Characterizing the Neural Substrates of Irritability in Women: an Experimental Neuroendocrine Model
Condition: Perinatal Depression; Post Partum Depression; Depression, Postpartum; Depression
MeSH terms: Depression, Postpartum; Depression; Depressive Disorder
Intervention: Leuprolide Acetate 3.75 MG/ML; Estradiol 2 Mg tablet; Micronized progesterone
Intervention description: 3.75 mg/month leuprolide acetate intramuscular injection; 2 mg estradiol tablet; 200 mg micronized progesterone tablets
Intervention MeSH terms: Leuprolide; Estradiol; Progesterone
Phase: Phase 2
Study type: Interventional
Primary purpose: Basic Science
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Enrollment: 23.0
Sex: Female
Minimum age: 22 Years
Maximum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Irritability; Estrogen; Progesterone; Lupron Depot; Mood Disorders; Perinatal Depression; Postpartum; Hormones; Physiological effects of drugs; Reproductive Control Agents; Mental Disorders; Hormone Intervention; Functional Magnetic Resonance Imaging

Summary:

      The proposed study involves experimentally manipulating reproductive hormones in nonpregnant,
      euthymic women to create a scaled down version of the changes that occur during pregnancy and
      the postpartum period. This endocrine manipulation paradigm, which the investigators have
      shown provokes irritability in past studies, will be used to examine the neurocircuitry
      underlying irritability under baseline and hormone challenge conditions among women who are
      hormone sensitive (HS+; n=15) and non-hormone sensitive (HS-; n=15). The long-term goal of
      this research is to advance understanding of the neural systems underlying both the
      triggering of and susceptibility to irritability in women. The objective of the current
      project is to examine whether HS+ show differences in the behavioral activation system
      relative to HS- under baseline and hormone challenge conditions using functional magnetic
      resonance imaging (fMRI) and behavioral tests.
    

Eligibility criteria:

        Inclusion Criteria:

        Participants will include healthy, euthymic 22-45 year old women with a history of
        postpartum depression (n=15) and women without such a history (n=15). Thus, only
        participants capable of giving informed consent will be enrolled. Participants will be
        compensated upon completion of the study.

        Inclusion Criteria. Group 1: Women with a history of perinatal depression

          -  A history of a the Diagnostic Statistic Manual of Mental Disorders - fifth edition
             (DSM-V) major depression episode that occurred within 6 weeks 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 22-45;

          -  medication free (including birth control pills);.

        Group 2: Healthy Controls

          -  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 for DSM-V (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 (based on a structured clinical interview for
             DSM-V (SCID);

          -  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 with aura;

          -  pregnancy-related medical conditions such as hyperemesis gravidarum, preeclampsia 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, the investigators 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.

        Pregnant women will be excluded from participation (patients will be warned not to become
        pregnant during the study and will be advised to employ barrier contraceptive methods), and
        women who become pregnant (although unlikely because of the hormone manipulation) will be
        withdrawn. The use of leuprolide acetate is not recommended during pregnancy. Prior to
        treatment, a complete physical, including a serum β-human chorionic gonadotropin (HCG) test
        for pregnancy. Participants will be seen at the outpatient clinic on a regular biweekly
        basis. All participants will be required to use non-hormonal forms of birth control (e.g.,
        barrier methods) to avoid pregnancy during this study. Participants will also undergo urine
        toxicology and pregnancy tests on the day of each of the two fMRI scans. If a woman becomes
        pregnant during the study, she will not complete the fMRI scan, and the hormone protocol
        will be discontinued.