Hormonal Causes of Menstrual-Related Mood Disorders

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.

- 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.