Transcript From Puberty to Menopause

Women’s Moods
Across the Life Cycle
Merry Miller, M.D.
Dept. Psychiatry & Behavioral Sciences
James H. Quillen College of Medicine
East Tennessee State University
Our Questions
What unique risks do women have for
mood problems?
What is the role of hormonal change
in these moods?
How can we best treat women at
every stage?
What are areas of controversy,
unanswered questions?
Observations about
depression in women
Women are twice as likely to develop major
depression as men
Women are also more likely to develop
dysthymic disorder (1.5-3 times) &
seasonal affective disorder(4 times)
Until recently, gender differences in
depressive disorders have received little
attention
Both the psychology and biology of women
have become areas of interest
Psychology of Women
Relational theory has received attention
in recent years for understanding the
psychology of women, with an emphasis
on the importance of connections rather
than individuation.
Jean Baker Miller, Toward a New
Psychology of Women (1976)
JB Miller et al, Women’s Growth in
Connection: Writings from the Stone Center
(1991)
Gender differences in stress
response
Women more likely to “tend and
befriend” under stress than “fight or
flight”-Shelley E. Taylor Ph.D.
Animal studies & humans: females more
likely to nurture & form alliances when
stressed vs. males withdraw
Oxytocin and endogenous opioids
suggested as possible mediators in
women; promote affiliative behavior
Depression & hormones
Increased rates of depression in females
begin at puberty
Concentrations of gonadal hormones are
stable and low in prepubertal children
After menarche, the female brain is
exposed to monthly surges of estrogen and
progesterone until menopause
Across the life cycle, mood symptoms often
correlate with hormonal changes
(Kessler et al 1993)
Correlation of hormonal &
mood changes in women
Estrogen & progesterone drop prior to
menses
Estrogen & progesterone levels drop
precipitiously after childbirth
Estrogen & progesterone levels drop (more
gradually) at menopause
Estrogen withdrawal theory (Schmidt
& Rubinow 1994)
The Spectrum of
Premenstrual Variations
Premenstrual Symptoms
Up to 95% of women have at least 1 symptom
Premenstrual Syndrome (PMS)
2-3 symptoms, 30-50% of women
Premenstrual Dysphoric Disorder (PMDD)
5 or more symptoms, difficulty functioning, 3-5% of women
Premenstrual exacerbation of depression (PMED),
and of many other psychiatric and medical
disorders
Major depression, Panic disorder, Generalized anxiety, PTSD,
OCD, Bulimia nervosa, Substance abuse, Mania, Psychosis
Acute porphyria, IBS, SLE, Meniere’s disease, Cyclic premenstrual
unconjugated hyperbilirubinemia, Genital herpes, Endometriosis,
Asthma, Epilepsy, Allergies, Migraines
Do hormonal changes cause
PMS?
Numerous studies have tested whether
women with PMS have increased or
decreased levels of progesterone or
estrogen during the luteal phase
No specific hormonal abnormalities have
been identified to account for reproductive
endocrine-linked mood disorders
(Nott et al 1976; Rubinow et al 1988; Schechter 1999)
Therefore, no reason to use hormonal
levels as part of diagnostic evaluation
for PMS
Do hormonal changes cause
PMS? Current Thought:
Some women may have a
vulnerability to depression that is
triggered by exposure to normal cyclic
fluctuations of ovarian hormones (as
well as sociocultural & psychological
variables)
Schmidt et al 1998
Controversies
about PMS/PMDD
Is it real and worth identifying?
Feminist concern about abuse of
diagnosis
Successful use as defense for
homicide!
Lack of good research until recently
Promotion of ineffective treatments
rampant until recently
Significance of PMDD
May cause 1400-2800 symptomatic
days across childbearing years of
affected women
Equivalent to 3-8 years of symptoms!
