Presentation on theme: "Y does X Make A Difference? Reproductive-Related Mood Disorders"— Presentation transcript:
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 GynecologyDirector, Asher Center for Research and Treatment of Depressive DisordersMember, Women’s Health Research InstituteMember, Institute for Public Health and MedicineFeinberg School of MedicineNorthwestern University, Chicago IL
2 Epidemiology: Major Depression- Major Public Health Impact Depression is commonTwice 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 menWomen 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 rangeThis 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 studyKessler 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 moodDiminished interest/pleasureWeight loss/ gain unrelated to dietingInsomnia/ hypersomniaPsychomotor agitation/ retardationFatigue or loss of energyFeelings of worthlessness/guiltDiminished ability to concentrateRecurrent thoughts of deathNIMH--MDD in Women brochure for patients:
6 Pathophysiology Biological Differences Major Depression and Mood Disorders are brain disordersDysregulated 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 moodAffected 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 anotherIf 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 lowMood 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=FOnset in mid to late teensMania/ 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 consequencesPostpartum onset particularly commonAntidepressant alone risks agitation, rapid cyclingScreen 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 severityInterpersonal Psychotherapy targets interpersonal distress and effect on moodCognitive Behavior Therapy – correct distorted and dysfunctional automatic thoughtsDialectical Behavior Therapy--combines standard CBT techniques with skill building - distress tolerance, acceptance, mindfulness
12 Personalize Antidepressant Choice All Antidepressants have Similar EfficacySerotonergic (SSRI-sertraline, fluoxetine; SNRI, venlafaxine)Comorbid Anxiety DisorderHot flashesSide effects=Sexual dysfunction, weight gain, nausea/ diarrhea, sleep disturbance, apathy and decreased motivationNorepinephrine (Tricyclics-nortriptyline)Serum level is meaningfulSide effects=Tremor, tachycardia, dry mouth, insomnia, weight gainDopamine/Norepinephrine (bupropion)Smoking cessationSide effects=Agitation, psychosis, weight neutral/ appetite suppressionReferences: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 TherapySeasonal and non-seasonal depression30-60 minutes of commercially available, UV-screened bright fluorescent light, within 10 mins of awakeningCenter for Environmental Therapeutics, tools at Wirz-Justice et al--Chronotherapeutics for Affective Disorders: A Clinician's Manual for Light and Wake TherapyAerobic 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 AgeMild Premenstrual Symptoms 75%PMS 20%-40%PMDD3%-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 womenRule out Major Depression with premenstrual worseningAverage age of onset= 26 yearsSymptoms increase across time until menopauseSomatic symptoms typically improve parallel to depressive symptomsSymptoms return when treatment is stoppedSymptoms of PMDD comparable in severity to major depression- irritability is prominent
18 Sequence of Menstrual Cycle Mood Symptoms Depression ScoreFollicularphaseLutealPhaseCycle 1Cycle 2Cycle 3Cycle 4= menses
19 Premenstrual Dysphoric Disorder Better than Placebo (SSRI/SNRI)=Fluoxetine, Sertraline, Citalopram, ParoxetineVenlafaxine/ desmethyl-venlafaxine/ DuloxetineContinuous OCP under studyDosing – luteal phaseMenstrual cycle monitoringDickerson et al,Am Fam Physician67(8): , 2003
20 Depression and Sequelae Affect Multiple Domains of Perinatal Health Symptoms of Depression=physiological dysregulationAppetite and Nutrition EffectsCognitive changes; attention to self and infant safetyPrenatal care complianceAlcohol, drug useLoss of Personal /Family resourcesPregnancy 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: , 201021
22 Reproductive Outcome Domains Major birth defects (approx 3% in the general population)Growth EffectsBehavioral TeratogenicityNeonatal SyndromeThese domains are impacted by both psychiatric disorders and antidepressantsThe drug free pregnancy is very rare in the US
23 Summary PointsPhysical 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 PointsNeonatal 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 dosethrough pregnancy!Standardized measure throughout pregnancy to monitor for symptom changePharmacokinetic changes in psychotropic drug levels during pregnancyBreastfeeding (Surgeon General’s report; excess risks with not breastfeeding26
