September 26 28, 2013 Westin Tampa Harbour Island. Co-sponsored by

September 26 28, 2013 Westin Tampa Harbour Island Co-sponsored by

Depression and Women Across the Reproductive Lifecycle David R. Rubinow, MD University of North Carolina at Chapel Hill School of Medicine Chapel Hill, NC

Learning Objective 1 Identify factors that increase the risk of mood disturbance in women at key time points when hormonally-related triggers are present (e.g., menses, pregnancy, postpartum, perimenopause)

Learning Objective 2 Design and implement treatment plans to manage the mood symptoms in women at various life stages

Audience Response Has the Women s Health Initiative impacted the way you treat your perimenopausal and menopausal patients A. Yes, I discourage patients from taking estrogen B. It has made no difference C. Data is mixed, so I am cautious D. I ignore it and recommend estrogen when appropriate

Gonadal Steroids, Like All Steroid Hormones, are Derivatives of Cholesterol Hu J, et al. Nutr Metab (Lond). 2010;7:47. PMID: 20515451.

Principles Reproductive hormones wire and rewire the brain Reproductive hormones regulate brain circuitry Changes in reproductive hormones alter brain states of clinical relevance Reproductive endocrine-related mood disorders account for a substantial amount of morbidity and mortality These disorders are NOT hormone deficiencies Reproductive steroids are both context-dependent and context-determining Rubinow DR et al. Hormones, Brain and Behavior, v4, 2395-2428, 2009. Rubinow, D.R., and Schmidt, P.J.: Gonadal steroids, brain, and behavior: role of context. Dial. Clin. Neurosci., 4:123-138, 2002. Schmidt PJ, et al. N Engl J Med. 1998;338(4):209-16. PMID:9435325.

Reproductive Hormones Wire and Rewire the Brain

Reproductive Hormones Regulate Brain Circuitry

Steroids Regulate PFC Functional Correlations With Left Hippocampal Formation Activity Leuprolide Alone Progesterone Add-Back Estrogen Add-Back PFC = prefrontal cortex K Berman et al. Unpublished data. Rolls ET. Front Hum Neurosci. 2013;7:74. PMID: 23508210. Ochsner KN, et al. Neuroimage. 2004;23(2):483-499. PMID: 15488398.

OFC Activity in Response to Emotional Stimuli in the Context of Behavioural Inhibition Across the Menstrual Cycle OFC = orbitofrontal cortex Protopopescu X, et al. Proc Natl Acad Sci USA. 2005;102(44):16060-5. PMID: 16247013.

Periods of Reproductive Endocrine Change are Associated With Altered Mood States and Reproductive Endocrine-Related Mood Disorders Account for Substantial Morbidity and Mortality Puberty Menstrual Cycle Puerperium Perimenopause

Images Courtesy of PJ Schmidt; DHEA = dehydroepiandrosterone Grumbach MM. Horm Res. 2002;57 Suppl 2:2-14. PMID: 12065920.

Gene Network Ojeda SR, et al. Mol Cell Endocrinol. 2010;324(1-2):3-11. PMID: 20005919.

Gene network regulating puberty Ojeda SR, et al. Mol Cell Endocrinol. 2010;324(1-2):3-11. PMID: 20005919.

Reproductive Endocrinerelated Mood Disorders Premenstrual dysphoria Perinatal depression Perimenopausal depression

Reproductive Endocrinerelated Mood Disorders Premenstrual dysphoria! Prevalence 5%! Cause of 14.5 million Disability Associated Live Events annually in US! Requires prospective confirmation of restriction of symptoms to the luteal phase Meltzer-Brody S, Stuebe, A. Best Pract Res Clin Obstet Gynecol. September 2013. [epub ahead of print]. doi:10.1016/j.bpobgyn.2013.08.009.