» Yonkers 1995
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Treatments for PMS &
PMDD
Lifestyle changes and psychosocial
interventions (no controlled trials)
Dietary modifications (reduce refined sugars,
caffeine, salt, alcohol), Exercise, ,Stress
management, Cognitive Psychotherapy,
Relaxation training, Group therapy,Charting
symptoms
Vitamins and nutritional supplements
Calcium, Linoleic acid (Evening primrose oil),
Pyridoxine (Vit. B6)-limited evidence, mixed
results
Bright light, Sleep deprivation
Parry et al (1987, 1989, 1993, 1995)
Treatments for PMS & PMDD
Selective serotonin reuptake
inhibitors (SSRIs):
20 placebo-controlled trials supporting efficacy of SSRIs
in PMDD, including 2 large multicenter trials
Citalopram, Fluoxetine, Paroxetine, Sertraline all have
been shown effective (Eriksson et al 2002)
Intermittent use (given for only a few days before
menses) also found effective!
Fluoxetine (Steiner et al 1997), Sertraline (Halbreich & Smoller 1997; Young et
al.1998), Paroxetine (Sunblad et al1997), Citalopram (Wikander et al.1998)
Treatments for Severe PMDD
Gonadotropin-releasing hormone
agonists (e.g. leuprolide or buserelin)
Induce “medical” menopause
Dramatically reduce PMS symptoms, clearly effective in
several trials
May be useful for severe cases, but significant side
effects
Surgery
Oophorectomy alleviates symptoms
If hysterectomy done without oophorectomy, symptoms
will persist
NOT
RECOMMENDED for
PMS
Progesterone
Until recently, progesterone was the most widely
prescribed treatment for PMS based on
uncontrolled studies & much promotion
(Greene and Dalton 1953; Mortola et al 2002)
Multiple RCTs & meta-analysis of progesterone
for PMS have found it to be no more effective
than placebo; instead may induce many of the
physical and emotional symptoms of PMS
(Wyatt K et al 2001; Mortola et al 2002)
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Role for Oral
Contraceptives?
Oral Contraceptives
Widely prescribed; previously found
inconsistent benefit
» Backstrom et al (1992); Graham et al (1992);
Yuk et al (1991); Mortola et al (2002)
Newer OCs with novel progestins &
dosing regimens found effective
Ethinyl estradiol/drospirenone 24/4 studied
in RCTs and found effective (Lopez et al,
Cochrane Review 2009), FDA approved for
PMDD
Extended cycle combined OCP
(EE/Levonorgestrel) create 3 month cycle,
also under study for PMDD
Premenstrual Exacerbation of
Depression (PMED)
Major depression may worsen
premenstrually: hospital admissions/ER
visits increase in late luteal and menstrual
phase (Wetzel et al 1972, Tonks et al 1963)
Should be distinguished from PMS and
PMDD
Patterns of symptom change:
Increased severity of symptoms
Appearance of new symptoms
Decreased impulse control
– Endicott (1993)
Variable Dosing for PMED
Many women with major depression show
“breakthrough” symptoms premenstrually
when on constant dose of antidepressant
Increasing dosage of antidepressant
premenstrually (double-blind, placebocontrolled, crossover design) shown
beneficial for women with PMED
Nefazodone (Miller et al 2002)
Sertraline (Miller et al 2008)
During months in which subjects received
supplemental doses, their cycling pattern
was eliminated
BECK DEPRESSION INVENTORY (BDI)
15
PLACEBO p=0.06
SERTRALINE p=0.32
ERROR BAR = Standard Error
p-value from t-test
BDI SCORE
10
5
0
FOLLICULAR
LUTEAL
MENSTRUAL PHASE
HAM-D
15
PLACEBO p=0.02
HAM-D SCORE
SERTRALINE p=0.53
10
5
0
FOLLICULAR
LUTEAL
MENSTRUAL PHASE
SCL90
Interpersonal Sensitivity Subscale
PLACEBO p=0.04
SCL90-IS SCORE
0.6
SERTRALINE p=0.20
0.4
0.2
0
FOLLICULAR
LUTEAL
MENSTRUAL PHASE
Depression During
Pregnancy
Pregnancy was previously believed to
be protective against depression, but
10-15% women have depressive
symptoms during pregnancy
Prevalence is higher among women
with mood disorder history
No RCTs of psychotropics in
pregnancy; evidence largely
retrospective, data inadequate
Consequences of untreated
