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  • 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 10-14. 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 1 st onset. The NCS was a congressionally mandated survey with the specific goal of studying the comorbidity of psychiatric disorders. 8000 individuals, ages 15-54 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
  • 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.
  • The side effects of antidepressants appear to be closely related to their acute effects on particular neurotransmitter systems. The time course of development of specific side effects is closely linked to that of acute synaptic effects in specific neurotransmitter systems. Side effects often occur within hours to days of initiation of antidepressant therapy, whereas therapeutic effects require weeks. 1 This observation suggests that much of the tolerability of antidepressants is directly a function of acute synaptic effects on monoaminergic and other systems that are brought about by the initiation of antidepressant treatment. 1,2 Clinical data show that specific neurotransmitter effects are associated with distinct side effects. These and other side effects are attributed to drug activity at central or peripheral synapses where the antidepressants either bind to receptors to influence cellular function or alter the concentration of endogenous neurotransmitters. Increasing the levels of specific neurotransmitters may result in different types of short-term and long-term side effects. 1,2 Serotonergic side effects include sexual dysfunction, sleep disturbance, and gastrointestinal upset. 1 –5 Noradrenergic side effects include tremor, tachycardia, dry mouth, and insomnia. 1 Psychomotor activation and aggravation of psychosis are dopaminergic side effects. 1 References: 1. Richelson E. Pharmacology of antidepressant—characteristics of the ideal drug. Mayo Clin Proc . 1994;69:1069 -1081. 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;153:466-476.
  • Massive placental and fetal hormone secretion produce dramatic rise in steroid hormones during pregnancy. 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). neuroplasticity, neurogenesis, and amplification of hormones and peptides have demonstrated relationships to evolutionarily beneficial adaptations in cognitive (ie: spatial navigation Kinsley), emotional (fear reduction; Lonstein, Neumann), and maternal function (Numan review) in preclinical studies. How brain preparations for maternity proceed in humans and how such preparation go awry in women with mental illness (or women with high levels of psychosocial stress) is an important area for future investigation. (do we know anything???) Because healthy maternal adaptation confers benefits to offspring at the level of emotional, cognitive, and physical development (insert refs), insights into mental illness-related aberrant maternal brain preparations could assist in the development of treatments to foster healthier adaptation to the maternal role.
  • <200pmol/L ==> <60 pg/ml BUT graph makes it look like < 100pmol/L or 30pg/ml 400 pmol/L ==> 110 pg/ml BUT graph makes it look like 500 pmol/L or >130pg/ml Study Design 23 women with MDD onset within 6 mos postpartum, severe illness, E2 concentrations < 60 pg/ml 8 wk open trial 17  -estradiol 1mg SL, 3-8x daily (to 110 pg/ml) Dramatic improvement within 1 week of E2. 91% Ss recovered by week 8 on E2 alone Gregoire et al (Gregoire et al., 1996) randomized 61 women with PPMD to placebo or transdermal 17  -E2 (200 mcg/day) delivered by transdermal patch for 6 months. The mean E2 concentration of actively treated women was 680 pmol/L (as a comparison, the mean E2 concentration across the menstrual cycle is 370 pmol/L). Both the E2 and placebo groups improved across time; however, the E2 treated group improved rapidly (within a month). The outcome measure was the Edinburgh Postnatal Depression Screening Scale (EPDS; Cox et al, 1987). The mean EPDS score for E2-treated subjects was consistent with remission (Peindl et al., 2004) and was 4 points lower than that of the placebo group at study completion. At 3 months of treatment, 80% of the E2 group had EPDS scores <14, but only 31% of placebo group had scores <14. Several lessons learned from Gregoire (a consultant for the proposed study) et al’s work have informed the proposed investigation. Because assessments were done once a month, the time course of response in the early weeks of treatment is unknown and may be substantially earlier. The inclusion of women who took concurrent antidepressant medications (47% and 37% in the E2 and placebo arms, respectively) limits the ability to discern an E2-specific treatment effect. The EPDS is a self-report scale; the validity of the findings would be increased if they were confirmed with a clinician interview-based measure. The exclusion of breastfeeding women and the inclusion of moderately depressed women (mean EPDS=21) also limit the study’s generalizability. An EPDS score of 21 is equivalent to a 17-item HRSD score of approximately 18 (based upon a correlational estimate from our study of 140 women with PPMD). In the Gregoire et al study, women who developed PPMD by 3 months but presented for treatment up to 18 months postpartum were included. This time frame is far removed from the E2 withdrawal at delivery that theoretically contributes to PPMD risk and is the primary rationale for E2 treatment. The dose of 17  -E2, 200 mcg/day, is high by today’s standards. A compelling question is whether response occurs at lower doses (personal communication, Alain Gregoire, M.D.), which will be answered in the proposed study
  • Pm 4.00 wisner

    1. 1. Depression in Women —Improving OutcomesKatherine L. Wisner, M.D., M.S.Director, Women’s Behavioral HealthCAREProfessor of Psychiatry, Obstetrics and Gynecology and Reproductive Sciences, Epidemiology, Clinical and Translational Science, and Women’s StudiesWestern Psychiatric Institute and Clinic/
    2. 2. DisclosureI have no financial conflicts of interest or disclosures.
