Major Depressive Disorder
Conditions
Brief summary
The primary objective of this study was to assess the maintenance of efficacy of LY2216684 compared with placebo as adjunctive therapy to selective serotonin reuptake inhibitors (SSRIs) as measured by the time-to-symptom reemergence among participants with major depressive disorder (MDD) who met randomization criteria with adjunctive LY2216684 during the stabilization period. This trial consists of two distinct periods: an open-label treatment period, which consists of two parts, 8 weeks acute open-label with movement to 12 weeks open-label stabilization if participants are in remission at end of 8 weeks (open-label for 20 weeks total) followed by a randomized, double-blind, placebo-controlled period for 24 weeks.
Detailed description
In order to enter the Stabilization Open-label Period, participants must have met remission criteria, defined as a Montgomery-Asberg Depression Rating Scale (MADRS) total score ≤10 at Week 8. In order to enter the Double-blind Randomization Withdrawal Period, participants must have met randomization criteria, defined as a MADRS total score ≤10 at Weeks 18, 19, and 20.
Interventions
DRUGLY2216684
DRUGPlacebo
DRUGSSRI
Participants should have been on their SSRI for at least 8 weeks prior and were to continue on their stable dose throughout the study.
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Outpatients with clinical diagnosis of Major Depressive Disorder (MDD) * Using a reliable method of birth control * Are taking a selective serotonin reuptake inhibitor (SSRI) approved for MDD treatment within the participant's country and the SSRI prescribed, including dose, should be consistent with labeling guidelines within the participating country * Have a partial response to SSRI treatment * Meet inclusion scores on pre-defined psychiatric scales to assess diagnosis of depression, disease severity, and response to SSRI treatment * Reliable and able to keep all scheduled appointments * Have had at least 1 previous episode of MDD prior to the current episode within the past 5 years
Exclusion criteria
* Have had or currently have any additional ongoing Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) Axis 1 condition other than major depression within 1 year of screening * Have a current or any previous diagnosis of a bipolar disorder, schizophrenia, or other psychotic disorder * Have a history of substance abuse and/or dependence within the past 1 year (drug categories defined by DSM-IV-TR), not including caffeine and nicotine. * Have a DSM-IV-TR Axis II disorder that, in the judgment of the investigator, would interfere with compliance with protocol * Have any diagnosed medical condition which could be exacerbated by noradrenergic agents, including unstable hypertension, unstable heart disease, tachycardia, tachyarrhythmia, narrow-angle glaucoma, or history of urinary hesitation or retention * Have initiated or discontinued hormone therapy (including birth control or thyroid hormone) within the previous 3 months prior to enrollment * Have a lifetime history of vagal nerve stimulation (VNS), transcranial magnetic stimulation (TMS), or psychosurgery * Have received electroconvulsive therapy (ECT) in the past year * Have a serious or unstable medical condition * Have a history of seizure disorders * Have initiated psychotherapy, change in intensity of psychotherapy or other nondrug therapies (such as acupuncture or hypnosis) within 6 weeks prior to enrollment or any time during the study * Participants who, in the opinion of the investigator, are judged to be at serious risk for harm to self or others * Are pregnant or breastfeeding * Meet criteria for treatment-resistant depression
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Meet Criteria for Re-emergence of Depressive Symptoms Estimated by Kaplan-Meier Product Limit Method (Double-blind Randomized Withdrawal Period) | Randomization up to 44 weeks | Participants meeting any of the following criteria were determined as having major depressive disorder symptom re-emergence: 1) a Montgomery-Asberg Depression Rating Scale (MADRS) total score greater ≥14 or a Clinical Global Impressions of Severity (CGI-S) increase of 2 or more points from Week 18 at 2 consecutive visits or 2) discontinuation due to lack of efficacy/worsening of depression/suicidality. Time from randomization to the first visit at which the participant met the reemergence criteria was calculated. The percentage of participants who meet criteria was estimated using the Kaplan-Meier product limit method. The MADRS is a rating scale for severity of depressive mood symptoms and has a 10-item checklist with items rated on a scale of 0-6, for a total score range of 0 (low severity) to 60 (high severity). CGI-S measures severity of depression at the time of assessment compared with the start of treatment. Scores range from 1 (normal, not at all ill) to 7 (extremely ill). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Randomization, Week 44 | Montgomery-Asberg Depression Rating Scale (MADRS) is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist (sadness \[apparent\], sadness \[reported\], inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis which includes terms for the fixed categorical effects of treatment, country, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline MADRS total score (individual item score) and baseline MADRS total score (individual item score)-by-visit interaction. |
| Change From Randomization in the Hospital Anxiety and Depression Scale (HADS) Depression and Anxiety Subscale Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Randomization, Week 44 | The Hospital Anxiety and Depression Scale (HADS) is a 14-item questionnaire with 2 subscales: anxiety and depression. Each item is rated on a 4-point scale (0-3), giving maximum scores of 21 for anxiety and depression. Scores of 11 or more on either subscale are considered to be a 'significant' case of psychological morbidity, while scores of 8-10 represent 'borderline' and 0-7 represent 'normal'. Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis which included terms for the fixed categorical effects of treatment, country, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline subscale score and baseline subscale score-by-visit interaction. |
| Change From Randomization in the Clinical Global Impression of Severity (CGI-S) Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Randomization, Week 44 | The Clinical Global Impression of Severity (CGI-S) instrument is used to record the severity of mental illness at the time of assessment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis which included terms for the fixed categorical effects of treatment, country, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline CGI-S score and baseline CGI-S score-by-visit interaction. |
| Change From Randomization in the Fatigue Associated With Depression (FAsD) Average Score, Experience Subscale Score, and Impact Subscale Score at Week 44 (Double-blind Randomized Withdrawal Period) | Randomization, Week 44 | The FAsD is a 13-item participant-rated scale. Items 1-6 ask how often participants experience different aspects of fatigue with responses from 1 (never) to 5 (always). Items 7-13 ask how often fatigue impacts various aspects of the participant's lives with responses from 1 (not at all) to 5 (very much). The experience subscale score is derived by taking the mean of Items 1-6. The impact subscale score is derived by taking the mean of applicable Items 7-13. The average score is the mean of applicable Items 1-13. Item 12 applies only to participants with a spouse or significant other and Item 13 applies to participants who had a job or who went to school. Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis which included terms for the fixed categorical effects of treatment, country, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline score and baseline score-by-visit interaction. |
| Change From Randomization in the Sheehan Disability Scale (SDS) Items at Week 44 (Double-blind Randomized Withdrawal Period) | Randomization, Week 44 | The Sheehan Disability Scale (SDS) is completed by the participant and used to assess the effect of the participant's symptoms on their work (work/school impairment score), social life (social life/leisure activities impairment score), and family life (family life/home responsibilities impairment score). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis which included terms for the fixed categorical effects of treatment, country, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline score and baseline score-by-visit interaction |
| Change From Randomization in the EuroQol Questionnaire-5 Dimension (EQ-5D) Index Scores, Visual Analog Scale up to Week 44 (Double-blind Randomized Withdrawal Period) | Randomization, up to Week 44 | The EQ-5D, a health-related, quality-of-life instrument, contains 2 parts: a health status profile and a visual analog scale (VAS). The profile allows participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and mood using a 3-level scale (no problem, some problems, and major problems). These dimensions are converted into weighted health-state index scores according to United States (US) and United Kingdom (UK) population-based algorithms. The US and UK based index scores range from -0.11 to 1.0 (where a score of 1.0 indicates perfect health) and from -0.59 (severe problems in all 5 dimensions) to 1.0 (no problem in any dimension), respectively. The VAS consists of participants rating their current health state from 0 (worst imaginable health state) to 100 (best imaginable health). Least Squares (LS) means were calculated using analysis of covariance (ANCOVA) model with main effects of treatment, country, and baseline score. |
