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

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.

Inclusion Criteria:

Group 1: Women with a history of PPD

1. 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;

2. has been well for a minimum of one year;

3. a regular menstrual cycle for at least three months;

4. age 22-50;

5. not pregnant, not lactating and in good medical health;

6. medication free (not including birth control pills; participants may opt to
temporarily discontinue birth control pills to participate);

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 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.