Neurophysiology of Postpartum Depression in an Experimental Model of Pregnancy and Parturition

Foundation of Hope, North Carolina, North Carolina Translational and Clinical Sciences Institute, National Institutes of Health (NIH), National Alliance for Research on Schizophrenia and Depression, National Institute of Mental Health (NIMH)

Understanding the neural and biological mechanisms by which reproductive hormones influence mood is critically important for public health given that postpartum depression (PPD) is the leading cause of morbidity and mortality associated with childbirth and has negative effects on infants. Using a hormone-withdrawal challenge to precipitate mood symptoms will improve our ability to identify the biological mechanisms underlying both the triggering of and susceptibility to depressive disorders in women; and will permit the prediction of those at risk for PPD and other reproductive-related mood disorders.

Affective disorders, such as PPD and other reproductive-related mood disorders, are common and constitute a significant burden for women, children, and society. However, little is known about the neurobiological mechanisms underlying depressive disorders in women. The long-term goal of this research is to 1) advance our understanding of the biological mechanisms underlying both the triggering of and susceptibility to depressive disorders in women; and 2) permit the prediction of those at risk for PPD. The objective of the current project is to examine whether those with a past episode of PPD (at "high risk" for recurrence) show differences in emotional arousal and reward processing domains relative to healthy control women (without a history of PPD) under baseline and hormone withdrawal-precipitated conditions. The central hypothesis is that reproductive hormone changes are associated with dysregulation of the neural circuits underlying emotional arousal and reward processing and consequent depressive symptoms in high-risk women. The rationale for the proposed study is that employing a scaled down model of puerperal hormonal events in high-risk women permits the identification of a group of individuals homogeneous for reproductive related affective dysfunction and, hence, the best opportunity for disentangling the specific changes in brain function due to reproductive hormones from those accompanying reproductive hormone-precipitated affective dysfunction. Moreover, identifying a neurophysiologic biomarker for hormone-related affective dysfunction provides a clear pathway for examining mechanisms of susceptibility to affective dysfunction across disorders. The investigators plan to accomplish the objectives of this application by pursuing the following specific aims: 1) to assess the effects of simulated postpartum reproductive hormone withdrawal, compared to baseline, on corticolimbic circuit activation in high-risk and control women; and 2) to examine the effects of reproductive hormone withdrawal, compared to baseline, on reward circuit activation in high-risk and control women. An additional exploratory aim is to identify a neural biomarker, characterized by corticolimbic and reward circuit dysfunction, that can be used to predict the onset of PPD. The proposed study involves experimentally manipulating reproductive hormones in euthymic women to create a scaled down version of the changes that occur at the puerperium. This endocrine manipulation paradigm will be used to examine the neurocircuitry underlying the regulation of affect and reward processing under baseline and hormone withdrawal-precipitated conditions among women who are expected to experience hormone-related affective dysregulation (n=15) and controls (n=15). In short, the investigators expect that relative to baseline, high-risk women will show greater dysregulation in neural circuits responsible for emotion processing and reward processing during hormone withdrawal than low-risk control women. The expected outcome of this research is the identification of neural circuits underlying both the susceptibility to and mediation of hormone-related affective dysfunction. Understanding these neurobiological mechanisms will subsequently improve the ability to identify those at risk for PPD, which may strengthen prevention efforts and ultimately prevent the deleterious effects of maternal depression on offspring.

4 monthly (intramuscular) IM injections of leuprolide acetate (Lupron) 3.75 mg; micronized estradiol will be started at a dose of 4 mg/day and increased progressively up to 10 mg/day; progesterone will be started at 400 mg/day and increased progressively up to 800 mg/day. Participants will also receive placebo.

4 monthly (intramuscular) IM injections of leuprolide acetate (Lupron) 3.75 mg; micronized estradiol will be started at a dose of 4 mg/day and increased progressively up to 10 mg/day; progesterone will be started at 400 mg/day and increased progressively up to 800 mg/day. Participants will also receive placebo.

