Vortioxetine for Menopausal Depression

Phase 4

Completed

Conditions: Menopause
Depression
Sleep
Vasomotor Disturbance
Hot Flashes

Interventions: Drug: vortioxetine

Registration Number: NCT02234362

Lead Sponsor: Massachusetts General Hospital

Brief Summary: The broad goal of this study was to examine the efficacy and tolerability of vortioxetine (flexible dose) for the treatment of major depressive disorder (MDD) in symptomatic women around the menopausal transition. We hypothesized that an eight-week treatment with vortioxetine would promote a significant improvement of depression symptoms and other menopause-related physical symptoms.

Detailed Description: Forty-seven peri- and postmenopausal women were enrolled in this open-label study. This was an 8-week intervention using open-label vortioxetine with flexible dose between 5-20 mg, dependent on participant response and tolerability. In addition to assessment of depressive symptoms, improvement of menopause-related physical and emotional symptoms that occur with MDD, including vasomotor symptoms, cognition, fatigue, anxiety, sleep complaints, and quality of life, were also examined.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 47

Inclusion Criteria

Women aged 40-62 years who are perimenopausal or early postmenopausal (within 5 years of the last menstrual period if not surgically postmenopausal), including:
1. Perimenopausal women who have experienced changes in menstrual cycle frequency or duration, and/or physical symptoms indicative of menopausal transition, as determined by clinician
2. Women who are using the Mirena Intrauterine Device (IUD), with Follicle-stimulating hormone (FSH) level > 20 milli-International unit/ml (mIU/mL)
Women meeting Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria for major depression (assessed by the Mini International Neuropsychiatric Interview - M.I.N.I.)
MADRS scores of at least 20 at baseline visit
Women with significant menopause-related physical symptoms, indicated by any of the following criteria:
1. Greene Climacteric Scale total scores > 20;
2. Greene Climacteric Scale sub-score for vasomotor symptoms >3;
3. 14 or more bothersome hot flashes per week (self-reported).
Signed informed consent.

Exclusion Criteria

Pregnancy (determined by urine pregnancy test), intending pregnancy, or breast feeding.
Women whose primary diagnosis is Panic Disorder, Obsessive Compulsive Disorder (OCD), Generalized Anxiety Disorder (GAD), Seasonal Affective Disorder (SAD), or any other Axis I pathology active within 6 months prior to screening visit (except for specific phobias). Anxiety disorders are allowable if secondary to MDD as the primary diagnosis.
History of or current mania/hypomania, psychosis, or bipolar disorder
Regular treatment with an Selective Serotonin Reuptake Inhibitor (SSRI) or Selective Norepinephrine Reuptake Inhibitors (SNRI) within 2 months prior to screening visit
Serious suicidal ideation or intent
Women who have used psychoactive or centrally acting medications within 2 weeks prior to study screening
Women who have received hormonal intervention within 1 month prior to study entry
Known hypersensitivity to vortioxetine or any of the inactive ingredients
Treatment with a monoamine oxidase inhibitor (MAOI) within 14 days of randomization or potential need to use an MAOI during the study or within 21 days of discontinuation of study drug
Treatment with linezolid or intravenous methylene blue
Patients with severe hepatic impairment
Uncontrolled hypertension (>160/90 mmHg)
Resting heart rate >110/minute
Any current severe or unstable medical illness
Not using a medically approved method of birth control, if sexually active and not 12 or more months since last menstrual period
Drug or alcohol abuse in the past 1 year
Use of any disallowed medications (specified in the Excluded Concomitant Medication section below)
Concurrent enrollment in another clinical trial

Excluded Concomitant Medications:

Selective estrogen-receptor modulators (SERMs)
Hormone replacement therapy
Hormonal contraceptives, excluding Mirena IUD
Natural menopause supplements
Episodic sleep medications (chronic, regular, stable-dose benzodiazepines are allowed)
Antidepressants
Phytoestrogens
Soy-based medications
Steroids
Anorectics, appetite depressants

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
open-label vortioxetine	vortioxetine	flexible-dose vortioxetine of 5-20 mg depending on tolerability

