1. 1 Healthy Transitions: Maintaining Mental Health though the Menopausal Transition Katherine L. Wisner, M.D., M.S. Norman and Helen Asher Professor of Psychiatry and Obstetrics and Gynecology Director, Asher Center for Research and Treatment of Depressive Disorders Member, Institute for Women’s Health Research Feinberg School of Medicine Northwestern University, Chicago IL

2. 2 Menarche Premenstruum Pregnancy Postpartum Menopause The Longitudinal Laboratory of Women’s Lives Menarche Premenstruum Pregnancy Postpartum Menopause

3. Menstrual Cycle Changes

4. 4 STRAW +10 Stages (Stages of Reproductive Aging Workshop) Menopause 2012. 19(4): 387-95.

5. Challenges for Midlife Women Average age 51 years Average age 51 years Systemic Problems related to estrogen decrease Systemic Problems related to estrogen decrease Hot flushesHot flushes Insomnia, Irritability, Depression, Mood labilityInsomnia, Irritability, Depression, Mood lability Memory changesMemory changes Bone lossBone loss Cardiovascular healthCardiovascular health Focal Problems Focal Problems Vaginal drynessVaginal dryness Vaginal atrophyVaginal atrophy Pain with intercoursePain with intercourse Urinary problemsUrinary problems

6. 6 Challenges for Midlife Women During the menopausal transition, depression affects between 12-23% of women aged 40-59 years >43 million women (14% of US population) who have among the highest rates of depression of any demographic The majority of women do not develop depression (“empty nest syndrome, involutional melancholia”) !!

7. 7 Menopause Risk for depression especially women with previous episodes Risk for depression especially women with previous episodes Estrogen withdrawal theory Estrogen enhances serotonergic and noradrenergic transmission Estrogen enhances serotonergic and noradrenergic transmission Domino theory Somatic symptoms, especially sleep disturbance, anxiety, sexual dysfunction, create risk for depression as a down-line effect Somatic symptoms, especially sleep disturbance, anxiety, sexual dysfunction, create risk for depression as a down-line effect Life stage perspective Changing family or professional roles, interpersonal losses, aging and physical illness Changing family or professional roles, interpersonal losses, aging and physical illness

8. 8 Epidemiology Major Depression- Major Public Health Impact Depression is common. Globally, >350 million people of all ages suffer. Depression is the leading cause of disability worldwide, and a major contributor to the global burden of disease. Twice as many women are affected as men. Lifetime, Female (F)=21%; Male (M)=12% Annual, F=13%, M=8% There are effective treatments for depression! www.who.int/mediacentre/factsheets/fs369/en/index.html

9. 9 Gender Differences in the Prevalence of Major Depression Women have twice the rate relative to men Kessler et al (1993) Journal of Affective Disorders

10. 10 Clinical Presentation: Major Depression For two weeks, most of the day nearly every day, 5 of these (one must be mood or interest): For two weeks, most of the day nearly every day, 5 of these (one must be mood or interest): Depressed mood Depressed mood Diminished interest/pleasure Diminished interest/pleasure Weight loss/ gain unrelated to dieting Weight loss/ gain unrelated to dieting Insomnia/ hypersomnia Insomnia/ hypersomnia Psychomotor agitation/ retardation Psychomotor agitation/ retardation Fatigue or loss of energy Fatigue or loss of energy Feelings of worthlessness/guilt Feelings of worthlessness/guilt Diminished ability to concentrate Diminished ability to concentrate Recurrent thoughts of death Recurrent thoughts of death NIMH--MDD in Women brochure for patients: www.nimh.nih.gov/health/publications/women-and- depression-discovering-hope/index.shtml

11. 11 Pathophysiology: Individual and Social Factors Personality traits (passive, unassertive; ruminative) associated with female gender and depression. Personality traits (passive, unassertive; ruminative) associated with female gender and depression. Close interpersonal relationships are relatively more important to women than men; disruptions in relationships are particularly stressful. Close interpersonal relationships are relatively more important to women than men; disruptions in relationships are particularly stressful. Women more likely ruminate about interpersonal difficulties and conflicts Women more likely ruminate about interpersonal difficulties and conflicts Less resource access: Full-time working women earn $0.77 per $1 a man earns: less money for needs of their families, more women living in poverty, and far less savings for retirement. Less resource access: Full-time working women earn $0.77 per $1 a man earns: less money for needs of their families, more women living in poverty, and far less savings for retirement.

12. 12 Pathophysiology: Life Stress and Trauma Women experience more stressors more frequently than men. Women experience more stressors more frequently than men. Childhood sexual abuse (6%-33%)Childhood sexual abuse (6%-33%) Adult sexual assault (estimate 15%)Adult sexual assault (estimate 15%) Male partner violence (WHO, 15%-71% across 10 countries)Male partner violence (WHO, 15%-71% across 10 countries) Women are more likely to react to stressors with depression. Women are more likely to react to stressors with depression. Frequent stressors and stress reactivity perpetuate and kindle women’s vulnerability to depression over time. Frequent stressors and stress reactivity perpetuate and kindle women’s vulnerability to depression over time. (Nolen-Hoeksema, S. -Wye River, Oct. 2000) (Nolen-Hoeksema, S. -Wye River, Oct. 2000)

13. 13 Biological Differences Pathophysiology Biological Differences Depressive illnesses are brain disorders Depressive illnesses are brain disorders Neural circuits for control of mood, thought, sleep, appetite, and behavior are dysregulated. Neural circuits for control of mood, thought, sleep, appetite, and behavior are dysregulated. Depression results from influence of multiple genes acting together with environmental factors. Depression results from influence of multiple genes acting together with environmental factors. Depressive symptoms are associated with ovarian hormone fluctuation, but there is no relationship between serum levels and depressed mood Depressive symptoms are associated with ovarian hormone fluctuation, but there is no relationship between serum levels and depressed mood Affected woman have enhanced neurobiological sensitivity to hormonal fluctuation. Affected woman have enhanced neurobiological sensitivity to hormonal fluctuation. Most women do not experience significant mood problems during reproductive transitions. Most women do not experience significant mood problems during reproductive transitions.