Efficacy of GnRH-A in the Symptoms of PMDD (Weekly Means + SEM) Most Anxiety Least Most 5 4 3 2 1 5 Baseline ANOVA-R Phase X Week X Group: F = 2.8 p < 0.05 Phase X Group: F = 42.0, p < 0.001 Leuprolide Anxiety 4 3 2 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):209-16. PMID:9435325.

Central Nervous System Effects of GnRH Agonist & Gonadal Steroid Replacement Leuprolide acetate (3.75 mg IM QM) Estradiol 0.1 mg/d Progesterone 200 mg BID Placebo Procedures OR Time (weeks) 0 12 24 GnRH-A = gonadotropin-releasing hormone agonist; IM = intramuscular; QM = every month; BID = twice a day. Schmidt PJ, et al. N Engl J Med. 1998;338(4):209-16. PMID:9435325.

Steroid Precipitation of PMDD Symptoms Most 3 PMDD ANOVA-R Phase X Group: F 1,23 = 19.6 p <.001 Sadness 2 1 Sadness 3 2 Controls Least 1 Leuprolide Alone E 2 Replacement P 4 Replacement PMDD = premenstrual dysphoric disorder Schmidt PJ, et al. N Engl J Med. 1998;338(4):209-16. PMID:9435325.

Differential Brain Regional Activation by Ovarian Steroids in PMDD Subgenual Cingulate Leuprolide Estradiol Progesterone (-6, 20, -10) p =.0002 Relative regional Cerebral Blood Flow (-mm/100g/min) 74 72 70 68 66 64 62 60 Controls (n = 32) Patients with PMDD (n = 16) PMDD = premenstrual dysphoric disorder Schmidt PJ, unpublished data.

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) 70 65 60 Subgenual Cingulate Controls Patients Medial Orbitofrontal Cortex (-12, 42, 12), p =.000015 Relative regional Cerebral Flow (-mm/100g/min) 63 61 59 57 55 Medial Orbitofrontal Cortex Controls Patients PMDD = premenstrual dysphoric disorder Schmidt PJ, unpublished data.

PMDD: Is it Triggered by the Level of Steroid or the Change in Level of Steroid?

Reproductive Endocrinerelated Mood Disorders Premenstrual Dysphoria Perinatal Depression Perimenopausal Depression

Perinatal Depression Prevalence 10% - 15% (MDE = 7.5%; mde = 6.5%) Suicide is the leading cause of maternal death MDE = major depressive episode; mde = minor depressive episode Meltzer-Brody S, Stuebe, A. Best Pract Res Clin Obstet Gynecol. September 2013. [epub ahead of print]. doi:10.1016/j.bpobgyn.2013.08.009.

Background: Perinatal Depression COMMON! 10%-15% prevalence! 4 million women give birth annually in U.S.; one-half million with perinatal depressive disorder! Most common, unrecognized complication of perinatal period! Compare to the prevalence rate of gestational diabetes at 2%-5% MORBID! Devastating consequences for patient and family! Low maternal weight gain, preterm birth! Impaired bonding between mother and infant! Increased risk of suicide and infanticide MISSED! No practice guidelines or routine screening! Symptoms often different from classic DSM-IV depression Meltzer-Brody S, et al. Arch Womens Ment Health. 2013 Aug 1. [Epub ahead of print] PMID: 23904137. Meltzer-Brody S, Stuebe, A. Best Pract Res Clin Obstet Gynecol. September 2013. [epub ahead of print]. doi:10.1016/j.bpobgyn.2013.08.009.

Distinguishing Characteristics of Perinatal Mood Symptoms Anxiety or agitation Depressed mood Sadness, weepiness Irritability Hypervigilance about the baby OR lack of interest in the newborn Impaired concentration or feeling overwhelmed Feelings of dependency or guilt Austin MP, et al. Acta Psychiatr Scand. 2005;112(2):97-104. PMID: 15992390.

