Characterizing the Neural Substrates of Irritability in Women: an Experimental Neuroendocrine Model

  • STATUS
    Recruiting
  • End date
    Jul 2, 2022
  • participants needed
    30
  • sponsor
    University of North Carolina, Chapel Hill
Updated on 2 March 2021
progesterone
depressive disorder
psychiatric disorder
scid
depressed mood
structured clinical interview
major depressive disorder
functional magnetic resonance imaging
reproductive hormones
postpartum depression
perinatal depression
axis i diagnosis

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.

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.

Details
Condition Endogenous depression, Depression, Postpartum depression, Depression (Major/Severe), Depression (Adolescent), Depression (Pediatric), Depression (Adult and Geriatric), Depression (Treatment-Resistant), Depressed, Perinatal Asphyxia, Perinatal Depression, Post-Partum Depression, depressive disorder, depressed mood, miserable, depressive disorders
Treatment Micronized progesterone, Leuprolide Acetate 3.75 MG/ML, Estradiol 2 Mg tablet
Clinical Study IdentifierNCT04051320
SponsorUniversity of North Carolina, Chapel Hill
Last Modified on2 March 2021

Eligibility

Yes No Not Sure

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, pretoxemia 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 -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
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