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Montgomery-Asberg Depression Rating Scale Score (MADRS) at Week 8 (Visit 5)	Baseline and Week 8 (Visit 5)	The efficacy of vortioxetine for trea-ting depressive symptoms was measured by mean change in Montgomery-Asberg Depression Rating Scale (MADRS) depression score from Baseline (Visit 1) to Week 8 (Visit 5). The MADRS score was assessed at every study visit (Visits 1-5). Participants were considered to have responded to vortioxetine if their MADRS score was reduced by 50% or more from baseline to the end of treatment, and to be in remission if their final MADRS score was less than 10. Higher MADRS score indicates more severe depression. The overall MADRS score ranges from 0 to 60.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Greene Climacteric Scale (GCS) Score at Week 8 (Visit 5)	Baseline and Week 8 (Visit 5)	Menopause related symptoms were assessed using the Greene Climacteric Scale (GCS). The Greene Scale provides a brief measure of menopause symptoms. It can be used to assess changes in different symptoms, before and after menopause treatment. Three main areas are measured: 1. Psychological (items 1-11). 2. Physical (items 12-18). 3. Vasomotor (items 19, 20). A higher score indicates that menopause symptoms are more bothersome. The range of scores is from 0 to 63.
Change From Baseline in Vasomotor Symptoms (VMS) Severity During Daytime at Week 8 (Visit 5)	Baseline and Week 8 (Visit 5)	Vasomotor symptoms (VMS) were tracked and quantified prospectively using a daily hot flash diary. The hot flash diary was adapted from a 7-day self-report tool for vasomotor symptoms originally developed by the North Central Cancer Treatment Group (NCCTG). The diary asks for the subject to log number of hot flashes during the day and night, severity of hot flashes during day and night, and how bothersome the hot flashes were during day and night. Severity of VMS: The range of scores for severity of VMS is 0-2, with higher scores indicating greater severity. 0=mild, 1=moderate, 2=severe
Change From Baseline in Cognitive and Physical Functioning Questionnaire (CPFQ) Score at Week 8 (Visit 5)	Baseline and Week 8 (Visit 5)	Cognition and physical functioning was measured by self-report responses to Cognitive and Physical Functioning Questionnaire (CPFQ).The range of scores is from 7-42. Higher scores indicate lower cognitive and executive functioning.
Change From Baseline in Beck Anxiety Inventory (BAI) Score at Week 8 (Visit 5)	Baseline and Week 8 (Visit 5)	Anxiety was measured by self-report responses to Beck Anxiety Inventory (BAI). It is a 21-question multiple-choice self-report inventory that is used for measuring the severity of anxiety in children and adults. Several studies have found the Beck Anxiety Inventory to be an accurate measure of anxiety symptoms in children and adults. Higher scores on the BAI indicate more anxiety symptoms. The range of BAI scores is from 0 to 63, with 0-9=Minimal anxiety, 10-16=Mild anxiety, 17-29=Moderate anxiety, and 30-63=Severe anxiety.
Change From Baseline in Clinical Global Impression-Fatigue (CGI-F) Scale Score at Week 8 (Visit 5)	Baseline and Week 8 (Visit 5)	Fatigue symptoms were assessed by the Clinical Global Impression-Fatigue (CGI-F) scale.The CGI-F is a single item global assessment scales to specifically evaluate symptoms of fatigue. Higher scores indicate more fatigue symptoms. The range of scores is from 0-7.
Change From Baseline in Vasomotor Symptoms (VMS) Frequency During Daytime at Week 8 (Visit 5)	Baseline and Week 8 (Visit 5)	Vasomotor symptoms (VMS) were tracked and quantified prospectively using a daily hot flash diary. The hot flash diary was adapted from a 7-day self-report tool for vasomotor symptoms originally developed by the North Central Cancer Treatment Group (NCCTG). The diary asks for the subject to log number of hot flashes during the day and night, severity of hot flashes during day and night, and how bothersome the hot flashes were during day and night.
Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Score at Week 8 (Visit 5)	Baseline and Week 8 (Visit 5)	Sleep quality and disturbances during the past month were assessed with the Pittsburgh Sleep Quality Index (PSQI). The PSQI also incorporates daytime functioning into the total score. In scoring the PSQI, seven component scores are derived, each scored 0 (no difficulty) to 3 (severe difficulty). The component scores are summed to produce a global score (range 0 to 21). Higher scores indicate worse sleep quality. The range of scores is 0-21.