| Number of Participants With Treatment-emergent Suicidal Ideation and Behaviors Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) (Double-blind Randomized Withdrawal Period) | Randomization through Week 44 | The Columbia-Suicide Severity Rating Scale (C-SSRS) captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal ideation is defined as a yes answer to any 1 of 5 suicidal ideation questions, which includes a wish to be dead and 4 different categories of active suicidal ideation. Suicidal behavior is defined as a yes answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation and behavior are defined as treatment-emergent (TE) if not present during the period up through randomization. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Event module. |
| Change From Randomization in the Arizona Sexual Experiences (ASEX) Questionnaire at Week 44 (Double-blind Randomized Withdrawal Period) | Randomization, Week 44 | Arizona Sexual Experiences (ASEX) Questionnaire is a 5-item rating scale that quantifies sex drive, arousal, vaginal lubrication/penile erection, ability to reach orgasm, and satisfaction from orgasm. Each item is rated from 1 (extremely) to 6 (no/never). Possible total scores ranged from 5 to 30, with the higher scores indicating more sexual dysfunction. Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis which included terms for the fixed categorical effects of treatment, country, visit, treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline ASEX total score and baseline ASEX total score-by-visit interaction. |
| Change From Randomization in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) Total Score at Week 44 (Double-blind Randomized Withdrawal Period) | Randomization, Week 44 | Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) is a 7-item participant-rated questionnaire pertaining to a participant's cognitive and physical well-being. It assesses motivation, wakefulness, energy, focus, recall, word-finding difficulty, and mental acuity. Each item is scored on a 6-point scale ranging from 1 (greater than normal) to 6 (totally absent). Total score is reported and ranges from 7 to 42, with higher scores indicating greater impairment. Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis which included terms for the fixed categorical effects of treatment, country, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline CPFQ total score and baseline CPFQ total score-by-visit interaction. |
| Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 8 (Acute Open-label Period) | Baseline, up to Week 8 | Montgomery-Asberg Depression Rating Scale (MADRS) is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist (sadness \[apparent\], sadness \[reported\], inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). |
| Change From Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 20 (Stabilization Open-label Period) | Week 8, up to Week 20 | Montgomery-Asberg Depression Rating Scale (MADRS) is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist (sadness \[apparent\], sadness \[reported\], inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). |
| Change From Baseline in the Hospital Anxiety and Depression Scale (HADS) Depression and Anxiety Subscale Scores up to Week 8 (Acute Open-label Period) | Baseline, up to Week 8 | The Hospital Anxiety and Depression Scale (HADS) is a 14-item questionnaire with 2 subscales: anxiety and depression. Each item is rated on a 4-point scale (0-3), giving maximum scores of 21 for anxiety and depression. Scores of 11 or more on either subscale were considered to be a 'significant' case of psychological morbidity, while scores of 8-10 represent 'borderline' and 0-7 represent 'normal'. |
| Change From Week 8 in the Hospital Anxiety and Depression Scale (HADS) Depression and Anxiety Subscale Scores up to Week 20 (Stabilization Open-label Period) | Week 8, up to Week 20 | The Hospital Anxiety and Depression Scale (HADS) is a 14-item questionnaire with 2 subscales: anxiety and depression. Each item is rated on a 4-point scale (0-3), giving maximum scores of 21 for anxiety and depression. Scores of 11 or more on either subscale are considered to be a 'significant' case of psychological morbidity, while scores of 8-10 represent 'borderline' and 0-7 represent 'normal'. |
| Percentage of Participants With Re-emergence of Depressive Symptoms (Double-blind Randomized Withdrawal Period) | Week 44 | Participants meeting any of the following criteria were determined as having major depressive disorder symptom re-emergence: 1) a Montgomery-Asberg Depression Rating Scale (MADRS) total score greater ≥14 or a Clinical Global Impressions of Severity (CGI-S) increase of 2 or more points from Week 18 at 2 consecutive visits or 2) discontinuation due to lack of efficacy/worsening of depression/suicidality. The percentage of participants with re-emergence of depressive symptoms was calculated by dividing the number of participants who meet any of the criteria by the total number of participants analyzed, multiplied by 100. The MADRS is a rating scale for severity of depressive mood symptoms and has a 10-item checklist with items rated on a scale of 0-6, for a total score range of 0 (low severity) to 60 (high severity). CGI-S measures severity of depression at the time of assessment compared with the start of treatment. Scores range from 1 (normal, not at all ill) to 7 (extremely ill). |
| Change From Week 8 in the Clinical Global Impression of Severity (CGI-S) Scores up to Week 20 (Stabilization Open-label Period) | Week 8, up to Week 20 | The Clinical Global Impression of Severity (CGI-S) instrument is used to record the severity of mental illness at the time of assessment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). |
| Change From Baseline in the Fatigue Associated With Depression (FAsD) Average Score, Experience Subscale Score, and Impact Subscale Score up to Week 8 (Acute Open-label Period) | Baseline, up to Week 8 | The Fatigue Associated With Depression (FAsD) is a 13-item participant-rated scale. Items 1-6 ask how often participants experience different aspects of fatigue with responses from 1 (never) to 5 (always). Items 7-13 ask how often fatigue impacts various aspects of the participant's lives with responses from 1 (not at all) to 5 (very much). The experience subscale score is derived by taking the mean of Items 1-6. The impact subscale score is derived by taking the mean of applicable Items 7-13. The average score is the mean of applicable Items 1-13. Item 12 applies only to participants with a spouse or significant other and Item 13 applies to participants who had a job or who went to school. |
| Change From Week 8 in the Fatigue Associated With Depression (FAsD) Average Score, Experience Subscale Score, and Impact Subscale Score up to Week 20 (Stabilization Open-label Period) | Week 8, up to Week 20 | The Fatigue Associated with Depression (FAsD) is a 13-item participant-rated scale. Items 1-6 ask how often participants experience different aspects of fatigue with responses from 1 (never) to 5 (always). Items 7-13 ask how often fatigue impacts various aspects of the participant's lives with responses from 1 (not at all) to 5 (very much). The experience subscale score is derived by taking the mean of Items 1-6. The impact subscale score is derived by taking the mean of applicable Items 7-13. The average score is the mean of applicable Items 1-13. Item 12 applies only to participants with a spouse or significant other and Item 13 applies to participants who had a job or who went to school. |
| Change From Baseline in the Sheehan Disability Scale (SDS) Items up to Week 8 (Acute Open-label Period) | Baseline, up to Week 8 | The Sheehan Disability Scale (SDS) is completed by the participant and used to assess the effect of the participant's symptoms on their work (work/school impairment score), social life (social life/leisure activities impairment score), and family life (family life/home responsibilities impairment score). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. |
| Change From Week 8 in the Sheehan Disability Scale (SDS) Items up to Week 20 (Stabilization Open-label Period) | Week 8, up to Week 20 | The Sheehan Disability Scale (SDS) is completed by the participant and used to assess the effect of the participant's symptoms on their work (work/school impairment score), social life (social life/leisure activities impairment score), and family life (family life/home responsibilities impairment score). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. |
| Change From Baseline in the EuroQol Questionnaire-5 Dimension (EQ-5D) Index Scores, Visual Analog Scale up to Week 20 (Open-label Period) | Baseline, up to Week 20 | The EQ-5D, a health-related, quality-of-life instrument, contains 2 parts: a health status profile and a visual analog scale (VAS). The profile allows participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and mood using a 3-level scale (no problem, some problems, and major problems). These dimensions are converted into weighted health-state index scores according to United States (US) and United Kingdom (UK) population-based algorithms. The US and UK based index scores range from -0.11 to 1.0 (where a score of 1.0 indicates perfect health) and from -0.59 (severe problems in all 5 dimensions) to 1.0 (no problem in any dimension), respectively. The VAS consists of participants rating their current health state from 0 (worst imaginable health state) to 100 (best imaginable health). |
