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

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ClinicalTrials.gov Identifier: NCT04051320
Recruitment Status : Recruiting
First Posted : August 9, 2019
Last Update Posted : February 21, 2021
Sponsor:
Collaborator:
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

Brief 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.

Condition or disease Intervention/treatment Phase
Perinatal Depression Post Partum Depression Depression, Postpartum Depression Drug: Leuprolide Acetate 3.75 MG/ML Drug: Estradiol 2 Mg tablet Drug: Micronized progesterone Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Characterizing the Neural Substrates of Irritability in Women: an Experimental Neuroendocrine Model
Actual Study Start Date : January 2, 2020
Estimated Primary Completion Date : July 2022
Estimated Study Completion Date : July 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Women with a history of perinatal depression
Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks.
Drug: Leuprolide Acetate 3.75 MG/ML
3.75 mg/month leuprolide acetate intramuscular injection
Other Name: Lupron

Drug: Estradiol 2 Mg tablet
2 mg estradiol tablet
Other Name: Estrace

Drug: Micronized progesterone
200 mg micronized progesterone tablets
Other Name: Prometrium

Experimental: Women without a history of perinatal depression
Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks.
Drug: Leuprolide Acetate 3.75 MG/ML
3.75 mg/month leuprolide acetate intramuscular injection
Other Name: Lupron

Drug: Estradiol 2 Mg tablet
2 mg estradiol tablet
Other Name: Estrace

Drug: Micronized progesterone
200 mg micronized progesterone tablets
Other Name: Prometrium




Primary Outcome Measures :
  1. Change from baseline to endpoint in irritability by dysfunctional threat processing during visual dot-probe paradigm. [ Time Frame: Baseline (week 3), Endpoint (week 6) ]

    This outcome measure determines the extent to which irritability is characterized by dysfunctional threat processing during reproductive hormone challenge relative to baseline in HS+ and HS-. By examining threat attention bias assessed during the visual dot-probe paradigm.

    The Visual Dot-Probe Paradigm asks participants to detect a target stimulus that is embedded in a matrix of distracting stimuli (e.g., a target stimulus, an angry face, might be embedded in a matrix of neutral distractor faces). Attention biases are inferred from faster response times to detect a threatening stimulus in a matrix of neutral stimuli relative to response time to detect neutral stimuli in neutral matrices.


  2. Change from baseline to endpoint in amygdala-medial prefrontal cortex connectivity during implicit emotion face processing task. [ Time Frame: Baseline (week 3), Endpoint (week 6) ]

    This outcome measure determines the extent to which irritability is characterized by dysfunctional threat processing during reproductive hormone challenge relative to baseline in HS+ and HS-. By examining amygdala-medial prefrontal cortex (PFC) connectivity in response to threatening faces on the implicit emotion face processing task in HS+ (compared with HS-) during hormone challenge relative to baseline.

    The implicit emotion face processing task asks participants to identify the gender of angry, happy, and fearful faces at 50%, 100% and 150% emotion intensity presented in random order for 2000 milliseconds followed by jittered fixation. Trials appear in 3 blocks, generating 30 trials of each emotion at each intensity and 90 neutral face emotion trials.


  3. Change from baseline to endpoint in reactive aggression during during hormone addback [ Time Frame: Baseline (week 3), Endpoint (week 6) ]

    This outcome measure determines the extent to which HS+ is characterized by reactive aggression during hormone addback relative to baseline in the target population. Reactive aggression will be defined as the number of point subtractions the participant makes during the Point Subtraction Aggression Paradigm.

    Point Subtraction Aggression Paradigm measures relational aggression (approach behavior) in response to frustration. In the task, participants are asked to press a button to accrue money or press another button to subtract money from a (fictional) partner at no direct gain to themselves. Frustration is induced by periodic subtractions of their own money, which is attributed to the partner.


  4. Change from baseline to endpoint in activation of the amygdala and ventral striatum during the affective posner task [ Time Frame: Baseline (week 3), Endpoint (week 6) ]
    This outcome measure determines the extent to which HS+ is characterized by activation of the amygdala and ventral striatum (caudate, putamen, nucleus accumbens) in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population.


Secondary Outcome Measures :
  1. Correlation between the Inventory of Depressive and Anxiety Symptoms (IDAS) Ill Temper Scale and threat attention bias. [ Time Frame: Baseline (week 3), Endpoint (week 6) ]
    This outcome measure determines the extent to which irritability is characterized by dysfunctional reward processing during reproductive hormone challenge relative to baseline in HS+ and HS-. By examining the correlation between the Inventory of Depressive and Anxiety Symptoms (IDAS) Ill Temper (i.e., irritability) Scale and threat attention bias.

  2. Correlation between the Inventory of Depressive and Anxiety Symptoms (IDAS) Ill Temper Scale and amygdala-medial prefrontal cortex (PFC) connectivity. [ Time Frame: Baseline (week 3), Endpoint (week 6) ]
    This outcome measure determines the extent to which irritability is characterized by dysfunctional reward processing during reproductive hormone challenge relative to baseline in HS+ and HS-. By examining the correlation between the IDAS Ill Temper (i.e., irritability) Scale and amygdala-medial PFC connectivity in HS+.

