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
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      Irritability, defined as a predisposition to exhibit anger, is a prominent, defining symptom
      of perinatal depression (PND) and many other neuropsychiatric disorders. Despite the near
      ubiquity of irritability across disorders, the neural dysfunction underlying the
      vulnerability to, onset of, and exacerbation of irritability is understudied and poorly
      understood. 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. The investigator's central hypothesis
      is that reproductive hormone changes are associated with dysregulated threat and reward
      processing and consequent irritability in HS+. The rationale for the proposed study is that
      employing a scaled down model of puerperal hormonal events permits the identification of a
      group of individuals homogeneous for hormone sensitivity (HS+), hence creating the best
      opportunity for disentangling the specific changes in brain function due to reproductive
      hormones (i.e., HS-) from those accompanying reproductive hormone-precipitated affective
      dysfunction (i.e., HS+). Because women will act as their own controls across time, this study
      design also allows for a powerful evaluation of state and trait variables that may contribute
      to irritability, including both threat and reward processing. Identifying both state and
      trait markers of irritability, and disentangling them from the effects of reproductive
      hormones on brain and behavior, will allow for the identification of neural substrates of
      irritability susceptibility that can be investigated across neuropsychiatric disorders. The
      expected outcome of this research is the identification of neural circuits underlying both
      the susceptibility to and mediation of irritability.
    

Intervention name(s): Leuprolide Acetate 3.75 MG/ML; Estradiol 2 Mg tablet; Micronized progesterone
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 3.75 mg/month leuprolide acetate intramuscular injection; 2 mg estradiol tablet; 200 mg micronized progesterone tablets
Other intervention name(s): Lupron; Estrace; Prometrium
Intervention MeSH terms: Leuprolide; Estradiol; Progesterone
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Basic Science
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