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| ID | Type | Description | Link |
|---|---|---|---|
| R21MH119615-01 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
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| National Institute of Mental Health (NIMH) | NIH |
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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Hormone Sensitive Women (HS+) | Experimental | 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. |
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| Hormone Insensitive Women (HS-) | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Leuprolide Acetate 3.75 MG/ML | Drug | 3.75 mg/month leuprolide acetate intramuscular injection |
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| Measure | Description | Time Frame |
|---|---|---|
| Mean Threat Processing Bias During Visual Dot-probe Paradigm Over Time | 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. Thus, positive times reflect attention bias toward threat, whereas negative times reflect attention bias away from threat. | up to 6 weeks |
| Mean Right Amygdala-medial Prefrontal Cortex BOLD Connectivity During Implicit Emotion Face Processing Task Over Time | 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) Blood-oxygen-level-dependent (BOLD) connectivity in response to threatening faces on the implicit emotion face processing fMRI 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. | up to 6 weeks |
| Mean Left Amygdala-medial Prefrontal Cortex BOLD Connectivity During Implicit Emotion Face Processing Task Over Time | 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 fMRI 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Correlation Between the Inventory of Depressive and Anxiety Symptoms (IDAS) Ill -0.8Scale and Threat Attention Bias | This outcome measure determines the extent to which irritability is characterized by dysfunctional reward processing during reproductive hormone challenge 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. |
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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
Group 2: Healthy Controls
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:
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.
Men will not be included in this study, given the stated purpose of studying irritability in women with and without perinatal depression.
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| Name | Affiliation | Role |
|---|---|---|
| Crystal E Schiller, PhD | UNC Dept of Psychiatry | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of North Carolina at Chapel Hill School of Medicine | Chapel Hill | North Carolina | 27514 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27343883 | Background | Vidal-Ribas P, Brotman MA, Valdivieso I, Leibenluft E, Stringaris A. The Status of Irritability in Psychiatry: A Conceptual and Quantitative Review. J Am Acad Child Adolesc Psychiatry. 2016 Jul;55(7):556-70. doi: 10.1016/j.jaac.2016.04.014. Epub 2016 May 6. | |
| Background | American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5®). (American Psychiatric Pub, 2013). | ||
| 19274052 |
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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.
Deidentified individual data that supports the results will be shared beginning 18 to 24 months following publication.
Approval from an IRB, IEC, or REB, as applicable and execution of a data use/sharing agreement with UNC.
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| ID | Title | Description |
|---|---|---|
| FG000 | Hormone Sensitive Women (HS+) | 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. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 6, 2020 |
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| Estradiol 2 Mg tablet | Drug | 2 mg estradiol tablet |
|
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| Micronized progesterone | Drug | 200 mg micronized progesterone tablets |
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| up to 6 weeks |
| Mean Reactive Aggression During Hormone Addback Over Time | 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. | up to 6 weeks |
| Mean BOLD Activation of the Right Amygdala During the Affective Posner Task Over Time | This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the right amygdala in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance. | up to 6 weeks |
| Mean BOLD Activation of the Left Amygdala During the Affective Posner Task Over Time | This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the left amygdala in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance. | up to 6 weeks |
| Mean BOLD Activation of the Right Caudate During the Affective Posner Task Over Time | This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the right caudate in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance. | up to 6 weeks |
| Mean BOLD Activation of the Left Caudate During the Affective Posner Task Over Time | This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the left caudate in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance. | up to 6 weeks |
| Mean BOLD Activation of the Right Putamen During the Affective Posner Task Over Time | This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the right putamen in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance. | up to 6 weeks |
| Mean BOLD Activation of the Left Putamen During the Affective Posner Task Over Time | This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the left putamen in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance. | up to 6 weeks |
| Mean BOLD Activation of the Right Nucleus Accumbens During the Affective Posner Task Over Time | This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the right nucleus accumbens in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance. | up to 6 weeks |
| Mean BOLD Activation of the Left Nucleus Accumbens During the Affective Posner Task Over Time | This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the left nucleus accumbens in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance. | up to 6 weeks |
