#CHAIR2015. Miami, Florida. September 24 26, JW Marriott Miami. Sponsored by

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1 #CHAIR2015 September 24 26, 2015 JW Marriott Miami Miami, Florida Sponsored by

2 If We Know So Much About Neurobiology, Why Do We Know So Little About Depression? David R. Rubinow, MD, PhD University of North Carolina at Chapel Hill School of Medicine Chapel Hill, NC

3 David R. Rubinow, MD Disclosures Grants: National Institutes of Health (NIH) (2 RO1s; T32); The Foundation of Hope Advisory Board Advisory Boards: Sage Therapeutics (Clinical Advisory Board); Sheppard Pratt-Lieber Research Institute (Scientific Advisory Board) Other Financial or Material Support: Editorial Board of Dialogues in Clinical Neuroscience.

4 Learning Objective Explore the role of hormones in the neurobiology of depression.

5 Why Do We Know So Little About Depression? Diagnostic heterogeneity Associational studies Group data Stimulus-specific Cross-sectional physiology Context

6 Group Data Meaningful subgroups are ignored

7 Why Do We Know So Little About Depression? Diagnostic heterogeneity Associational studies Group data Stimulus-specific Cross-sectional physiology CONTEXT

8 Physiology is Context- Dependent Developmental Stage Age Gender Species/tissue/cell Environment Genome

9 Context-Dependent (and Determining) Processes in Depression STATE SWITCH SUSCEPTIBILITY How does the reproductive endocrine system help us understand these processes?

10 PMDD: A State Model Poor affective/behavioral modulation/ inhibition Negative cognitive bias Amplified interpersonal sensitivity Disturbed social cognition Decreased reward Impaired state change

11 Steinberg E, et al. Depress Anxiety. 2012;29(6): PMID:

12 Best 100 Menstrual Cycle Switch- Patient C. Day 1 Day 2 Day 3 Day 4 Day Worst 0 ANXIETY Menses April Steinberg E, et al. Depress Anxiety. 2012;29(6): PMID:

13 100 Menstrual Cycle Switch- Patient N. Day 1 Day 2 Day 3 Day April Menses Steinberg E, et al. Depress Anxiety. 2012;29(6): PMID: Anxiety

14 Context-Dependent Affective Regulation: Reproductive Insights What is the signal? How do we account for variance in response? What are the determinants of the composition and regulation of affective state?

15 Steroid Cascade Hu J, et al. Nutr Metab (Lond). 2010;7:47. PMID:

16 Testosterone: Metabolism Determines Actions Estradiol Dihydrotestosterone Androsterone Etiocholanolone Kushner PJ, et al. J Steroid Biochem Mol Biol 2000;74: Wu RC, et al. Endocr Rev 2005;26: PMID: McEwen BS. J Appl Physiol 2001;91: PMID: αAndrostanediol

17 Growth Factors EGF TGFa IGF-1 Neurotransmitters Dopamine Pl 2 E R Hormones E 2 Ca ++ camp G R SRC-1 Estrogen Receptors r Akt Mitogen-activated protein kinase (MAPK) CREB CBP P300 c-jun/c-fos Co Regulator CRE AP-1 ERE PRE Courtesy of David Rubinow, MD

18 Hormones E 2 Estrogen Receptor CoReg ERE Courtesy of David Rubinow, MD

19 LEU384 LEU525 HIS524 GLU353 11β! ARG394 MET421 Ligand 250Å 3! Pocket 350Å 3! 7α! 16α! Courtesy of J. Katzenellenbogen PHE404 Estradiol-ERα Ligand Volume 250 Å 3! Actual Pocket Volume 450 Å 3!

20 ASP351 LEU525 HIS524 GLU353 ARG394 PHE404 MET421 Courtesy of J. Katzenellenbogen Raloxifene-ERα

21 Gonadal Steroids: A Window into Affective Dysregulation Why do we think that gonadal steroids have a role in affect regulation?

