Postpartum Depression
Conditions
Keywords
Postpartum Disorders, Mood, Hormones, GnRH Agonist, Postpartum Depression
Brief summary
The present protocol is designed to create a scaled-down hormonal milieu of pregnancy and the puerperium in order to determine whether it is the abrupt withdrawal of gonadal steroids or the prolonged exposure to gonadal steroids that is associated with mood symptoms.
Detailed description
The appearance of mood and behavioral symptoms during pregnancy and the postpartum period has been extensively reported. While there has been much speculation about possible biologically based etiologies for postpartum disorders (PPD), none has ever been confirmed. The present protocol is designed to create a scaled-down hormonal milieu of pregnancy and the puerperium in order to determine whether women who have had a previous episode of postpartum major affective episode will experience differential mood and behavioral effects during ovarian hormone exposure and/or withdrawal compared with controls and to determine whether it is the abrupt withdrawal of gonadal steroids or the prolonged exposure to gonadal steroids that is associated with mood symptoms. Supraphysiologic plasma levels of gonadal steroids will be established, maintained, and then rapidly reduced, simulating the hormonal events that occur during pregnancy and parturition. This will be accomplished by administering estradiol and progesterone to women who are pretreated with a gonadotropin releasing hormone (GnRH) agonist (Lupron). After eight weeks, administration of gonadal steroids will be stopped in one group of patients and controls, and a sudden decline in the plasma hormone levels will be precipitated. Another group will be maintained on supraphysiologic levels of estrogen and progesterone for an additional month.
Interventions
DRUGEstradiol
Participants receive 17 beta-estradiol as oral capsule twice daily
OTHERPlacebo
Participants receive placebo as oral capsule twice daily
DRUGProgesterone
Participants receive progesterone as oral capsule twice daily
DRUGleuprolide acetate
Leuprolide acetate is a gonadotropin releasing hormone (GnRH) agonist, given via intramuscular injection monthly
Sponsors
National Institute of Mental Health (NIMH)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: A. Group 1: Women with a history of postpartum depression: 1. A history of Diagnostic and Statistical Manual (DSM)-IV major depression or hypomanic/manic episode that occurred within three months of childbirth (as determined by a Structured Clinical Interview for the DSM (SCID) interview)); 2. has been well for a minimum of one year; 3. a regular menstrual cycle for at least three months; 4. age 18-50; 5. not pregnant, not lactating and in good medical health; 6. medication free (including birth control pills); 7. no history of puerperal suicide attempts or psychotic episodes requiring hospitalization. B. Group 2: Women with a history of Major Depressive Disorder 1. A history of DSM-IV major depression episode(s) occurring outside of pregnancy and not within three months postpartum; 2. has been well for a minimum of one year; 3. a regular menstrual cycle for at least three months; 4. age 18-50; 5. not pregnant, not lactating and in good medical health; 6. medication free (including birth control pills); 7. no history of suicide attempts or psychotic episodes requiring hospitalization. C. Group 3: Normal Controls 1\) Controls will meet all criteria specified except they must not have any past or present Axis I diagnosis or evidence of menstrual related mood disorders.
Exclusion criteria
Patients will not be permitted to enter this protocol if they have important clinical or laboratory abnormalities including any history of the following: * 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 headaches; * pregnancy (patients will be warned not to become pregnant during the study and will be advised to employ barrier contraceptive methods; * 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 the perimenopause will be excluded from participation. Specifically, we will exclude any woman with an elevated plasma follicle stimulating hormone (FSH) level (greater than or equal to 14 IU/L) and with menstrual cycle variability of \> 7 days different from their normal cycle length; * Subjects who are unable to provide informed consent; * National Institute of Mental Health (NIMH) employees and staff and their immediate family members will be excluded from the study per NIMH policy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Edinburgh Postnatal Depression Scale (EPDS) Mean Total Score | Weeks 16, 18, and 20 | The Edinburgh Postnatal Depression Scale (EPDS) is a self-reported 10 item questionnaire to asses a participant's mood over the past week. Each question has four possible answers, scored from 0 to 3 with total score ranging from 0 to 30. Higher scores indicate more severe mood symptoms. EPDS was administered once every 2 weeks for the duration of the study. Analysis was calculated as the mean of scores for baseline (week 16) and weeks 18 and 20. |
Countries
United States
Participant flow
Pre-assignment details
74 participants were consented: * 21 participants were screen failure * 2 participants withdrew after signing consent * 4 participants dropped out prior to randomization * 1 participant dropped out after randomization and prior to start of intervention * 46 participants were randomized and received study intervention
Participants by arm
| Arm | Count |
|---|---|
| Arm 1a - Postpartum Depression: Hormone Withdrawal Group Female participants with history of postpartum depression (PPD) received 3.75 mg of gonadotropin releasing hormone (GnRH) agonist leuprolide acetate (Lupron) via intramuscular injection on a monthly basis for five months (20 weeks), administered during visit for weeks 0, 4, 8, 12, & 16. Participants received oral capsules twice daily under single blind conditions for the same 5 months (20 weeks). During weeks 0 through 7, all participants received placebo via oral capsule twice daily. During weeks 8 through 15, all participants received 2 mg of 17 beta-estradiol via oral capsule twice daily and 200 mg of progesterone via oral capsule twice daily. During weeks 16 through 20, all participants received placebo capsules to be taken twice daily. | 16 |
