Menopause, Irritable Mood
Conditions
Keywords
Perimenopause, Menopause transition, Estrogen, Stress, Mood, Irritability
Brief summary
Women in the menopause transition (perimenopause) experience substantial day-to-day variability in estradiol and have a 2-4-fold increase in major depression risk. About 40% of perimenopausal women are susceptible to the emergence of affective symptoms tied to changes in estradiol. Among the perimenopausal women with affective impairment, most report irritability, not depression, is their primary source of impairment and distress. The purpose of this research is to determine the neurophysiologic basis of susceptibility to estradiol fluctuations and irritability symptoms in perimenopausal women.
Detailed description
Using a within-subjects, cross-over design and transdermal estradiol to stabilize estradiol fluctuations (and increase levels) the investigators will test if neural dynamics (oscillatory activity in the theta and beta frequencies assessed via EEG) associated with key constructs of irritability (attentional bias to threat and frustration to non-reward) represent a biomarker target of irritability symptom response to transdermal estradiol.
Interventions
0.1 mg/day transdermal patch administered for 3 weeks
DRUGPlacebo
Estradiol-matched placebo patch administered for 3 weeks
200 mg tablet administered by mouth once per day for 10 days after completion of the experimental phase of the study
Sponsors
National Institute of Mental Health (NIMH)
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
There will be one unblinded Research Assistant administering interventions to preserve masking of research personnel and participants involved. Care provider may be unmasked for specific participants if there are adverse events requiring referral.
Eligibility
Sex/Gender
FEMALE
Age
45 Years to 59 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy women 45 - 59 years of age * In the early menopause transition (defined by variable menstrual cycle length that is 7+ days longer or shorter than usual) * Increase in irritability since the onset of menstrual cycle changes * Moderate to severe irritability symptoms, as defined by IDAS ill-temper scale score \>10 * Have experienced 1+ very stressful life event (e.g. divorce, death of family member) within the past 6 months * Negative mammogram within the past two years * BMI between 18 - 45 kg/m\^2
Exclusion criteria
* Use of psychotropic agents or hormonal preparations, or herbal supplements (other than multivitamins) believed to affect mood or menopausal symptoms * History of psychosis, bipolar disorder, or substance dependence * Active psychological symptoms severe enough to require treatment * Current suicidal intent or recent history of suicide attempts (within past 10 years) * Personal or family history of cancer indicative of more than average risk for breast, ovarian or endometrial cancers * Personal history of any cardiovascular disease including coronary artery disease, arteriosclerosis, heart attack, stroke * Personal history of thromboembolic disorders * History of E2-dependent neoplasia * History of gallbladder disease * Recent history of migraine with aura * Blood pressure classified as higher than stage 2 hypertension (≥160 mmHg systolic or ≥100 mmHg diastolic) * Liver dysfunction or disease * Undiagnosed abnormal genital bleeding * Type I diabetes * Known sensitivities to the matrix patch system in Climara® or allergy to peanut oil used in Prometrium®
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean IDAS Ill Temper Scale Score Over Time | 3 weeks during each intervention | The 5-item ill temper scale of the Inventory of Depression and Anxiety Symptoms (IDAS) will be the primary measure of irritability symptom severity. Each symptom item is rated 1 (not at all) to 5 (extremely). The total IDAS ill temper scale score may range from 5-25. Higher scores indicate more severe irritability symptoms. The average daily irritability scores will be evaluated for each 3-week treatment condition (Active Estradiol vs. Placebo). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Reward Positivity (RewP) in Response to the Affective Posner Paradigm | At the end of each three-week treatment period. | Dysfunctional reward construct of irritability was indexed by the Reward Positivity (RewP), an event-related potential (ERP), that occurs 250-350 ms after feedback indicating a reward (e.g., a monetary win) compared to non-reward (e.g., too slow). The difference waveform is extracted from the frontal midline electrode (Fz). The average ERP is reported to represent the amplitude in response to stimulus presentation. |
| Mean LPP Amplitude During Implicit Viewing Task Dysfunctional Threat Processing Was Indexed by Greater Late Positive Potential (LPP) Component for Emotional Face Stimuli, Elicited 400-900 Milliseconds After the Stimulus Presentation. | At the end of each 3-week treatment period | Implicit Viewing Task: Participants will complete the Implicit Viewing Task while EEG is recorded to examine brain responses (late positive potentials (LPP) to anger stimuli. During the task, participants will be presented with a happy, fear or calm faces and the participant is asked to indicate whether the image shows someone with long or short hair (neutral feature, not emotion related). LPP will be extracted from the midline-parietal electrode (Pz), from 400-900 ms after the stimulus presentation. The average LPP amplitude will be assessed at the end of each 3-week treatment period. Additionally, average LPP amplitude will be evaluated for each condition (Active Estradiol vs. Placebo). |
Countries
United States
Participant flow
Recruitment details
Participants were recruited through medical clinics, UNC Massmail, research listservs (e.g., Research4Me), community flyers, and social media to maximize outreach and participation opportunities.
