Women’s Moods Across the Life Cycle

Merry Miller, M.D.Dept. Psychiatry & Behavioral

SciencesJames H. Quillen College of

MedicineEast 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 SymptomsUp 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 phaseNo 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

Controversiesabout 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 supplementsCalcium, Linoleic acid (Evening primrose oil), Pyridoxine (Vit. B6)-limited evidence, mixed results

Bright light, Sleep deprivationParry 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” menopauseDramatically reduce PMS symptoms, clearly effective in several trialsMay be useful for severe cases, but significant side effects

SurgeryOophorectomy alleviates symptomsIf hysterectomy done without oophorectomy, symptoms will persist

NOT RECOMMENDED for PMS

ProgesteroneUntil 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 ContraceptivesWidely 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 PMDDExtended 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 PMDDPatterns of symptom change:

Increased severity of symptomsAppearance of new symptomsDecreased 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, placebo-controlled, 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

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FOLLICULAR LUTEAL

MENSTRUAL PHASE

BECK DEPRESSION INVENTORY (BDI)

SERTRALINE p=0.32

PLACEBO p=0.06

ERROR BAR = Standard Error

p-value from t-test

0

5

10

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MENSTRUAL PHASE

HAM-D

SERTRALINE p=0.53

PLACEBO p=0.02

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0.6

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FOLLICULAR LUTEAL

MENSTRUAL PHASE

SCL90Interpersonal Sensitivity Subscale

SERTRALINE p=0.20

PLACEBO p=0.04

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 weightsHigher risk of premature birth and complicationsSmaller head circumferenceLower Apgar scoresDelayed cognitive and language developmentMore 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 freeWeigh risks of fetal exposure to a medication versus risks of untreated depression and relapse associated with discontinuationInclude patient, husband in decision-making, document informed consentBegin 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 postpartumApprox. 10-20% mothers develop

depression within first postpartum yearFor 60% of women with PPD, this represents their 1st episode of depression

Consequences of Postpartum Depression

Effect on motherLoss of expectationsInjury to self-esteem

Effect on marriageIncrease in conflict, irritability, withdrawal; decreased libido

Effect on childrenIncreased rates of insecure attachmentWorse cognitive developmentBehavior problems later in childhood

Risk Factors for Postpartum Depression

History of postpartum depressionRisk=12-16% overall; 25% if prior history depression; 50-62% if history of prior pospartum depression

– Altschuler 2001

Personal &/or family history of mood disorderMarital discordRecent adverse life eventsDepression/anxiety during pregnancyInfant-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 regionsIncreases availability, concentration & utilization of 5HT (serotonin)

Regulates free Tryptophan that reaches brain by displacing Tryptophan from its binding sites to plasma albuminEnhances 5HT transportIncreases MAO degradation rateStimulates 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, placebo-controlled studies. (Schmidt et al, 2000; Soares et al, 2001)

Recent open trial of transdermal 17ß-estradiol also suggested possible benefit for perimenopausal but not postmenopausal depression (Cohen et al, 2003)

Estrogen Monotherapy & Postmenopausal DepressionOther 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 MDD-Rasgon 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

Conclusions

SSRIs are effective for PMDDIntermittent dosing with several SSRIs has now been shown to be effective for severe PMS & PMDDContinuous oral contraceptives may decrease PMDDVariable 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