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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!

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 Women are approximately 1.7 times as likely as men to report a lifetime history of MDE. Sex difference begins in early adolescence (age 10) and persists through the mid-50s. The sharp divergence in the 50’s is based upon a small sample size and not thought to be reliable. Sex difference in depression is most pronounces among early adolescents, with the highest relative hazard of first onset (OR=2.3) in the age range This is a consistent finding throughout the world, regardless of how depression is diagnosed. Since women are no more likely than men to be chronically depressed or to have ana acute recurrence in the past year – therefore higher prevalence is due to higher risk of 1st onset. The NCS was a congressionally mandated survey with the specific goal of studying the comorbidity of psychiatric disorders individuals, ages interviewed. Used a supplemental nonresponse survey, with financial incentive, based on previous evidence that survey nonresponders tend to have higher rates of psychiatric d/o. A structured psychiatric interview (DIS-diagnositc interiew schedule – can be administered by trained interviewers who are not clinicians) was administered to a representative US sample. Based on results that respondents underreport stem questions once they recognize that positive responses lead to more detailed questions, they used a life review section before probing any positive stem responses and to facilitate active memory search for lifetime episodes. Anxiety d/o have an approximately 5% 1-yr prevalence form the same study 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:

6 Pathophysiology Biological 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): 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)

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 Cognitive Behavior Therapy – correct distorted and dysfunctional automatic thoughts Dialectical Behavior Therapy--combines standard CBT techniques with skill building - distress tolerance, acceptance, mindfulness

12 Personalize Antidepressant Choice
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 References: 1. Richelson E. Pharmacology of antidepressant—characteristics of the ideal drug. Mayo Clin Proc. 1994;69: 2. Sussman N, Ginsburg D. Weight gain associated with SSRIs. Prim Psychiatry. 1998;5:28-37. 3. Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 2nd ed. New York, NY: Cambridge University Press; 2000. 4. Richelson E. Prim Psychiatry. 1998;5:40-41. 5. Kapur S, Remington G. Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry. 1996;153:

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 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 Lives Menarche Premenstruum Pregnancy Postpartum Menopause

15 AGE OR: Gender = 1.63 (1.42-1.89)** PROBABILITY Boys Girls
(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): 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed

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

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): , 2003

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): )

21 Risks are More Heavily Weighted Than Benefits
Antidepressant treatment during pregnancy: Are we asking the right questions? Wisner, Depression and Anxiety: 27: , 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: 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: , 2009). SGA and PTB associated with MDD (Grote et al, Arch Gen Psychiatry 67(10): , 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: , 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: , 2012). Casper et al (J Pediatr 142: , 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: , 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 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%)

29 Endocrinology of Childbearing
ESTROGENS PROGESTINS Estradiol increases from 100 pg/ml (mean conc across the menstrual cycle) to 16,000 pg/ml (an over 100-fold increase) Within 24 hours of parturition, estrogen drops below follicular levels, and then reequilibrates within a few days. Progesterone rises from 25 ng/ml (mid luteal peak) to 150 ng/ml by term (6-fold higher) and then drops within 24 hours to luteal phase levels and then further to follicular levels by 1 wk postpartum. Estradiol increases 100-fold across pregnancy relative to mean menstrual cycle concentrations and falls to early follicular levels within the 1st week postpartum. Large increases in dihydroepiandosterone via the fetal adrenal gland contribute to pregnancy estrogen increases (ParkerJr 1999). Progesterone reaches concentrations 10-fold higher than mid-luteal levels of the menstrual cycle in late pregnancy, and falls to follicular phase levels within the 1st week postpartum. Allopregnanolone concentration increases follow those of progesterone across childbearing (Luisi et al. 2000). Due to prolonged suppression of the hypothalamic pituitary ovarian axis during pregnancy, ovulation and the associated rise in estradiol and progesterone is generally absent until 6 weeks postpartum. Corticotrophin releasing hormone (CRH) and cortisol produced by the placenta increase 1000-fold and 3-fold in pregnancy, respectively and revert to normal states within 12 weeks postpartum (Chrousos et al. 1998; Mastorakos et al. 2000; Smith et al. 1992). Oxytocin mRNA expression, synthesis, and receptor density are increased several-fold in lactating relative to non-lactating mammals (Numan et al. 2003).

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 Stages Menopause 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 E 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 Health is Fundamental to Health
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 a 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, Patient Resource (NIMH): Treatment of Bipolar Disorder: A Guide For Patients and Families 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:

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

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

44 MedEd PPD www.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 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: , 2006. SERT, mg/day, N=24 % remitted <100 100 125 or 150 200 1 (4%) 12 (50%) 4 (17%) 7 (29%) <100 100 125 or 150 15 (58%) 7 (27%) 4 (15%) 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 Evolution of Episode and the ‘5 R’s’ for Major Depressive Disorder
High --- Symptom Level -–Low Normal mood Symptoms Depression Relapse Response Remission Recurrence 50% improvement + Recovery Acute Phase Continuation Maintenance Three terms are used to describe improvement of a depressed patient after treatment with an antidepressant: response, remission, and recovery. Generally, response refers to at least a 50% reduction in symptoms of depression as assessed by a psychiatric rating scale. Remission is the resolution of essentially all symptoms (e.g., HAMD score  7). If remission lasts for 6 to 12 months, the remission is considered to be recovery. The terms relapse and recurrence are used to describe a worsening in a patient with depression. If the patient worsens before they have achieved recovery, the term relapse is employed to describe the worsening of symptoms. If the patient experiences a new depressive episode within a few months of recovery, the term recurrence is used. Treatment of MDD can be divided into three phases: acute, continuation, and maintenance. During the acute phase, in which the patient is experiencing depressive symptoms, a primary goal of treatment is to elicit a response to medication or therapy. During the continuation phase, the period after the patient’s symptoms have responded to acute intervention(s), a primary goal of treatment is to prevent a relapse of depressive symptoms. During the maintenance phase, a primary goal of treatment is to prevent a recurrence or another acute episode of depression. Reference: Kupfer DJ. Long-term treatment of depression. J Clin Psychiatry. 1991;52(Suppl):28-34. Time Adapted from Kupfer DJ. J Clin Psychiatry. 1991;52(Suppl):28-34.


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