| Number of Participants With Treatment-emergent Suicidal Ideation and Behaviors Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) (Open-label Period) | Baseline through Week 20 | The Columbia-Suicide Severity Rating Scale (C-SSRS) captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal ideation is defined as a yes answer to any 1 of 5 suicidal ideation questions, which included a wish to be dead and 4 different categories of active suicidal ideation. Suicidal behavior is defined as a yes answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation and behavior are defined as treatment-emergent (TE) if not present at baseline. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Event module. |
| Change From Baseline in the Arizona Sexual Experiences (ASEX) Questionnaire up to Week 20 (Open-label Period) | Baseline, up to Week 20 | Arizona Sexual Experiences (ASEX) Questionnaire is a 5-item rating scale that quantifies sex drive, arousal, vaginal lubrication/penile erection, ability to reach orgasm, and satisfaction from orgasm. Each item is rated from 1 (extremely) to 6 (no/never). Possible total scores ranged from 5 to 30, with the higher scores indicating more sexual dysfunction. |
| Change From Baseline in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) Total Score at Week 20 (Open-label Period) | Baseline, up to Week 20 | Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) is a 7-item participant-rated questionnaire pertaining to a participant's cognitive and physical well-being. It assesses motivation, wakefulness, energy, focus, recall, word-finding difficulty, and mental acuity. Each item is scored on a 6-point scale ranging from 1 (greater than normal) to 6 (totally absent). Total score is reported and ranges from 7 to 42, with higher scores indicating greater impairment. |
| Change From Randomization in Blood Pressure at Week 44 (Double-blind Randomized Withdrawal Period) | Randomization, Week 44 | Blood pressure measurements were taken 3 times at each visit in a sitting position. The average of the 3 values was used for analysis. Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis which included terms for the fixed categorical effects of treatment, country, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline and baseline-by-visit interaction. |
| Change From Baseline in Blood Pressure up to Week 20 (Open-label Period) | Baseline, up to Week 20 | Blood pressure measurements were taken 3 times at each visit in a sitting position. The average of the 3 values was used for analysis. |
| Change From Randomization in Pulse Rate at Week 44 (Double-blind Randomized Withdrawal Period) | Randomization, Week 44 | Pulse rate measurements were collected when the participant was in a sitting position. Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis which included terms for the fixed categorical effects of treatment, country, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline and baseline-by-visit interaction. |
| Change From Baseline in Pulse Rate up to Week 20 (Open-label Period) | Baseline, up to Week 20 | Pulse measurements were collected when the participant was in a sitting position. |
| Change From Baseline in the Clinical Global Impression of Severity (CGI-S) Scores up to Week 8 (Acute Open-label Period) | Baseline, up to Week 8 | The Clinical Global Impression of Severity (CGI-S) instrument is used to record the severity of mental illness at the time of assessment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). |
Countries
Argentina, Belgium, Croatia, France, Germany, Greece, Italy, Mexico, Puerto Rico, Romania, Russia, Slovakia, South Korea, Spain, Turkey (Türkiye), United States
Participant flow
Pre-assignment details
All enrolled participants entered the Acute Open-label (OL) Period. At Week 8, if remission criteria were met, participants entered the Stabilization OL Period. At Week 20, if randomization criteria were met, participants entered the 24-week Double-blind Randomized Withdrawal Period. Those who discontinued early entered the Discontinuation Period.
Participants by arm
| Arm | Count |
|---|---|
| All Enrolled Participants All enrolled participants started on a flexible dose of 12 or 18 milligrams (mg) LY2216684, administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI). At 8 weeks, participants meeting remission criteria continued on the same, stable dose of LY2216684 and SSRI, orally, QD, for an additional 12 weeks. At 20 weeks, participants meeting criteria for randomization either 1) continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks or 2) were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks. | 1,249 |
| Total | 1,249 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Acute Open-label (OL) Period | Adverse Event | 140 | 0 | 0 | 0 |
| Acute Open-label (OL) Period | Lack of Efficacy | 10 | 0 | 0 | 0 |
| Acute Open-label (OL) Period | Lost to Follow-up | 14 | 0 | 0 | 0 |
| Acute Open-label (OL) Period | Physician Decision | 5 | 0 | 0 | 0 |
| Acute Open-label (OL) Period | Protocol Violation | 36 | 0 | 0 | 0 |
| Acute Open-label (OL) Period | Remission Criteria Not Met | 140 | 0 | 0 | 0 |
| Acute Open-label (OL) Period | Sponsor Decision | 13 | 0 | 0 | 0 |
| Acute Open-label (OL) Period | Withdrawal by Subject | 56 | 0 | 0 | 0 |
| Double-blind (DB) Randomized Period | Adverse Event | 0 | 0 | 8 | 9 |
| Double-blind (DB) Randomized Period | Lack of Efficacy | 0 | 0 | 20 | 10 |
| Double-blind (DB) Randomized Period | Lost to Follow-up | 0 | 0 | 5 | 5 |
| Double-blind (DB) Randomized Period | Physician Decision | 0 | 0 | 2 | 1 |
| Double-blind (DB) Randomized Period | Protocol Violation | 0 | 0 | 8 | 7 |
| Double-blind (DB) Randomized Period | Reemergence of Study Condition Symptoms | 0 | 0 | 4 | 10 |
| Double-blind (DB) Randomized Period | Sponsor Decision | 0 | 0 | 1 | 1 |
| Double-blind (DB) Randomized Period | Withdrawal by Subject | 0 | 0 | 22 | 15 |
| Stabilization Open-label (OL) Period | Adverse Event | 0 | 42 | 0 | 0 |
| Stabilization Open-label (OL) Period | Lack of Efficacy | 0 | 11 | 0 | 0 |
| Stabilization Open-label (OL) Period | Lost to Follow-up | 0 | 9 | 0 | 0 |
| Stabilization Open-label (OL) Period | Physician Decision | 0 | 3 | 0 | 0 |
| Stabilization Open-label (OL) Period | Protocol Violation | 0 | 44 | 0 | 0 |
| Stabilization Open-label (OL) Period | Randomization Criteria Not Met | 0 | 80 | 0 | 0 |
| Stabilization Open-label (OL) Period | Reemergence of Study Condition Symptoms | 0 | 6 | 0 | 0 |
| Stabilization Open-label (OL) Period | Sponsor Decision | 0 | 12 | 0 | 0 |
| Stabilization Open-label (OL) Period | Withdrawal by Subject | 0 | 42 | 0 | 0 |
Baseline characteristics
| Characteristic | All Enrolled Participants |
|---|---|
| Age, Continuous | 47.4 years STANDARD_DEVIATION 12.54 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 254 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 622 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 373 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 50 Participants |
| Race (NIH/OMB) Asian | 21 Participants |
| Race (NIH/OMB) Black or African American | 99 Participants |
| Race (NIH/OMB) More than one race | 13 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1066 Participants |
| Region of Enrollment Argentina | 62 Participants |
| Region of Enrollment Belgium | 11 Participants |
| Region of Enrollment Croatia | 9 Participants |
| Region of Enrollment France | 61 Participants |
| Region of Enrollment Germany | 73 Participants |
| Region of Enrollment Greece | 43 Participants |
| Region of Enrollment Italy | 44 Participants |
| Region of Enrollment Mexico | 63 Participants |
| Region of Enrollment Puerto Rico | 77 Participants |
| Region of Enrollment Romania | 19 Participants |
| Region of Enrollment Russia | 96 Participants |
| Region of Enrollment Slovakia | 65 Participants |
| Region of Enrollment South Korea | 18 Participants |
| Region of Enrollment Spain | 43 Participants |
| Region of Enrollment Turkey | 30 Participants |
| Region of Enrollment United States | 535 Participants |
| Sex: Female, Male Female | 917 Participants |
| Sex: Female, Male Male | 332 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 505 / 1,244 | 112 / 831 | 37 / 294 | 21 / 292 | 9 / 128 | 4 / 132 | 16 / 267 | 32 / 434 |
| serious Total, serious adverse events | 19 / 1,244 | 15 / 831 | 2 / 294 | 6 / 292 | 2 / 128 | 0 / 132 | 2 / 267 | 8 / 434 |
Outcome results
Primary
Percentage of Participants Who Meet Criteria for Re-emergence of Depressive Symptoms Estimated by Kaplan-Meier Product Limit Method (Double-blind Randomized Withdrawal Period)
Participants meeting any of the following criteria were determined as having major depressive disorder symptom re-emergence: 1) a Montgomery-Asberg Depression Rating Scale (MADRS) total score greater ≥14 or a Clinical Global Impressions of Severity (CGI-S) increase of 2 or more points from Week 18 at 2 consecutive visits or 2) discontinuation due to lack of efficacy/worsening of depression/suicidality. Time from randomization to the first visit at which the participant met the reemergence criteria was calculated. The percentage of participants who meet criteria was estimated using the Kaplan-Meier product limit method. The MADRS is a rating scale for severity of depressive mood symptoms and has a 10-item checklist with items rated on a scale of 0-6, for a total score range of 0 (low severity) to 60 (high severity). CGI-S measures severity of depression at the time of assessment compared with the start of treatment. Scores range from 1 (normal, not at all ill) to 7 (extremely ill).
