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Y does X Make A Difference? Reproductive-Related Mood Disorders

Y does X Make A Difference? Reproductive-Related Mood Disorders. 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, Women’s Health Research Institute

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Y does X Make A Difference? Reproductive-Related Mood Disorders

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  1. Y does X Make A Difference?Reproductive-Related Mood Disorders 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, Women’s Health Research Institute Member, Institute for Public Health and Medicine Feinberg School of Medicine Northwestern University, Chicago IL

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

  3. Personal Disease Burden of Depression It was devastating to my whole family. I had gone through numerous attempts to have a baby and when I did finally have this perfect, beautiful, healthy baby -- it all but destroyed me. I couldn’t hold the baby, I couldn’t do anything for the baby, I couldn’t look at the baby. Every time I got near her, even the smell of the diapers of the baby-- I would… My knees would get weak. I would… I just cried all day long and I thought I’d made the worst mistake of my life. 3

  4. Gender Differences in the Prevalence of Major Depression Women have twice the rate of MDD as men Kessler et al (1993) Journal of Affective Disorders

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

  6. PathophysiologyBiological Differences • Major Depression and Mood Disorders are brain disorders • Dysregulated neural circuits for control of mood, thought, sleep, appetite, and behavior. • Depression results from multiple genes acting together with environmental factors. • Depressive symptoms are associated with ovarian hormone fluctuation, but no relationship between serum levels and depressed mood • Affected woman have enhanced neurobiological sensitivity to hormonal fluctuation. • Most women do not experience significant mood problems during reproductive transitions.

  7. Pathophysiology:Life Stress and Trauma • Women experience more stressors more frequently than men. • Childhood sexual abuse (6%-33%) • Adult sexual assault (estimate 15%) • Male partner violence (WHO, 15%-71% across 10 countries) • 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. • 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.

  8. Prognosis Recurrence Risk increases with the number of episodes: With 1 episode of major depression, the woman has a 60% probability of another If 2 episodes, 70% If 3 episodes, 90%, likely to be chronic, consider maintenance treatment

  9. Paucity of (any!) Treatment in U.S. • Vesga-Lopez et al, Arch Gen Psychiatry 2008;65(7):805-815 • Mental health service utilization among women with Psychiatric Disorders is very low • Mood disorder past 12 months: Non-pregnant 25.5% Past-year pregnant 14.3%

  10. What is Bipolar Disorder? • Prevalence=1-1.5%; to 5% for spectrum, M=F • Onset in mid to late teens • Mania/ hypomania alternates with depression • “Plugged in” symptoms: grandiosity, less need for sleep but not tired, pressured speech, flight of ideas, distractibility, increased involvement in activities, excessive involvement in pleasurable activities with no regard for painful consequences • Postpartum onset particularly common • Antidepressant alone risks agitation, rapid cycling • Screen for bipolar disorder (Mood Disorders Questionnaire) www.dbsalliance.org/pdfs/MDQ.pdf

  11. Depression: Evidence Based Treatment- Psychotherapy • Several types of short-term (8-16 sessions, focused psychotherapy) • Patient choice, access, depression severity • 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 www.beckinstitute.org/what-is-cognitive-behavioral-therapy • Dialectical Behavior Therapy--combines standard CBT techniques with skill building - distress tolerance, acceptance, mindfulness http://behavioraltech.org/index.cfm

  12. All Antidepressants have Similar Efficacy Serotonergic (SSRI-sertraline, fluoxetine; SNRI, venlafaxine) Comorbid Anxiety Disorder Hot flashes Side effects=Sexual dysfunction, weight gain, nausea/ diarrhea, sleep disturbance, apathy and decreased motivation Norepinephrine (Tricyclics-nortriptyline) Serum level is meaningful Side effects=Tremor, tachycardia, dry mouth, insomnia, weight gain Dopamine/Norepinephrine (bupropion) Smoking cessation Side effects=Agitation, psychosis, weight neutral/ appetite suppression Personalize Antidepressant Choice

  13. Environmental Treatments • Bright Morning Light Therapy Seasonal and non-seasonal depression • 30-60 minutes of commercially available, UV-screened bright fluorescent light, within 10 mins of awakening • Center for Environmental Therapeutics, tools at www.cet.org; Wirz-Justice et al--Chronotherapeutics for Affective Disorders: A Clinician's Manual for Light and Wake Therapy • 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

