Overview Perimenopause-related mood disturbance 1. Depressive symptoms vs. clinical depression Depression in the Menopause Transition: Role of Female Reproductive Hormones, Hot Flashes, and Sleep 2. Causal factors – Prior depression Hadine Joffe, MD, MSc – Impact of reproductive hormones Director, Women � s Hormone & Aging Research Program www.brighamwharp.org – Role of hot flashes and sleep disruption Associate Professor, Harvard Medical School Vice Chair for Research & Director of Women’s Mental Health Division, Department of Psychiatry, BWH Director, Psycho � Oncology Research, DFCI 3. Treatment approaches Depressive symptoms vs. major depression Clinical considerations when evaluating Not just a matter of degree contribution of menopause to depression 1. Depressive symptoms vs. clinical depression 2. Extent of interference with function 3. Past history of depression Depressive symptoms Major depression – Milder – Clinical syndrome 4. Co-occurring / precipitating stressful life events – Emotions out of control – Worthlessness, guilt 5. Presence of / temporal relationship to – Brief awakenings – Pervasive, persistent – Menstrual pattern changes – Hot flashes – More extensive sleep – Hot flashes & night sweats – – On/off distress disruption Associated sleep interruption – Interference with function – Variable trajectories 1 6. Severity and nature of sleep disturbance – Suicide risk – Brief awakenings only symptom severity 3% 3% symptom severity – Insomnia: Sleep onset +/or maintenance / early morning awakening 9% 9% Depressive – Depressive Hypersomnia �� – 9% 9% Snoring, gasping, kicking, daytime sleepiness 8 80% 80% Years Years Years 1 Hickey M, Menopause 2016
Associations with hormones, hot flashes, & sleep Factors associated with depressive symptoms and major depression during peri/postmenopause disturbance vary by depression presentation y y p p Menopause Hot flashes and night sweats 1-3 Depressive symptoms associated with: Depressive symptoms associated with: h: First lifetime clinical depression First lifetime clinical depression symptoms Sleep disturbance 4 associated with: associated with: h: 1. Perimenopausal hormone profile 1-3 1. Perimenopausal hormone profile 1-3 or 2. Hot flashes 4 2. Hot flashes 4 Hot flashes (trend) 6 Hot flashes (trend) 6 1. 1. ↑ FSH, ↑ LH, ↓ inhibin 5,6 Hormone 3. 3. Demographic and psychosocial factors Demographic and psychosocial factors Demographic and psychosocial factors 2. 2. Demographic and psychosocial factors Demographic and psychosocial factors Variability in estradiol and FSH 5,6 dynamics typical of clinical depression 5,6 typical of clinical depression 5,6 Surgical menopause 7 Medical problems preceding menopause 6 3. Recurrent clinical depression Prior depression 1,5,8 anxiety 9 Psychiatric associated with: Prior premenstrual symptoms 10 1. Anxiety preceding menopause ↑ BMI, smoking, ↓ education, Hispanic, 2. Demographic and psychosocial factors Demographic factors typical of clinical depression 5 Japanese 11 NOT with perimenopausal hormone profile 6 3. Stressful life events, financial strain, 4. NOT with hot flashes 4 Psychosocial factors poor social support 9, 11 FSH = follicle-stimulating hormone; LH = luteinizing hormone 1 Avis NE, Ann Epidemiol 1994; 2 Joffe H, Menopause 2002; 3 Cohen LS, Arch Gen Psych 2006; 4 Joffe H, JCEM 2011; 5 Freeman E, Arch Gen Psychiatry 2004; 6 Freeman 1 Joffe H, J Clin Endo Metab 2011; 2 Freeman EW, Arch Gen Psych 2006; 3 Daly, Am J Psychiatry 2003; 4 Worsley R, Maturitas 2014; 5 E,. Arch Gen Psychiatry 2006; 7 McKinlay JB, Am J Epidemiol . 1987; 8 Bromberger JT, Psych Med 2011; 9 Bromberger JT, Psych Med 2009; 10 Freeman EW, Obstet Gynecol . Bromberger JT, Arch Gen Psych 2010; 6 Bromberger JT, Psychol Med 2015 2004; 11 Bromberger JT, Arch Gen Psych 2010 Risk of Depressive Symptoms and Major Depression Good Potential pathways to menopausal Decreases With Time After Final Menstrual Period News! depression Standard CNS Changes in Risk of major depressive 2yr from Psychosocial reproductive factors FMP FMP episodes decreases with and other factors hormones time after FMP 3 Years from FMP OR 5.0 ≤ 2 yrs 4 OR 2.93 >2 yrs 1 2 Hot Sleep Depression flashes disturbance Freeman EW, et al. JAMA Int Med 2014 Bromberger, J Psychol Med 2011