Time frame: Randomization up to 44 weeks
Population: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2216684 + SSRI | Percentage of Participants Who Meet Criteria for Re-emergence of Depressive Symptoms Estimated by Kaplan-Meier Product Limit Method (Double-blind Randomized Withdrawal Period) | 10.43 percentage of participants |
| Placebo + SSRI | Percentage of Participants Who Meet Criteria for Re-emergence of Depressive Symptoms Estimated by Kaplan-Meier Product Limit Method (Double-blind Randomized Withdrawal Period) | 8.24 percentage of participants |
p-value: 0.485Log Rank
Secondary
Change From Baseline in Blood Pressure up to Week 20 (Open-label Period)
Blood pressure measurements were taken 3 times at each visit in a sitting position. The average of the 3 values was used for analysis.
Time frame: Baseline, up to Week 20
Population: All participants who have non-missing values at baseline and at least one post-baseline value. Last observation carried forward (LOCF) methodology was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline in Blood Pressure up to Week 20 (Open-label Period) | Systolic blood pressure | 2.30 millimeters of mercury (mmHg) | Standard Deviation 11.95 |
| LY2216684 + SSRI | Change From Baseline in Blood Pressure up to Week 20 (Open-label Period) | Diastolic blood pressure | 2.81 millimeters of mercury (mmHg) | Standard Deviation 8.63 |
Secondary
Change From Baseline in Pulse Rate up to Week 20 (Open-label Period)
Pulse measurements were collected when the participant was in a sitting position.
Time frame: Baseline, up to Week 20
Population: All participants who have non-missing values at baseline and at least one post-baseline value. Last observation carried forward (LOCF) methodology was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline in Pulse Rate up to Week 20 (Open-label Period) | 10.80 beats per minute (bpm) | Standard Deviation 12.47 |
Secondary
Change From Baseline in the Arizona Sexual Experiences (ASEX) Questionnaire up to Week 20 (Open-label Period)
Arizona Sexual Experiences (ASEX) Questionnaire is a 5-item rating scale that quantifies sex drive, arousal, vaginal lubrication/penile erection, ability to reach orgasm, and satisfaction from orgasm. Each item is rated from 1 (extremely) to 6 (no/never). Possible total scores ranged from 5 to 30, with the higher scores indicating more sexual dysfunction.
Time frame: Baseline, up to Week 20
Population: All participants who have non-missing values at baseline and at least one post-baseline value. Last observation carried forward (LOCF) methodology was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline in the Arizona Sexual Experiences (ASEX) Questionnaire up to Week 20 (Open-label Period) | -1.78 units on a scale | Standard Deviation 4.98 |
Secondary
Change From Baseline in the Clinical Global Impression of Severity (CGI-S) Scores up to Week 8 (Acute Open-label Period)
The Clinical Global Impression of Severity (CGI-S) instrument is used to record the severity of mental illness at the time of assessment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants).
Time frame: Baseline, up to Week 8
Population: All participants who have non-missing values at baseline and at least one post-baseline value. Last observation carried forward (LOCF) methodology was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline in the Clinical Global Impression of Severity (CGI-S) Scores up to Week 8 (Acute Open-label Period) | -1.51 units on a scale | Standard Deviation 1.17 |
Secondary
Change From Baseline in the EuroQol Questionnaire-5 Dimension (EQ-5D) Index Scores, Visual Analog Scale up to Week 20 (Open-label Period)
The EQ-5D, a health-related, quality-of-life instrument, contains 2 parts: a health status profile and a visual analog scale (VAS). The profile allows participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and mood using a 3-level scale (no problem, some problems, and major problems). These dimensions are converted into weighted health-state index scores according to United States (US) and United Kingdom (UK) population-based algorithms. The US and UK based index scores range from -0.11 to 1.0 (where a score of 1.0 indicates perfect health) and from -0.59 (severe problems in all 5 dimensions) to 1.0 (no problem in any dimension), respectively. The VAS consists of participants rating their current health state from 0 (worst imaginable health state) to 100 (best imaginable health).
Time frame: Baseline, up to Week 20
Population: All participants who have non-missing values at baseline and at least one post-baseline value. Last observation carried forward (LOCF) methodology was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline in the EuroQol Questionnaire-5 Dimension (EQ-5D) Index Scores, Visual Analog Scale up to Week 20 (Open-label Period) | EQ-5D US | 0.15 units on a scale | Standard Deviation 0.19 |
| LY2216684 + SSRI | Change From Baseline in the EuroQol Questionnaire-5 Dimension (EQ-5D) Index Scores, Visual Analog Scale up to Week 20 (Open-label Period) | EQ-5D UK | 0.21 units on a scale | Standard Deviation 0.29 |
| LY2216684 + SSRI | Change From Baseline in the EuroQol Questionnaire-5 Dimension (EQ-5D) Index Scores, Visual Analog Scale up to Week 20 (Open-label Period) | VAS | 18.07 units on a scale | Standard Deviation 22.15 |
Secondary
Change From Baseline in the Fatigue Associated With Depression (FAsD) Average Score, Experience Subscale Score, and Impact Subscale Score up to Week 8 (Acute Open-label Period)
The Fatigue Associated With Depression (FAsD) is a 13-item participant-rated scale. Items 1-6 ask how often participants experience different aspects of fatigue with responses from 1 (never) to 5 (always). Items 7-13 ask how often fatigue impacts various aspects of the participant's lives with responses from 1 (not at all) to 5 (very much). The experience subscale score is derived by taking the mean of Items 1-6. The impact subscale score is derived by taking the mean of applicable Items 7-13. The average score is the mean of applicable Items 1-13. Item 12 applies only to participants with a spouse or significant other and Item 13 applies to participants who had a job or who went to school.
Time frame: Baseline, up to Week 8
Population: All participants who have non-missing values at baseline and at least one post-baseline value. Last observation carried forward (LOCF) methodology was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline in the Fatigue Associated With Depression (FAsD) Average Score, Experience Subscale Score, and Impact Subscale Score up to Week 8 (Acute Open-label Period) | FAsD Experience Subscale Score | -0.82 units on a scale | Standard Deviation 0.99 |
| LY2216684 + SSRI | Change From Baseline in the Fatigue Associated With Depression (FAsD) Average Score, Experience Subscale Score, and Impact Subscale Score up to Week 8 (Acute Open-label Period) | FAsD Impact Subscale Score | -0.88 units on a scale | Standard Deviation 1.03 |
| LY2216684 + SSRI | Change From Baseline in the Fatigue Associated With Depression (FAsD) Average Score, Experience Subscale Score, and Impact Subscale Score up to Week 8 (Acute Open-label Period) | FAsD Average Score | -0.85 units on a scale | Standard Deviation 0.93 |
Secondary
Change From Baseline in the Hospital Anxiety and Depression Scale (HADS) Depression and Anxiety Subscale Scores up to Week 8 (Acute Open-label Period)
The Hospital Anxiety and Depression Scale (HADS) is a 14-item questionnaire with 2 subscales: anxiety and depression. Each item is rated on a 4-point scale (0-3), giving maximum scores of 21 for anxiety and depression. Scores of 11 or more on either subscale were considered to be a 'significant' case of psychological morbidity, while scores of 8-10 represent 'borderline' and 0-7 represent 'normal'.
