1. LAURA J. MILLER MD DIRECTOR, WOMEN’S MENTAL HEALTH DIVISION BRIGHAM AND WOMEN’S HOSPITAL HARVARD MEDICAL SCHOOL Perinatal Depression Update

2. What we’ll cover “Perinatal” depression is major (clinical) depression occurring during pregnancy and/or postpartum We’ll review findings from recent research about  Causes of perinatal depression  Risks of untreated perinatal depression for offspring  Treatments for perinatal depression  Models of delivering care for perinatal depression

4. Perinatal perturbations Hormonal flux Neurotransmitter alterations Inflammatory response Social role transitions Sleep & circadian changes Physical activity changes Social rhythm changes Stressors and genetic susceptibility Pain

5. Genetic susceptibility to stress “Orchid” alleles more susceptible to stress “Cactus” alleles more resilient in the face of stress The 5-HTTLPR-ss allele predicts postpartum depressive symptoms only in the presence of negative life events. Mehta D et al: J Affect Disord 136(3):1192-7, 2012

6. Hormonal flux affects stress response In this study, rats were given estrogen and progesterone to simulate the hormonal state of pregnancy. In half of the rats, these hormones were abruptly discontinued. In the other half, the hormones were gradually tapered. Abrupt withdrawal had a greater effect on stress reactivity, as measured by startle response to noises. Doornbos B et al: Life Sci 84(3-4):69-74, 2009

7. Bloch M et al: J Clin Endocrinol Metab 90(2):695-9, 2005 Estrogen and progesterone were given to healthy women with and without history of postpartum depression, and then abruptly withdrawn to simulate birth. The women were then given corticotropin releasing hormone (CRH) and their cortisol levels were measured. This is a test for the physiologic reactivity of their stress response systems. PPD- women had no “perinatal” change in stress reactivity. PPD+ women had greater “perinatal” stress reactivity. Hormonal flux and stress reactivity in women

8. Postpartum depressed ( ) relative to postpartum control subjects ( ○ ): left lateral orbitofrontal cortex (LLO), mesiotemporal cortex (MTC) and subgenual anterior cingulate (SUB) Serotonin (5HT-1A) receptor binding is reduced in women with postpartum depression compared to controls. 1 Estrogen regulates serotonergic function. 2 Tryptophan 3  Trytophan, found in food, is a “building block” for serotonin.  In pregnancy, serum tryptophan is reduced, especially relative to competing amino acids (t/caa).  Postpartum, tryptophan rises but t/caa is even lower. 1. Moses-Kolko EL et al: Fertil Steril 88(3):685-92, 2008; 2. Donner N, Handa RJ: Neurosci 163(2):705-18, 2009; 3. Maes M et al: Psychol Med 31:847-58, 2001; 2004 Perinatal changes in serotonin

9. Perinatal inflammation  A woman’s body “gets ready” for birth by increasing inflammation (pro- inflammatory cytokines).  Levels of inflammation are further increased by stress, sleep deprivation and pain.  Levels of inflammation correlate with increase in postpartum depressive symptoms. Kendall-Tackett K: Int Breastfeed J 2:6-19, 2007; Maes M et al: Psychoneuroendocrinol 25(2):121-37, 2000 Mean serum concentrations of pro-inflammatory cytokines in pregnant women who are ZDS reactors (– – –) versus nonreactors (—), at the end of term (PRE) and 1 (DAY1) and 3 (DAY3) days postpartum.

10. Perinatal social role transitions Changing from a known to an unknown reality Taking on a new maternal identity, with associated feelings, behaviors and skills Renegotiating prior social roles, such as employment status, relationship with partner, and roles within the extended family Balancing multiple demands and disruptions Experiencing losses, such as loss of control, freedom, and sense of self Strongly influenced by sociocultural context Emmanuel E, St. John W: J Advanced Nurs 66(9):2104-15, 2010

11. Risk factors for perinatal depression Stressful negative life events Lack of social support Intimate partner violence Unintended pregnancy Low socioeconomic status Lancaster CA et al: Am J Obstet Gynecol 5-14, Jan 2010

12. Protective transition rituals Ceremonies Cleansing rituals Seclusion Rest Solicitude Return to home of origin Eberhard-Gran M et al: Arch Womens Ment Health 13(6):459-66, 2010

14. Circadian and social rhythm changes Sleep quality declines throughout pregnancy and postpartum 1  Reduced sleep efficiency  Reduced restorative sleep  Disrupted sleep architecture and circadian rhythm even when naps allow for normal total sleep time Physical activity declines throughout pregnancy and only partially rebounds postpartum 2 Daily routines and social zeitgebers can be far less predictable 3 1. Ross LE et al: J Psychiatry Neurosci 30(4):247-56, 2005; 2. Pereira MA et al: Am J Prev Med 32(4):312-9, 2007; 3. Grandin LD et al: Clin Psychol Rev 26(6):679-94, 2006

15. Obstetric risks of antenatal depression 1. Marcus SM: Can J Clin Pharmacol 16:15-22, 2009. 2. Li D et al: Hum Reprod 24:146- 53, 2009; 3. Bansil P et al: J Womens Health 19:329-34, 2010; 4. Henrichs J et al: Psychol Med 40:633-43, 2010 Reduced prenatal care and health maintenance 1 Preterm birth 2,3 Reduced birth weight 4