Pre-assignment details
Forty participants signed informed consent and were enrolled into the study. Of the 40 enrolled participants, 34 met eligibility criteria and proceeded directly to study assignment. Participants who were excluded prior to assignment were those who did not complete initial eligibility confirmation or withdrew consent.
Participants by arm
| Arm | Count |
|---|---|
| Estradiol, Then Placebo Participants will first receive 0.1 mg/day of transdermal estradiol patch for 3 weeks. After a washout period of 3 weeks, participants will then receive transdermal placebo patch (matching transdermal estradiol 0.1 mg/day patch) for 3 weeks. Upon completion of the second intervention, all participants will receive 200 mg/day of progesterone for 10 days. | 18 |
| Placebo, Then Estradiol Participants will first receive transdermal placebo patch (matching transdermal estradiol 0.1 mg/day patch) for 3 weeks. After a washout period of 3 weeks, participants will then receive 0.1 mg/day of transdermal estradiol patch for 3 weeks. Upon completion of the second intervention, all participants will receive 200 mg/day of progesterone for 10 days. | 16 |
| Total | 34 |
Baseline characteristics
| Characteristic | Estradiol, Then Placebo | Placebo, Then Estradiol | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 16 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 15 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| IDAS- 5 question Scale | 6.41 scores on a scale STANDARD_DEVIATION 2.44 | 6.04 scores on a scale STANDARD_DEVIATION 1.97 | 6.24 scores on a scale STANDARD_DEVIATION 2.23 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 11 Participants | 13 Participants | 24 Participants |
| Region of Enrollment United States | 18 Participants | 16 Participants | 34 Participants |
| Sex: Female, Male Female | 18 Participants | 16 Participants | 34 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 31 | 0 / 31 |
| other Total, other adverse events | 18 / 33 | 16 / 31 | 7 / 31 |
| serious Total, serious adverse events | 0 / 33 | 0 / 31 | 0 / 31 |
Outcome results
Primary
Mean IDAS Ill Temper Scale Score Over Time
The 5-item ill temper scale of the Inventory of Depression and Anxiety Symptoms (IDAS) will be the primary measure of irritability symptom severity. Each symptom item is rated 1 (not at all) to 5 (extremely). The total IDAS ill temper scale score may range from 5-25. Higher scores indicate more severe irritability symptoms. The average daily irritability scores will be evaluated for each 3-week treatment condition (Active Estradiol vs. Placebo).
Time frame: 3 weeks during each intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Estradiol | Mean IDAS Ill Temper Scale Score Over Time | 6.19 score on a scale | Standard Deviation 1.33 |
| Placebo | Mean IDAS Ill Temper Scale Score Over Time | 6.02 score on a scale | Standard Deviation 1.02 |
p-value: 0.09Mixed Models Analysis
Secondary
Mean LPP Amplitude During Implicit Viewing Task Dysfunctional Threat Processing Was Indexed by Greater Late Positive Potential (LPP) Component for Emotional Face Stimuli, Elicited 400-900 Milliseconds After the Stimulus Presentation.
Implicit Viewing Task: Participants will complete the Implicit Viewing Task while EEG is recorded to examine brain responses (late positive potentials (LPP) to anger stimuli. During the task, participants will be presented with a happy, fear or calm faces and the participant is asked to indicate whether the image shows someone with long or short hair (neutral feature, not emotion related). LPP will be extracted from the midline-parietal electrode (Pz), from 400-900 ms after the stimulus presentation. The average LPP amplitude will be assessed at the end of each 3-week treatment period. Additionally, average LPP amplitude will be evaluated for each condition (Active Estradiol vs. Placebo).
Time frame: At the end of each 3-week treatment period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Estradiol | Mean LPP Amplitude During Implicit Viewing Task Dysfunctional Threat Processing Was Indexed by Greater Late Positive Potential (LPP) Component for Emotional Face Stimuli, Elicited 400-900 Milliseconds After the Stimulus Presentation. | 2.92 Microvolts | Standard Deviation 1.62 |
| Placebo | Mean LPP Amplitude During Implicit Viewing Task Dysfunctional Threat Processing Was Indexed by Greater Late Positive Potential (LPP) Component for Emotional Face Stimuli, Elicited 400-900 Milliseconds After the Stimulus Presentation. | 2.99 Microvolts | Standard Deviation 1.49 |
p-value: 0.0108Mixed Models Analysis
Secondary
Reward Positivity (RewP) in Response to the Affective Posner Paradigm
Dysfunctional reward construct of irritability was indexed by the Reward Positivity (RewP), an event-related potential (ERP), that occurs 250-350 ms after feedback indicating a reward (e.g., a monetary win) compared to non-reward (e.g., too slow). The difference waveform is extracted from the frontal midline electrode (Fz). The average ERP is reported to represent the amplitude in response to stimulus presentation.
Time frame: At the end of each three-week treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Estradiol | Reward Positivity (RewP) in Response to the Affective Posner Paradigm | -2.59 Microvolts | Standard Deviation 3.19 |
| Placebo | Reward Positivity (RewP) in Response to the Affective Posner Paradigm | -2.13 Microvolts | Standard Deviation 3.13 |
p-value: 0.0018Mixed Models Analysis