depression during pregnancy
Lower birth weights
Higher risk of premature birth and
complications
Smaller head circumference
Lower Apgar scores
Delayed cognitive and language
development
More behavioral problems
Wrate et al (1985); Korebrits et al (1998); Orr and Miller (1995);
Stott (1973); Steer et al (1992);Zuckerman et al (1990)
Medications during
pregnancy: SSRIs
No evidence of increase in congenital
major malformations (Ericson et al 1999, Hendrick et al
2003, Goldstein et al 1997, Pastuszak et al 1993, Chambers et al 1996,
Nulman and Koren 1996, Kulin et al 1998, Heikkinen et al 2002)
Possible neonatal toxicity/withdrawal
syndromes after 3rd trimester exposure
(respiratory distress, feeding problems, jitteriness,
irritability, and poor neonatal adaptation) (Chambers et
al 1996,Spencer 1993, Nordeng et al 2001, Simon et al 2002, Costei et al
2002, Dahl et al 1997, Zeskind and Stephens 2004)
Neonatal abstinence syndrome may occur in 30%
neonates exposed in utero(Levinson-Castiel et al 2006)
Possible increase in complications at birth (earlier
delivery, lower birth weight, lower Apgar scores)
(Simon et al 2002; Nordeng et al 2001, Hendrick et al 2003)
Medications during
pregnancy: SSRIs
Inconsistent evidence suggests
possible association between late
pregnancy exposure to SSRIs and
persistent pulmonary hypertension of
the newborn (PPHN) (Chambers et al 2006)
Lower association (Kallen and Olausson, 2008)
No association (Andrade et al 2009)
Medications during
pregnancy: SSRIs
Long-term behavioral sequelae
uncertain
2 studies followed cohorts of children 86 and 71
mo. after exposure, found no differences (Nulman
et al 1997,2002)
Another study found subtle differences in motor
development and motor control
(Casper et al 2003)
Recent animal studies suggest behavioral &
neurochemical changes that persist into
adulthood including “depressed” behavior
(Ansorge et al 2004, Maciag 2006)
Need more data!
Medications during
pregnancy: SSRI Warnings
FDA issued warning December 2005 that use of paroxetine
in first trimester may be associated with increased risk of
birth defects, especially cardiac
American College of Obstetricians and Gynecologists issued
opinion December 2006 that women pregnant or planning to
become pregnant avoid paroxetine (ACOG, Obstet Gynecol 2006)
Fetal exposure to citalopram and sertraline linked with
increased risk of septal heart defects (Pederson 2009; Chambers 2009)
No SSRI absolutely contraindicated
Medications during Pregnancy
No decision is risk free
Weigh risks of fetal exposure to a
medication versus risks of untreated
depression and relapse associated
with discontinuation
Include patient, husband in decisionmaking, document informed consent
Begin antidepressant at delivery if
past history of postpartum depression
Resources on web
OTIS (Organization of Teratology
Information Specialists):
www.otispregnancy.org
Motherisk www.motherisk.org
Postpartum Depression
Most likely time for a woman to
become depressed is postpartum
Approx. 10-20% mothers develop
depression within first postpartum year
For 60% of women with PPD, this represents
their 1st episode of depression
Consequences of Postpartum
Depression
Effect on mother
Loss of expectations
Injury to self-esteem
Effect on marriage
Increase in conflict, irritability, withdrawal; decreased
libido
Effect on children
Increased rates of insecure attachment
Worse cognitive development
Behavior problems later in childhood
Risk Factors for Postpartum
Depression
History of postpartum depression
Risk=12-16% overall; 25% if prior history
depression; 50-62% if history of prior
pospartum depression
– Altschuler 2001
Personal &/or family history of mood
disorder
Marital discord
Recent adverse life events
Depression/anxiety during pregnancy
Infant-related stressors
Treatment during pregnancy
and postpartum
Consider psychotherapy (poorly studied)
Breastfeeding complicates treatment decisions!!
