From Puberty to Menopause Womens Changing Moods Across PowerPoint Presentation

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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

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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?

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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

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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)

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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

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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)

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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)

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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

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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

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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

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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

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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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Internet treatments: (the net is never wrong!) Drink some water! The total kit! Castus berries

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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)

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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)

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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

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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) PROGESTERONE SHOULD NOT BE RECOMMENDED FOR PMS! Happy PMS Moisturizing Body Cream $19.99 Each - Free Shipping

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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

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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)

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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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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

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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)

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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)

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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)

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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!

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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

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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 decision-making, document informed consent Begin antidepressant at delivery if past history of postpartum depression

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Resources on web OTIS (Organization of Teratology Information Specialists): www.otispregnancy.org Motherisk www.motherisk.org

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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

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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

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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

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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

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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

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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)

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Estrogen Evidence suggests that estrogen may serve as “Nature’s psychoprotectant” Fink et al, 1996

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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)

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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)

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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)

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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)

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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

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Conclusions Treatment of depression during pregnancy requires assessment of risks of untreated depression vs. risks of medication. More data is needed, recommend therapy first

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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

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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