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

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by University of North Carolina, Chapel Hill
Sponsor:
Collaborators:
Foundation of Hope, North Carolina
North Carolina Translational and Clinical Sciences Institute
National Alliance for Research on Schizophrenia and Depression
Information provided by (Responsible Party):
Crystal Schiller, PhD, University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier:
NCT01762943
First received: November 13, 2012
Last updated: February 12, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention
Postpartum Depression
Drug: Leuprolide Acetate
Drug: Micronized estradiol
Drug: Micronized progesterone

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by University of North Carolina, Chapel Hill:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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 ]

Other Outcome Measures:
  • Change in Hamilton Rating Scale for Depression (HRSD) scores [ Time Frame: Assessed at baseline and at week 27 ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 32
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)
Arms Assigned Interventions
Experimental: Hormone Challenge
Following baseline assessments, participants will receive five monthly intramuscular injections of leuprolide acetate (Lupron) 3.75 mg. After the second month of Lupron-alone treatment, high plasma levels of estradiol and progesterone will be attained via micronized progesterone and estradiol tablets for eight weeks (with continued Lupron administration). 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. After eight weeks of hormone replacement, active hormone tablets will be replaced with placebo to induce a precipitous drop in plasma estradiol and progesterone levels. Lupron will maintain hypogonadal levels for a four-week withdrawal phase. Participants will then be followed for eight weeks additional while unmedicated.
Drug: Leuprolide Acetate
All subjects will receive one i.m. injection (3.75 mg) each month for five months.
Drug: 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: Estrace
Drug: Micronized 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.

  Eligibility

Ages Eligible for Study:   22 Years to 45 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Group 1: Women with a history of postpartum depression

  1. A history of a major depression episode that occurred within three months of childbirth (as determined by a SCID interview) and remitted at least one year prior to enrollment in the study;
  2. has been well for a minimum of one year;
  3. a regular menstrual cycle for at least three months;
  4. age 18-50;
  5. not pregnant, not lactating and in good medical health;
  6. medication free (including birth control pills);
  7. 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 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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01762943

Contacts
Contact: Crystal E Schiller, Ph.D. 919-966-4810 crystal_schiller@med.unc.edu

Locations
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    crystal_schiller@med.unc.edu   
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.         
Sponsors and Collaborators
University of North Carolina, Chapel Hill
Foundation of Hope, North Carolina
North Carolina Translational and Clinical Sciences Institute
National Alliance for Research on Schizophrenia and Depression
Investigators
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
  More Information

Additional Information:
Publications:
Responsible Party: Crystal Schiller, PhD, Postdoctoral Fellow, University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT01762943     History of Changes
Other Study ID Numbers: 12-1758
Study First Received: November 13, 2012
Last Updated: February 12, 2014
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Estrogens
Depression
Depressive Disorder
Depression, Postpartum
Behavioral Symptoms
Mood Disorders
Mental Disorders
Puerperal Disorders
Pregnancy Complications
Estradiol
Polyestradiol phosphate
Progesterone
Estradiol valerate
Estradiol 17 beta-cypionate
Estradiol 3-benzoate
Leuprolide
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Contraceptive Agents
Reproductive Control Agents
Therapeutic Uses
Contraceptive Agents, Female
Progestins
Fertility Agents, Female
Fertility Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents

ClinicalTrials.gov processed this record on August 27, 2014