| Endpoint (week 6) |
| Correlation Between the Inventory of Depressive and Anxiety Symptoms (IDAS) Ill Temper Scale and Right Amygdala-medial Prefrontal Cortex (PFC) BOLD Connectivity. | This outcome measure determines the extent to which irritability is characterized by dysfunctional reward processing during reproductive hormone challenge in HS+ and HS- by examining the correlation between the IDAS Ill Temper (i.e., irritability) Scale and amygdala-medial PFC connectivity in HS+. | Endpoint (week 6) |
| Correlation Between the Inventory of Depressive and Anxiety Symptoms (IDAS) Ill Temper Scale and Left Amygdala-medial Prefrontal Cortex (PFC) BOLD Connectivity. | This outcome measure determines the extent to which irritability is characterized by dysfunctional reward processing during reproductive hormone challenge in HS+ and HS- by examining the correlation between the IDAS Ill Temper (i.e., irritability) Scale and amygdala-medial PFC connectivity in HS+. | Endpoint (week 6) |
| Correlation Between Irritability and Reactive Aggression During Hormone Addback | 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 | Endpoint (week 6) |
| Correlation Between Irritability Subcortical Activation in HS+ During Hormone Addback | 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 tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance. | Endpoint (week 6) |
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| 23798350 | Background | Hommer RE, Meyer A, Stoddard J, Connolly ME, Mogg K, Bradley BP, Pine DS, Leibenluft E, Brotman MA. Attention bias to threat faces in severe mood dysregulation. Depress Anxiety. 2014 Jul;31(7):559-65. doi: 10.1002/da.22145. Epub 2013 Jun 24. |
| FG001 | Hormone Insensitive Women (HS-) | 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. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets |
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| ID | Title | Description |
|---|---|---|
| BG000 | Hormone Sensitive Women (HS+) | 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. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets |
| BG001 | Hormone Insensitive Women (HS-) | 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. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets |
| BG002 | Total | Total of all reporting groups |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Region of Enrollment | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Primary | Mean Threat Processing Bias During Visual Dot-probe Paradigm Over Time | 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. Thus, positive times reflect attention bias toward threat, whereas negative times reflect attention bias away from threat. | All available data are reported. Data are missing for participants who had insufficient time to complete the task or due to computer malfunction. | Posted | Mean | Standard Deviation | attention bias in milliseconds | up to 6 weeks |
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| Primary | Mean Right Amygdala-medial Prefrontal Cortex BOLD Connectivity During Implicit Emotion Face Processing Task Over Time | 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) Blood-oxygen-level-dependent (BOLD) connectivity in response to threatening faces on the implicit emotion face processing fMRI 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. | Participants exceeding the motion threshold and those completing the task incorrectly were excluded. | Posted | Mean | Standard Deviation | arbitrary units | up to 6 weeks |
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| Primary | Mean Left Amygdala-medial Prefrontal Cortex BOLD Connectivity During Implicit Emotion Face Processing Task Over Time | 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 fMRI 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. | Participants exceeding the motion threshold and those completing the task incorrectly were excluded. | Posted | Mean | Standard Deviation | arbitrary units | up to 6 weeks |
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| Primary | Mean Reactive Aggression During Hormone Addback Over Time | 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. | Posted | Mean | Standard Deviation | Number of subtraction responses | up to 6 weeks |
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| Primary | Mean BOLD Activation of the Right Amygdala During the Affective Posner Task Over Time | This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the right amygdala in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance. | Participants exceeding the motion threshold were excluded as were those with signal loss. | Posted | Mean | Standard Deviation | Arbitrary Units | up to 6 weeks |
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| Primary | Mean BOLD Activation of the Left Amygdala During the Affective Posner Task Over Time | This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the left amygdala in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance. | Participants exceeding the motion threshold were excluded. | Posted | Mean | Standard Deviation | Arbitrary Units | up to 6 weeks |
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| Primary | Mean BOLD Activation of the Right Caudate During the Affective Posner Task Over Time | This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the right caudate in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance. | Posted | Mean | Standard Deviation | Arbitrary Units | up to 6 weeks |
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| Primary | Mean BOLD Activation of the Left Caudate During the Affective Posner Task Over Time | This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the left caudate in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance. | Participants with signal loss were excluded. | Posted | Mean | Standard Deviation | Arbitrary Units | up to 6 weeks |