Change From Baseline in Menopause Specific Quality of Life (MENQOL) Score at Week 8 (Visit 5)	Baseline and Week 8 (Visit 5)	Quality of life, menopause-specific, is assessed by the Menopause Specific Quality of Life (MENQOL). The MENQOL is self-administered and consists of a total of 29 items in a Likert-scale format. Each item assesses the impact of one of four domains of menopausal symptoms, as experienced over the last month: vasomotor (items 1-3), psychosocial (items 4-10), physical (items 11-26), and sexual (items 27-29). Items pertaining to a specific symptom are rated as present or not present, and if present, how bothersome on a zero (not bothersome) to six (extremely bothersome) scale. Means are computed for each subscale by dividing the sum of the domain's items by the number of items within that domain. Non-endorsement of an item is scored a "1" and endorsement a "2", plus the number of the particular rating, so that the possible score on any item ranges from 1-8. Total score also ranges from 1-8. Higher scores indicate that menopause symptoms are more bothersome.
Change From Baseline in Clinical Global Impression-Severity (CGI-S) Scale Score at Week 8 (Visit 5)	Baseline and Week 8 (Visit 5)	Severity of illness was assessed by the Clinical Global Impression-Severity (CGI-S) Scale. The CGI-S is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Considering total clinical experience, a patient is assessed on severity of mental illness at the time of rating 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill. The range of scores is 0-7. Higher scores indicate greater severity of illness.
Change From Baseline in Vasomotor Symptoms (VMS) Frequency During Nighttime at Week 8 (Visit 5)	Baseline and Week 8 (Visit 5)	Vasomotor symptoms (VMS) were tracked and quantified prospectively using a daily hot flash diary. The hot flash diary was adapted from a 7-day self-report tool for vasomotor symptoms originally developed by the North Central Cancer Treatment Group (NCCTG). The diary asks for the subject to log number of hot flashes during the day and night, severity of hot flashes during day and night, and how bothersome the hot flashes were during day and night.
Change From Baseline in Vasomotor Symptoms (VMS) Severity During Nighttime at Week 8 (Visit 5)	Baseline and Week 8 (Visit 5)	Vasomotor symptoms (VMS) were tracked and quantified prospectively using a daily hot flash diary. The hot flash diary was adapted from a 7-day self-report tool for vasomotor symptoms originally developed by the North Central Cancer Treatment Group (NCCTG). The diary asks for the subject to log number of hot flashes during the day and night, severity of hot flashes during day and night, and how bothersome the hot flashes were during day and night. Severity of VMS: The range of scores for severity of VMS is 0-2, with higher scores indicating greater severity. 0=mild, 1=moderate, 2=severe
Change From Baseline in Pain Assessment (PEG) Score at Week 8 (Visit 5)	Baseline and Week 8 (Visit 5)	Pain symptoms were assessed by the Pain Assessment (PEG). The PEG is a three-item scale assessing pain intensity and interference. A higher score indicates more pain symptoms. The range of scores is from 0 to 30.
Change From Baseline in Digit Symbol Substitution Test (DSST) Score at Week 8 (Visit 5)	Baseline and Week 8 (Visit 5)	Processing speed, working memory, visuospatial processing and attention was assessed by the Digit Symbol Substitution Test (DSST). The DSST test requires the examinee to transcribe a unique geometric symbol with its corresponding Arabic number. The examinee is initially shown a key containing the numbers from 1 to 9. Under each number there is a corresponding geometric symbol. The examinee is then shown a series of boxes containing numbers in the top boxes, and blank boxes below them. After a short practice trial, they are then asked to copy the corresponding geometric symbol under each number. The raw score is the number of correct items completed within the prescribed time limit. Higher scores indicate faster processing speed, working memory, and visuospatial processing and attention. The range of scores is 0-63.