Time frame: Baseline, up to Week 8
Population: All participants who have non-missing values at baseline and at least one post-baseline value. Last observation carried forward (LOCF) methodology was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline in the Hospital Anxiety and Depression Scale (HADS) Depression and Anxiety Subscale Scores up to Week 8 (Acute Open-label Period) | HADS Anxiety Subscale Score | -3.02 units on a scale | Standard Deviation 3.92 |
| LY2216684 + SSRI | Change From Baseline in the Hospital Anxiety and Depression Scale (HADS) Depression and Anxiety Subscale Scores up to Week 8 (Acute Open-label Period) | HADS Depression Subscale Score | -3.98 units on a scale | Standard Deviation 4.41 |
Secondary
Change From Baseline in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) Total Score at Week 20 (Open-label Period)
Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) is a 7-item participant-rated questionnaire pertaining to a participant's cognitive and physical well-being. It assesses motivation, wakefulness, energy, focus, recall, word-finding difficulty, and mental acuity. Each item is scored on a 6-point scale ranging from 1 (greater than normal) to 6 (totally absent). Total score is reported and ranges from 7 to 42, with higher scores indicating greater impairment.
Time frame: Baseline, up to Week 20
Population: All participants who have non-missing values at baseline and at least one post-baseline value. Last observation carried forward (LOCF) methodology was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) Total Score at Week 20 (Open-label Period) | -6.68 units on a scale | Standard Deviation 7.03 |
Secondary
Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 8 (Acute Open-label Period)
Montgomery-Asberg Depression Rating Scale (MADRS) is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist (sadness \[apparent\], sadness \[reported\], inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms).
Time frame: Baseline, up to Week 8
Population: All participants who have non-missing values at baseline and at least one post-baseline value. Last observation carried forward (LOCF) methodology was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 8 (Acute Open-label Period) | MADRS Total Score | -13.21 units on a scale | Standard Deviation 8.3 |
| LY2216684 + SSRI | Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 8 (Acute Open-label Period) | Item 1: Apparent Sadness | -1.82 units on a scale | Standard Deviation 1.37 |
| LY2216684 + SSRI | Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 8 (Acute Open-label Period) | Item 2: Reported Sadness | -1.86 units on a scale | Standard Deviation 1.39 |
| LY2216684 + SSRI | Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 8 (Acute Open-label Period) | Item 3: Inner Tension | -1.24 units on a scale | Standard Deviation 1.37 |
| LY2216684 + SSRI | Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 8 (Acute Open-label Period) | Item 4: Reduced Sleep | -1.29 units on a scale | Standard Deviation 1.57 |
| LY2216684 + SSRI | Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 8 (Acute Open-label Period) | Item 5: Reduced Appetite | -0.65 units on a scale | Standard Deviation 1.47 |
| LY2216684 + SSRI | Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 8 (Acute Open-label Period) | Item 6: Concentration Difficulties | -1.49 units on a scale | Standard Deviation 1.43 |
| LY2216684 + SSRI | Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 8 (Acute Open-label Period) | Item 7: Lassitude | -1.74 units on a scale | Standard Deviation 1.44 |
| LY2216684 + SSRI | Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 8 (Acute Open-label Period) | Item 8: Inability to Feel | -1.65 units on a scale | Standard Deviation 1.42 |
| LY2216684 + SSRI | Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 8 (Acute Open-label Period) | Item 9: Pessimistic Thoughts | -1.23 units on a scale | Standard Deviation 1.28 |
| LY2216684 + SSRI | Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 8 (Acute Open-label Period) | Item 10: Suicidal Thoughts | -0.24 units on a scale | Standard Deviation 0.7 |
Secondary
Change From Baseline in the Sheehan Disability Scale (SDS) Items up to Week 8 (Acute Open-label Period)
The Sheehan Disability Scale (SDS) is completed by the participant and used to assess the effect of the participant's symptoms on their work (work/school impairment score), social life (social life/leisure activities impairment score), and family life (family life/home responsibilities impairment score). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption.
Time frame: Baseline, up to Week 8
Population: All participants who have non-missing values at baseline and at least one post-baseline value. Last observation carried forward (LOCF) methodology was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 + SSRI | Change From Baseline in the Sheehan Disability Scale (SDS) Items up to Week 8 (Acute Open-label Period) | Work Impairment Score | -2.17 units on a scale | Standard Deviation 2.65 |
| LY2216684 + SSRI | Change From Baseline in the Sheehan Disability Scale (SDS) Items up to Week 8 (Acute Open-label Period) | Social Life Impairment Score | -2.38 units on a scale | Standard Deviation 2.85 |
| LY2216684 + SSRI | Change From Baseline in the Sheehan Disability Scale (SDS) Items up to Week 8 (Acute Open-label Period) | Family Life Impairment Score | -2.16 units on a scale | Standard Deviation 2.81 |
Secondary
Change From Randomization in Blood Pressure at Week 44 (Double-blind Randomized Withdrawal Period)
Blood pressure measurements were taken 3 times at each visit in a sitting position. The average of the 3 values was used for analysis. Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis which included terms for the fixed categorical effects of treatment, country, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline and baseline-by-visit interaction.
Time frame: Randomization, Week 44
Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 + SSRI | Change From Randomization in Blood Pressure at Week 44 (Double-blind Randomized Withdrawal Period) | Systolic blood pressure | -0.20 millimeters of mercury (mmHg) | Standard Error 0.75 |
| LY2216684 + SSRI | Change From Randomization in Blood Pressure at Week 44 (Double-blind Randomized Withdrawal Period) | Diastolic blood pressure | 0.24 millimeters of mercury (mmHg) | Standard Error 0.55 |
| Placebo + SSRI | Change From Randomization in Blood Pressure at Week 44 (Double-blind Randomized Withdrawal Period) | Systolic blood pressure | -4.19 millimeters of mercury (mmHg) | Standard Error 0.75 |
| Placebo + SSRI | Change From Randomization in Blood Pressure at Week 44 (Double-blind Randomized Withdrawal Period) | Diastolic blood pressure | -4.18 millimeters of mercury (mmHg) | Standard Error 0.55 |
Secondary
Change From Randomization in Pulse Rate at Week 44 (Double-blind Randomized Withdrawal Period)
Pulse rate measurements were collected when the participant was in a sitting position. Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis which included terms for the fixed categorical effects of treatment, country, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline and baseline-by-visit interaction.
Time frame: Randomization, Week 44
Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 + SSRI | Change From Randomization in Pulse Rate at Week 44 (Double-blind Randomized Withdrawal Period) | -2.54 beats per minute (bpm) | Standard Error 0.74 |
| Placebo + SSRI | Change From Randomization in Pulse Rate at Week 44 (Double-blind Randomized Withdrawal Period) | -10.76 beats per minute (bpm) | Standard Error 0.74 |
Secondary
Change From Randomization in the Arizona Sexual Experiences (ASEX) Questionnaire at Week 44 (Double-blind Randomized Withdrawal Period)
Arizona Sexual Experiences (ASEX) Questionnaire is a 5-item rating scale that quantifies sex drive, arousal, vaginal lubrication/penile erection, ability to reach orgasm, and satisfaction from orgasm. Each item is rated from 1 (extremely) to 6 (no/never). Possible total scores ranged from 5 to 30, with the higher scores indicating more sexual dysfunction. Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis which included terms for the fixed categorical effects of treatment, country, visit, treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline ASEX total score and baseline ASEX total score-by-visit interaction.
Time frame: Randomization, Week 44
Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 + SSRI | Change From Randomization in the Arizona Sexual Experiences (ASEX) Questionnaire at Week 44 (Double-blind Randomized Withdrawal Period) | -0.39 units on a scale | Standard Error 0.33 |
| Placebo + SSRI | Change From Randomization in the Arizona Sexual Experiences (ASEX) Questionnaire at Week 44 (Double-blind Randomized Withdrawal Period) | -0.08 units on a scale | Standard Error 0.33 |
Secondary
Change From Randomization in the Clinical Global Impression of Severity (CGI-S) Scores at Week 44 (Double-blind Randomized Withdrawal Period)
The Clinical Global Impression of Severity (CGI-S) instrument is used to record the severity of mental illness at the time of assessment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis which included terms for the fixed categorical effects of treatment, country, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline CGI-S score and baseline CGI-S score-by-visit interaction.
