Neurophysiology of Postpartum Depression in an Experimental Model of Pregnancy and Parturition
Understanding the neural and biological mechanisms by which reproductive hormones influence mood is critically important for public health given that postpartum depression 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.
Drug: Leuprolide Acetate
Drug: Micronized estradiol
|Study Design:||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Outcomes Assessor)
Primary Purpose: Basic Science
|Official Title:||Neurophysiology of Postpartum Depression in an Experimental Model of Pregnancy and Parturition|
- Blood-oxygen-level-dependent (BOLD) contrast during functional magnetic resonance imaging (fMRI) [ Time Frame: up to week 27 ] [ Designated as safety issue: No ]FMRI analyses will include a block-design analysis for the Emotional Face Matching Task and an event-related analysis for the Monetary Reward Task. For both tasks, the BOLD response will be examined within a priori selected regions of interest, including corticolimbic regions for the Emotional Face Matching Task and the ventral striatum for the Monetary Reward Task. Contrasts of interest will include negative versus neutral face blocks in the Emotional Face Matching Task, and win versus non-win outcomes in the Monetary Reward Task. Image analyses will control for any group differences in reaction time or accuracy.
- Change in Inventory of Depression and Anxiety Symptoms (IDAS) scores [ Time Frame: Assessed at baseline and at week 27 ] [ Designated as safety issue: Yes ]
- Change in Edinburgh Postnatal Depression Scale (EPDS) scores [ Time Frame: Assessed at baseline and at week 27 ] [ Designated as safety issue: No ]
- Change in Mood and Anxiety Symptom Questionnaire - Anhedonic Depression Subscale (MASQ-AD) scores [ Time Frame: Assessed at baseline and at week 27 ] [ Designated as safety issue: No ]
- Change in Hamilton Rating Scale for Depression (HRSD) scores [ Time Frame: Assessed at baseline and at week 27 ] [ Designated as safety issue: Yes ]
|Study Start Date:||August 2013|
|Estimated Study Completion Date:||December 2015|
|Estimated Primary Completion Date:||December 2015 (Final data collection date for primary outcome measure)|
Experimental: Hormone Challenge
5 monthly 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.
Drug: Leuprolide Acetate
All subjects will receive one IM injection (3.75 mg) each month for four months.
Other Name: LupronDrug: Micronized estradiol
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.
Other Name: EstraceDrug: Progesterone
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.
Other Name: Micronized progesterone
Affective disorders, such as postpartum depression (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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01762943
|Contact: Crystal E Schiller, Ph.D.||email@example.com|
|United States, North Carolina|
|University of North Carolina at Chapel Hill||Recruiting|
|Chapel Hill, North Carolina, United States, 27599-7175|
|Contact: Crystal E Schiller, Ph.D. 919-966-4810 firstname.lastname@example.org|
|Principal Investigator: Crystal E Schiller, Ph.D.|
|Principal Investigator: David R Rubinow, M.D.|
|Sub-Investigator: Aysenil Belger, Ph.D.|
|Sub-Investigator: Samantha Meltzer-Brody, M.D.|
|Sub-Investigator: John Steege, M.D.|
|Principal Investigator:||Crystal E Schiller, Ph.D.||University of North Carolina, Chapel Hill|
|Principal Investigator:||David R Rubinow, M.D.||University of North Carolina, Chapel Hill|