16. Effects of intrauterine problems on offspring development Vrekoussis T et al: Ann N Y Acad Sci 1205:69-75, 2010

17. Fetal programming “Epigenetic” means something that influences whether a gene is expressed A woman’s mood and stress while pregnant can have epigenetic effects on fetal development, leading to enduring effects on emotions, behavior or cognitive abilities This is posited to be a way of “reading” and adapting to the outside world Severe, prolonged stress or depression can elevate cortisol, which binds to promoter regions of fetal genes Studies show that maternal depression is associated with increased methylation at promoter regions of genes that affecting glucocorticoid receptors (part of the stress response system) Denslow SA, Wade PA: Oncogene 26:5433-8, 2007 Glover V et al. Psychoneuroendocrinology. 2009;34(3):430-435

18. Effects of antenatal depression on offspring Newborns: excessive crying; more inconsolable 1 Babies: poorer growth; increased risk of infection 2-3 Children: more difficult temperaments - more distress, sadness, fear, shyness, frustration 4 1. Zuckerman et al: J Dev Behav Pediatr 11:190-4,1990; 2. Rahman et al: Arch Gen Psychiatry 61:941- 52, 2004; 3. Traviss GD et al: PLoS One 7(2): e30707,2012; 4. Huot RL et al: Ann N Y Acad Sci 1032:234-6, 2004

19. Postpartum depression and parenting Parenting may be intact despite depression Risks can include  Reduced ability to read baby’s cues 1  Reduced responsiveness to infant distress 2  Reduced ability to communicate range of emotions 1  Reduced enrichment 1  Less healthy feeding and sleeping practices 1 Postpartum stressors can compound antenatal biological vulnerability 3 1. Paulson JF et al: Pediatrics 118:659-68, 2006; 2. Pearson RM et al: Psychol Med 40:621-31, 2010; 3. Rice F et al: Psychol med 40:335-45, 2010

20. Infanticide due to postpartum depression Rare; greater risk with psychotic symptoms Rarely has a history of abusing children Most often part of a suicide attempt No anger toward baby; wish not to abandon baby and/or not to burden others with baby Rarely attempt to conceal; often self-report D’Orban PT: Br J Psychiatry 134:560-71, 1979; Silverman RA, Kennedy LW: Violence Vict 3:113-27, 1988; Haapasalo J, Petaja S: Violence Vict 14:219-39, 1999; Kauppi A et al: Arch Womens Ment Health 11(3):201-6, 2008

21. Ego-dystonic thoughts of harming babies “These fears always started with the words “what if” and left me questioning my sanity as well as the safety of my family. “What if I accidentally dropped my baby out of a second story window?” What if I dropped her on purpose?” “What if I grabbed a hammer and smashed it against my husbands skull as he slept?” “What if I tossed my infant into the swimming pool and walked away?” And countless other unnerving what if questions.” “I need to pause and make a very clear distinction. I never wanted to do those things. I knew they were wrong. I desperately loved my babies. This added to my shame and confusion.” http://www.incourage.me/2010/03/battles.html

22. “She turned up in so many of my dreams – watching me, following me, but never saying anything. In my dreams, she never helped. She just stared at me, as if to say, ‘Well?’ During the various stages of my life, I often wondered if I was responsible for her illness and incarceration. After all, she was taken away at my birth, so who else could be blamed? Buchwald A: Leaving Home: A Memoir. New York: Putnam, 1993

23. Postpartum depression: long-term risks for offspring Poorer health-related quality of life 1 Higher rates of depression  Maternal PPD predicts childhood HPA abnormalities, which in turn predict offspring depressive symptoms in adolescence 2 Higher rates of behavioral disturbance 3 Lower cognitive abilities  PPD affects adolescent IQ 4  Postpartum maternal mood predicts performance on high school entrance exams 5 1. Darcy JM et al: J Am Board Fam Med 24(3):249-57, 2011; 2. Halligan SL et al: Biol Psychiatry 62:40-6, 2007; 3. Brennan PA et al: Dev Psychol 36:759-66,l 2000; 4. Hay DF et al: J Child Psychol Psychiatry 49:1079-88, 2008; 5. Galler et al: J Child Psychol Psychiatry 45:1064-75, 2004

25. Established treatments Antidepressant medication  Studies show risks are same or less than risks of untreated major depression Electroconvulsive therapy  Used for severe episodes Psychotherapy  Interpersonal Psychotherapy and Cognitive- Behavioral Therapy both work  Treatment burden reduces access  Technology-enabled versions are being developed and studied Miller LJ et al: Perinatal depression screening and treatment. In Handler A, Kennelly J, Peacock N, eds.: Women's Reproductive and Perinatal Health: Interventions and Evidence for Reducing Racial and Ethnic Disparities. Springer 2010

26. Emerging treatments Estrogen therapy Phototherapy (light therapy) Transcranial magnetic stimulation Omega-3 essential fatty acids Family and couples therapy Support groups; warm lines; doula support Miller LJ et al: Perinatal depression screening and treatment. In Handler A, Kennelly J, Peacock N, eds.: Women's Reproductive and Perinatal Health: Interventions and Evidence for Reducing Racial and Ethnic Disparities. Springer 2010

27. Models of delivering care Screening all perinatal women for depression with validated tools can greatly improve detection Unfortunately, screening alone does not improve outcomes Integrating mental health assessment and care directly into perinatal care settings can improve entry into treatment  Treatment entry went from 0% - 90% in recently studied model in a community health center Miller LJ et al, J Womens Health 20(10):1046-52, 2012