Overview Perimenopause-related mood disturbance 1. Depressive - - PDF document

Depression in the Menopause Transition: Role of Female Reproductive Hormones, Hot Flashes, and Sleep

Hadine Joffe, MD, MSc

Director, Womens Hormone & Aging Research Program www.brighamwharp.org Associate Professor, Harvard Medical School Vice Chair for Research & Director of Women’s Mental Health Division, Department of Psychiatry, BWH Director, PsychoOncology Research, DFCI

• 1. Depressive symptoms vs. clinical depression
• 2. Causal factors

– Prior depression – Impact of reproductive hormones – Role of hot flashes and sleep disruption

• 3. Treatment approaches

Overview

Perimenopause-related mood disturbance

Depressive symptoms vs. major depression

Not just a matter of degree Depressive symptoms

– Milder – Emotions out of control – Brief awakenings – Hot flashes – On/off distress – Variable trajectories1

Major depression

– Clinical syndrome – Worthlessness, guilt – Pervasive, persistent – More extensive sleep disruption – Interference with function – Suicide risk

1Hickey M, Menopause 2016

Years

Depressive symptom severity

3% 9% 9% 80%

Years Years

Depressive symptom severity

3% 9% 9% 80% 8

• 1.

Depressive symptoms vs. clinical depression 2. Extent of interference with function 3. Past history of depression 4. Co-occurring / precipitating stressful life events 5. Presence of / temporal relationship to

– Menstrual pattern changes – Hot flashes & night sweats – Associated sleep interruption

Clinical considerations when evaluating contribution of menopause to depression

6. Severity and nature of sleep disturbance

– Brief awakenings only – Insomnia: Sleep onset +/or maintenance / early morning awakening – Hypersomnia – Snoring, gasping, kicking, daytime sleepiness

Factors associated with depressive symptoms and major depression during peri/postmenopause

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

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. 2004; 11 Bromberger JT, Arch Gen Psych 2010

Menopause symptoms

Hot flashes and night sweats 1-3 Sleep disturbance 4

Hormone dynamics

↑ FSH, ↑ LH, ↓ inhibin 5,6 Variability in estradiol and FSH 5,6 Surgical menopause 7

Psychiatric

Prior depression 1,5,8 anxiety 9 Prior premenstrual symptoms 10

Demographic factors

↑ BMI, smoking, ↓ education, Hispanic, Japanese 11

Psychosocial factors

Stressful life events, financial strain, poor social support 9, 11

FSH = follicle-stimulating hormone; LH = luteinizing hormone

First lifetime clinical depression associated with:

1. Hot flashes (trend) 6 2. Demographic and psychosocial factors typical of clinical depression 5,6 3. Medical problems preceding menopause6

Associations with hormones, hot flashes, & sleep disturbance vary by depression presentation

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

Bromberger JT, Arch Gen Psych 2010; 6 Bromberger JT, Psychol Med 2015

Depressive symptoms associated with:

• 1. Perimenopausal hormone profile1-3
• 2. Hot flashes4

3. Demographic and psychosocial factors

Recurrent clinical depression associated with:

1. Anxiety preceding menopause 2. Demographic and psychosocial factors typical of clinical depression5 3. NOT with perimenopausal hormone profile6 4. NOT with hot flashes4

y y p

h:

3. Demographic and psychosocial factors

Depressive symptoms associated with:

• 1. Perimenopausal hormone profile1-3
• 2. Hot flashes4

Demographic and psychosocial factors

• r

First lifetime clinical depression associated with:

1. Hot flashes (trend) 6 2. Demographic and psychosocial factors typical of clinical depression 5,6

p

h:

Risk of Depressive Symptoms and Major Depression Decreases With Time After Final Menstrual Period

Freeman EW, et al. JAMA Int Med 2014

FMP

Good News!