    3. 3. Major Depression:Public Health Impact The World Health Organization estimated that major depression is the leading cause of disease- related disability among women world-wide. (Murray & Lopez, 1996)
    4. 4. Gender Differences in Prevalence of Major DepressionWomen: 1.5-2.5 X rate relative to men 15-54 Kessler et al (1993) Journal of Affective Disorders
    5. 5. Improving Outcomes Consider Differential Diagnosis Treat to Remission; Response at Minimum Measure Symptom Improvement Use Evidence Based Interventions Personalize Antidepressant Choice to the Woman Optimize the Dose Special Considerations for Reproductive Related Depressions (PMDD, Perinatal, Perimenopausal) Provide Self-Help Resources
    6. 6. 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 deathNIMH--MDD in Women for depression-discovering-hope/index.shtml
    7. 7. Diff Dx: Bipolar Disorder Unopposed Antidepressant is not Appropriate, risks agitation/ rapid cycling Prevalence=1-1.5%; to 5% for spectrum, Males=Females Mania/ hypomania alternate with depressive episodes. Onset in mid to late teens Postpartum onset particularly common “Plugged in” symptoms: grandiosity, less need for sleep but not tired, pressured speech, flight of ideas, distractibility, increased involvement in goal-directed activities, psychomotor agitation, excessive involvement in pleasurable activities with likelihood of painful consequences Screen for bipolar disorder MDQ (Mood Disorders Questionnaire)
    8. 8. Treatment and the ‘5 R’s’ for MDD Remission Recovery Relapse Recurrence Normal mood Pro gre Relapse + SymptomsSeverity ssi Response o 50% improvement nt + od iso Depression rde r Acute Continuation Maintenance Time Adapted from Kupfer DJ. J Clin Psychiatry. 1991;52(Suppl):28-34.
    9. 9. Measure Symptomatic Improvement: Free Self-Report Measures PHQ-9 (Patient Health Questionnaire) %20Questions.pdf CES-D (Center for Epidemiologic Studies- Depression Screen www.depression-help- EPDS (Edinburgh Postnatal Depression Scale, for pregnancy/postpartum) scale.pdf
    10. 10. Evidence Based Interventions: Psychotherapy Several types of short-term (12-16 sessions, focused psychotherapy) Patient choice, access, depression severity Monotherapy or combined with other treatment 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, and mindfulness Computerized applications
    11. 11. Evidence Based Interventions: Which Antidepressant? Neurotransmitters and Impact on Mood, Cognition, and Behavior Bupropion TCA=desipramine, nortriptyline SNRI=venlafaxine/ desmethylvenlafaxine,SSRI=fluoxetine, sertraline, duoxetinecitalopram/escitalopram, paroxetine; TCA clomipramine Stahl SM. Essential Psychopharmacology. 2nd ed. New York, NY: Cambridge University Press; 2000. Foote SL et al. In: Bloom FE, Kupfer CJ, eds. Psychopharmacology. 1995.