  14. The Longitudinal Laboratory of Women’s LivesMenarchePremenstruumPregnancyPostpartumMenopause

  15. OR: Gender = 1.63 (1.42-1.89)** Boys Girls PROBABILITY AGE (adapted from Angold and Rutter, 1992)

  16. Prevalence of Premenstrual Symptoms Women of Reproductive Age Mild Premenstrual Symptoms 75% PMS 20%-40% PMDD 3%-8% 1. Steiner M. J Psychiatry Neurosci 2000;25(5):459-468. 2.American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. 1994.

  17. Premenstrual Dysphoric Disorder • Approximately 5% of menstruating women • Rule out Major Depression with premenstrual worsening • Average age of onset= 26 years • Symptoms increase across time until menopause • Somatic symptoms typically improve parallel to depressive symptoms • Symptoms return when treatment is stopped • Symptoms of PMDD comparable in severity to major depression- irritability is prominent

  18. Follicular phase Luteal Phase Follicular phase Luteal Phase Follicular phase Luteal Phase Follicular phase Luteal Phase Cycle 1 Cycle 2 Cycle 3 Cycle 4 = menses Sequence of Menstrual Cycle Mood Symptoms Depression Score

  19. Premenstrual Dysphoric Disorder • Better than Placebo (SSRI/SNRI)= Fluoxetine, Sertraline, Citalopram, Paroxetine Venlafaxine/ desmethyl-venlafaxine/ Duloxetine • Continuous OCP under study • Dosing – luteal phase • Menstrual cycle monitoring • Dickerson et al, Am Fam Physician 67(8):1743-1752, 2003 http://www.aafp.org/afp/2003/0415/afp20030415p1743-f2.gif

  20. Depression and Sequelae Affect Multiple Domains of Perinatal Health • Symptoms of Depression=physiological dysregulation • Appetite and Nutrition Effects • Cognitive changes; attention to self and infant safety • Prenatal care compliance • Alcohol, drug use • Loss of Personal /Family resources • Pregnancy Outcomes: low birthweight, preterm birth (Grote NK et al,Arch Gen Psychiatry. 2010;67(10):1012-1024)

  21. Risks are More Heavily Weighted Than Benefits Antidepressant treatment during pregnancy: Are we asking the right questions? Wisner, Depression and Anxiety: 27:695-698, 2010 21

  22. Reproductive Outcome Domains • Major birth defects (approx 3% in the general population) • Growth Effects • Behavioral Teratogenicity • Neonatal Syndrome These domains are impacted by both psychiatric disorders and antidepressants The drug free pregnancy is very rare in the US

  23. Summary Points Physical Malformations-Specific defects (if any) are rare and absolute risks are small. Greene, M. F. (2007). Teratogenicity of SSRIs -- Serious Concern or Much Ado about Little? NEJM 356: 2732-2733 Growth- Pregnancy duration, Birth weight-SGA inconsistently reported with SSRI exposure. PTB--a converging finding for SSRI exposure-- MDD associated with a similar level of risk for PTB (Wisner et al, Am J Psychiatry 166:557-566, 2009). SGA and PTB associated with MDD (Grote et al, Arch Gen Psychiatry 67(10):1012-1024, 2010)

  24. Summary Points Behavioral Teratogenicity Mental development WNL Offspring exposed to antidepressants similar to controls in cognitive function, expressive language, mood, activity levels, distractibility, behavior problems, temperament (Nulman et al, NEJM 336:258-262, 1997) Pedersen et al (Pediatrics, Feb, 2010) normal milestone development in SSRI exposed vs. depressed and controls. Prenatal antidepressant exposure not associated with behavioral or emotional problems. (Pedersen, Acta Psychiatrica Scand, Nov, 2012). No difference in neuromotor function at 6 months in SSRI exposed vs. controls (Johnson et al, Arch Gen Psych 69:787-794, 2012). Casper et al (J Pediatr 142:402-408, 2003)found less favorable motor (not mental) development in SSRI vs. depression exposed in toddlers

