary visual cortex Corpus callosum, optic tract

9 Key Brain Abnormalities Implicated in Major Depressive Disorder Amygdala Hippocampus Hypothalamus (PVN, VMN, LHA) Orbital / Medial Prefrontal Cortex Cingulate gyrus (anterior & subgenual) MD Thalamus Basal Ganglia White Matter Abnormalities

10 Brain Regions Implicated in the Neural Control of Heart Rate Subcortical Regions Amygdala- Hippocampus Hypothalamus Brainstem: PAG Cortical Regions Medial/vmPFC Anterior Cingulate Insula Cerebellar vermis

11 Hormones, Depression & the Brain: Study Stress Response Circuitry & HPA Circuitry Stress Response Circuitry & MDD c.amygdala Hypothalamus (e.g. PVN, VMN, LHA) Hippocampus Ant. Cingulate Medial PFC & Orbitofrontal Cortex Brainstem (e.g. LC, PPN, PAG)

12 Hormonal Dysregulation in HPA & HPG in Depression Hypercortesolemia & Cortisol : DHEAS Ovarian dysfunction in women Low estrogen, high testosterone in women Low testosterone in men Nemeroff et al, 1984; Rubinow et al, 1999; Halbreich et al., 2001; Harlow et al., 2003

13 International Affective Picture System Stimuli Neutral Valence, Low Arousal Negative Valence, High Arousal Lang, et al., Psychopathology, 1993

14 Stress Response Hypoactivation in Recurrent MDD Women compared with Healthy Women Data Not Shown Here Manuscript under review, Holsen et al. 2010

15 In MDD: Parasympathetic control ( High Frequency HRV) Regions associated with HF-HRV and E 2 in MDD vs Controls Data Not Shown Here Manuscript in preparation, Lee, J-H, et al. 2010

16 ORWH-NIMH SCOR P50 MH : Fetal Antecedents to Sex Differences in Depression (Goldstein, PI; Tobet, Co-PI; Handa; Buka) NIMH-NHLBI RO1 MH074679: Shared Fetal Antecedents to Depression & Risk for CVD (Goldstein, PI) N=17,741 pregnancies in Boston & Providence, Mental, motor, sensory, and physical development of the offspring assessed through age 7 Maternal & cord blood stored; placental pathology assessed Re-recruit, interview & brain image as adults Offspring followed from prenatal through age 48 Case-Control Study (ORWH-NIMH SCOR P50 MH082679) Major Depressive Disorder: 500 cases; 700 controls Cohort Study (NIMH-NHLBI RO1 MH074679) : 300 Offspring exposed to FGR or Pre-eclampsia, known to disrupt HPA axis (from animal work) 300 Unaffected sibling controls

17 HF HRV in Adulthood -- Assessed under a Stress Challenge Significantly Associated with Fetal Inflammation, Depression and Gender Data Not Shown Here Manuscript in preparation, Goldstein et al. 2010

18 fmriof Stress Response Circuitry Deficits in Adults Exposed to Fetal Growth Restriction Data Not Shown Here In preparation, Goldstein et al. 2010

19 Summary Understanding sex differences in depression and its comorbid conditions is critical for sex-specific drug discovery One must take a life-course perspective for understanding medical implications of sex differences in the brain including the healthy brain and models of disease Taking a brain-body approach for understanding the impact of sex differences in the brain is fruitful Clinical and population-level research is critical for stimulating basic mechanistic animal models and vice versa

20 Clinical Neuroscience of Sex Differences in the Brain Director: Jill Goldstein, Ph.D. BWH HMS Harvard Departments of Psychiatry & Brigham & Women s Hospital v Laura Holsen, Ph.D. v Brandon Abbs, Ph.D. v Jennifer Walch, M.A. v Sarah Spaeth, B.A. v Ryann Milne-Price, B.A. v Eunice Ko, B.A. v Jill MacRae, B.A. v Kelimer Milad, Ph.D. v Nikos Makris, M.D., Ph.D. Other Primary Collaborators v Stuart Tobet, Ph.D. v Robert Handa, Ph.D. v Richard Sloan, Ph.D. v Susan Whitfield-Gabrieli, Ph.D Massachusetts General Hospital v Sara Cherkerzian, Sc.D. v Sharon O Toole, B.A. v Harlin Aizley, M.Ed. v Anne Peters Remington, M.A. v Larry J. Seidman, Ph.D. (BIDMC) v Stephen L. Buka, Sc.D. (Brown U) v Anne Klibanski, M.D. v Verne Caviness, Jr., M.D., D. Phil. Funding v National Institute of Mental Health v NIH Office for Research in Women s Health v Connors Center for Women s Health & Gender Biology, BWH

21 Extra Slides

22 Fetal Antecedents to Sex Differences in Depression: A Translational Approach (Goldstein, PI/ Tobet, Co-PI) ORWH-NIMH P50 MH082679:

23 Jill M. Goldstein, Ph.D., Director MISSION STATEMENT Interdisciplinary and translational focus on the roles of hormones, genes, and inflammatory factors on sex differences in brain development and adult brain morphology and function Investigating fetal and neonatal programming of sex differences in psychiatric disorders Disorders of study: psychoses, depression, anorexia nervosa, disorders of aging, & co-morbidity of psychiatric with general medical disorders Domains of study: stress response circuitry, memory, working memory, and food motivation reward circuitry Visit for more information.

24 Significant Normal Sex Differences in the Brain, Relative to Brain Size Indicates structures that are larger in the female brain, relative to cerebrum size Indicates structures that are larger in the male brain, relative to cerebrum size Goldstein et al. Cerebral Cortex, 2001

25 Sex Differences in Stress Response Circuitry Men Women during Early follicular Men Women during Late follicular / Mid-cycle ACC ACC mpfc vmpfc L_AMYG L_AMYG Hipp mpfc/ sfg OFC HYPOTH HYPOTH PAG Hipp 0 Advisory Committee to the Connors Center for Women s Health and Goldstein, Gender Biology: et al. t-scalemeeting #1 J Neuroscience, 2005; 2010