    12. 12. Neurotransmitter-Related Side Effects Serotonin • Sexual dysfunction • Weight gain, rarely appetite suppression • Nausea/ diarrhea • Sleep disturbance • Apathy and decreased motivation Norepinephrine • Tremor • Tachycardia • Dry Mouth • Insomnia Dopamine • Agitation • Psychosis • Appetite suppression
    13. 13. Bright Light Therapy Effective for seasonal (winter) MDD and non-seasonal MDD Effective augmentation for antidepressant partial responses 30-60 minutes of a commercially available, UV-screened bright fluorescent light, within 10 mins of awakening, determine optimal time Center for Environmental Therapeutics, Wirz-Justice et al--Chronotherapeutics for Affective Disorders: A Clinicians Manual for Light and Wake Therapy
    14. 14. The Longitudinal Laboratory of Women’s Lives Menarche Premenstruum Pregnancy Postpartum Menopause
    15. 15. Premenstrual Dysphoric Disorder Average age of onset= 26 years Symptoms increase across time until menopause Symptoms of PMDD comparable in severity to major depression Somatic symptoms typically improve parallel to depressive symptoms Symptoms return when treatment is stopped
    16. 16. Prevalence of Premenstrual Symptoms Menstruating Women Mild 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. 17. Sequence of Menstrual Cycle Mood Symptoms 120 100Depression Score 80 60 40 20 0 Follicular Luteal Follicular Luteal Follicular Luteal Follicular Luteal phase Phase phase Phase phase Phase phase Phase Cycle 1 Cycle 2 Cycle 3 Cycle 4= menses
    18. 18. Premenstrual Dysphoric Disorder Better than Placebo (SSRI/SNRI) Fluoxetine Sertraline Citalopram Paroxetine Venlafaxine/ desmethyl-/ Duloxetine Dosing – luteal phase clinics/pms-and-pmdd/
    19. 19. Depression Recurrence during Pregnancy Recurrence risk for women who either maintained or discontinued antidepressants proximal to conception (Cohen et al- JAMA. 2006;295:499-507) Significantly more women who discontinued (44/65, 68%) compared to women who maintained (21/82, 26%) antidepressant treatment suffered recurrent major depressive disorder. Most recurrences emerged rapidly (50% in the first trimester, and 90% by the end of second trimester).
    20. 20. 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
    21. 21. Summary Points Intrauterine Fetal Death- No conclusive evidence; women with SRI and/or NDD exposure have higher risk for miscarriage 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- Maternal Weight Gain, pregnancy duration, infant birth weight- SGA inconsistently reported with SSRI exposure. PTB is a converging finding for SRI exposed neonates-- MDD is associated with the same level of risk for preterm birth. PTB and SGA for depression.
    22. 22. Summary Points Behavioral Teratogenicity- No differences in cognitive function, verbal comprehension, expressive language, mood, activity levels, distractibility, behavior problems, temperament (Nulman et al-- TCA, FLX); Casper et al (2003) and Pederson et al (2010) reported less favorable motor (not mental) development in SSRI exposed vs. depression controls in toddlers. Resolved by 19 months. Neonatal Syndrome- Time-limited < 2 weeks, rarely requires medical intervention; most commonly associated agents are paroxetine>fluoxetine>sertraline> fluvoxamine= citalopram= escitalopram PPHN- Risk increased from 1-2/1000 to 6-12/1000 with exposure to SSRI after 20 weeks gestation; subsequent studies have not consistently replicated this finding
    23. 23. The Clinician’s Conundrum: Dosing How do I treat to get the best result for the maternal-fetal pair? Toxicity is related to dose! Should I keep the dose low to reduce exposure? Does the dose change across pregnancy? Guidance document by FDA in October, 2004 RegulatoryInformation/Guidances/ucm072133.pdf
    24. 24. Screening for Depression in an Obstetrical Hospital N=10,000 screened, 14%+ 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 (N=826) was: - during pregnancy, N=276 (33.4%) - postpartum (within 4 weeks of birth), N= 331 (40.1%) - prior to pregnancy, N=219 (26.5%)
    25. 25. NIMH-funded StudyWisner KL, Hanusa BH, Perel JM, PeindlKS, Piontek CM, Findling RL, Moses-Kolko EL. Postpartum depression: Arandomized trial of sertraline vs.nortriptyline. J Clin Psychopharm26:353-360, 2006.8 week acute phase parallel design,6 month continuation phase,no placebo