Estrogen potentially beneficial (Gregoire et al 1996),
needs further study (Gentile 2005)
ECT
Highly effective but much resistance among
new mothers
Specialized inpatient perinatal units being
developed
Depression & Menopause
Previous concept of Involutional
Melancholia (increased depression at
menopause) has been disputed
Current evidence does suggest
increased risk for depression during
perimenopause for women with past
history of depression
Effects of Estrogen
Multiple interactions with CNS including
effects on neurotransmitters, intracellular &
membrane receptors in multiple regions
Increases availability, concentration &
utilization of 5HT (serotonin)
Regulates free Tryptophan that reaches brain by
displacing Tryptophan from its binding sites to plasma
albumin
Enhances 5HT transport
Increases MAO degradation rate
Stimulates increased 5HT binding in cerebral cortex
and nucleus accumbens
Schechter (1999)
Polymorphisms in estrogen receptors may be
linked to risk of late-life depression (Ryan et al 2011)
Estrogen
Evidence suggests that
estrogen may serve as
“Nature’s psychoprotectant”
» Fink et al, 1996
Estrogen Monotherapy for
Perimenopausal Depression
Possible efficacy of transdermal estradiol
for perimenopausal depression suggested
by two double-blind, randomized, placebocontrolled studies. (Schmidt et al, 2000; Soares et al, 2001)
Recent open trial of transdermal 17ßestradiol also suggested possible benefit
for perimenopausal but not
postmenopausal depression (Cohen et al, 2003)
Estrogen Monotherapy &
Postmenopausal Depression
Other controlled studies of transdermal
estradiol have failed to show benefit for
women with postmenopausal depression
– Saletu et al (1995),Morrison et al (2004)
Needs more study!!
Estrogen may induce mania and increase
risk of endometrial cancer-use with caution
(may need endometrial biopsies if given
unopposed)
Estrogen augmentation of
antidepressants
Recent research of the potential benefit of
estrogen to augment antidepressants in
postmenopausal women with MDD has been
suggestive but inconsistent
Schneider et al (1997), Schneider et al (2001),
Amsterdam et al (1999)
ERT may augment SSRI in perimenopausal MDDRasgon et al (2002)
Addition of progestin to hormone replacement
therapy reduces the benefit from estrogen on
mood in a dose-dependent manner
Sherwin (1991)
Antidepressants at
menopause
Antidepressants shown to be effective for
depression at menopause that has failed to
respond to HRT (Joffe et al 2001, Soares et al 2003, Liu et al 2004)
Premenopausal women may respond
better to SSRI than Tricyclic antidepressant
vs. postmenopausal women show similar
rates of response (Kornstein et al 2000)
Antidepressants effective for
vasomotor symptoms in menopausal
women, may be alternative to HRT
(Hall et al 2011)
Conclusions
SSRIs are effective for PMDD
Intermittent dosing with several SSRIs
has now been shown to be effective
for severe PMS & PMDD
Continuous oral contraceptives may
decrease PMDD
Variable dosing of antidepressants
may benefit women with PMED &
warrants further study
Conclusions
Treatment of depression during
pregnancy requires assessment of
risks of untreated depression vs. risks
of medication. More data is needed,
recommend therapy first
Conclusions
Some women with perimenopausal
depressive symptoms may benefit from
estrogen alone.
Evidence for benefit of estrogen as adjunct
to SSRIs in postmenopausal MDD
inconsistent. Further study is needed.
Antidepressants may provide relief from
menopausal symptoms, may be alternative
to HRT
Conclusions
Remember to be attentive to
associations between reproductive
cycle and mood
Encourage female patients with
depression to resist the urge to
withdraw & instead seek to strengthen
their support network