Y does X Make A Differenc

Reproductive-Related Mood Disorder

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 1
 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!
www.who.int/mediacentre/factsheets/fs369/en/index.html
2
 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
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

 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:

www.nimh.nih.gov/health/publications/women-and-depression-
discovering-hope/index.shtml 5
 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.
6
 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.
7
 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

8
Paucity of (any!) Treatment in U.S.
 Vesga-Lopez et al, Arch Gen Psychiatry
2008;65(7):805-815
 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%
9
 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) www.dbsalliance.org/pdfs/MDQ.pdf 10
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
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, mindfulness
http://behavioraltech.org/index.cfm 11
 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 12
 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
www.cet.org; 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 13
The Longitudinal Laboratory
of Women’s Lives

Menarche
Premenstruum
Pregnancy
Postpartum
Menopause

14
 OR: Gender = 1.63 (1.42-1.89)**

0.30

0.25 Boys
Girls
PROBABILITY

0.20

0.15

0.10

0.05

0.00
8 9 10 11 12 13 14 15 16

AGE
(adapted from Angold and Rutter, 1992)
 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):459-468.
2.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. 1994.
 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

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
 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):1743-1752, 2003

http://www.aafp.org/afp/2003/0415/afp20030415p1743-f2.gif

19
 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):1012-
1024) 20
Risks are More Heavily Weighted
Than Benefits

Antidepressant treatment during pregnancy:

Are we asking the right questions?
Wisner, Depression and Anxiety: 27:695-698, 2010 21
 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

22
 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: 2732-2733
 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 166:557-566, 2009). SGA and
PTB associated with MDD (Grote et al, Arch Gen
Psychiatry 67(10):1012-1024, 2010)
 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 336:258-262, 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 69:787-794, 2012).
Casper et al (J Pediatr 142:402-408, 2003) found less favorable
motor (not mental) development in SSRI vs. depression exposed in
toddlers
 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
294:2299-2300, 2005)
 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
http://www.ncbi.nlm.nih.gov/books/NBK52680/ )
26
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

27
 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%)
www.MedEdPPD.org www.postpartum.net
 Endocrinology of
Childbearing
ESTROGENS PROGESTINS
 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
 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
 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

32
 STRAW +10 Stages
Menopause 2012. 19(4): 387-95.

33
 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 E2 50-100 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
34
 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

35
 Mental Health
is Fundamental to
Health
David Satcher, M.D.

We must prioritize
the mental health
of the mothers of
our next generation!
 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 50-54 year old woman with 5
years of unopposed estrogen from 13/1000
women (no exposure) to 14.94/1000 women

37
 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
 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
 Resources: Bipolar Disorder
 Is Your Depressed Patient Bipolar? Kaye NS,
www.jabfm.org/content/18/4/271.full
 Patient Resource (NIMH):
www.nimh.nih.gov/health/publications/bipolar-disorder/c
omplete-index.shtml
 Treatment of Bipolar Disorder: A Guide For Patients
and Families
www.psychguides.com/sites/psychguides.com/files/
docs/Bipolar%20Handout.pdf
 Famous Women with Bipolar Disorder
Carrie Fisher, Patty Duke, Mariette Hartley, Catherine
Zeta-Jones, Jane Pauley, Marilyn Monroe, Judy Garland
40
 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:

www.womensmentalhealth.org/specialty-clinics/pms-
and-pmdd

41
 More Information- Pregnancy

 Developmental and Reproductive Toxicity:

www.toxnet.nlm.nih.gov (DART database)
 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 et al, Edss; Elsevier, p 1249-1288, 2007.

42
 More Information:
Postpartum Depression
 Miller LJ. Postpartum Depression.
JAMA 287:762-765, 2002.
 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
Population-Based Register Study.
JAMA 2006;296:2582-2589
43
 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 44
 Resources: Menopause
 Parry BL. Treatment in Psychiatry: Perimeno-pausal
Depression. Am J Psych 165:23-27, 2008
 North American Menopause Society
http://www.menopause.org/
 Soares CN, Frey BN. Challenges and
Opportunities to manage depression
during the menopausal transition and beyond.
Psychiatric Clin N Am 33:295–308, 2010

45
 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, N=26, <100 100 125 or 150

% remitted
15 (58%) 7 (27%) 4 (15%)

*Start with 25 mg of sertraline or 25 mg of nortriptyline; 46

half of usual starting dose of any antidepressant
 Evolution of Episode and
the ‘5 R’s’ for
Major Depressive Disorder
Remission Recovery
High --- Symptom Level -–Low

Relapse Recurrence
Normal mood
Relapse +
Symptoms
Response
50% improvement
+
Depression

Acute Phase Continuation Maintenance

Time
47
Adapted from Kupfer DJ. J Clin Psychiatry. 1991;52(Suppl):28-34.