  25. Summary Points Neonatal Syndrome-Time-limited < 2 weeks, rarely requires medical intervention; most commonly associated agents are paroxetine>fluoxetine>sertraline> fluvoxamine= citalopram= escitalopram(Moses-Kolko et al, JAMA 294:2299-2300, 2005)

  26. Optimize Maternal Treatment • Minimum effective dose through pregnancy! • Standardized measure throughout pregnancy to monitor for symptom change • Pharmacokinetic changes in psychotropic drug levels during pregnancy • Breastfeeding (Surgeon General’s report; excess risks with not breastfeeding http://www.ncbi.nlm.nih.gov/books/NBK52680/) 26

  27. Pregnancy Treatment: Conclusions • There is no 0-risk option • We will always need more data • It is impossible to prove 0 additional risk from drug or depression exposure above general population • There will always be women who require or prefer pharmacologic treatment • Pharmacokinetic and Pharmacogenetic studies: tools to improve efficacy and reduce side effects

  28. Postpartum Depression Screening in an Obstetrical Hospital • 10,000 screened, 14% positive on screen (Edinburgh Postnatal Depression Scale -EPDS)Cox JL, et al. Br J Psychiatry 1987; 150:782-86 • The onset of the identified episodes for the women was: - during pregnancy, N=276 (33.4%) - postpartum (within 4 weeks of birth), N= 331 (40.1%) - prior to pregnancy, N=219 (26.5%) www.MedEdPPD.orgwww.postpartum.net

  29. Endocrinology of Childbearing ESTROGENS PROGESTINS

  30. Transdermal Estradiol for Postpartum Depression • Replicate Gregoire et al (1996, Lancet) rapid response to E2 vs. PL with antidepressant comparator • Random assignment to E2 patch, sertraline or PL for 8 weeks • Women with response enter blinded continuation phase through 28 weeks postpartum • Infant growth and developmental outcomes at 6.5 months • 84 randomized; no adverse events

  31. Eligibility for Study • Ages 18-45 (855) 99 ASHER • Women less than 3 mo postpartum • Breastfeeding or formula feeding • Medically healthy • Not taking an antidepressant • Nonsmoking or <10 cigarettes/day

  32. Depression in Menopausal Transition • Average age 51 years • Risk for depression in the perimenopause; especially women with previous episodes Estrogen withdrawal theory • 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 Life stage perspective • Changing family or professional roles, interpersonal losses, aging and physical illness

  33. STRAW +10 StagesMenopause 2012. 19(4): 387-95.

  34. Perimenopausal Depression Treatment • Antidepressants and Psychotherapy are first line • Post-meno. women respond more favorably to tricyclics (e.g., nortriptyline) than to SSRI • Transdermal estradiol (E2), small RCTs positive • 3-12 wk RCTs of E2 50-100 ug/d) vs Placebo • 68-80% response of E2 vs 20% to Placebo • Joffe et al, N=72 • 8 wk RCT E2 (50 ug/day), zolpidem, Placebo • Similar improvement across 3 groups • Morrison et al, N=72 • E2 (100 mcg/day) not efficacious compared to PL after 8 weeks in older (mean=62 years) post-menopausal women

  35. Estradiol Treatment • 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 • E2 has antidepressant properties • 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 • Proposed Study -- For Transdermal E2 vs. Sertraline vs. Placebo RCT: STRAW -1 to +1a and 1b • Hypothesis- E2 stabilizes dramatic fluctuations in E2 levels, reduces variability

  36. Mental Healthis Fundamental toHealth David Satcher, M.D. We must prioritize the mental health of the mothers of our next generation!