Bromberger, J Psychol Med 2011

Risk of major depressive episodes decreases with time after FMP Years from FMP

OR 5.0 ≤2 yrs OR 2.93 >2 yrs 2yr from FMP

Potential pathways to menopausal depression

1 2

Depression Sleep disturbance Hot flashes Changes in reproductive hormones Psychosocial and other factors

4

Standard CNS factors

3

Perimenopausal hormone changes are dynamic

50 100 150 200 5 10 15 20 25 30 1 2 4 5 6 7

FSH (IU/L) E2 (pg/mL)

P4 (ng/mL)

Time (Weeks) 50 yrs, LMP 3 mo prior, No Hot Flashes

CD1 CD1 50 100 150 200 5 10 15 20 25 30 1 2 3 4 5 6 FSH (IU/L) E2 (pg/mL) P4 (ng/mL)

Time (Weeks) 51 yrs, LMP 3 mo prior, Infrequent Hot Flashes

Spot CD1

49 yrs, LMP 4 mo prior, Frequent Hot Flashes

50 100 150 200 5 10 15 20 25 30 1 2 3 4 FSH (IU/L) E2 (pg/mL) P4 (ng/mL)

Time (Weeks) P4 E2 FSH

Aims

1. To determine if perimenopausal hormone dynamics are associated with depressive symptom severity

a. Estradiol variability b. Progesterone peaks

1 + 5 1 0 1 5 2 0 # o f P ro g e s te ro n e P e a k s (> 6 n g /d l) M A D R S

Perimenopause-associated depressive symptoms and reproductive hormone dynamics

1 Joffe H, ENDO 2015; 2Joffe H, J Clin Endo Metab 2011; 3Daly Am J Psychiatry 2003

• 200
• 100

100 200

• 40
• 30
• 20
• 10

10 20 Change in estradiol (pg/ml) Change in MADRS

• 200
• 100

100 200

• 40
• 30
• 20
• 10

10 20 Change in estradiol (pg/ml) Change in MADRS

Estradiol

r=–0.36 p=0.007

Mood is better when FSH decreases 3 Mood is better when estradiol is less variable 1 Mood is better when progesterone is produced /

• vulation occurs 1

0 -1 0 1 0 -2 0 2 0 -3 0 3 0 -4 0 5 1 0 1 5 2 0 C o efficien t o f V ariatio n in (ln )E strad io l (% ) M A D R S

Mood improves when estradiol increases 2

Clinical studies show that mood is better as ovarian activity is more normalized in perimenopausal women. Conversely, the more abnormal the hormonal profile, the worse the mood.

Aims

1. To determine if hot flashes are associated with depressive symptom onset

a. Nighttime hot flashes? b. Daytime hot flashes?

2. To examine if sleep fragmentation mediates the association between hot flashes and depressive symptoms

MADRS = Montgomery Asberg Depression Rating Scale

Adverse impact of nighttime hot flashes and sleep disruption on mood

Joffe, J Clin Endo Metab 2016

Nocturnal, but not daytime, hot flashes, result in an increase in depressive symptoms

None (n=9) Infrequent (n=10) Frequent (n=10)

Hot flashes Worsening of sleep fragmentation and sleep quality result in an increase in depressive symptoms

N o In c re a s e In c re a s e

• 5

5 1 0 1 5 2 0 2 5 3 0 C h a n g e in M A D R S S c o re

(A) # of Transitions to Wake

N o In c r e a s e In c r e a s e

• 5

5 1 0 1 5 2 0 2 5 3 0 C h a n g e in M A D R S S c o re

(B) % of Time in Stage N1 (C) PSQI Score

No Increase Increase

• 5

5 10 15 20 25 30 C hange in MA DR S S core

p=0.04 p=0.05 p=0.02

N o n e In fr e q u e n t F r e q u e n t

• 5

5 1 0 1 5 2 0 2 5 3 0 C h a n g e in M A D R S S c o re

(A) Nighttime Hot Flashes

p=0.006

N o n e In fr e q u e n t F r e q u e n t

• 5

5 1 0 1 5 2 0 2 5 3 0 C h a n g e in M A D R S S c o re

(B) Daytime Hot Flashes

p=0.28X

Why are women at increased risk for depressive symptoms in perimenopause?

