Depression In Women Leading Cause Of Disease Related Disability Among Women In The World Today*

Stephen F. Pariser, M.D.

Psychiatric Medications Pregnancy and Lactation • 500,000 pregnancies in U.S. each year involve have psychiatric illness that either predate or emerge during pregnancy

Professor of Psychiatry and Obstetrics and Gynecology

Nick Votolato, Pharm BCPP Clinical Assistant Professor

• Advising a pregnant or breastfeeding woman to discontinue medication exchanges fetal or neonatal risk of medication exposure for the risks of untreated maternal illness

Ohio State University Medical Center *Kessler, R. C. (2003). "Epidemiology of women and depression." J Affect Disord 74(1): 5-13.*The World Health Organization’s Global Burden (Murray and Lopez, 1996). Kessler, R. C., P. Berglund, et al. (2003).

Depression In Women • • • • • •

Introduction/Epidemiology Comorbidity Menstrual Cycle (PMS) Pregnancy/Postpartum Depression Menopause Summary

ACOG Practice Bulletin, Clinical Management Guidelines for Obstetrician-Gynecologists, Number 87, November 2007.

Impact Inadequate or Untreated Maternal Psychiatric Illness • Poor compliance with prenatal care • Inadequate nutrition • Exposure to additional medication or herbal remedies • Increased alcohol and tobacco use • Deficits in maternal-infant bonding • Disruptions within family environment ACOG Practice Bulletin, Clinical Management Guidelines for Obstetrician-Gynecologists, Number 87, November 2007.

1

Interaction of 5-HTT Gene Polymorphism and Life Stress in Depression Outcomes

All Psychotropic Medications

Depressive Episodes

Suicide/Suicidal Ideation 0.16

• All psychotropic medications studied to date cross the placenta • Are present in amniotic fluid

s/s

0.40

0.30

l/s

0.20

l/l

0.10

0.00

• Can enter breast milk

1

2

l/s (long/short allele) l/l (long/long allele)

•

2 forms of 5-HTT gene: the short form (“s” allele) and the long form (“l” allele)

•

Each person inherits 1 copy of the gene from each parent; an individual may inherit: 2 short copies (s/s),1 short and 1 long copy (s/l) or 2 long copies (l/l)

•

In relation to stressful life events, people with 1 or 2 copies of the short form of the 5-HTT gene exhibit more diagnosable depression and suicidality than people with 2 copies of the long allele Caspi A et al. Science. 2003;301:386; Lesch KP et al. Science. 1996;274:1527 Taylor SE, Way BM, Welch WT, Hilmert CJ, Lehman BJ, Eisenberger NI. Early Family Environment, Current Adversity, the Serotonin Transporter Promoter Polymorphism, and Depressive Symptomatology. Biol Psychiatry. Aug 23 2006. Gonda X, Rihmer Z, Zsombok T, Bagdy G, Akiskal KK, Akiskal HS. The 5HTTLPR polymorphism of the serotonin transporter gene is associated with affective temperaments as measured by TEMPS-A. J Affect Disord. Apr 2006;91(2-3):125-131.

3

No. of stressful life events

Caspi A et al. Science. 2003;301:386

Genetic Variation: A Polymorphism in 5-HTT Gene

s/s

0.14 0.1 2 0.10

l/s

0.08 0.06

l/l 0.04 0.02 0.00

0

s/s (short/short allele)

ACOG Practice Bulletin, Clinical Management Guidelines for Obstetrician-Gynecologists, Number 87, November 2007.

Probability of suicide ideation/attempt

Probability of major depression episode

0.50

4+

0

1

2

3

4+

No. of stressful life events Results of multiple regression analyses estimating the association between number of stressful life events (between ages 21 and 26 years) and depression outcomes at age 26 as a function of 5-HTT genotype

17% s/s; 31% l/l; 51% s/l

Development of Depression:

Sex and the Interaction Between Environment and a Promoter Polymorphism of the Serotonin Transporter Gene •

Boys and girls (16-19 years old) carrying short 5HTTLPR allele react to different kinds of environmental stressors: a) Males affected by living in public housing rather than in own owned homes and by living with separated parents b) Females were affected by traumatic conflicts within the family

Sjoberg RL, Nilsson KW, Nordquist N, et al. Development of depression: sex and the interaction between environment and a promoter polymorphism of the serotonin transporter gene. Int J Neuropsychopharmacol. Aug 2006;9(4):443-449.

