Effect of the Menstrual Cycle on the Symptoms of Depression and Treatment Response
Effect of the Menstrual Cycle on the Symptoms of Depression and Treatment Response
Objectives: This prospective investigation will compare premenopausal, perimenopausal and
 postmenopausal women's response to antidepressant medication. The effects of the menstrual
 cycle on the symptoms of depression and antidepressant response will also be examined.

 Hypotheses: Premenopausal women will show a significantly better response to a selective
 serotonin reuptake inhibitor (SSRI) than peri- or postmenopausal women. Premenopausal women
 during lower estrogen phases of the menstrual cycle will complain of increased depressive
 symptoms despite treatment. Perimenopausal and postmenopausal women with irregular periods
 and generally low estrogen levels will show less symptom variability over time.

 Method

 Subjects: Eighty-four women (28 premenopausal, 28 perimenopausal, 28 postmenopausal) meeting
 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for
 major depressive disorder will be enrolled in the study.

 Procedure: All the subjects will be followed prospectively for 12 weeks and through 2
 menstrual cycles while receiving treatment with a standard SSRI antidepressant agent. All
 eligible women will have a structured clinical interview and will complete questionnaires
 assessing their depressive symptoms. Blood samples will be collected to evaluate for
 reproductive hormone levels during the late follicular, midluteal and late luteal phases of
 the menstrual cycle for two consecutive cycles. Serum SSRI levels will also be collected at
 these times. As the women in the perimenopausal and postmenopausal groups either have
 irregular menstrual cycles or no longer cycle, they will have blood samples drawn at baseline
 and on 6 other occasions.

 Research Implications: As the majority of psychiatric medication is prescribed to women,
 understanding the interplay between the menstrual cycle and antidepressant medication will
 ultimately translate into more diverse and improved patient care. The proposed study is one
 within a developing research program, which will in part be further guided by this study.
Rationale: The lifetime prevalence of depression is twice as high in women as in men; this is
 a robust and frequently replicated finding in cross national epidemiology studies. Women are
 also more prone to various depressive disorders at certain stages of the life cycle yet the
 etiologic mechanisms and therapeutic implications for these increased rates of depression
 especially at certain life stages remain largely unknown. The hormonal milieu appears to have
 an independent impact on the occurrence of depression and potentially on treatment response
 as the disparity between the sexes only emerges after the onset of puberty and persists until
 the age of 55.

 There is accumulating evidence suggesting differential antidepressant drug effects between
 men and women and recent preliminary evidence that there may be some differences in treatment
 response in women by age. Younger women with depression may be more responsive to
 serotonergic antidepressants and this may relate to changes in menstrual status and estrogen
 levels. Postmenopausal women have lower estrogen levels and may lack the enhancing effect of
 estrogen on serotonergic mechanisms and, thus, may not be able to achieve the full
 therapeutic potential of the serotonergic antidepressants.

 The reported differences in response rates between premenopausal and postmenopausal women may
 be related to the presence or absence of a menstrual cycle as well as lowered estrogen levels
 found in postmenopausal women although this hypothesis has not been formally tested. A
 prospective study is therefore proposed to primarily characterize the rates of response
 following SSRI therapy in depressed women who meet criteria for Major Depressive Disorder
 (MDD) and are treated for a current depressive episode. Menstrual status will be confirmed
 based on reproductive hormone levels. Perimenopausal and postmenopausal women will be studied
 separately because of their different hormonal profile. All women will rate their symptoms of
 depression on a daily basis and in addition, independent raters will rate depressive symptoms
 prospectively to determine the relationship between change in depressive symptoms and
 antidepressant response across the menstrual cycle. All women will be treated with citalopram
 and paroxetine will be the secondary alternative.

 Objectives

 Primary objective: To compare reduction in severity of depression in premenopausal,
 perimenopausal and postmenopausal women.

 Secondary objective: To assess the symptoms of depression and antidepressant response across
 the menstrual cycle in premenopausal women with comparisons to peri- and postmenopausal
 women.

 Exploratory objective: To examine the relationship between estrogen and SSRI level across the
 menstrual cycle.

 Hypotheses

 Primary hypothesis: The mean reduction in HRSD scores following SSRI antidepressant therapy
 will be significantly higher in premenopausal compared to peri-and postmenopausal women.

 Secondary hypotheses:

 1. Depression scores (based on HRSD and the Prospective Record of the Impact and Severity
 of Menstrual Symptoms [PRISM] calendar) will be significantly higher during the lower
 estrogen phases of the menstrual cycle than the higher estrogen phases in premenopausal
 women who remain on constant doses of citalopram.

 2. The above relationship will not be discernable in perimenopausal and postmenopausal
 women over a comparable time period and during comparable antidepressant treatment.

 Exploratory hypothesis: There will be a positive correlation between estrogen levels and SSRI
 levels.

 Significance: This study takes an innovative approach to increasing our understanding of the
 hormonal contribution to symptom severity and antidepressant treatment response. Since the
 majority of psychotropic medication is prescribed to women, understanding the interactive
 process between the menstrual cycle and antidepressant medication has the potential to change
 clinical practice by allowing for more individualized pharmacological treatment within an
 evidence based approach.
Inclusion Criteria:

 -  Women, ages 18-65 years old

 -  Fulfilling DSM-IV criteria for major depressive disorder, which is not secondary to
 another pre-existing psychiatric condition or to a medical condition

 -  Hamilton Depression Rating Scale (HAM-D-17) total score of at least 16

 -  Able and willing to give meaningful written consent

 -  28 women premenopausal (having monthly periods); 28 women perimenopausal (having
 irregular periods); and 28 women menopausal (without a period for at least one year).

 -  In good physical health.

 Exclusion Criteria:

 -  Subjects who are taking the birth control pill currently or within the last 3 months

 -  Subjects who plan to become pregnant or were pregnant within the last year

 -  Subjects who are taking hormone replacement therapy (or received it within the last
 three [3] months)

 -  Subjects who meet DSM-IV criteria for substance abuse (consume > 4 alcoholic beverages
 per day)

 -  Subjects who have tried 2 antidepressants for this episode

 -  Subjects who have additional diagnosed psychiatric conditions (i.e. anxiety, substance
 use and psychotic disorders)

 -  Subjects who have had both ovaries surgically removed.