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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.

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Presentation on theme: "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."— Presentation transcript:

1 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 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 33 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.

4 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 5 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: depression-discovering-hope/index.shtml

6 6 Biological Differences Pathophysiology Biological Differences Major Depression and Mood Disorders are brain disorders Major Depression and Mood Disorders are brain disorders Dysregulated neural circuits for control of mood, thought, sleep, appetite, and behavior. Dysregulated neural circuits for control of mood, thought, sleep, appetite, and behavior. Depression results from multiple genes acting together with environmental factors. 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 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. 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.

7 7 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. 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.

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

9 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 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 11 Depression: Evidence Based Treatment- 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 Interpersonal Psychotherapy targets interpersonal distress and effect on mood 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

12 12 All Antidepressants have Similar Efficacy Serotonergic (SSRI-sertraline, fluoxetine; SNRI, venlafaxine) Comorbid Anxiety DisorderComorbid Anxiety Disorder Hot flashesHot flashes Side effects=Sexual dysfunction, weight gain, nausea/ diarrhea, sleep disturbance, apathy and decreased motivationSide effects=Sexual dysfunction, weight gain, nausea/ diarrhea, sleep disturbance, apathy and decreased motivation Norepinephrine (Tricyclics-nortriptyline) 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

13 13 Environmental Treatments Bright Morning Light Therapy Bright Morning Light Therapy Seasonal and non-seasonal depression minutes of commercially available, UV-screened bright fluorescent light, within 10 mins of awakening 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 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 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 14 Menarche Premenstruum Pregnancy Postpartum Menopause The Longitudinal Laboratory of Women’s Lives Menarche Premenstruum Pregnancy Postpartum Menopause

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

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): American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed

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

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

19 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): , 2003http://www.aafp.org/afp/2003/0415/afp p1743-f2.gif

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

21 2121 Risks are More Heavily Weighted Than Benefits Antidepressant treatment during pregnancy: Are we asking the right questions? Wisner, Depression and Anxiety: 27: , 2010

22 22 Reproductive Outcome Domains Major birth defects (approx 3% in the general population) Major birth defects (approx 3% in the general population) Growth Effects Growth Effects Behavioral Teratogenicity Behavioral Teratogenicity Neonatal Syndrome 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: 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) 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 Behavioral Teratogenicity Mental development WNL 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) 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 fluoxetine>sertraline> fluvoxamine= citalopram= escitalopram (Moses-Kolko et al, JAMA 294: , 2005) Neonatal Syndrome- Time-limited fluoxetine>sertraline> fluvoxamine= citalopram= escitalopram (Moses-Kolko et al, JAMA 294: , 2005)

26 2626 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 )

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

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 (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 32 Depression in Menopausal Transition Average age 51 years Average age 51 years Risk for depression in the perimenopause; especially women with previous episodes Risk for depression in the perimenopause; 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

33 33 STRAW +10 Stages Menopause (4):

34 34 Perimenopausal Depression Treatment Antidepressants and Psychotherapy are first line Antidepressants and Psychotherapy are first line Post-meno. women respond more favorably to Post-meno. women respond more favorably to tricyclics (e.g., nortriptyline) than to SSRI tricyclics (e.g., nortriptyline) than to SSRI Transdermal estradiol (E2), small RCTs positive Transdermal estradiol (E2), small RCTs positive 3-12 wk RCTs of E ug/d) vs Placebo3-12 wk RCTs of E 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

35 35 Estradiol Treatment 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 Proposed Study -- For Transdermal E2 vs. Sertraline vs. Placebo RCT: STRAW -1 to +1a and 1b 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 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 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. 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. 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 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

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

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 40 Resources: Bipolar Disorder Is Your Depressed Patient Bipolar? Kaye NS, Patient Resource (NIMH): disorder/complete-index.shtml disorder/complete-index.shtml Treatment of Bipolar Disorder: A Guide For Patients and Families es/docs/Bipolar%20Handout.pdf Famous Women with Bipolar Disorder 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: 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: Information for patients: Information for patients: clinics/pms-and-pmdd clinics/pms-and-pmdd 41

42 42 More Information- Pregnancy Developmental and Reproductive Toxicity: (DART database)www.toxnet.nlm.nih.gov Organization of Teratology Information Specialists (OTIS) (866) 626-OTIS, or (866) www.otispregnancy.org 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 43 More Information: Postpartum Depression Miller LJ. Postpartum Depression. Miller LJ. Postpartum Depression. JAMA 287: , JAMA 287: , Wisner KL et al.. Clinical Practice: Postpartum depression. NEJM 347: , Wisner KL et al.. Clinical Practice: Postpartum depression. NEJM 347: , Wisner KL et al. A major public health problem: Postpartum depression. JAMA 296: , Wisner KL et al. A major public health problem: Postpartum depression. JAMA 296: , Munk-Olsen T. New Parents and Mental Disorders: A Population-Based Register Study. JAMA 2006;296: Munk-Olsen T. New Parents and Mental Disorders: A Population-Based Register Study. JAMA 2006;296:

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

46 46 Antidepressants: One Dose Does NOT Fit All< or (4%) 1 (4%) 12 (50%) 4 (17%) 4 (17%) 7 (29%) 7 (29%) SERT, mg/day, N=24 % remitted< or (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 Wisner et al, J Clin Psychopharm 26: , 2006.

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


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