Perimenopausal hormone changes Aims are dynamic 1. To determine if perimenopausal hormone dynamics are associated with depressive symptom severity a. Estradiol variability b. Progesterone peaks 51 yrs, LMP 3 mo prior, Infrequent Hot Flashes 50 yrs, LMP 3 mo prior, No Hot Flashes 49 yrs, LMP 4 mo prior, Frequent Hot Flashes 30 CD1 200 Spot 30 200 CD1 30 CD1 200 E2 (pg/mL) FSH (IU/L) E2 (pg/mL) 25 E2 (pg/mL) 25 25 150 150 150 20 20 20 P4 (ng/mL) P4 (ng/mL) P4 (ng/mL) 15 100 15 100 15 100 FSH (IU/L) FSH (IU/L) 10 10 10 50 50 50 5 5 5 0 0 0 0 0 0 0 1 2 4 5 6 7 0 1 2 3 4 5 6 0 1 2 3 4 Time (Weeks) Time (Weeks) Time (Weeks) P4 E2 FSH Aims Perimenopause-associated depressive symptoms and reproductive hormone dynamics 1. To determine if hot flashes are associated with depressive symptom onset Mood is better when Mood is better when Mood is better when FSH progesterone is produced / estradiol is less variable 1 decreases 3 ovulation occurs 1 a. Nighttime hot flashes? 2 0 Clinical studies show that mood is b. Daytime hot flashes? 2 0 1 5 1 5 M A D R S M A D R S 2. To examine if sleep fragmentation mediates the 1 0 1 0 better as ovarian activity is more 5 5 association between hot flashes and depressive 0 normalized in perimenopausal women. 0 0 -1 0 1 0 -2 0 2 0 -3 0 3 0 -4 0 symptoms 0 1 + C o efficien t o f V ariatio n in (ln )E strad io l (% ) # o f P ro g e s te ro n e P e a k s (> 6 n g /d l) Mood improves when estradiol increases 2 Conversely, the more abnormal the Estradiol 20 20 r= – 0.36 10 10 p=0.007 hormonal profile, the worse the mood. Change in MADRS Change in MADRS 0 0 -10 -10 -20 -20 -30 -30 -40 -40 -200 -200 -100 -100 0 0 100 100 200 200 Change in estradiol (pg/ml) Change in estradiol (pg/ml) 1 Joffe H, ENDO 2015; 2 Joffe H, J Clin Endo Metab 2011; 3 Daly Am J Psychiatry 2003 MADRS = Montgomery Asberg Depression Rating Scale
Adverse impact of nighttime hot flashes Why are women at increased risk for depressive and sleep disruption on mood symptoms in perimenopause? Hot flashes None (n=9) Infrequent (n=10) Frequent (n=10) p=0.28 X (A) Nighttime Hot Flashes (B) Daytime Hot Flashes ↓↑ estradiol Nighttime 3 0 3 0 Nocturnal, but M A D R S S c o re p=0.006 C h a n g e in M A D R S S c o re 2 5 2 5 not daytime, ^ VMS ↓ progesterone 2 0 2 0 hot flashes, 1 5 1 5 result in an 1 0 1 0 C h a n g e in increase in 5 5 3,5 depressive 1 0 0 symptoms -5 -5 2,3 N o n e In fr e q u e n t F r e q u e n t N o n e In fr e q u e n t F r e q u e n t ↓ sleep (A) # of Transitions to Wake (B) % of Time in Stage N1 (C) PSQI Score Worsening of sleep 30 fragmentation and 3 0 3 0 C hange in M A DR S S co r e M A D R S S c o re p=0.04 p=0.05 p=0.02 M A D R S S c o re 3 − 5 25 sleep quality result 2 5 2 5 20 in an increase in 2 0 2 0 15 depressive 1 5 1 5 ↓ mood 10 symptoms 1 0 1 0 C h a n g e in C h a n g e in 5 5 5 0 0 0 -5 -5 -5 N o In c re a s e In c re a s e N o In c r e a s e In c r e a s e No Increase Increase Joffe, J Clin Endo Metab 2016 1 Joffe H, ENDO 2015; 2 Joffe, Sleep 2013; 3 Burleson, Menopause 2010; 4 Joffe, J Clin Endo Metab 2011; 5 Joffe, J Clin Endo Metab 2016 Perimenopause and depression Patient considerations Relevance of menopause to mood state? 1. Depressive symptoms and clinical depression 1. Coincident vs. linked vs. susceptibility factor during the perimenopause are distinct entities with 2. Stressful life events, precipitants different risk profiles 3. Midlife and menopause experience and attitudes Menopause and risk profile 2. Major depression associated with: 1. Perimenopause (early vs. late) vs. postmenopause • Prior depression episodes 2. Presence of hot flashes 3. Psychiatric history/antidepressant benefits and risk 3. Depressive symptoms associated with: 4. Estrogen therapy risk profile • Changing hormone dynamic Symptom presentation • Hot flashes and sleep disturbance 1. Temporal relationship to hormonal and perimenopausal changes 2. Co-occurrence of hot flashes and sleep disturbance 4. Implications for treatment approaches Mild depressive symptoms vs. 1 st lifetime onset clinical depression vs. 3. recurrent depression episode
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