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September 26 – 28, 2013 | Westin Tampa Harbour Island
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
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)
1
Learning Objective
Design and implement treatment plans to manage the mood symptoms in women at various life stages
2
Audience Response
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
Has the Women’s Health Initiative impacted the way you treat your peri-menopausal and menopausal patients
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
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 Unpublished data.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.
Estrogen Add-Back
Leuprolide Alone
Progesterone Add-Back
Steroids Regulate PFC Functional Correlations With Left Hippocampal Formation Activity
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.
Ojeda SR, et al. Mol Cell Endocrinol. 2010;324(1-2):3-11. PMID: 20005919.
Gene network regulating puberty
Reproductive Endocrine-related Mood Disorders
● Premenstrual dysphoria
● Perinatal depression
● Perimenopausal depression
Reproductive Endocrine-related 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
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.
(Weekly Means + SEM)
Most ANOVA-R Phase X Week X Group: F = 2.8 p < 0.05
Phase X Group: F = 42.0, p < 0.001
Anx
iety
Least Baseline
Baseline
Leuprolide
Placebo
5
4
3
2
1
5
4
3
2
1
Most
Anx
iety
Least
Central Nervous System Effects of GnRH Agonist & Gonadal Steroid Replacement
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.
OR Estradiol 0.1 mg/d Progesterone 200 mg BID Placebo
Time (weeks) • 0 • 12 • 24
Leuprolide acetate (3.75 mg IM QM)
Procedures
Steroid Precipitation of PMDD Symptoms
PMDD = premenstrual dysphoric disorder Schmidt PJ, et al. N Engl J Med. 1998;338(4):209-16. PMID:9435325.
Most
Sad
ness
Leuprolide Alone P4 Replacement
3
2
1 Least
Sad
ness
Controls
E2 Replacement
PMDD ANOVA-R Phase X Group: F1,23 = 19.6 p < .001 3
2
1
Differential Brain Regional Activation by Ovarian Steroids in PMDD
PMDD = premenstrual dysphoric disorder Schmidt PJ, unpublished data.
Subgenual Cingulate
(-6, 20, -10) p = .0002
Controls (n = 32) R
elat
ive
regi
onal
Cer
ebra
l Blo
od F
low
(-m
m/1
00g/
min
)
74
72
70
68
66
64
62
60
Estradiol Leuprolide Progesterone
Patients with PMDD
(n = 16)
Differential Brain Regional Activation by Ovarian Steroids in PMDD
PMDD = premenstrual dysphoric disorder Schmidt PJ, unpublished data.
Subgenual Cingulate
Rel
ativ
e re
gion
al C
ereb
ral F
low
(-m
m/1
00g/
min
)
Estradiol Leuprolide Progesterone
Controls Patients
70
65
60
Medial Orbitofrontal Cortex
55
57
59
61
63
Rel
ativ
e re
gion
al C
ereb
ral F
low
(-m
m/1
00g/
min
)
Controls Patients Medial Orbitofrontal Cortex (-12, 42, 12), p = .000015
Subgenual Cingulate (-6, 20, -10), p = .0002
PMDD: Is it Triggered by the Level of Steroid or the
Change in Level of Steroid?
Reproductive Endocrine-related 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
Rel
ativ
e H
orm
one
Con
cent
ratio
n
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.
E2+ PROG PLACEBO PLACEBO
BASELINE HYPO- GONADAL
ADDBACK WITHDRAWAL 0 4 8 12 16 20 24
Leuprolide acetate
What Is the Hormone Trigger in Perinatal Depression?
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)
Bloch M, et al. Am J Psychiatry. 2000;157(6):924-930. PMID: 10831472.
0
5
10
15
20
25
30
35
40
45
Baseline Week 6 Week 8 Week 2 Week 4 Week 6 Week 8 Week 2 Week 4
Add back
Sco
re
Early Late Follow-up
Withdrawal
PPD Study: Cornell Depression Score
(Mean ±SEM) PPD = Postpartum depression Bloch M, et al. Am J Psychiatry. 2000;157(6):924-930. PMID: 10831472.
BASELINE ADDBACK WITHDRAWL FOLLOW UP
Cor
nell
D
epre
ssio
n S
core
0
5
10
15
20
25
PPD Normal
These Disorders Are NOT Hormone Deficiencies
Reproductive Endocrine-related 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 = estradiol; PMD = perimenopausal depression; CESD = Center for Epidemiologic Studies Depression Scale; DB = double. Schmidt PJ, et al. unpublished data
• 15
• 10
• 5
• CESD
• PMD -
• PMD + (n = 26) • PMD - (n = 30)
• E2 Continuous
• Placebo
• E2 DB Blind
• E2 Open
• p < 0.01 • p < 0.01
• p < 0.01
• 0
• PMD + • E2 Withdrawal • E2 Withdrawal
Therapeutic Trial of Estradiol, SERM, and Phytoestrogen in Perimenopausal Depression (n = 38)
SERM = selective estrogen-receptor modulator; HDRS = Hamilton Rating Scale for Depression; Tx*Time = treatment by time. Schmidt PJ. Unpublished data.
0 5
10
15
20
25
HDRS-17
Baseline Week 8
Estradiol
p < .01
*Week 8 E2 vs. Placebo: p < .05
ANOVA-R: Tx*Time F1,34 = 8.8 p < .001
* 0 5
10
15
20
25
Baseline Week 8
p < .05
Raloxifene
0 5
10
15
20
25
Baseline Week 8
p = NS Placebo
0 5
10
15
20
25
HDRS-17
Rimostil p = NS
Baseline Week 8
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,% 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
Previous or current HT, % 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 - - - - - - - - -
Baseline Characteristics of Participants in Randomized, Controlled Trials
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.
Outcome E+P vs. Placebo E vs. Placebo
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)* Cancer
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
Results of Hormone Therapy Trials
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.
E+P vs. Placebo E vs. Placebo
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)
* Fractures
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
Mortality 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)
1.61 (1.30–2.00) 20 (11–29) more 1.79 (1.44–2.22) 33 (20–45) more
Cognitive function 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
Results of Hormone Therapy Trials
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
Koss WA, et al. Physiol Behav. 2012;106(2):81-6. PMID: 22266677.
Immobility
Vehicle Estradiol Withdrawal
Wistar Long Evans
Sec
onds
300
250
200
150
100
50 0
*
*
N = 12 N = 12 N = 12 N = 6 N = 7 N = 7
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
Questions & Answers
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