Effect of the Menstrual Cycle on the Symptoms of Depression and Treatment Response
Condition: Major Depressive Disorder; Depression
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Citalopram
Intervention type(s): Drug
Intervention MeSH terms: Citalopram
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Major Depressive Disorder; Women's Mental Health; Hormones; Citalopram; Antidepressive agents; Mental Health