  3. Correlation between irritability, reactive aggression during hormone addback and target population [ Time Frame: Baseline (week 3), Endpoint (week 6) ]

    This outcome measure determines the degree of irritability and reactive aggression in HS+ during hormone addback and its relationship to the target population. Irritability will be defined as score on the IDAS Ill Temper Scale. Reactive aggression will be defined as the number of point subtractions the participant makes during the Point Subtraction Aggression Paradigm.

    The Point Subtraction Aggression Paradigm measures relational aggression (approach behavior) in response to frustration. In the task, participants are asked to press a button to ac


  4. Correlation between subcortical activation during hormone addback and target population [ Time Frame: Baseline (week 3), Endpoint (week 6) ]

    This outcome measure determines the degree of subcortical (amygdala, caudate, putamen, and nucleus accumbens) activation in HS+ during hormone addback and it's relationship to the target population. The activation in amygdala and ventral striatum (caudate, putamen, nucleus accumbens) regions of interest (ROIs) will be assessed during the Affective Posner Task.

    The Affective Posner Task will test whether HS+ is characterized by reduced activation of the amygdala and ventral striatum in response to frustration. This event related task is divided into 3 runs: during Run 1 (practice run conducted outside of the scanner), subjects receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, subjects receive accurate feedback about their performance on the task and win or lose 50 cents per trial, based on their accuracy and reaction time; and during Run 3 (FNR), subjects are told they must respond accurately to win money, but participants are




Information from the National Library of Medicine

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Ages Eligible for Study:   22 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Men will not be included in this study, given the stated purpose of studying irritability in women with and without perinatal depression.
Accepts Healthy Volunteers:   Yes
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, 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 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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04051320


Contacts
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Contact: Laura C Lundegard, BA (919) 966-5243 laura_lundegard@med.unc.edu

Locations
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United States, North Carolina
University of North Carolina at Chapel Hill School of Medicine Recruiting
Chapel Hill, North Carolina, United States, 27514
Contact: Laura C Lundegard, BA    919-966-5243    laura_lundegard@med.unc.edu   
Principal Investigator: Crystal E Schiller, PhD         
Sponsors and Collaborators
University of North Carolina, Chapel Hill
National Institute of Mental Health (NIMH)
Investigators
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Principal Investigator: Crystal E Schiller, PhD UNC Dept of Psychiatry
Publications:
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5®). (American Psychiatric Pub, 2013).
Gray, J. A. The Psychology of Fear and Stress. (CUP Archive, 1987).
First, M. B., Spitzer, R. L., Gibbon, M. & Williams, J. B. W. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Non-patient Edition. (SCID-I/NP). (Biometrics Research, New York State Psychiatric Institute, 2002).
Clark, L. A. Schedule for Nonadaptive and Adaptive Personality (SNAP). (University of Minnesota Press, 1993).
Carver, C. S. & White, T. L. Behavioral Inhibition, Behavioral Activation, and Affective Responses to Impending Reward and Punishment: The Bis/bas Scales. J. Pers. Soc. Psychol. 67, 319-333 (1994).
Wright, K. A., Lam, D. H. & Brown, R. G. Reduced approach motivation following nonreward: Extension of the BIS/BAS scales. Personal. Individ. Differ. 47, 753-757 (2009).
Mogg, K. & Bradley, B. P. Attentional Bias in Generalized Anxiety Disorder Versus Depressive Disorder. Cogn. Ther. Res. 29, 29-45 (2005).
Nieman, L. K. & Loriaux, D. L. Estrogens and progestins. in Textbook of pharmacology 695-716 (W.B. Saunders Company, 1992).
Grady, D. & Ernster, V. Invited Commentary: Does Postmenopausal Hormone Therapy Cause Breast Cancer? Am. J. Epidemiol. 134, 1396-1400 (1991).
Henzel, M. R. Contraceptive hormones and their clinical use. in Reproductive endocrinology: physiology, pathophysiology and clinical management 643-682 (W.B. Saunders Company, 1986).

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Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT04051320    
Other Study ID Numbers: 19-0401
R21MH119615-01 ( U.S. NIH Grant/Contract )
First Posted: August 9, 2019    Key Record Dates
Last Update Posted: February 21, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Deidentified individual data that supports the results will be shared beginning 18 to 24 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.
Supporting Materials: Statistical Analysis Plan (SAP)
Analytic Code
Time Frame: Deidentified individual data that supports the results will be shared beginning 18 to 24 months following publication.
Access Criteria: Approval from an IRB, IEC, or REB, as applicable and execution of a data use/sharing agreement with UNC.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by University of North Carolina, Chapel Hill:
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
Additional relevant MeSH terms:
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Depression, Postpartum
Depression
Depressive Disorder
Behavioral Symptoms
Mood Disorders
Mental Disorders
Puerperal Disorders
Pregnancy Complications
Leuprolide
Estradiol
Progesterone
Estrogens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Reproductive Control Agents
Progestins
Fertility Agents, Female
Fertility Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents