1. Depression in Women
—Improving Outcomes
Katherine L. Wisner, M.D., M.S.
Director, Women’s Behavioral HealthCARE
Professor of Psychiatry, Obstetrics and Gynecology
and Reproductive Sciences, Epidemiology, Clinical
and Translational Science, and Women’s Studies
Western Psychiatric Institute and Clinic/UPMC
WisnerKL@upmc.edu

2. Disclosure
I have no financial conflicts of
interest or disclosures.

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. Gender Differences in Prevalence of
Major Depression
Women: 1.5-2.5 X rate relative to men 15-54
Kessler et al (1993) Journal of Affective Disorders

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. 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 for patients:
www.nimh.nih.gov/health/publications/women-and-
depression-discovering-hope/index.shtml

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) www.dbsalliance.org/pdfs/MDQ.pdf

8. Treatment and the ‘5 R’s’ for
MDD
Remission Recovery
Relapse Recurrence
Normal mood Pro
gre Relapse +
Symptoms
Severity
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. Measure Symptomatic Improvement:
Free Self-Report Measures
 PHQ-9 (Patient Health Questionnaire)
www.integration.samhsa.gov/images/res/PHQ%20-
%20Questions.pdf
 CES-D (Center for Epidemiologic Studies-
Depression Screen www.depression-help-
resource.com/cesd-depression-test.pdf
 EPDS (Edinburgh Postnatal Depression
Scale, for pregnancy/postpartum)
www.fcmc.weebly.com/uploads/3/4/8/9/3489838/edinburgh
scale.pdf

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
www.apa.org/divisions/div12/rev_est/ipt_depr.html
 Cognitive Behavior Therapy – correct distorted and
dysfunctional automatic thoughts
www.beckinstitute.org/what-is-cognitive-behavioral-therapy/
 Dialectical Behavior Therapy--combines standard CBT
techniques with skill building - distress tolerance,
acceptance, and mindfulness
http://behavioraltech.org/index.cfm
 Computerized applications

11. Evidence Based Interventions:
Which Antidepressant?
Neurotransmitters and Impact on Mood, Cognition, and Behavior
Bupropion
TCA=desipramine,
nortriptyline
SNRI=venlafaxine/
desmethylvenlafaxine,
SSRI=fluoxetine, sertraline, duoxetine
citalopram/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. 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. 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,
www.cet.org
 Wirz-Justice et al--Chronotherapeutics for
Affective Disorders: A Clinician's Manual for Light
and Wake Therapy

14. The Longitudinal Laboratory
of Women’s Lives
Menarche
Premenstruum
Pregnancy
Postpartum
Menopause

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. 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. Sequence of Menstrual Cycle
Mood Symptoms
120
100
Depression 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. Premenstrual Dysphoric Disorder
 Better than Placebo (SSRI/SNRI)
 Fluoxetine
 Sertraline
 Citalopram
 Paroxetine
 Venlafaxine/ desmethyl-/ Duloxetine
 Dosing – luteal phase
 http://www.womensmentalhealth.org/specialty-
clinics/pms-and-pmdd/

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. 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. 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. 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. 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
http://www.fda.gov/downloads/Drugs/GuidanceCompliance
RegulatoryInformation/Guidances/ucm072133.pdf

26. 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%)
www.MedEdPPD.org www.postpartum.net

27. NIMH-funded Study
Wisner KL, Hanusa BH, Perel JM, Peindl
KS, Piontek CM, Findling RL, Moses-
Kolko EL. Postpartum depression: A
randomized trial of sertraline vs.
nortriptyline. J Clin Psychopharm
26:353-360, 2006.
8 week acute phase parallel design,
6 month continuation phase,
no placebo

28. 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

29. Antidepressants: One Dose Does not Fit All
Wisner et al, J Clin Psychopharm 26:353-360, 2006.
SERT, <100 100 125 or 150 200
mg/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

30. Endocrinology of
Childbearing
ESTROGENS PROGESTINS

31. Estrogen Treatment of
Postpartum Depression
Gregoire (1996) Lancet

32. 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

33. 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

34. 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

35. Iterative Steps in a Comprehensive
Detection
Program Model
Diagnosis
Treatment engagement
Treatment
Symptom improvement
Improved outcomes
courtesy L. Miller (e.g. function, quality of life, parenting, offspring,
relationships, family, health, prognosis)

36. International Biennial Congress of The Marcé Society
www.marcesociety.com
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 O'Hara,
Dr. Oguz Omay, Dr. Anne Laure Sutter, Prof. Katherine Wisner.
INFORMATION & Relations Médicales - Raphaël GASSIN
REGISTRATIONS Web: www.info-congres.com

37. Questions

38. That’s amazing!
Tell me more!

39. More Information-
Pregnancy
 Developmental and Reproductive Toxicity:
www.toxnet.nlm.nih.gov (DART database-free)
 Organization of Teratology Information Specialists (OTIS)
www.otispregnancy.org, (866) 626-OTIS, or (866) 626-6847
 ACOG Practice bulletin: Use of psychiatric medications
during pregnancy and lactation. Obstetrics and Gynecology
110:1179-1198
 Wisner KL et al: Psychiatric Disorders, in Obstetrics:
Normal and Problem Pregnancies, 5th edition. Gabbe SG,
Niebyl JR, Simpson JL, Galan H, Goetzl L, Jauniaux ERM,
Landon M, Editors; Elsevier, pages 1249-1288, 2007.

40. More Information:
Postpartum Depression
 Miller LJ. Postpartum Depression.
JAMA 287:762-765, 2002.
 www.hfs.illinois.gov/mch
 www.psych.uic.edu/clinical/HRSA; 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

41. MedEd PPD www.MedEdPPD.org
Professional 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 discussions
Mothers 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

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

43. WARNING!
Insufficient Medical Research
Can be Hazardous
to your Health
C. Everett Koop, M.D.