2

Development of Depression:

Sex and the Interaction Between Environment and a Promoter Polymorphism of the Serotonin Transporter Gene

12-month Prevalence MDD* 6.6% of Adults in USA (13-14 million adults) 90

•

a) With environmental stress, females tend to develop depressive symptoms b) Males seem to be protected from depression

78.5

80

Short allele response to environmental stress:

Comorbid CICI/DSM-IV disorders Received healthcare treatment Treatment was adequate

70 60 %

51.6

50

41.9

40 30

21.7

month cases being-12 adequately treated

20

•

The results suggest that both the molecular and the psychosocial mechanisms underlying depression may differ between boys and girls

Sjoberg RL, Nilsson KW, Nordquist N, et al. Development of depression: sex and the interaction between environment and a promoter polymorphism of the serotonin transporter gene. Int J Neuropsychopharmacol. Aug 2006;9(4):443-449.

Mood Disorders Lifetime Prevalences

10

*Major Depressive Disorder

0 12-month cases

Kessler RC, Berglund P, Demler MS, et al. The Epidemiology of major depressive disorder. JAMA, June 18, 2003-Vol. 289, 3095-3105.

Mood Disorders Lifetime Prevalences 25.00%

25.00%

24%

24% 21%

18.75%

15%

12.50%

13%

Maj Dep Episode Manic episode Dysthymia Any Affective Episode

18.75%

21%

15%

12.50%

13%

Any Affective Episode 8%

6.25% 8%

6.25%

5% 5%

0.00%

2%

Women

Maj Dep Episode Manic episode Dysthymia

2%

0.00%

2%

Women

2%

Men

Men

Kessler RC, McGonagle KA, Zhao S, et al. Arch Gen Psych 1994; 51:8-19. http://www.nimh.nih.gov/healthinformation/stard_qa_general.cfm

Kessler RC, McGonagle KA, Zhao S, et al. Arch Gen Psych 1994; 51:8-19. http://www.nimh.nih.gov/healthinformation/stard_qa_general.cfm

3

Depression In Mid Adolescence (ages 14-16*) Increases the Risk* (ages 16-21) of: • Later MDD, anxiety disorders -13% of cohort developed depression between ages 14 and 16 • Nicotine dependence • Alcohol abuse or dependence • Suicide attempt, educational underachievement

Gender Differences in Depression: Findings From the STAR*D Study Women 35 30 25 20 % 15 10 5 0

Men 26.3

26.3

19.7 13.8 8.3

Prior suicide attempt Hazzardous drinking

• Unemployment

29.4

• Early parenthood

Hazzardous use of other drugs (including Rx)

(P4 symptoms) PMDD. 904 women were screened.

50.0% 50.0%

Current Current PMS PMS symptoms symptoms PMS PMS symptoms symptoms but but not not interested interested in in research research project project PMS PMS symptoms symptoms not not eligible eligible for for research research project project because because of of lack lack of of symptom symptom severity severity Lost Lost to to follow-up follow-up or or incomplete incomplete chart chart PMS PMS Symptoms Symptoms and and agreed agreed to to chart chart 47% 47%

37.5% 37.5%

41% 41%

PMDD Treatment Efficacy • Accepted treatments have similar overall efficacy (60%) • Suppression of ovulation ameliorates broad range of behavioral and physical symptoms

36% 36%

25.0% 25.0% 12.5% 12.5% 10% 10%

10% 10%

0.0% 0.0%

Halbreich U, O'Brien PM, Eriksson E, Backstrom T, Yonkers KA, Freeman EW. Are there differential symptom profiles that improve in response to different pharmacological treatments of

Endorsed Endorsed Symptoms Symptoms Yonkers KA, Pearlstein T, Rosenheck RA. Premenstrual disorders: bridging research and clinical reality. Arch Womens Ment Health. Nov 2003;6(4):287-292.