27 Pregnancy Treatment: Conclusions There is no 0-risk optionWe will always need more dataIt is impossible to prove 0 additional risk from drug or depression exposure above general populationThere will always be women who require or prefer pharmacologic treatmentPharmacokinetic 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; 150:782-86The 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 ESTROGENSPROGESTINSEstradiol 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 comparatorRandom assignment to E2 patch, sertraline or PL for 8 weeksWomen with response enter blinded continuation phase through 28 weeks postpartumInfant growth and developmental outcomes at 6.5 months84 randomized; no adverse events
31 Eligibility for Study Ages 18-45 (855) 99 ASHER Women less than 3 mo postpartumBreastfeeding or formula feedingMedically healthyNot taking an antidepressantNonsmoking or <10 cigarettes/day
32 Depression in Menopausal Transition Average age 51 yearsRisk for depression in the perimenopause; especially women with previous episodesEstrogen withdrawal theoryEstrogen enhances serotonergic and noradrenergic transmissionDomino theorySomatic symptoms, especially sleep disturbance, anxiety, sexual dysfunction, create risk for depression as a down-line effectLife stage perspectiveChanging family or professional roles, interpersonal losses, aging and physical illness
34 Perimenopausal Depression Treatment Antidepressants and Psychotherapy are first linePost-meno. women respond more favorably totricyclics (e.g., nortriptyline) than to SSRITransdermal estradiol (E2), small RCTs positive3-12 wk RCTs of E ug/d) vs Placebo68-80% response of E2 vs 20% to PlaceboJoffe et al, N=728 wk RCT E2 (50 ug/day), zolpidem, PlaceboSimilar improvement across 3 groupsMorrison et al, N=72E2 (100 mcg/day) not efficacious compared to PL after 8 weeks in older (mean=62 years) post-menopausal women
35 Estradiol TreatmentNot a hormone deficiency: Levels of FSH and E2 do not distinguish women with/ without depressionResponse to E2 is not predicted by baseline or post-treatment E2 levelsE2 has antidepressant propertiesThe mood enhancing effects of E2 occurs independent of the presence of hot flashesSSRI/SNRI reduce vasomotor symptoms, but not as effective as E2Proposed Study -- For Transdermal E2 vs. Sertraline vs. Placebo RCT: STRAW -1 to +1a and 1bHypothesis- E2 stabilizes dramatic fluctuations in E2 levels, reduces variability
36 Mental Health is Fundamental to Health David Satcher, M.D.We must prioritizethe mental healthof the mothers ofour next generation!
37 Estradiol TreatmentCVD-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 women37
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 vaginitisSSRI treatment is associated with a significantly increased risk of fracture even after adjustment for depression38
39 Inclusion/ Exclusions Acceptability of all 3 interventionsSmoke < ½ pack cigarettes per day or are willing to cut down or quitNo clotting disorder or DVT (self or first degree relatives); cardiac disease, breast cancerBirth control: non-estrogen containing: implanon,depo-provera, progestin-only OCP, IUD, double barrierBleeding assessment each week; medroxyprogesterone withdrawal at end of acute phase if no bleed (and no source of progestogen); followed through continuationLabs: 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 FamiliesFamous Women with Bipolar DisorderCarrie Fisher, Patty Duke, Mariette Hartley, Catherine Zeta-Jones, Jane Pauley, Marilyn Monroe, Judy Garland
41 Resources for PMDDSteiner 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 InformationProvides professionals with tools to screen, diagnose, treat, refer, engage women with PPD:Interactive case studiesProvider tools including diagnostic instrumentsVideo presentations and discussionsMothers and OthersPatient-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: MenopauseParry BL. Treatment in Psychiatry: Perimeno-pausal Depression. Am J Psych 165:23-27, 2008North American Menopause SocietySoares CN, Frey BN. Challenges andOpportunities to manage depressionduring 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<100100125 or 1502001 (4%)12 (50%)4 (17%)7 (29%)<100100125 or 15015 (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 -–LowNormal moodSymptomsDepressionRelapseResponseRemissionRecurrence50% improvement+RecoveryAcute PhaseContinuationMaintenanceThree 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.TimeAdapted from Kupfer DJ. J Clin Psychiatry. 1991;52(Suppl):28-34.
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