| Conditions: |
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Mood Disorders - Premenstrual Syndrome - PMS - PMDD - Depression - Healthy |
| Purpose: |
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This study will explore possible hormonal causes of menstrual-related mood disorders (MRMD)
by stopping the menstrual cycle with a drug called Lupron and then giving in sequence two
menstrual cycle hormones, progesterone and estrogen. The study will first evaluate Lupron's
effectiveness in treating MRMD and will then examine the effects of giving estrogen and
progesterone on mood and behavior. In addition, positron emission tomography (PET) and
magnetic resonance imaging (MRI) will be used to study serotonin receptors and transporters
- molecules in the brain that are thought to play a major role in mood changes related to
the menstrual cycle.
Menstruating women between 18 and 50 years of age who are in good health, not pregnant, and
not taking medications may be eligible for this study. Women with MRMD must have had at
least moderately severe MRMD or behavioral disturbances for at least 6 months within 2 years
of entering the study. Healthy controls must have no history of MRMD or behavioral
disturbances. Candidates undergo physical and neurological examinations, chest x-ray,
electrocardiogram, and blood and urine tests. Results of a recent Pap smear (no longer than
12 months before beginning the study) must be available.
Participants undergo the following tests and procedures:
- Drug treatment: Lupron is injected into a muscle once a month for 5 months. After the
second month, participants receive estrogen or progesterone, or both, daily. Estrogen
is delivered through a skin patch (20 micrograms per day) and the progesterone is taken
as a rectal or vaginal suppository twice a day for the remaining 12 weeks of the study.
Every day, all participants wear a skin patch and insert two suppositories, but at some
point during the 12 weeks, active medication is replaced with placebo to allow the
drugs to wash out of the body.
- Physical examination and blood draw: A physical examination and blood tests are done at
the start of the study and several times during the study to assess general health,
evaluate liver and kidney function, and measure blood cell counts.
- Response to treatment drugs: Responses to Lupron, estrogen, and progesterone are
evaluated periodically with interviews and symptoms self-rating scales. Control
subjects also take paper and pencil psychological tests.
- PET imaging: A total of six PET scans are done at three time points during hormone
treatment. PET uses small amounts of a radioactive chemical called a tracer that
"labels" active areas of the brain. For the procedure, the subject lies on the scanner
bed. A special mask is fitted to the head and attached to the bed to help keep the
subject's head still during the scan so the images will be clear. A brief scan is done
just before the radioactive tracer is injected to help in analyzing the PET data. After
the tracer is injected through a catheter (plastic tube) placed in the arm, pictures
are taken for about 2 hours, during which the subject lies still on the scanner bed.
- MRI scan: MRI uses a magnetic field and radio waves to produce images of body tissues
and organs. For this procedure, the patient lies on a table that is moved into the
scanner (a narrow cylinder) and wears earplugs to muffle loud knocking and thumping
sounds that occur during the scanning process. The procedure lasts about 1 hour.
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| Study Summary: |
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The central serotonergic (5HT) system is one of the candidate systems that may mediate the
abnormal mood and behavioral response to ovarian steroids observed in women with
menstrual-related mood disorders (MRMD). Numerous studies have attempted to measure 5HT
system function in women with MRMD and controls; however, previous studies were restricted
to the evaluation of indirect measures of 5HT function (e.g., platelet 5HT uptake or
responses to serotonergic pharmacologic challenges). Radioligand imaging of specific
components of the 5HT system currently represents the most direct measure of central
serotonergic function available. In this study we will image serotonergic measures during
pharmacological conditions previously demonstrated to induce a remission and a subsequent
provocation of mood symptoms in women with MRMD but not controls.
This protocol has two outcome measures (5HT(1A) binding and SERT binding), two groups of
subjects (women with MRMD and controls), and three distinct hormonal conditions
(hypogonadism, estrogen replacement, and progesterone replacement). Our principal aim in
this study is to investigate differences in the outcome measures in women with MRMD compared
to controls. Our primary hypothesis is that 5HT(1A) binding will be decreased and SERT
binding will be increased in women with MRMD. A secondary hypothesis is that women with
MRMD, but not controls, will display reproductive steroid modulation of 5HT(1A) and SERT
binding. This study will help test existing hypotheses about the pathophysiologic relevance
of serotonin function in MRMD and the role of reproductive steroids in serotonergic
regulation. First, we selected 5HT(1A) receptor binding as an outcome measure for the
following reasons: 5HT(1A) function is modulated by both estradiol and progesterone,
abnormalities of 5HT(1A) binding have been reported in both depressive and anxiety disorders
as well as possibly MRMD, 5HT(1A) receptors have been identified as potential mediators of
estradiol's antidepressant-like effects in the forced swim test, and the 5HT(1A) system is
involved in the regulation of GABA activity abnormalities of which have been implicated in
MRMD. Second, we selected SERT binding as an outcome measure for the following reasons:
selective serotonin reuptake inhibitors, but not traditional antidepressants, are effective
treatments for MRMD; abnormalities of SERT binding have been reported in depressive
disorders in women, preliminary data suggest that women with MRMD are characterized by an
elevated frequency of the long, more transcriptionally active polymorphism of the serotonin
transporter (5HTTLPR) (Roca et al); women with MRMD have altered imipramine binding and
platelet 5HT uptake compared to controls as well as altered platelet paroxetine binding
(which normalize with successful treatment with GnRH agonist); and, finally, SERT message,
binding and protein have been reported to be changed by ovarian steroids in preclinical
studies.