Other Facts and Dilemmas There is no free lunch Inadequacy of database During pregnancy, there are medications to avoid, but. Pregnancy affects medication levels! Increased volume of distribution, hepatic blood flow! Decreased plasma binding proteins! Effects of reproductive steroid on metabolic enzymes Koren G. J Popul Ther Clin Pharmacol. 2011;18(3):e523-527. PMID: 22113390. Bodén R, et al. Arch Gen Psychiatry. 2012;69(7):715-21. PMID: 22752236.

Profound Neuroendocrine Changes at Time of Birth Relative Hormone Concentration Russell JA, et al. Brain preparations for maternity adaptive changes in behavioral and neuroendocrine systems during pregnancy and lactation. An overview. In: Progress in Brain Research; 2001.

What Is the Hormone Trigger in Perinatal Depression? PLACEBO E2+ PROG PLACEBO Leuprolide acetate BASELINE 0 4 8 12 16 20 24 HYPO- GONADAL ADDBACK WITHDRAWAL E2 = estradiol; PROG = progesterone Bloch M, et al. Am J Psychiatry. 2000;157(6):924-930. PMID: 10831472.

Weekly Cornell Depression Scale Scores (One Subject) Score 45 40 35 30 25 20 15 10 5 0 Baseline Week 6 Week 8 Week 2 Week 4 Week 6 Week 8 Week 2 Week 4 Add back Early Late Follow-up Withdrawal Bloch M, et al. Am J Psychiatry. 2000;157(6):924-930. PMID: 10831472.

PPD Study: Cornell Depression Score Cornell Depression Score 25 20 15 10 5 BASELINE ADDBACK WITHDRAWL FOLLOW UP 0 PPD (Mean ±SEM) PPD = Postpartum depression Bloch M, et al. Am J Psychiatry. 2000;157(6):924-930. PMID: 10831472. Normal

These Disorders Are NOT Hormone Deficiencies

Reproductive Endocrinerelated Mood Disorders Premenstrual Dysphoria Perinatal Depression Perimenopausal Depression

Perimenopausal Depression Prevalence 20% Is associated with a 50% increase in cardiovascular mortality Rubinow DR, Girdler SS. Depress Anxiety. 2011;28(6):E1-E15. PMID: 21648024.

E2 Withdrawal Precipitates Depressive Symptoms in Asymptomatic Women With a Past Perimenopausal Depression E2 Open E2 DB Blind 15 p < 0.01 p < 0.01 Placebo p < 0.01 10 CESD PMD + (n = 26) PMD - (n = 30) 5 0 E2 Continuous E2 Withdrawal E2 Withdrawal PMD + PMD - E2 = estradiol; PMD = perimenopausal depression; CESD = Center for Epidemiologic Studies Depression Scale; DB = double. Schmidt PJ, et al. unpublished data

Therapeutic Trial of Estradiol, SERM, and Phytoestrogen in Perimenopausal Depression (n = 38) 25 Estradiol p <.01 25 Raloxifene p <.05 ANOVA-R: Tx*Time F 1,34 = 8.8 p <.001 20 20 15 HDRS-17 10 5 * 15 10 5 0 Baseline Week 8 0 Baseline Week 8 25 Rimostil p = NS 25 Placebo p = NS 20 20 15 HDRS-17 10 15 10 5 5 0 Baseline Week 8 0 Baseline Week 8 *Week 8 E2 vs. Placebo: p <.05 SERM = selective estrogen-receptor modulator; HDRS = Hamilton Rating Scale for Depression; Tx*Time = treatment by time. Schmidt PJ. Unpublished data.