Time frame: Randomization, Week 44
Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 + SSRI | Change From Randomization in the Clinical Global Impression of Severity (CGI-S) Scores at Week 44 (Double-blind Randomized Withdrawal Period) | 0.01 units on a scale | Standard Error 0.05 |
| Placebo + SSRI | Change From Randomization in the Clinical Global Impression of Severity (CGI-S) Scores at Week 44 (Double-blind Randomized Withdrawal Period) | -0.00 units on a scale | Standard Error 0.05 |
Secondary
Change From Randomization in the EuroQol Questionnaire-5 Dimension (EQ-5D) Index Scores, Visual Analog Scale up to Week 44 (Double-blind Randomized Withdrawal Period)
The EQ-5D, a health-related, quality-of-life instrument, contains 2 parts: a health status profile and a visual analog scale (VAS). The profile allows participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and mood using a 3-level scale (no problem, some problems, and major problems). These dimensions are converted into weighted health-state index scores according to United States (US) and United Kingdom (UK) population-based algorithms. The US and UK based index scores range from -0.11 to 1.0 (where a score of 1.0 indicates perfect health) and from -0.59 (severe problems in all 5 dimensions) to 1.0 (no problem in any dimension), respectively. The VAS consists of participants rating their current health state from 0 (worst imaginable health state) to 100 (best imaginable health). Least Squares (LS) means were calculated using analysis of covariance (ANCOVA) model with main effects of treatment, country, and baseline score.
Time frame: Randomization, up to Week 44
Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value. Last observation carried forward (LOCF) methodology was used.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 + SSRI | Change From Randomization in the EuroQol Questionnaire-5 Dimension (EQ-5D) Index Scores, Visual Analog Scale up to Week 44 (Double-blind Randomized Withdrawal Period) | EQ-5D US | 0.01 units on a scale | Standard Error 0.01 |
| LY2216684 + SSRI | Change From Randomization in the EuroQol Questionnaire-5 Dimension (EQ-5D) Index Scores, Visual Analog Scale up to Week 44 (Double-blind Randomized Withdrawal Period) | EQ-5D UK | 0.01 units on a scale | Standard Error 0.02 |
| LY2216684 + SSRI | Change From Randomization in the EuroQol Questionnaire-5 Dimension (EQ-5D) Index Scores, Visual Analog Scale up to Week 44 (Double-blind Randomized Withdrawal Period) | VAS | 1.87 units on a scale | Standard Error 1.39 |
| Placebo + SSRI | Change From Randomization in the EuroQol Questionnaire-5 Dimension (EQ-5D) Index Scores, Visual Analog Scale up to Week 44 (Double-blind Randomized Withdrawal Period) | EQ-5D US | 0.01 units on a scale | Standard Error 0.01 |
| Placebo + SSRI | Change From Randomization in the EuroQol Questionnaire-5 Dimension (EQ-5D) Index Scores, Visual Analog Scale up to Week 44 (Double-blind Randomized Withdrawal Period) | EQ-5D UK | 0.01 units on a scale | Standard Error 0.02 |
| Placebo + SSRI | Change From Randomization in the EuroQol Questionnaire-5 Dimension (EQ-5D) Index Scores, Visual Analog Scale up to Week 44 (Double-blind Randomized Withdrawal Period) | VAS | 0.61 units on a scale | Standard Error 1.39 |
Secondary
Change From Randomization in the Fatigue Associated With Depression (FAsD) Average Score, Experience Subscale Score, and Impact Subscale Score at Week 44 (Double-blind Randomized Withdrawal Period)
The FAsD is a 13-item participant-rated scale. Items 1-6 ask how often participants experience different aspects of fatigue with responses from 1 (never) to 5 (always). Items 7-13 ask how often fatigue impacts various aspects of the participant's lives with responses from 1 (not at all) to 5 (very much). The experience subscale score is derived by taking the mean of Items 1-6. The impact subscale score is derived by taking the mean of applicable Items 7-13. The average score is the mean of applicable Items 1-13. Item 12 applies only to participants with a spouse or significant other and Item 13 applies to participants who had a job or who went to school. Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis which included terms for the fixed categorical effects of treatment, country, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline score and baseline score-by-visit interaction.
Time frame: Randomization, Week 44
Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 + SSRI | Change From Randomization in the Fatigue Associated With Depression (FAsD) Average Score, Experience Subscale Score, and Impact Subscale Score at Week 44 (Double-blind Randomized Withdrawal Period) | FAsD Experience Subscale Score | -0.05 units on a scale | Standard Error 0.05 |
| LY2216684 + SSRI | Change From Randomization in the Fatigue Associated With Depression (FAsD) Average Score, Experience Subscale Score, and Impact Subscale Score at Week 44 (Double-blind Randomized Withdrawal Period) | FAsD Impact Subscale Score | -0.06 units on a scale | Standard Error 0.05 |
| LY2216684 + SSRI | Change From Randomization in the Fatigue Associated With Depression (FAsD) Average Score, Experience Subscale Score, and Impact Subscale Score at Week 44 (Double-blind Randomized Withdrawal Period) | FAsD Average Score | -0.05 units on a scale | Standard Error 0.05 |
| Placebo + SSRI | Change From Randomization in the Fatigue Associated With Depression (FAsD) Average Score, Experience Subscale Score, and Impact Subscale Score at Week 44 (Double-blind Randomized Withdrawal Period) | FAsD Experience Subscale Score | 0.05 units on a scale | Standard Error 0.05 |
| Placebo + SSRI | Change From Randomization in the Fatigue Associated With Depression (FAsD) Average Score, Experience Subscale Score, and Impact Subscale Score at Week 44 (Double-blind Randomized Withdrawal Period) | FAsD Impact Subscale Score | -0.01 units on a scale | Standard Error 0.05 |
| Placebo + SSRI | Change From Randomization in the Fatigue Associated With Depression (FAsD) Average Score, Experience Subscale Score, and Impact Subscale Score at Week 44 (Double-blind Randomized Withdrawal Period) | FAsD Average Score | 0.02 units on a scale | Standard Error 0.05 |
Secondary
Change From Randomization in the Hospital Anxiety and Depression Scale (HADS) Depression and Anxiety Subscale Scores at Week 44 (Double-blind Randomized Withdrawal Period)
The Hospital Anxiety and Depression Scale (HADS) is a 14-item questionnaire with 2 subscales: anxiety and depression. Each item is rated on a 4-point scale (0-3), giving maximum scores of 21 for anxiety and depression. Scores of 11 or more on either subscale are considered to be a 'significant' case of psychological morbidity, while scores of 8-10 represent 'borderline' and 0-7 represent 'normal'. Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis which included terms for the fixed categorical effects of treatment, country, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline subscale score and baseline subscale score-by-visit interaction.
Time frame: Randomization, Week 44
Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 + SSRI | Change From Randomization in the Hospital Anxiety and Depression Scale (HADS) Depression and Anxiety Subscale Scores at Week 44 (Double-blind Randomized Withdrawal Period) | HADS Anxiety Subscale Score | -0.00 units on a scale | Standard Error 0.22 |
| LY2216684 + SSRI | Change From Randomization in the Hospital Anxiety and Depression Scale (HADS) Depression and Anxiety Subscale Scores at Week 44 (Double-blind Randomized Withdrawal Period) | HADS Depression Subscale Score | -0.18 units on a scale | Standard Error 0.23 |
| Placebo + SSRI | Change From Randomization in the Hospital Anxiety and Depression Scale (HADS) Depression and Anxiety Subscale Scores at Week 44 (Double-blind Randomized Withdrawal Period) | HADS Anxiety Subscale Score | 0.15 units on a scale | Standard Error 0.22 |
| Placebo + SSRI | Change From Randomization in the Hospital Anxiety and Depression Scale (HADS) Depression and Anxiety Subscale Scores at Week 44 (Double-blind Randomized Withdrawal Period) | HADS Depression Subscale Score | 0.15 units on a scale | Standard Error 0.23 |
Secondary
Change From Randomization in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) Total Score at Week 44 (Double-blind Randomized Withdrawal Period)
Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) is a 7-item participant-rated questionnaire pertaining to a participant's cognitive and physical well-being. It assesses motivation, wakefulness, energy, focus, recall, word-finding difficulty, and mental acuity. Each item is scored on a 6-point scale ranging from 1 (greater than normal) to 6 (totally absent). Total score is reported and ranges from 7 to 42, with higher scores indicating greater impairment. Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis which included terms for the fixed categorical effects of treatment, country, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline CPFQ total score and baseline CPFQ total score-by-visit interaction.
