Tibolone and Placebo in Adjunct to Antidepressant Medication for Women With Menopausal Depression

Study Overview
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Brief Summary
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Longitudinal epidemiological studies have shown that many women experience significant physical and psychological changes as they approach menopause and for a long time following. Vasomotor symptoms (such as hot flushes, night sweats), sleep disturbances and changes in libido are common, and impact significantly on the quality of life, social and personal well-being. However, the major reason that many women seek help from menopause clinics or their doctors, is for depression and anxiety symptoms. As such, treatment commonly draws on traditional approaches for the management of major depression including the use of antidepressants such as selective serotonin reuptake inhibitors (SSRIs) or Selective Norepinephrine Reuptake Inhibitors (SNRIs) as the first line response. However, standard treatment of menopausal depression using antidepressants has only shown small improvements at best and at worst, is associated with severe side effects. Some SSRIs have been shown to be less effective in postmenopausal women compared to child bearing age women. Newer therapies directly targeting the disrupted hormonal systems (in particular estrogen) through the administration of such compounds as tibolone, have shown significant potential to treat depression with the added benefit of fewer adverse side effects. With growing evidence supporting the use of tibolone as a viable and improved treatment for menopausal depression, the investigators propose to investigate the potential of tibolone, a selective Hormone Replacement Therapy (HRT), to ameliorate de-novo or first onset depression occurring in the menopausal period.

Detailed Description
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All women experience menopause and a significant number suffer from ongoing, severe depression beginning with the major hormone fluctuations in this middle stage of life. Longitudinal epidemiological studies have shown that many women experience significant physical and psychological changes as they approach menopause and for a long time following. Vasomotor symptoms (such as hot flushes, night sweats), sleep disturbances and changes in libido are common, and impact significantly on the quality of life, social and personal well-being. However, the major reason that many women seek help from menopause clinics or their doctors is for depression and anxiety symptoms. Indeed, many menopausal women with no past psychiatric history experience severe mood symptoms during menopause for the first time in their life, and this has serious and debilitating long term consequences. Treatment for such depression commonly draws on traditional approaches for the management of major depression including the use of antidepressants such as selective serotonin reuptake inhibitors (SSRIs) or selective norepinephrine reuptake inhibitors (SNRIs) as the first line response. However, standard treatment of menopausal depression using antidepressants has only shown small improvements at best and at worst, is associated with severe side effects. Some SSRIs have been shown to be less effective in postmenopausal women compared to women of child bearing age. Newer therapies directly targeting the fluctuations in reproductive hormonal hormone systems (in particular estrogen, progesterone and testosterone) through the administration of such compounds as tibolone, have shown significant potential to treat depression with the added benefit of fewer adverse side effects. With growing evidence supporting the use of tibolone as a viable and improved treatment for menopausal depression, the investigators propose to investigate the potential of tibolone, a selective Hormone Replacement Therapy (HRT), to ameliorate de-novo or relapsing depression occurring in the menopausal period. Women with menopausal depression either currently using or not using an SSRI or SNRI medication will be involved in a 12 week randomized control trial in which they may be randomised to one of two groups: i) Tibolone (2.5mg oral/day) or ii) placebo. It is hypothesized that women receiving Tibolone in adjunct to standard antidepressant medication, will have the same as or a significantly greater improvement in depressive symptoms compared with women receiving placebo in adjunct to standard antidepressant medication and women not using any psychotropic/hormone treatment.

Official Title
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Double-Blind Randomised Investigation of Tibolone Alone or in Adjunct to Standard Antidepressant Treatment for Depression in Menopausal Women

Conditions
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Menopausal Depression

Intervention / Treatment
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* Drug: Tibolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females who are currently physically well and between 45 and 65 years of age Current DSM-IV diagnosis of depression disorder Able to give informed consent Menopausal as determined by standardized classification guidelines for female reproductive aging were proposed at the Stages of Reproductive (STRAW) -Aging Workshop and symptom profile on the STRAW First-onset or relapse depression during menopause Currently taking either an SSRI or SNRI, or no psychotropic medication at all Evidence of a normal mammogram in the preceding 12 months. Exclusion Criteria: Patients with known abnormalities in the hypothalamic-pituitary gonadal axis, thyroid dysfunction, central nervous system tumours, active or past history of a venous thromboembolic event, breast pathology, undiagnosed vaginal bleeding or abnormal Pap smear results in the previous 2 years. Patients with any significant unstable medical illness such as epilepsy and diabetes or known active cardiac, renal or liver disease; or the presence of illness causing immobilisation. Patients experiencing severe melancholia, neurovegetative symptoms or current suicidality necessitating acute hospitalisation or intensive psychiatric treatment. Patients with psychotic symptoms or past history of severe mental illness including schizophrenia. Use of any form of estrogen, progestin or androgen as hormonal therapy, or antiandrogen including Tibolone or use of phytoestrogen supplements as powder or tablet Pregnancy / Lactation Smoking cigarettes or other nicotine products Illicit drug use More than 3 standard drinks per day

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tibolone<br>Subjects will take 2.5mg of oral Tibolone daily for the duration of the 12 week trial either alone or in adjunct to currently prescribed anti-depressant medication. | Drug: Tibolone<br>* Subjects will take 2.5mg of oral Tibolone daily for the duration of the 12 week trial either alone or in adjunct to currently prescribed antidepressant medication.<br>* Other names: Livial;|
| No Intervention: Placebo<br>Subjects will take oral placebo tablets packaged daily for the duration of the 12 week trial either alone or in adjunct to currently prescribed antidepressant medication. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Montgomery and Asberg Depression Rating Scale | A 10-item clinician rated scale validated to be most strongly sensitive to change in depression associated with treatment. This scale will be used to measure change in depression associated with treatment at weeks 2, 4, 8 and 12 compared to baseline. | Baseline, then at weeks 2,4, 8 and 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Beck Depression Inventory Second Edition | A subjective rating scale of depressive symptoms that compliments the MADRS to measure the change of subjective rating of depressive symptoms at week 12 compared to baseline. | Baseline and week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Menopause, Depression