| Arm 1b - Depression, Non-reproductive: Hormone Withdrawal Group Female participants with history of non-reproductive related depression received 3.75 mg of gonadotropin releasing hormone (GnRH) agonist leuprolide acetate (Lupron) via intramuscular injection on a monthly basis for five months (20 weeks), administered during visit for weeks 0, 4, 8, 12, & 16. Participants received oral capsules twice daily under single blind conditions for the same 5 months (20 weeks). During weeks 0 through 7, all participants received placebo via oral capsule twice daily. During weeks 8 through 15, all participants received 2 mg of 17 beta-estradiol via oral capsule twice daily and 200 mg of progesterone via oral capsule twice daily. During weeks 16 through 20, all participants received placebo capsules to be taken twice daily. | 1 |
| Arm 1c- Healthy Volunteer: Hormone Withdrawal Group Female participants without history of depression received 3.75 mg of gonadotropin releasing hormone (GnRH) agonist leuprolide acetate (Lupron) via intramuscular injection on a monthly basis for five months (20 weeks), administered during visit for weeks 0, 4, 8, 12, & 16. Participants received oral capsules twice daily under single blind conditions for the same 5 months (20 weeks). During weeks 0 through 7, all participants received placebo via oral capsule twice daily. During weeks 8 through 15, all participants received 2 mg of 17 beta-estradiol via oral capsule twice daily and 200 mg of progesterone via oral capsule twice daily. During weeks 16 through 20, all participants received placebo capsules to be taken twice daily. | 13 |
| Arm 2a: Postpartum Depression; Hormone Continuation Group Female participants with history of postpartum depression (PPD) received 3.75 mg of gonadotropin releasing hormone (GnRH) agonist leuprolide acetate (Lupron) via intramuscular injection on a monthly basis for five months (20 weeks), administered during visit for weeks 0, 4, 8, 12, & 16. Participants received oral capsules twice daily under single blind conditions for the same 5 months (20 weeks). During weeks 0 through 7, all participants received placebo via oral capsule twice daily. During weeks 8 through 20, all participants received 2 mg of 17 beta-estradiol via oral capsule twice daily and 200 mg of progesterone via oral capsule twice daily. | 7 |
| Arm 2b - Depression, Non-reproductive: Hormone Continuation Group Female participants with history of non-reproductive related depression received 3.75 mg of gonadotropin releasing hormone (GnRH) agonist leuprolide acetate (Lupron) via intramuscular injection on a monthly basis for five months (20 weeks), administered during visit for weeks 0, 4, 8, 12, & 16. Participants received oral capsules twice daily under single blind conditions for the same 5 months (20 weeks). During weeks 0 through 7, all participants received placebo via oral capsule twice daily. During weeks 8 through 20, all participants received 2 mg of 17 beta-estradiol via oral capsule twice daily and 200 mg of progesterone via oral capsule twice daily. | 2 |
| Arm 2c- Healthy Volunteer: Hormone Continuation Group Female participants without history of depression received 3.75 mg of gonadotropin releasing hormone (GnRH) agonist leuprolide acetate (Lupron) via intramuscular injection on a monthly basis for five months (20 weeks), administered during visit for weeks 0, 4, 8, 12, & 16. Participants received oral capsules twice daily under single blind conditions for the same 5 months (20 weeks). During weeks 0 through 7, all participants received placebo via oral capsule twice daily. During weeks 8 through 20, all participants received 2 mg of 17 beta-estradiol via oral capsule twice daily and 200 mg of progesterone via oral capsule twice daily. | 7 |
| Total | 46 |
Baseline characteristics
| Characteristic | Arm 1a - Postpartum Depression: Hormone Withdrawal Group | Arm 1b - Depression, Non-reproductive: Hormone Withdrawal Group | Arm 1c- Healthy Volunteer: Hormone Withdrawal Group | Arm 2a: Postpartum Depression; Hormone Continuation Group | Arm 2b - Depression, Non-reproductive: Hormone Continuation Group | Arm 2c- Healthy Volunteer: Hormone Continuation Group | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 3 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 5 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 1 Participants | 13 Participants | 5 Participants | 2 Participants | 7 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 1 Participants | 12 Participants | 6 Participants | 2 Participants | 7 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 7 Participants | 2 Participants | 1 Participants | 4 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 12 Participants | 1 Participants | 5 Participants | 4 Participants | 1 Participants | 1 Participants | 24 Participants |
| Sex: Female, Male Female | 16 Participants | 1 Participants | 13 Participants | 7 Participants | 2 Participants | 7 Participants | 46 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 1 | 0 / 13 | 0 / 7 | 0 / 2 | 0 / 7 |
| other Total, other adverse events | 3 / 16 | 0 / 1 | 0 / 13 | 1 / 7 | 0 / 2 | 1 / 7 |
| serious Total, serious adverse events | 0 / 16 | 0 / 1 | 0 / 13 | 0 / 7 | 0 / 2 | 0 / 7 |
Outcome results
Primary
Edinburgh Postnatal Depression Scale (EPDS) Mean Total Score
The Edinburgh Postnatal Depression Scale (EPDS) is a self-reported 10 item questionnaire to asses a participant's mood over the past week. Each question has four possible answers, scored from 0 to 3 with total score ranging from 0 to 30. Higher scores indicate more severe mood symptoms. EPDS was administered once every 2 weeks for the duration of the study. Analysis was calculated as the mean of scores for baseline (week 16) and weeks 18 and 20.