Time frame: Randomization, Week 44
Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 + SSRI | Change From Randomization in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) Total Score at Week 44 (Double-blind Randomized Withdrawal Period) | -0.27 units on a scale | Standard Error 0.31 |
| Placebo + SSRI | Change From Randomization in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) Total Score at Week 44 (Double-blind Randomized Withdrawal Period) | -0.05 units on a scale | Standard Error 0.31 |
Secondary
Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period)
Montgomery-Asberg Depression Rating Scale (MADRS) is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist (sadness \[apparent\], sadness \[reported\], inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis which includes terms for the fixed categorical effects of treatment, country, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline MADRS total score (individual item score) and baseline MADRS total score (individual item score)-by-visit interaction.
Time frame: Randomization, Week 44
Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Item 3: Inner Tension | 0.06 units on a scale | Standard Error 0.07 |
| LY2216684 + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Item 6: Concentration Difficulties | 0.07 units on a scale | Standard Error 0.06 |
| LY2216684 + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Item 2: Reported Sadness | 0.09 units on a scale | Standard Error 0.06 |
| LY2216684 + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Item 7: Lassitude | 0.02 units on a scale | Standard Error 0.06 |
| LY2216684 + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Item 4: Reduced Sleep | -0.02 units on a scale | Standard Error 0.07 |
| LY2216684 + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Item 8: Inability to Feel | -0.00 units on a scale | Standard Error 0.05 |
| LY2216684 + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Item 1: Apparent Sadness | 0.09 units on a scale | Standard Error 0.05 |
| LY2216684 + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Item 9: Pessimistic Thoughts | -0.01 units on a scale | Standard Error 0.05 |
| LY2216684 + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Item 5: Reduced Appetite | 0.00 units on a scale | Standard Error 0.04 |
| LY2216684 + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Item 10: Suicidal Thoughts | 0.02 units on a scale | Standard Error 0.02 |
| LY2216684 + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | MADRS Total Score | 0.40 units on a scale | Standard Error 0.33 |
| Placebo + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Item 10: Suicidal Thoughts | 0.01 units on a scale | Standard Error 0.02 |
| Placebo + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | MADRS Total Score | 0.34 units on a scale | Standard Error 0.33 |
| Placebo + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Item 1: Apparent Sadness | 0.08 units on a scale | Standard Error 0.05 |
| Placebo + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Item 2: Reported Sadness | 0.05 units on a scale | Standard Error 0.06 |
| Placebo + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Item 3: Inner Tension | 0.14 units on a scale | Standard Error 0.06 |
| Placebo + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Item 4: Reduced Sleep | -0.06 units on a scale | Standard Error 0.07 |
| Placebo + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Item 5: Reduced Appetite | -0.00 units on a scale | Standard Error 0.04 |
| Placebo + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Item 6: Concentration Difficulties | 0.08 units on a scale | Standard Error 0.06 |
| Placebo + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Item 7: Lassitude | 0.07 units on a scale | Standard Error 0.06 |
| Placebo + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Item 8: Inability to Feel | -0.05 units on a scale | Standard Error 0.05 |
| Placebo + SSRI | Change From Randomization in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores at Week 44 (Double-blind Randomized Withdrawal Period) | Item 9: Pessimistic Thoughts | -0.02 units on a scale | Standard Error 0.04 |
Secondary
Change From Randomization in the Sheehan Disability Scale (SDS) Items at Week 44 (Double-blind Randomized Withdrawal Period)
The Sheehan Disability Scale (SDS) is completed by the participant and used to assess the effect of the participant's symptoms on their work (work/school impairment score), social life (social life/leisure activities impairment score), and family life (family life/home responsibilities impairment score). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis which included terms for the fixed categorical effects of treatment, country, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline score and baseline score-by-visit interaction
Time frame: Randomization, Week 44
Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 + SSRI | Change From Randomization in the Sheehan Disability Scale (SDS) Items at Week 44 (Double-blind Randomized Withdrawal Period) | Work Impairment Score | -0.24 units on a scale | Standard Error 0.17 |
| LY2216684 + SSRI | Change From Randomization in the Sheehan Disability Scale (SDS) Items at Week 44 (Double-blind Randomized Withdrawal Period) | Social Life Impairment Score | -0.17 units on a scale | Standard Error 0.14 |
| LY2216684 + SSRI | Change From Randomization in the Sheehan Disability Scale (SDS) Items at Week 44 (Double-blind Randomized Withdrawal Period) | Family Life Impairment Score | -0.26 units on a scale | Standard Error 0.14 |
| Placebo + SSRI | Change From Randomization in the Sheehan Disability Scale (SDS) Items at Week 44 (Double-blind Randomized Withdrawal Period) | Work Impairment Score | 0.02 units on a scale | Standard Error 0.17 |
| Placebo + SSRI | Change From Randomization in the Sheehan Disability Scale (SDS) Items at Week 44 (Double-blind Randomized Withdrawal Period) | Social Life Impairment Score | -0.15 units on a scale | Standard Error 0.14 |
| Placebo + SSRI | Change From Randomization in the Sheehan Disability Scale (SDS) Items at Week 44 (Double-blind Randomized Withdrawal Period) | Family Life Impairment Score | -0.08 units on a scale | Standard Error 0.14 |
Secondary
Change From Week 8 in the Clinical Global Impression of Severity (CGI-S) Scores up to Week 20 (Stabilization Open-label Period)
The Clinical Global Impression of Severity (CGI-S) instrument is used to record the severity of mental illness at the time of assessment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants).
Time frame: Week 8, up to Week 20
Population: All participants who have non-missing values at Week 8 and at least one post-Week 8 value. Last observation carried forward (LOCF) methodology was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LY2216684 + SSRI | Change From Week 8 in the Clinical Global Impression of Severity (CGI-S) Scores up to Week 20 (Stabilization Open-label Period) | -0.25 units on a scale | Standard Deviation 0.95 |
Secondary
Change From Week 8 in the Fatigue Associated With Depression (FAsD) Average Score, Experience Subscale Score, and Impact Subscale Score up to Week 20 (Stabilization Open-label Period)
The Fatigue Associated with Depression (FAsD) is a 13-item participant-rated scale. Items 1-6 ask how often participants experience different aspects of fatigue with responses from 1 (never) to 5 (always). Items 7-13 ask how often fatigue impacts various aspects of the participant's lives with responses from 1 (not at all) to 5 (very much). The experience subscale score is derived by taking the mean of Items 1-6. The impact subscale score is derived by taking the mean of applicable Items 7-13. The average score is the mean of applicable Items 1-13. Item 12 applies only to participants with a spouse or significant other and Item 13 applies to participants who had a job or who went to school.
Time frame: Week 8, up to Week 20
Population: All participants who have non-missing values at Week 8 and at least one post-Week 8 value. Last observation carried forward (LOCF) methodology was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 + SSRI | Change From Week 8 in the Fatigue Associated With Depression (FAsD) Average Score, Experience Subscale Score, and Impact Subscale Score up to Week 20 (Stabilization Open-label Period) | FAsD Experience Subscale Score | -0.22 units on a scale | Standard Deviation 0.93 |
| LY2216684 + SSRI | Change From Week 8 in the Fatigue Associated With Depression (FAsD) Average Score, Experience Subscale Score, and Impact Subscale Score up to Week 20 (Stabilization Open-label Period) | FAsD Impact Subscale Score | -0.15 units on a scale | Standard Deviation 0.87 |
| LY2216684 + SSRI | Change From Week 8 in the Fatigue Associated With Depression (FAsD) Average Score, Experience Subscale Score, and Impact Subscale Score up to Week 20 (Stabilization Open-label Period) | FAsD Average Score | -0.19 units on a scale | Standard Deviation 0.84 |
Secondary
Change From Week 8 in the Hospital Anxiety and Depression Scale (HADS) Depression and Anxiety Subscale Scores up to Week 20 (Stabilization Open-label Period)
The Hospital Anxiety and Depression Scale (HADS) is a 14-item questionnaire with 2 subscales: anxiety and depression. Each item is rated on a 4-point scale (0-3), giving maximum scores of 21 for anxiety and depression. Scores of 11 or more on either subscale are considered to be a 'significant' case of psychological morbidity, while scores of 8-10 represent 'borderline' and 0-7 represent 'normal'.