22 Models of Depression Neurotransmitter deficiency Stress/CRH Neuroplasticity Cellular Energetics Signal Trafficking (e.g., p11) Network dysregulation Inflammation Rubinow DR, Girdler SS. Depress Anxiety. 2011;28(4): Erratum in: Depress Anxiety ;28(6):519. PMID:

23 How Does the Brain Work? Signal transmission and processing Clusters of neurons into networks: functional outcome Networks dynamically assemble Synchronization of neuronal firing conveys information Distributed neurons provide context Pessoa L. Nat Rev Neurosci. 2008;9(2): PMID: ; Fröhlich F. Dialogues Clin Neurosci. 2014;16(1): PMID:

24 Estradiol Rapidly Induces Synaptic Connections Srivastava DP, et al. J Neurosci. 2011;31(45): PMID:

25 Models of Depression Neurotransmitter deficiency Stress/CRH Neuroplasticity Cellular energetics Signal trafficking (e.g., p11) Inflammation Network dysregulation Schiller CE, et al. Comprehensive Physiology. In press, 2015; Greicius MD, et al. Biol Psychiatry. 2007; 62: PMID: ; Liston C, et al. Biol Psychiatry. 2014;76(7):517-26; Sheline YI, et al. Proc Natl Acad Sci U S A. 2009;106(6): PMID: ; Sheline YI, et al. Proc Natl Acad Sci U S A. 2010;107(24): PMID: ; Mars RB, et al. Front Hum Neurosci. 2012;6:189. PMID:

26 Network Dysfunction in Depression Default Mode Network Social Cognition Network Reward Network Affective Regulation Network Salience Network Schiller CE, et al., Comprehensive Physiology. In press, 2015.

27 PMDD: A State Model Poor affective/behavioral modulation/ inhibition (affective regulation network) Reduced social interaction; disturbed social cognition; amplified interpersonal sensitivity (social cognition network; salience network) Decreased reward (reward network) Impaired state change Schiller CE, et al. Comprehensive Physiology. In press, 2015.

28 E2 Activates the Default Network Estradiol vs. Leuprolide (n = 32) 80 Medial Prefrontal Cortex Relative rcbf Est Leup Prog As compared with ovarian suppression, estradiol replacement increases regional cerebral blood flow (rcbf) in regions of the default network, including the medial prefrontal cortex and precuneus p =.005, uncorrected; Est = estradiol; Leup = leuprolide; Prog = progesterone Schmidt PJ, et al., Unpublished data. Relative rcbf 85.5 Precuneus Est Leup Prog

29 Steroids Regulate Prefrontal Cortex Functional Correlations With Hippocampal Formation Activity Leuprolide Alone Progesterone Add-Back Estrogen Add-Back Berman KF, et al., Proc Natl Acad Sci U S A. 1997;94(16): PMID:

30 Self-stimulation of NTS mpoa Neurons Varies Across the Estrous Cycle ChR2 female in proestrous Optical self stimulation 20 Hz Is this effect modulated by steroid hormones? McHenry J, et al., Unpublished data. Magnitude of operant responding is highest in proestrous

31 Greater reward circuitry activation in the follicular phase: anticipation of uncertain rewards Dreher JC, et al. Proc Natl Acad Sci U S A. 2007;104(7): PMID:

32 Gonadal Steroids: A Window Into Affective Dysregulation Why think that gonadal steroids have a role in affect regulation? Modulate all pathophysiologic systems implicated in depression Modulate brain regions and networks disturbed in depression Antidepressant effects Schmidt PJ, et al., Am J Obstet Gynecol. 2000;183(2): PMID:

33 E2 Efficacy in Treatment of Perimenopausal Depression 30 Depression ± Hot Flushes (n = 34) p <.01 Baseline Placebo CES-D Score E 2 0 Baseline Weeks 2 4 Baseline CES-D = Center for Epidemiologic Studies Depression Scale Weeks 2 4 Schmidt PJ, et al., Am J Obstet Gynecol. 2000;183(2): PMID:

34 Effect of Estradiol on Perimenopausal Symptoms Schmidt PJ, et al. Unpublished.

35 Time From Menopause Determines Effects of 17β-Estradiol (E2) on the Expression of Inflammatory Biomarkers in Uterine Arteries Novella S, et al. Arterioscler Thromb Vasc Biol. 2012;32: PMID:

36 A drug can be an inert substance, a poison, or a therapeutic agent dependent upon how it is used and the dosage in which it is given. Alle Ding' sind Gift und nichts ohn' Gift; allein die Dosis macht, dass ein Ding kein Gift ist. "All things are poison and nothing is without poison, only the dose permits something not to be poisonous. Paracelsus,

37 E2 Withdrawal Schematic PMD + Baseline W0 W3 W6 W7 Clinic visits(weekly) PMD + = Asymptomatic women with a past perimenopausal depression disorder (PMD) are responsive to estrogen Estradiol 100 µg/day (open-label) Estradiol 100 µg/day (double-blind) Placebo (skin patch) Medroxyprogesterone 5 mg daily (PO) Schmidt PJ, et al. JAMA Psychiatry. 2015;72(7): PMID:

38 E2 Withdrawal Precipitates Depressive Symptoms But Not in Women With No History of Perimenopausal Depression (PMD) CES-D PMD+ (n = 21) E2 Open E2 DB Blind Placebo CES-D PMD- (n = 12) ANOVA-R: Dx*Tx* phase* week F 2,58 = 5.5, p <.01 0 w1 w2 w3 w4 w5 w6 w1 w2 w3 w4 w5 w6 E2 Continuous CES-D = Center for Epidemiologic Studies Depression Scale Schmidt PJ, et al. Unpublished data. E2 Withdrawal

39 Efficacy of GnRH-A in the Symptoms of PMDD (Weekly Means + SEM) Most Anxiety Least Most Baseline ANOVA-R Phase X Week X Group: F = 2.8 p < 0.05 Phase X Group: F = 42.0, p < Leuprolide Anxiety Least 1 Baseline Placebo GnRH-A = gonadotropin-releasing hormone agonist; PMDD premenstrual dysphoric disorder. Schmidt PJ, et al. N Engl J Med. 1998;338(4): PMID:

40 Steroid Precipitation of PMDD Symptoms Most 3 PMS Sadness 2 Least 1 Most Sadness 3 2 Controls ANOVA-R Phase X Group: F 1, 23 = 19.6 p <.001 Least 1 Leuprolide Alone E 2 Replacement P 4 Replacement Schmidt PJ, et al. N Engl J Med. 1998;338(4): PMID

41 Endocrine Clamp Study Baseline Leuprolide (3.75 mg im) Progesterone (200 mg BID) Estradiol (100 µg qd) Increase in symptoms over month BID = twice a day; qd = every day Schmidt PJ, et al. Unpublished data.

42 Effects of GnRH Agonist & Gonadal Steroid Replacement on PMDD S & C Self-Rated Scores S & C Rater Scores Leuprolide (3.75 mg im) Progesterone (200 mg BID) Estradiol (100 µg qd) Weeks Schmidt PJ, et al. Unpublished data.

43 Effects of Dutasteride on Symptoms of PMDD: 15 worse 4 ANOVA-R: Treatment Condition* Week F 6,42 = 7.9, p<.001 Plasma Progesterone (ng/ml) Irritability 2 none 1 W1 W2 W3 W4 W1 W2 W3 W4 W1 W2 W3 W4 Baseline Dutasteride Placebo High Dose (2.5 mg/day) (n = 8) - weekly means (SEM) Dutasteride is indicated for the treatment of benign prostatic hyperplasia in men with an enlarged prostate. This agent is not approved by the US FDA for the treatment of PMDD Martinez, et al. Neuropsychopharmacology (In Press).

44 The Change is the Signal, but Only in the Context of Susceptibility Do reproductive steroids differentially affect brain regional activation in women with PMDD?

45 Differential Brain Regional Activation by Ovarian Steroids in PMDD Leuprolide Estradiol Progesterone Subgenual Cingulate (-6, 20, -10), p =.0002 Relative regional Cerebral Flow (-mm/100g/min) Subgenual Cingulate Controls Patients Medial Orbitofrontal Cortex (-12, 42, 12), p = Relative regional Cerebral Flow (-mm/100g/min) Medial Orbitofrontal Cortex Controls Patients PMDD = premenstrual dysphoric disorder Schmidt PJ et al., unpublished data.

46 DLPFC Overactivation in PMDD Correlated With Symptom-Related Impairment A B PET PET-GAF fmri fmri-gaf DLPFC = dorsolateral prefrontal cortex; PMDD = premenstrual dysphoric disorder Baller E, et al. Am J Psychiatry. 2013;170(3): PMID:

47 PMDD: Significant Associations With SNPs Genotyped in ESR1 (6q25.1) Exons marker L0017 L0018 L0019 L0020 L0024 L0058 L0026 L0021 L0025 L0060 L0056 L0023 L0055 L0057 L0061 L0022 Intermarker distance (kb) Target region:16.7kb Huo L, et al. Biol Psychiatry. 2007;62(8): PMID:

48 ESC/E(Z) Complex Genes Schmidt PJ, et al., Unpublished data.

49 Physiology is Context- Dependent Developmental Stage Age Gender Species/tissue/cell Environment Genome

50 Questions & Answers