Baseline Characteristics of Participants in Randomized, Controlled Trials Trials and Hormone Regimens (E+P or E vs. Placebo) Characteristic (Hormone Therapy; Placebo) WHI E+P WHI E WHIMS E+P WHIMS E WHISCA E+P WHISCA E HERS E+P ESPRIT E EMS E+P WISDOM E +P ULTRA E Number 8506;8102 5310;5429 2229;2303 1464;1483 690;726 434;452 1380;1383 513;504 70;72 2196;2189 191;185 Mean age, y 63.2;63.3 63.6;63.6 63.2;63.3 63.6;63.6 73.69;73.86 74.01;74.02 67;67 62.3;62.9 75;74.5 63.3;63.3 66.8;66.7 Nonwhite race, % Previous or current HT, % 16.1;16.0 24.5;24.9-17.3;16.4 8.4;7.0 14.09;13.08 12;10 3;3 4.3;9.7 1;1.4 7.2;8.1 26.1;25.6 47.8;48.9 21.8;22.4 45.8;44.7 21.2;22.6 49.54;46.24 1.7;1.7 12;10 31.4;23.6 55;54.3 - Hysterectomy age <40 y, % - 39.8;39.8 - - - - - - - - - Hysterectomy age 40 49 y, % - 43.2;42.2 - - - - - - - - - Bilateral oophorectom, % - 39.5;42.0 - - - - - - - - - Never pregnant, % 10.1;10.3 9.3;8.5 - - - - - - - - - Marjoribanks J, et al. Cochrane Database Syst Rev. 2012;7:CD004143. PMID: 22786488. Nelson HD, et al. Ann Intern Med. 2012;157(2):104-113. PMID: 22786830. Schierbeck LL, et al. BMJ. 2012;345:e6409. PMID: 23048011.

Results of Hormone Therapy Trials Cancer Outcome HR (95% CI) E+P vs. Placebo Differences in events per 10,000 women-years (95% CI) * HR (95% CI) E vs. Placebo Differences in events per 10,000 women-years (95% CI) * Invasive breast 1.25 (1.07 1.46) 8 (3 14) more 0.77 (0.62 0.95) 8 (1 14) less Colorectal 0.75 (0.57 1.00) Not significant 1.11 (0.82 1.50) Not significant Lung 1.23 (0.92 1.63) Not significant 1.17 (0.81 1.69) Not significant Endometrial 0.78 (0.52 1.16) Not significant Not reported Not reported Ovarian 1.58 (0.77 3.24 Not significant Not reported Not reported Cervical 1.44 (0.47 4.42) Not significant Not reported Not reported Cardiovascular events Coronary heart disease (CHD death and total MI) 1.22 (0.99 1.51) Not significant 0.95 (0.78 1.15) Not significant Stroke 1.34 (1.05 1.71) 9 (2 15) more 1.36 (1.08 1.71) 11 (2 20) more Thromboembolic events Deep vein thrombosis 1.88 (1.38 2.55) 12 (6 17) more 1.47 (1.06 2.05) 7 (1 14) more Pulmonary embolism 1.98 (1.36 2.87) 9 (4 14) more 1.37 (0.90 2.07) Not significant Diabetes Self-reported new diagnosis requiring treatment with drugs 0.79 (0.67 0.93) 15 (4 26) less 0.88 (0.77 1.01) Not significant Marjoribanks J, et al. Cochrane Database Syst Rev. 2012;7:CD004143. PMID: 22786488. Nelson HD, et al. Ann Intern Med. 2012;157(2):104-113. PMID: 22786830. Schierbeck LL, et al. BMJ. 2012;345:e6409. PMID: 23048011.