We hypothesize that the effects of hormonal condition on 5HT(1A) (receptor) binding will
differ in patients and controls. Specifically, we anticipate that 5HT1A binding will be
decreased in hippocampus and prefrontal cortex in patients with MRMD but not controls. Such
a decrease, if a trait characteristic, will be demonstrable irrespective of hormonal state.
However, as symptoms of MRMD are directly precipitated by estradiol or progesterone (see
below), it is possible that symptoms are accompanied by state and steroid-dependent changes
in 5HT(1A) binding and function. Consequently, our secondary hypothesis is that estradiol
or progesterone induces changes in 5HT(1A) (receptor) binding in women with MRMD but not in
control women.
Similarly, we hypothesize that women with MRMD will have increased SERT binding activity
compared to controls, consistent with the therapeutic efficacy of selective serotonin
reuptake inhibitors in this condition. However, a secondary hypothesis is that estradiol or
progesterone-induced changes in SERT binding will occur in a hormone-dependent and mood
state-dependent manner. Specifically, consistent with the literature in rodents, acute
changes in ovarian steroids will increase SERT binding in association with the induction of
symptoms in women with MRMD but not controls.
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| Criteria: |
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- INCLUSION CRITERIA:
Women who meet the criteria for MRMD will have participated in Protocol No. 81-M-0126, The
Evaluation of Women with Menstrually Regulated Mood and Behavior Disorders:
Women with MRMD:
- History within the last two years of at least six months with menstrually-related
mood or behavioral disturbances of at least moderate severity-i.e., disturbances that
are distinct in appearance and associated with a notable degree of subjective
distress.
- Symptoms should have a sudden onset and offset.
- age 18-50.
- Not pregnant and in good medical health.
- Medication free.
- No prior DSM-IV Axis I disorder.
- No prior history of treatment with antidepressant medications
All patients participating in this protocol will have already participated in protocol No.
81-M-0126 and will have a prospectively confirmed and predictable relationship between
their mood disorder and the premenstrual phase of the menstrual cycle; i.e., a 30% change
in severity of symptom self rating scales, relative to the range of the scale employed,
during the seven days premenstrually compared with the seven days post-menstrually in two
out of three months of study.
Women without MRMD:
- No history of menstrual-related mood or behavioral disturbances;
- Age 18 and 50 years;
- Not pregnant;
- Good medical health;
- Medication free.
- The absence of menstrual-related mood disorders will be prospectively confirmed
during a two month period prior to the study entry when subjects will complete daily
visual analogue rating scales monitoring both mood and behavior as outlined in NIMH
protocol # 81-M-0126.
- The Structured Clinical Interview for DSM-IV will be administered to all women prior
to study entry. Any patient or control with a current and any control with a past
Axis I psychiatric diagnosis will be excluded from participating in this protocol.
- Prior to treatment, a complete physical and neurological examination will have been
performed (with normal chest X-ray and EKG) and the following routine laboratory data
obtained:
A. Blood
--Complete blood count; thyroid function tests; renal function tests, such as BUN and
creatinine; electrolytes; glucose; liver function tests, B-hCG for pregnancy test.
B. Urine
- Routine urinalysis.
- GnRH agonist will not be administered to any subject with significant clinical or
laboratory abnormalities.
- Additional tests and exclusion criteria.
- Results of PAP smear performed not longer than 12 months prior to onset of treatment
will be obtained. Subjects taking birth control pills or diuretics will be excluded
from the study, as will patients taking psychotropic agents (e.g., lithium carbonate,
tricyclic antidepressants). All subjects will be required to use non-hormonal forms
of birth control (e.g., barrier methods) to avoid pregnancy during this study.
EXCLUSION CRITERIA:
The following conditions will constitute contraindications to treatment with hormonal
therapy and will preclude a subject's participation in this protocol.
- History consistent with endometriosis.
- Diagnosis of ill-defined, obscure pelvic lesions, particularly undiagnosed ovarian
enlargement.
- Hepatic disease as manifested by abnormal liver function test.
- History of mammary carcinoma.
- History of pulmonary embolism or phlebothrombosis.
- Undiagnosed vaginal bleeding.
- Porphyria.
- Diabetes mellitus.
- History of malignant melanoma.
- Cholecystitis or pancreatitis.
- Cardiovascular or renal disease.
- Pregnancy.
- Any woman meeting the Stages of Reproductive Aging Workshop Criteria (STRAW) for the
perimenopause. Specifically, we will exclude any woman with an elevated plasma FSH
level (> 14 IU/L) and with menstrual cycle variability of > 7 days different from
their normal cycle length.
Further, subjects will be warned not to become pregnant during the study and will be
required to employ barrier contraceptive methods.
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| NCT ID: |
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NCT00100360 |
| Primary Contact: |
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Principal Investigator
Peter J Schmidt, M.D.
National Institute of Mental Health (NIMH)
Peter J Schmidt, M.D.
Phone: (301) 496-6120
Email: PeterSchmidt@mail.nih.gov
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| Backup Contact: |
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N/A |
| Location Contact: |
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Bethesda, Maryland 20892
United States
For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)
Phone: 800-411-1222
Email: prpl@mail.cc.nih.gov
Site Status: Recruiting |