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| Primary | Mean BOLD Activation of the Right Putamen During the Affective Posner Task Over Time | This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the right putamen in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance. | Participants with signal loss were excluded. | Posted | Mean | Standard Deviation | Arbitrary Units | up to 6 weeks |
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| Primary | Mean BOLD Activation of the Left Putamen During the Affective Posner Task Over Time | This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the left putamen in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance. | Posted | Mean | Standard Deviation | Arbitrary Units | up to 6 weeks |
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| Primary | Mean BOLD Activation of the Right Nucleus Accumbens During the Affective Posner Task Over Time | This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the right nucleus accumbens in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance. | Participants with signal loss were excluded. | Posted | Mean | Standard Deviation | Arbitrary Units | up to 6 weeks |
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| Primary | Mean BOLD Activation of the Left Nucleus Accumbens During the Affective Posner Task Over Time | This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the left nucleus accumbens in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance. | Participants with signal loss were excluded. | Posted | Mean | Standard Deviation | Arbitrary Units | up to 6 weeks |
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| Secondary | Correlation Between the Inventory of Depressive and Anxiety Symptoms (IDAS) Ill -0.8Scale and Threat Attention Bias | This outcome measure determines the extent to which irritability is characterized by dysfunctional reward processing during reproductive hormone challenge 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. | All available data are reported. Data are missing for participants who had insufficient time to complete the task or due to computer malfunction. | Posted | Number | 95% Confidence Interval | correlation coefficient | Endpoint (week 6) |
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| Secondary | Correlation Between the Inventory of Depressive and Anxiety Symptoms (IDAS) Ill Temper Scale and Right Amygdala-medial Prefrontal Cortex (PFC) BOLD Connectivity. | This outcome measure determines the extent to which irritability is characterized by dysfunctional reward processing during reproductive hormone challenge in HS+ and HS- by examining the correlation between the IDAS Ill Temper (i.e., irritability) Scale and amygdala-medial PFC connectivity in HS+. | Participants exceeding the motion threshold and those completing the task incorrectly were excluded. | Posted | Number | 95% Confidence Interval | correlation coefficient | Endpoint (week 6) |
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| Secondary | Correlation Between the Inventory of Depressive and Anxiety Symptoms (IDAS) Ill Temper Scale and Left Amygdala-medial Prefrontal Cortex (PFC) BOLD Connectivity. | This outcome measure determines the extent to which irritability is characterized by dysfunctional reward processing during reproductive hormone challenge in HS+ and HS- by examining the correlation between the IDAS Ill Temper (i.e., irritability) Scale and amygdala-medial PFC connectivity in HS+. | Participants exceeding the motion threshold and those completing the task incorrectly were excluded. | Posted | Mean | 95% Confidence Interval | correlation coefficient | Endpoint (week 6) |
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| Secondary | Correlation Between Irritability and Reactive Aggression During Hormone Addback | 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 | Posted | Number | 95% Confidence Interval | correlation coefficient | Endpoint (week 6) |
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| Secondary | Correlation Between Irritability Subcortical Activation in HS+ During Hormone Addback | 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 tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance. | The a priori hypothesis focused on the HS+ group only. | Posted | Number | 95% Confidence Interval | correlation coefficient | Endpoint (week 6) |
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From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Hormone Sensitive Women (HS+) | 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. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets | 0 | 13 | 0 | 13 | 12 | 13 |
| EG001 | Hormone Insensitive Women (HS-) | 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. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets | 0 | 10 | 0 | 10 | 9 | 10 |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Bloating | Gastrointestinal disorders | Systematic Assessment |
| ||
| Low back pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| General musculoskeletal pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Cramps | Reproductive system and breast disorders | Systematic Assessment |
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| Headache | General disorders | Systematic Assessment |
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| Migraine | Vascular disorders | Systematic Assessment |
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| Occular migraine | Vascular disorders | Systematic Assessment |
| ||
| Fatigue | General disorders | Systematic Assessment |
| ||
| Arm soreness (Lupron IM injection) | Musculoskeletal and connective tissue disorders | Systematic Assessment |
| ||
| Arm soreness (COVID vaccine IM injection) | Musculoskeletal and connective tissue disorders | Systematic Assessment |
| ||
| Hot flashes | Reproductive system and breast disorders | Systematic Assessment |
| ||
| Fever (COVID-19 infection) | Infections and infestations | Systematic Assessment |
| ||
| Anosmia (COVID-19 infection) | Infections and infestations | Systematic Assessment |
| ||
| COVID-19 Infection | Infections and infestations | Systematic Assessment |
| ||