^ VMS ↓ sleep ↓ mood

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

Nighttime

2,3 3−5 3,5

↓↑ estradiol ↓progesterone

1

1. Depressive symptoms and clinical depression during the perimenopause are distinct entities with different risk profiles 2. Major depression associated with:

• Prior depression episodes

3. Depressive symptoms associated with:

• Changing hormone dynamic
• Hot flashes and sleep disturbance

4. Implications for treatment approaches

Perimenopause and depression

Patient considerations

Relevance of menopause to mood state?

1. Coincident vs. linked vs. susceptibility factor 2. Stressful life events, precipitants 3. Midlife and menopause experience and attitudes

Menopause and risk profile

1. Perimenopause (early vs. late) vs. postmenopause 2. Presence of hot flashes 3. Psychiatric history/antidepressant benefits and risk 4. Estrogen therapy risk profile

Symptom presentation

1. Temporal relationship to hormonal and perimenopausal changes 2. Co-occurrence of hot flashes and sleep disturbance 3. Mild depressive symptoms vs. 1st lifetime onset clinical depression vs. recurrent depression episode

• Peri- and early postmenopausal women with hot

flashes with depressive symptoms are main group to benefit from hormone therapy1,2 – Ineffective for older postmenopausal women further from FMP without hot flashes3

• Estrogen is not primary therapy for women with an

episode of clinical depression – Secondary benefit in women with hot flashes?

1 Soares, Arch Gen Psych 2001; 2 Schmidt, Am J OBGYN 2000; 3 Morrison Bio Psych 2004

Hormone therapy and menopause-associated depression

FMP = final menstrual period

So are s CN, Arch Gen Psych 2001

Plac e bo 17-E

2

5 10 15 20 25 Base line We e k 4 We e k 8 We e k 12 Washo ut

MADRS Me an Sc o re s

E stro g e n-Base d T he rapy (T ransde rmal 17-E

2) fo r the

T re atme nt o f MDD in Pe rime no pausal Wo me n

• 1. Antidepressants (all serotonergic agents)

– Desvenlafaxine, citalopram, escitalopram, mirtazapine, duloxetine, venlafaxine1-5 – Response to SSRI and SRNI does not vary by menopause status or co-treatment with hormone therapy6-7 – No advantage of specific agents

• 2. Psychotherapy
• 3. May need to augment with specific therapy

targeting nighttime hot flashes and sleep disturbance

1 Kornstein, J Clin Psych 2010; 2 Joffe, J Clin Psych 2007; 3 Joffe, J Womens Health Gend Based Med 2001; 4 Soares, J

Clin Psych 2003; 5 Dias, Menopause 2006; 6 Kornstein, Menopause 2014; 7 Kornstein, JCP2014

Treatment of Menopause-Associated Depression

SSRI and SNRI RCT for menopause- associated major depression

Clayton, J Clin Psychiatry 2013 Soares, Menopause 2010

Summary: Depression during peri/postmenopause

1. Mood disturbance is a common problem during the menopause transition 2. Presents as major depression or mild subsyndromal depressive symptoms

– Risk factors and treatment implications

3. Major depression

– Primarily recurrent episodes – Not associated with perimenopausal hormone changes or hot flashes – Sleep disturbance not restricted to brief awakenings – First line therapy is traditional psychotropic agents (SSRI/SNRI) and psychotherapy

4. Depressive symptoms

– Associated with changing perimenopausal hormone dynamics – Associated with nighttime (not daytime) hot flashes and sleep interruption – Off-label benefit of estrogen therapy (and hormonal contraceptives)