Results of Hormone Therapy Trials E+P vs. Placebo E vs. Placebo Fractures Mortality Outcome HR (95% CI) Differences in events per 10,000 women-years (95% CI) * HR (95% CI) Differences in events per 10,000 women-years (95% CI) * Hip 0.67 (0.47 0.95) 6 (1 10) less 0.61 (0.41 0.91) 7 (1 12) less Vertebral 0.68 (0.48 0.96) 6 (1 11) less 0.62 (0.42 0.93) 6 (1 12) less Total fractures 0.76 (0.69 0.83) 46 (29 63) less 0.70 (0.63 0.79) 56 (37 75) less All-cause mortality 1.04 (0.91 1.18) Not significant 1.02 (0.91 1.15) Not significant Breast cancer mortality 1.96 (1.00 4.04) Not significant 0.37 (0.13 0.91) 2 (1 3) less Lung cancer mortality 1.71 (1.16 2.52) 5 (1 8) more Not reported Not reported Gallbladder Gallbladder disease (cholecystitis and cholelithiasis) Cognitive function 1.61 (1.30 2.00) 20 (11 29) more 1.79 (1.44 2.22) 33 (20 45) more Probable dementia 2.05 (1.21 3.48) 22 (5 39) more 1.49 (0.83 2.66) Not significant Mild cognitive impairment 1.07 (0.74 1.55) Not significant 1.34 (0.95 1.89) Not significant Urinary incontinence Overall urinary incontinence (stress, urge, or mixed) 1.39 (1.27 1.52) 872 (591 1153) more 1.53 (1.37 1.71) 1271 (883 1660) more Marjoribanks J, et al. Cochrane Database Syst Rev. 2012;7:CD004143. PMID: 22786488. Nelson HD, et al. Ann Intern Med. 2012;157(2):104-113. PMID: 22786830. Schierbeck LL, et al. BMJ. 2012;345:e6409. PMID: 23048011.

Reproductive Steroids Are Both Context-Dependent and Context-Determining Susceptibility What do we mean by gene : environment interactions? Rubinow DR, et al. Dialogues Clin Neurosci. 2002;4(2):123-37. PMID: 22033695.

Estradiol Effects in the Forced Swim Test: Strain Differences Wistar Hannover rat and Long Evans rat. Koss WA, et al. Physiol Behav. 2012;106(2):81-6. PMID: 22266677.

Strain-dependent Effects of Estradiol in the Forced Swim Test 300 Vehicle Estradiol Withdrawal Immobility Seconds 250 200 150 100 50 0 * * N = 12 N = 12 N = 12 N = 6 N = 7 N = 7 Wistar Long Evans Koss WA, et al. Physiol Behav. 2012;106(2):81-6. PMID: 22266677.

Biology and Environment Meet at the Level of the Dance Partners SMRT, high-fat diet, and obesity/insulin resistance SMRT = silencing mediator of retinoid and thyroid hormone receptors Fang S, et al. Proc Natl Acad Sci USA. 2011;108(8):3412-7. PMID: 21300871.

High-Fat Diet Induced Severe Obesity in SMRTmRID1 Mice SMRT = silencing mediator of retinoid and thyroid hormone receptors; WT = wild type NC = normal control; HFD = high-fat diet. Fang S, et al. Proc Natl Acad Sci USA. 2011;108(8):3412-7. PMID: 21300871.

Effects of Genetic Differences are Unmasked by Environment SMRT mutation, high-fat diet, and obesity/insulin resistance GABA-A receptor mutation, pregnancy, and depression SMRT = silencing mediator of retinoid and thyroid hormone receptors Fang S, et al. Proc Natl Acad Sci USA. 2011;108(8):3412-7. PMID: 21300871.

Deficient NS Signaling: Postpartum Depression and Infanticide NS = neurosteroid ; WT = wild type Wistar; THIP = 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol Maguire J, Mody I. Neuron. 2008;59(2):207-13. PMID: 18667149.

Embrace the Uncertainty!

Abbreviations EMS = Estrogen Memory Study ESPRIT = Oestrogen in the Prevention of Reinfarction Trial HERS = Heart and Estrogen/Progestin Replacement Study HT = hormone therapy MI = myocardial infarction P = progestin PE = pulmonary embolism SBP = systolic blood pressure ULTRA = Ultra-Low-Dose Transdermal Estrogen Assessment WHI = Women s Health Initiative WHIMS = Women s Health Initiative Memory Study WHISCA = Women s Health Initiative Study of Cognitive Aging WISDOM = Women s Intl Study of Long Duration Oestrogen After Menopause CHD = coronary heart disease HR = hazards ratio CI = confidence intervals E + P; estrogen plus progestin E = estrogen only RCT = randomized controlled trial

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