  37. Estradiol Treatment CVD-risks of HT related to the timing of treatment, with beneficial/neutral effects for women who initiate therapy close to the FMP. MDD is a risk factor for CVD, which is the leading killer of women in the U.S. Breast cancer, The Endocrine Society Scientific Statement reported a “worst case scenario” for increased risk in a50-54 year old woman with 5 years of unopposed estrogen from 13/1000 women (no exposure) to 14.94/1000 women 37

  38. Estradiol Treatment Risk of VTE reduced by the use of transdermal E2 E2 for D-MT offers advantages over SSRIs for VMS, osteoporosis, atrophic vaginitis SSRI treatment is associated with a significantly increased risk of fracture even after adjustment for depression 38

  39. Inclusion/ Exclusions • Acceptability of all 3 interventions • Smoke < ½ pack cigarettes per day or are willing to cut down or quit • No clotting disorder or DVT (self or first degree relatives); cardiac disease, breast cancer • Birth control: non-estrogen containing: implanon, depo-provera, progestin-only OCP, IUD, double barrier • Bleeding assessment each week; medroxyprogesterone withdrawal at end of acute phase if no bleed (and no source of progestogen); followed through continuation • Labs: free T4 and TSH; metabolic screen; CBC, platelets; urinalysis; UDS; urine pregnancy test • “Normal” lipids

  40. Resources: Bipolar Disorder • Is Your Depressed Patient Bipolar? Kaye NS, www.jabfm.org/content/18/4/271.full • Patient Resource (NIMH): www.nimh.nih.gov/health/publications/bipolar-disorder/complete-index.shtml • Treatment of Bipolar Disorder: A Guide For Patients and Families www.psychguides.com/sites/psychguides.com/files/docs/Bipolar%20Handout.pdf • Famous Women with Bipolar Disorder Carrie Fisher, Patty Duke, Mariette Hartley, Catherine Zeta-Jones, Jane Pauley, Marilyn Monroe, Judy Garland

  41. Resources for PMDD Steiner M et al. Expert Guidelines for the Treatment of Severe PMS, PMDD, and Comorbidities: the Role of SSRIs. J Women’s Health 2006:15:57-69. Information for patients: www.womensmentalhealth.org/specialty-clinics/pms-and-pmdd

  42. More Information- Pregnancy • Developmental and Reproductive Toxicity: www.toxnet.nlm.nih.gov (DART database) • Organization of Teratology Information Specialists (OTIS) www.otispregnancy.org, (866) 626-OTIS, or (866) 626-6847 • ACOG Practice bulletin: Use of psychiatric medications during pregnancy and lactation. Obstetrics and Gynecology 110:1179-1198 • Wisner KL et al: Psychiatric Disorders, in Obstetrics: Normal and Problem Pregnancies, 5th edition. Gabbe SG et al, Edss; Elsevier, p 1249-1288, 2007.

  43. More Information: Postpartum Depression • Miller LJ. Postpartum Depression. JAMA 287:762-765, 2002. • Wisner KL et al.. Clinical Practice: Postpartum depression. NEJM 347:194-199, 2002. • Wisner KL et al. A major public health problem: Postpartum depression. JAMA 296:2616-2618, 2006. • Munk-Olsen T. New Parents and Mental Disorders: A Population-Based Register Study.JAMA 2006;296:2582-2589

  44. MedEd PPDwww.MedEdPPD.org Professional Information • Provides professionals with tools to screen, diagnose, treat, refer, engage women with PPD: • Interactive case studies • Provider tools including diagnostic instruments • Video presentations and discussions Mothers and Others • Patient-oriented section contains: • Easy-to-use online diagnostic test; • The myths and realities of PPD; • Experiences of women with PPD; • Answers to frequently asked questions from experts in the field

  45. Resources: Menopause Parry BL. Treatment in Psychiatry: Perimeno-pausal Depression. Am J Psych 165:23-27, 2008 North American Menopause Society http://www.menopause.org/ Soares CN, Frey BN. Challenges and Opportunities to manage depression during the menopausal transition and beyond. Psychiatric Clin N Am 33:295–308, 2010

  46. Antidepressants:One Dose Does NOT Fit All Wisner et al, J Clin Psychopharm 26:353-360, 2006. SERT,mg/day, N=24 % remitted NTP, mg/day, N=26, % remitted *Start with 25 mg of sertraline or 25 mg of nortriptyline; half of usual starting dose of any antidepressant

  47. Remission Recovery Relapse Recurrence Normal mood + Relapse Symptoms Response High --- Symptom Level -–Low 50% improvement + Depression Continuation Maintenance Acute Phase Evolution of Episode and the ‘5 R’s’ for Major Depressive Disorder Time Adapted from Kupfer DJ. J Clin Psychiatry. 1991;52(Suppl):28-34.

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