    26. 26. Nortriptyline vs. Sertraline Response and remission rates did not differ; At 8 weeks, responders: SERT=56%, NTP=69%: remitters SERT=46%, NTP=48% Time to response and remission did not differ Psychosocial functioning improved similarly The total side effect burden of each drug similar No clinical (including O/C) or demographic variables ID’d responders from nonresponders Medications similarly efficacious in women with non-postpartum depression
    27. 27. Antidepressants: One Dose Does not Fit All Wisner et al, J Clin Psychopharm 26:353-360, 2006.SERT, <100 100 125 or 150 200mg/day,N=24 1 (4%) 12 (50%) 4 (17%) 7 (29%)% remitted NTP, mg/day, <100 100 125 or 150 N=26, 15 (58%) 7 (27%) 4 (15%) % remitted *Start with 25 mg of sertraline or 25 mg of nortriptyline; half of usual starting dose of any antidepressant
    28. 28. Endocrinology of ChildbearingESTROGENS PROGESTINS
    29. 29. Estrogen Treatment ofPostpartum Depression Gregoire (1996) Lancet
    30. 30. Transdermal Estradiol for Postpartum Depression NIMH funded, 80 randomized Replicate Gregoire et al (1996, Lancet) rapid response to E2 vs. PL with an 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
    31. 31. Perimenopausal Depression E2 has psychotropic properties independent of hormone deficiency/withdrawal Not a simple hormone deficiency: Basal plasma levels E2 do not distinguish women with/without depression Mood enhancing effects of E2 in perimenopausal depression occurs independent of hot flashes Antidepressants decrease hot flashes independent of depressive symptoms
    32. 32. Dosing: Estradiol Patch for Perimenopausal Depression Schmidt et al 2000 • 3 week RCT of E2 vs Placebo • 34 confirmed perimenopausal women • 50 ug/d transdermal E2 • 80% response rate to E2 vs 20% to Placebo Soares et al 2001 • 12 week RCT of E2 vs Placebo • 50 confirmed perimenopausal women • 100 ug/d transdermal E2 • 70% response rate to E2 vs 20% to Placebo
    33. 33. Iterative Steps in a Comprehensive Detection Program Model Diagnosis Treatment engagement Treatment Symptom improvement Improved outcomescourtesy L. Miller (e.g. function, quality of life, parenting, offspring, relationships, family, health, prognosis)
    34. 34. International Biennial Congress of The Marcé Society Acting Together Around Childbirth Paris, October 3-5, 2012 Scientific committee:Prof. Anne Buist, Dr. Nine Glangeaud-Freudenthal (Congress President), Prof. Vivette Glover, Ms. Jane Hanley, Prof. Michael OHara, Dr. Oguz Omay, Dr. Anne Laure Sutter, Prof. Katherine Wisner. INFORMATION & Relations Médicales - Raphaël GASSIN REGISTRATIONS Web:
    35. 35. Questions
    36. 36. That’s amazing! Tell me more!
    37. 37. More Information- Pregnancy Developmental and Reproductive Toxicity: (DART database-free) Organization of Teratology Information Specialists (OTIS), (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, Niebyl JR, Simpson JL, Galan H, Goetzl L, Jauniaux ERM, Landon M, Editors; Elsevier, pages 1249-1288, 2007.
    38. 38. More Information: Postpartum Depression Miller LJ. Postpartum Depression. JAMA 287:762-765, 2002.; 1-800-573-6121 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 Populatio Based Register Study. JAMA 2006;296:2582-2589
    39. 39. MedEd PPD www.MedEdPPD.orgProfessional Information, Free Provides professionals with the tools to successfully screen, diagnose, treat, refer, and engage women with PPD. These include: • Interactive case studies • Provider tools including diagnostic instruments • Educational video presentations and discussionsMothers and Others, Free The patient-oriented section of the site contains many features: • An easy-to-use online diagnostic test; • Information about the myths and realities of PPD; • Experiences of real women with PPD; • Answers to frequently asked questions from experts in the field; and
    40. 40. Resources: Bipolar Disorder Is Your Depressed Patient Bipolar? Kaye NS, JABFM Patient Resource (NIMH): Treatment of Bipolar Disorder: A Guide For Patients and Families ar%20Handout.pdf Famous Women with Bipolar Disorder Carrie Fisher, Patty Duke, Mariette Hartley, Catherine Zeta- Jones, Jane Pauley, Marilyn Monroe, Judy Garland
    41. 41. WARNING!Insufficient Medical ResearchCan be Hazardous to your HealthC. Everett Koop, M.D.
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