PMDD Treatment Options • Antidepressants (SSRIs-3 have indications*) • GnRH agonists require hormonal add-back • Non-pharmacologic: phototherapy, aerobic exercise, cognitive behavior therapy (CBT) • OCs - 24/4 regimen of drospirenone 3 mg and ethinyl estradiol 20 mug* *fluoxetine, sertraline and paroxetine

• SSRIs (considered first line therapy by many) most effective for irritability and anxiety symptoms

*Indicated for the treatment of symptoms of PMDD in women who choose to use an oral contraceptive as their method of contraception. The effectiveness of YAZ for PMDD when used for more than three menstrual cycles has not been evaluated.

premenstrual syndrome/ premenstrual dysphoric disorder? CNS Drugs. 2006;20(7):523-547. Kroll R, Rapkin AJ. Treatment of premenstrual disorders. J Reprod Med. Apr 2006;51(4 Suppl):359-370. Steiner M, Pearlstein T, Cohen LS, et al. Expert guidelines for the treatment of severe PMS, PMDD, and comorbidities: the role of SSRIs. J Womens Health (Larchmt). Jan-Feb 2006;15(1):5769.

Depression In Women • Introduction/Epidemiology • Mood Disorder Issues • Menstrual Cycle (PMS) • Pregnancy/Postpartum Depression • Menopause • Summary

Yonkers KA, Brown C, Pearlstein TB, Foegh M, Sampson-Landers C, Rapkin A. Efficacy of a New Low-Dose Oral Contraceptive With Drospirenone in Premenstrual Dysphoric Disorder. Obstet Gynecol. Sep 2005;106(3):492-501. Parry BL, Mahan AM, Mostofi N, Klauber MR, Lew GS, Gillin JC. Light therapy of late luteal phase dysphoric disorder: an extended study. Am J Psychiatry. Sep 1993;150(9):1417-1419 Halbreich U, O'Brien PM, Eriksson E, Backstrom T, Yonkers KA, Freeman EW. Are there differential symptom profiles that improve in response to different pharmacological treatments of premenstrual syndrome/ premenstrual dysphoric disorder? CNS Drugs. 2006;20(7):523-547.

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Early Pregnancy Loss Major Depressive Disorder (MDD) In The 6 Months After Miscarriage (229 women evaluated following spontaneous pregnancy loss before 28 weeks gestation were compared to a population based cohort of 230 women)

• 10.9% of miscarrying women experienced an episode of MDD compared with 4.3% of community women (RR 2.5)

Depression Not Ideal For Pregnancy • Independent of biomedical risk, perceived life-event stress and anxiety during pregnancy significantly predicted infant birth weight and gestational age

• Among miscarrying women, 72% of cases of MDD began within the first month

• Low birth weight and prematurity mediated by peptides derived from activated HPA axis, including ACTH and beta endorphin

• Among miscarrying women with a history of MDD, 54% experienced a recurrence

• Activation of HPA axis well established in nonpregnant depressed patients

Neugebauer R, Kline J, Shrout P, et al. Major depressive disorder in the 6 monthsafter miscarriage. JAMA 1997;277:383-8.

JAMA

Increased Risk of Depression in Pregnancy* • • • • • • •

Prior history of depression *20% of women affirm Maternal youth depressive symptoms during pregnancy Maternal isolation Insufficient social support Marital discord Ambivalence toward pregnancy Greater number of children Uncontrolled depression during pregnancy triples the risk of postpartum depression.

Burt VK and Stein K. Epidemiology of depression throughout the female life cycle. J Clin Psychiatry 2002;63 (suppl 7)9-15.

Wisner KL, Gelenberg AJ, Leonard H, et al. Pharmacologic treatment of depression during pregnancy JAMA 1999;282:1264-1269. Sandman CA, Wadhwa PD, Dunkel-Schretter C, et al. Psychobiological influences of stress and HPA regulation on the human fetus and infant birth outcome. Ann NY Acad Sci 1994;739:198-210. Dayan, J., C. Creveuil, et al. (2002). "Role of anxiety and depression in the onset of spontaneous preterm labor." Am J Epidemiol 155(4): 293-301. Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. Jama. Feb 1 2006;295(5):499-507. Yonkers KA, Wisner KL, Stowe Z, et al. Management of bipolar disorder during pregnancy and the postpartum period. Am J Psychiatry. Apr 2004;161(4):608-620.

Untreated Maternal Depression • Premature low birthweight infants • Fetal growth restrictions • Postnatal complication • Newborns cry more and are more difficult to console Dayan, J., C. Creveuil, et al. (2002). "Role of anxiety and depression in the onset of spontaneous preterm labor." Am J Epidemiol 155(4): 293-301. Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. Jama. Feb 1 2006;295(5):499507. Yonkers KA, Wisner KL, Stowe Z, et al. Management of bipolar disorder during pregnancy and the postpartum period. Am J Psychiatry. Apr 2004;161(4):608-620. ACOG Practice Bulletin, Clinical Management Guidelines for Obstetrician-Gynecologists, Number 87, November 2007.