14. 14 Evidence Based Interventions: Psychotherapy Several types of short-term (8-16 sessions, focused psychotherapy) Several types of short-term (8-16 sessions, focused psychotherapy) Patient choice, access, depression severity Patient choice, access, depression severity Interpersonal Psychotherapy targets interpersonal distress and effect on mood www.apa.org/divisions/div12/rev_est/ipt_depr.html Interpersonal Psychotherapy targets interpersonal distress and effect on mood www.apa.org/divisions/div12/rev_est/ipt_depr.html Cognitive Behavior Therapy – correct distorted and dysfunctional automatic thoughts Cognitive Behavior Therapy – correct distorted and dysfunctional automatic thoughtswww.beckinstitute.org/what-is-cognitive-behavioral-therapy Dialectical Behavior Therapy--combines standard CBT techniques with skill building - distress tolerance, acceptance, mindfulness Dialectical Behavior Therapy--combines standard CBT techniques with skill building - distress tolerance, acceptance, mindfulnesshttp://behavioraltech.org/index.cfm

15. 15 All Antidepressants have Similar Efficacy Serotonergic (SSRI-sertraline, fluoxetine; SNRI, venlafaxine) Comorbid Obsessive-compulsive disorderComorbid Obsessive-compulsive disorder Hot flashesHot flashes Side effects=Sexual dysfunction, weight gain, nausea/ diarrhea, sleep disturbance, apathySide effects=Sexual dysfunction, weight gain, nausea/ diarrhea, sleep disturbance, apathy Norepinephrine (Tricyclics-nortriptyline, SNRI) Serum level is meaningfulSerum level is meaningful Side effects=Tremor, tachycardia, dry mouth, insomnia, weight gainSide effects=Tremor, tachycardia, dry mouth, insomnia, weight gain Dopamine/Norepinephrine (bupropion) Smoking cessationSmoking cessation Side effects=Agitation, psychosis, weight neutral/ appetite suppressionSide effects=Agitation, psychosis, weight neutral/ appetite suppression Personalize Antidepressant Choice

16. 16 Perimenopausal Depression Treatment Antidepressants and Psychotherapy first line Antidepressants and Psychotherapy first line Transdermal estradiol (E2), small RCTs positive Transdermal estradiol (E2), small RCTs positive 3-12 wk RCTs of E 2 50-100 ug/d) vs Placebo3-12 wk RCTs of E 2 50-100 ug/d) vs Placebo 68-80% response of E 2 vs 20% to Placebo68-80% response of E 2 vs 20% to Placebo Joffe et al, N=72 Joffe et al, N=72 8 wk RCT E2 (50 ug/day), zolpidem, Placebo8 wk RCT E2 (50 ug/day), zolpidem, Placebo Similar improvement across 3 groupsSimilar improvement across 3 groups Morrison et al, N=72 Morrison et al, N=72 E2 (100 mcg/day) not efficacious compared to PL after 8 weeks in older (mean=62 years) post-menopausal womenE2 (100 mcg/day) not efficacious compared to PL after 8 weeks in older (mean=62 years) post-menopausal women For E2 treatment: STRAW -1 to +1a and 1bFor E2 treatment: STRAW -1 to +1a and 1b Post-meno. women respond more favorably to Post-meno. women respond more favorably to tricyclics (nortriptyline) than to SSRI tricyclics (nortriptyline) than to SSRI

17. 17 Estradiol Treatment Complex relationship between gonadal hormones and depression Complex relationship between gonadal hormones and depression Not a hormone deficiency: Levels of FSH and E2 do not distinguish women with/ without depression Not a hormone deficiency: Levels of FSH and E2 do not distinguish women with/ without depression Response to E2 is not predicted by baseline or post- treatment E2 levels Response to E2 is not predicted by baseline or post- treatment E2 levels E2 has antidepressant properties E2 has antidepressant properties The mood enhancing effects of E2 occurs independent of the presence of hot flashes The mood enhancing effects of E2 occurs independent of the presence of hot flashes SSRI/SNRI reduce vasomotor symptoms, but not as effective as E2 SSRI/SNRI reduce vasomotor symptoms, but not as effective as E2

18. Environmental Approaches Aerobic Exercise (> 30 minutes of moderate intensity physical exercise, 3 to 5 days per week) Dunn et al, Am J Prev Med 2005;28:1-8, 2005 Nutritional status; Vitamin D. EMAS position statement: Vitamin D and postmenopausal health Perez-Lopez et al, Maturitas 71:83-88, 2012 Essential Fatty Acids for Cardiac Health/ Depression/ Immune Function 1-2 grams of EFA/day as in AHA recommendations; Reviews: Freeman et al. J Clin Psych 67, 2006; Parker et al, Am J Psych 163:969-978, 2006

19. Bright Morning Light Therapy Bright Morning Light Therapy, 10,000 lux commercial UV blocked box Center for Environmental Therapeutics, tools at www.cet.org APA review and meta-analysis- Am J Psych 162:656-662, 2005 www.cet.org Data support efficacy in non-seasonal depression: a non-pharmacologic somatic RX for depression

20. 20 WARNING! Insufficient Medical Research Can be Hazardous to your Health C. Everett Koop, M.D.