All participants will receive micronized estradiol daily for eight weeks. Estradiol will be started at a dose of 4 mg/day and increased progressively up to 10 mg/day.

All subjects will receive micronized progesterone daily for eight weeks. Progesterone will be started at 400 mg/day and increased progressively up to 800 mg/day.

Blood-oxygen-level-dependent (BOLD) Response During Functional Magnetic Resonance Imaging (fMRI) z Statistic

The primary outcome measure was functional magnetic resonance imaging (fMRI) data collected during a Monetary Incentive Delay (MID) Task. The BOLD response was examined within the nucleus accumbens, a brain region that responds to monetary rewards. The z statistic represents the maximum contrast between win versus non-win outcomes during the MID task in the nucleus accumbens, averaged across the participants in each group. The mean BOLD response ranged from z=1.7 to 2.3; higher z scores indicate greater activation of the nucleus accumbens during reward. Individual z scores were generated using the Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB) software library (FSL), which is a library of brain imaging analysis tools for fMRI.

The IDAS Dysphoria Scale consists of 10 items and uses a 5-point Likert-type scale, ranging from 1 to 5 with 1 indicating "not at all" and 5 indicating "extremely". As such, the range of possible scores is 10 to 50. The Dysphoria scale includes items assessing feelings of depression, inadequacy, psychomotor agitation, guilt, discouragement, anhedonia, poor concentration, difficulty with decision-making, psychomotor retardation, and worry. Higher scores indicate greater dysphoria.

Inclusion Criteria: Group 1: Women with a history of PPD A history of a major depression episode that occurred within two months of childbirth (as determined by a SCID interview) and remitted at least one year prior to enrollment in the study; has been well for a minimum of one year; a regular menstrual cycle for at least three months; age 22-50; not pregnant, not lactating and in good medical health; medication free (not including birth control pills; participants may opt to temporarily discontinue birth control pills to participate); no history of puerperal suicide attempts or psychotic episodes requiring hospitalization. Group 2: Healthy Controls 1) Controls will meet all inclusion criteria specified above except they must not have any past or present Axis I diagnosis or evidence of menstrually related mood disorders. A structured clinical interview (SCID) will be administered to all women prior to study entry. Any woman with a current axis I psychiatric diagnosis will be excluded from participating in this protocol. Exclusion Criteria: Patients will not be permitted to enter this protocol if they have important clinical or laboratory abnormalities including any of the following: current axis I psychiatric diagnosis endometriosis; undiagnosed enlargement of the ovaries; liver disease; breast cancer; a history of blood clots in the legs or lungs; undiagnosed vaginal bleeding; porphyria; diabetes mellitus; malignant melanoma; gallbladder or pancreatic disease; heart or kidney disease; cerebrovascular disease (stroke); cigarette smoking; a history of suicide attempts or psychotic episodes requiring hospitalization; recurrent migraine headaches; pregnancy (patients will be warned not to become pregnant during the study and will be required to agree to employ barrier contraceptive methods); pregnancy-related medical conditions such as hyperemesis, pre-toxemia and toxemia, deep vein thrombosis (DVT) and bleeding diathesis; Any woman with a first degree relative (immediate family) with either ovarian cancer, premenopausal breast cancer or breast cancer presenting in both breasts or any woman who has multiple family members (greater than three relatives) with postmenopausal breast cancer will also be excluded from participating in this protocol; Any woman meeting the Stages of Reproductive Aging Workshop Criteria (STRAW) for perimenopause will be excluded from participation. Specifically, we will exclude any woman with an elevated plasma follicle stimulating hormone (FSH) level (> 14 IU/L) and with menstrual cycle variability of > 7 days different from their normal cycle length.

Bloch M, Schmidt PJ, Danaceau M, Murphy J, Nieman L, Rubinow DR. Effects of gonadal steroids in women with a history of postpartum depression. Am J Psychiatry. 2000 Jun;157(6):924-30. doi: 10.1176/appi.ajp.157.6.924.