Time frame: Weeks 16, 18, and 20
Population: Analysis applies to participants in study 2. Two participants did not complete rating in week 16. One participant did not complete rating in week 18. Two participants did not complete rating in week 20.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1a - Postpartum Depression: Hormone Withdrawal | Edinburgh Postnatal Depression Scale (EPDS) Mean Total Score | Week 18 | 1.22 Units on a scale | Standard Deviation 3.31 |
| Arm 1a - Postpartum Depression: Hormone Withdrawal | Edinburgh Postnatal Depression Scale (EPDS) Mean Total Score | Week 16 | 3.75 Units on a scale | Standard Deviation 6.32 |
| Arm 1a - Postpartum Depression: Hormone Withdrawal | Edinburgh Postnatal Depression Scale (EPDS) Mean Total Score | Week 20 | 1 Units on a scale | Standard Deviation 1.93 |
| Arm 1b - Depression, Non-reproductive: Hormone Withdrawal | Edinburgh Postnatal Depression Scale (EPDS) Mean Total Score | Week 18 | 0 Units on a scale | — |
| Arm 1b - Depression, Non-reproductive: Hormone Withdrawal | Edinburgh Postnatal Depression Scale (EPDS) Mean Total Score | Week 16 | 3 Units on a scale | — |
| Arm 1b - Depression, Non-reproductive: Hormone Withdrawal | Edinburgh Postnatal Depression Scale (EPDS) Mean Total Score | Week 20 | 0 Units on a scale | — |
| Arm 1c - Healthy Volunteer: Hormone Withdrawal | Edinburgh Postnatal Depression Scale (EPDS) Mean Total Score | Week 20 | 0.2 Units on a scale | Standard Deviation 0.45 |
| Arm 1c - Healthy Volunteer: Hormone Withdrawal | Edinburgh Postnatal Depression Scale (EPDS) Mean Total Score | Week 16 | 0 Units on a scale | Standard Deviation 0 |
| Arm 1c - Healthy Volunteer: Hormone Withdrawal | Edinburgh Postnatal Depression Scale (EPDS) Mean Total Score | Week 18 | 0 Units on a scale | Standard Deviation 0 |
| Arm 2a - Postpartum Depression: Hormone Continuation | Edinburgh Postnatal Depression Scale (EPDS) Mean Total Score | Week 20 | 3.71 Units on a scale | Standard Deviation 4.54 |
| Arm 2a - Postpartum Depression: Hormone Continuation | Edinburgh Postnatal Depression Scale (EPDS) Mean Total Score | Week 18 | 2.29 Units on a scale | Standard Deviation 2.36 |
| Arm 2a - Postpartum Depression: Hormone Continuation | Edinburgh Postnatal Depression Scale (EPDS) Mean Total Score | Week 16 | 1.14 Units on a scale | Standard Deviation 1.07 |
| Arm 2b - Depression, Non-reproductive: Hormone Continuation | Edinburgh Postnatal Depression Scale (EPDS) Mean Total Score | Week 20 | 0.5 Units on a scale | Standard Deviation 0.71 |
| Arm 2b - Depression, Non-reproductive: Hormone Continuation | Edinburgh Postnatal Depression Scale (EPDS) Mean Total Score | Week 16 | 0.5 Units on a scale | Standard Deviation 0.71 |
| Arm 2b - Depression, Non-reproductive: Hormone Continuation | Edinburgh Postnatal Depression Scale (EPDS) Mean Total Score | Week 18 | 0 Units on a scale | — |
| Arm 2c - Healthy Volunteer: Hormone Continuation | Edinburgh Postnatal Depression Scale (EPDS) Mean Total Score | Week 16 | 0.67 Units on a scale | Standard Deviation 1.21 |
| Arm 2c - Healthy Volunteer: Hormone Continuation | Edinburgh Postnatal Depression Scale (EPDS) Mean Total Score | Week 20 | 0.67 Units on a scale | Standard Deviation 0.82 |
| Arm 2c - Healthy Volunteer: Hormone Continuation | Edinburgh Postnatal Depression Scale (EPDS) Mean Total Score | Week 18 | 0.29 Units on a scale | Standard Deviation 0.49 |