7

Antenatal Depression and Birthweight 3050

3022

3000 Weight in 2950 Grams

2910

Depressed Non-depressed

2900 2850

rr=1.9

Familiality of Postpartum Depression in Parous Female/Female Sibling Pairs (N=45) With Recurrent Major Depressive Disorder by Week of Postpartum Depression Onset • Episodes of depression with onset within 4 weeks of delivery clustered in families, but there was no significant evidence of familial clustering of broadly defined postpartum depression (onset within 6 months). The evidence for familiality maximized with a postpartum onset definition of 6–8 weeks

Depressed Infant Birth Weights There is a high prevalence of depression in south Asian women. Examined the association between antenatal depression and low birthweight (LBW) in infants in a rural community in Rawalpindi, Pakistan. METHOD: 143 physically healthy mothers with ICD-10 depression in the third trimester of pregnancy and 147 non-depressed mothers of similar gestation were followed from birth. Infant weight was measured and information collected on socioeconomic status, maternal bodymass index and sociodemographic factors. Rahman, A., J. Bunn, et al. (2007). "Association between antenatal depression and low birthweight in a developing country." Acta Psychiatr Scand 115(6): 481-6. Stewart, R. C. (2007). "Maternal depression and infant growth: a review of recent evidence." Matern Child Nutr 3(2): 94-107.

• Among women with a family history of narrowly defined postpartum episodes, 42% experienced depression following their first delivery, whereas only 15% of women with no such family history experienced depression following first delivery. Forty L, Jones L Macgregor s, et al. American Journal of Psychiatry 163:1549-1553, September 2006

Postpartum Depression Risk Factors

Bipolar Disorder and Pregnancy

(Major Depression within first 4-6 weeks postpartum)

• Prenatal diagnosis is key; prenatal counseling is ideal

• History of major depression

• Teratogenesis is a treatment issue (lithium, carbamazepine, valproate, lamotrigine); second generation antipsychotics (olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole) (?)

• History of mania (also increases risk of postpartum mania) • History of PMDD • Psychosocial stress

• Breast-feeding issues (unsafe: lithium); other agents? • Patients can be symptomatic during pregancy; postpartum mania or depression is common (20%-45%)

• Inadequate social support Miller LJ. Postpartum depression. JAMA 2002;287:762-765.

Gentile S. Prophylactic treatment of bipolar disorder in pregnancy and breastfeeding: focus on emerging mood stabilizers. Bipolar Disord. Jun 2006;8(3):207-220. Yonkers KA, Wisner KL, Stowe Z, et al. Management of bipolar disorder during pregnancy and the postpartum period. Am J Psychiatry. Apr 2004;161(4):608-620.

8

Suicide Deaths and Attempts During Pregnancy and Postpartum

The American College of Obstetricians and Gynecologists

suicides are untreated at time of death Lower during pregnancy and postpartum than in the general population of women Suicides account for up to 20% of postpartum deaths During pregnancy and postpartum 5%-14% have self-harm ideation Best predictor of suicide appears to be prior attempt

• The potential risk of SSRIs during pregnancy must be weighed against the risk of depression relapse if the medication is discontinued. Untreated depression has its own risks, including low weight gain, alcohol and substance abuse, and sexually transmitted diseases, all of which have negative maternal and fetal health implications. Fetal echocardiography should be considered for women who were exposed to Paxil® in early pregnancy.

• >90% of suicides have a psychiatric illness • Mood disorders associated with 60% of 80% of • • • •

Lindahl V, Pearson JL, Colpe L. Prevalence of suicidality during pregnancy and the postpartum.Arch Women Ment Health. Jun 2005;8(2):77-87. Mann JJ, Apter A, Bertolote J, et al. Suicide prevention strategies: a systematic review. Jama. Oct 26 2005;294(16):2064-2074.

Relapse Of Major Depression During Pregnancy 80 68

70 60 50

43

% 40 30

26

Relapsed during pregnancy Maintained medication Discontinued medication

20 (hazard ratio, 5.0, p