| Dry cough (Seasonal allergies) | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Gastrointestinal upset | Gastrointestinal disorders | Systematic Assessment |
| ||
| Mood swings | Psychiatric disorders | Systematic Assessment |
| ||
| Spotting | Reproductive system and breast disorders | Systematic Assessment |
| ||
| Intrusive thoughts | Psychiatric disorders | Systematic Assessment |
| ||
| Anxiety | Psychiatric disorders | Systematic Assessment |
| ||
| Anhedonia | Psychiatric disorders | Systematic Assessment |
| ||
| Depressed mood | Psychiatric disorders | Systematic Assessment |
| ||
| Irritability | Psychiatric disorders | Systematic Assessment |
| ||
| Low libido | Psychiatric disorders | Systematic Assessment |
| ||
| Weight gain | Metabolism and nutrition disorders | Systematic Assessment |
| ||
| Concussion | Injury, poisoning and procedural complications | Systematic Assessment |
| ||
| Early insomnia | Psychiatric disorders | Systematic Assessment |
| ||
| Late insomnia | Psychiatric disorders | Systematic Assessment |
| ||
| Breast tenderness | Reproductive system and breast disorders | Systematic Assessment |
| ||
| Decreased appetite | Metabolism and nutrition disorders | Systematic Assessment |
| ||
| Increased appetite | Metabolism and nutrition disorders | Systematic Assessment |
| ||
| Dizziness | Nervous system disorders | Systematic Assessment |
| ||
| Difficulty concentrating | Psychiatric disorders | Systematic Assessment |
| ||
| Emotional sensitivity | Psychiatric disorders | Systematic Assessment |
| ||
| Insomnia | Psychiatric disorders | Systematic Assessment |
| ||
| Heartburn | Gastrointestinal disorders | Systematic Assessment |
| ||
| Hematoma (IM injection) | Musculoskeletal and connective tissue disorders | Systematic Assessment |
| ||
| Yeast infection | Reproductive system and breast disorders | Systematic Assessment |
| ||
| Hormonal acne | Skin and subcutaneous tissue disorders | Systematic Assessment |
| ||
| Hair loss | Skin and subcutaneous tissue disorders | Systematic Assessment |
| ||
| Cervical mucus | Reproductive system and breast disorders | Systematic Assessment |
| ||
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
| ||
| Fever | Infections and infestations | Systematic Assessment |
| ||
| Hip pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
| ||
| Frequent urination | Renal and urinary disorders | Systematic Assessment |
| ||
| Vivid dreams | Psychiatric disorders | Systematic Assessment |
| ||
| Passive suicidal ideation | Psychiatric disorders | Systematic Assessment |
|
Not provided
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Crystal Schiller, PhD | University of North Carolina at Chapel Hill | 919-966-5243 | crystal_schiller@med.unc.edu |
| May 18, 2023 |
| Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Nov 5, 2020 | May 18, 2023 | ICF_001.pdf |
Not provided
| ID | Term |
|---|---|
| D019052 | Depression, Postpartum |
| D003863 | Depression |
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
| ID | Term |
|---|---|
| D011644 | Puerperal Disorders |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D003866 | Depressive Disorder |
| D001526 | Behavioral Symptoms |
| D001519 | Behavior |
Not provided
Not provided
| ID | Term |
|---|---|
| D016729 | Leuprolide |
| D004958 | Estradiol |
| D013607 | Tablets |
| D011374 | Progesterone |
| ID | Term |
|---|---|
| D007987 | Gonadotropin-Releasing Hormone |
| D010906 | Pituitary Hormone-Releasing Hormones |
| D007028 | Hypothalamic Hormones |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D009479 | Neuropeptides |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D009842 | Oligopeptides |
| D009419 | Nerve Tissue Proteins |
| D011506 | Proteins |
| D004963 | Estrenes |
| D004962 | Estranes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D045166 | Estradiol Congeners |
| D012739 | Gonadal Steroid Hormones |
| D042341 | Gonadal Hormones |
| D004304 | Dosage Forms |
| D004364 | Pharmaceutical Preparations |
| D011282 | Pregnenediones |
| D011283 | Pregnenes |
| D011278 | Pregnanes |
| D003339 | Corpus Luteum Hormones |
| D045167 | Progesterone Congeners |
Not provided
Not provided
| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
|
| Unknown or Not Reported |
|
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. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets |
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|
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. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets |
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| Hormone Insensitive Women (HS-) |
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. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets |
|
|
|
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. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets |
|
|
|
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.
Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection
Estradiol 2 Mg tablet: 2 mg estradiol tablet
Micronized progesterone: 200 mg micronized progesterone tablets
|
|
|
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. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets |
|
|
|
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. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets |
|
|
|
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.
Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection
Estradiol 2 Mg tablet: 2 mg estradiol tablet
Micronized progesterone: 200 mg micronized progesterone tablets
|
|
|
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. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets |
|
|
|
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. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets |
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| OG001 | Hormone Insensitive Women (HS-) | 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. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone Insensitive women did not experience a 30% increase in negative mood symptoms during hormone addback. |
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