Time frame: Week 8, up to Week 20
Population: All participants who have non-missing values at Week 8 and at least one post-Week 8 value. Last observation carried forward (LOCF) methodology was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 + SSRI | Change From Week 8 in the Hospital Anxiety and Depression Scale (HADS) Depression and Anxiety Subscale Scores up to Week 20 (Stabilization Open-label Period) | HADS Anxiety Subscale Score | -0.77 units on a scale | Standard Deviation 3.73 |
| LY2216684 + SSRI | Change From Week 8 in the Hospital Anxiety and Depression Scale (HADS) Depression and Anxiety Subscale Scores up to Week 20 (Stabilization Open-label Period) | HADS Depression Subscale Score | -0.74 units on a scale | Standard Deviation 3.57 |
Secondary
Change From Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 20 (Stabilization Open-label Period)
Montgomery-Asberg Depression Rating Scale (MADRS) is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist (sadness \[apparent\], sadness \[reported\], inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms).
Time frame: Week 8, up to Week 20
Population: All participants who have non-missing values at Week 8 and at least one post-Week 8 value. Last observation carried forward (LOCF) methodology was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 + SSRI | Change From Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 20 (Stabilization Open-label Period) | Item 6: Concentration Difficulties | -0.06 units on a scale | Standard Deviation 1.19 |
| LY2216684 + SSRI | Change From Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 20 (Stabilization Open-label Period) | Item 7: Lassitude | 0.02 units on a scale | Standard Deviation 1.19 |
| LY2216684 + SSRI | Change From Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 20 (Stabilization Open-label Period) | Item 10: Suicidal Thoughts | 0.03 units on a scale | Standard Deviation 0.47 |
| LY2216684 + SSRI | Change From Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 20 (Stabilization Open-label Period) | MADRS Total Score | -0.38 units on a scale | Standard Deviation 6.09 |
| LY2216684 + SSRI | Change From Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 20 (Stabilization Open-label Period) | Item 1: Apparent Sadness | -0.01 units on a scale | Standard Deviation 1.01 |
| LY2216684 + SSRI | Change From Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 20 (Stabilization Open-label Period) | Item 2: Reported Sadness | -0.08 units on a scale | Standard Deviation 1.15 |
| LY2216684 + SSRI | Change From Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 20 (Stabilization Open-label Period) | Item 3: Inner Tension | -0.05 units on a scale | Standard Deviation 1.18 |
| LY2216684 + SSRI | Change From Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 20 (Stabilization Open-label Period) | Item 4: Reduced Sleep | -0.12 units on a scale | Standard Deviation 1.28 |
| LY2216684 + SSRI | Change From Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 20 (Stabilization Open-label Period) | Item 5: Reduced Appetite | 0.00 units on a scale | Standard Deviation 0.89 |
| LY2216684 + SSRI | Change From Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 20 (Stabilization Open-label Period) | Item 8: Inability to Feel | -0.09 units on a scale | Standard Deviation 1.08 |
| LY2216684 + SSRI | Change From Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Item Scores up to Week 20 (Stabilization Open-label Period) | Item 9: Pessimistic Thoughts | -0.04 units on a scale | Standard Deviation 0.87 |
Secondary
Change From Week 8 in the Sheehan Disability Scale (SDS) Items up to Week 20 (Stabilization Open-label Period)
The Sheehan Disability Scale (SDS) is completed by the participant and used to assess the effect of the participant's symptoms on their work (work/school impairment score), social life (social life/leisure activities impairment score), and family life (family life/home responsibilities impairment score). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption.
Time frame: Week 8, up to Week 20
Population: All participants who have non-missing values at Week 8 and at least one post-Week 8 value. Last observation carried forward (LOCF) methodology was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LY2216684 + SSRI | Change From Week 8 in the Sheehan Disability Scale (SDS) Items up to Week 20 (Stabilization Open-label Period) | Work Impairment Score | -0.58 units on a scale | Standard Deviation 2.61 |
| LY2216684 + SSRI | Change From Week 8 in the Sheehan Disability Scale (SDS) Items up to Week 20 (Stabilization Open-label Period) | Social Life Impairment Score | -0.47 units on a scale | Standard Deviation 2.54 |
| LY2216684 + SSRI | Change From Week 8 in the Sheehan Disability Scale (SDS) Items up to Week 20 (Stabilization Open-label Period) | Family Life Impairment Score | -0.50 units on a scale | Standard Deviation 2.5 |
Secondary
Number of Participants With Treatment-emergent Suicidal Ideation and Behaviors Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) (Double-blind Randomized Withdrawal Period)
The Columbia-Suicide Severity Rating Scale (C-SSRS) captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal ideation is defined as a yes answer to any 1 of 5 suicidal ideation questions, which includes a wish to be dead and 4 different categories of active suicidal ideation. Suicidal behavior is defined as a yes answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation and behavior are defined as treatment-emergent (TE) if not present during the period up through randomization. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Event module.
Time frame: Randomization through Week 44
Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LY2216684 + SSRI | Number of Participants With Treatment-emergent Suicidal Ideation and Behaviors Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) (Double-blind Randomized Withdrawal Period) | TE Suicidal Behavior | 1 participants |
| LY2216684 + SSRI | Number of Participants With Treatment-emergent Suicidal Ideation and Behaviors Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) (Double-blind Randomized Withdrawal Period) | TE Suicidal Ideation | 5 participants |
| Placebo + SSRI | Number of Participants With Treatment-emergent Suicidal Ideation and Behaviors Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) (Double-blind Randomized Withdrawal Period) | TE Suicidal Ideation | 4 participants |
| Placebo + SSRI | Number of Participants With Treatment-emergent Suicidal Ideation and Behaviors Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) (Double-blind Randomized Withdrawal Period) | TE Suicidal Behavior | 0 participants |
Secondary
Number of Participants With Treatment-emergent Suicidal Ideation and Behaviors Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) (Open-label Period)
The Columbia-Suicide Severity Rating Scale (C-SSRS) captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal ideation is defined as a yes answer to any 1 of 5 suicidal ideation questions, which included a wish to be dead and 4 different categories of active suicidal ideation. Suicidal behavior is defined as a yes answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation and behavior are defined as treatment-emergent (TE) if not present at baseline. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Event module.
Time frame: Baseline through Week 20
Population: All participants who have non-missing values at baseline and at least one post-baseline value.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LY2216684 + SSRI | Number of Participants With Treatment-emergent Suicidal Ideation and Behaviors Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) (Open-label Period) | TE Suicidal Ideation | 66 participants |
| LY2216684 + SSRI | Number of Participants With Treatment-emergent Suicidal Ideation and Behaviors Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) (Open-label Period) | TE Suicidal Behavior | 5 participants |
Secondary
Percentage of Participants With Re-emergence of Depressive Symptoms (Double-blind Randomized Withdrawal Period)
Participants meeting any of the following criteria were determined as having major depressive disorder symptom re-emergence: 1) a Montgomery-Asberg Depression Rating Scale (MADRS) total score greater ≥14 or a Clinical Global Impressions of Severity (CGI-S) increase of 2 or more points from Week 18 at 2 consecutive visits or 2) discontinuation due to lack of efficacy/worsening of depression/suicidality. The percentage of participants with re-emergence of depressive symptoms was calculated by dividing the number of participants who meet any of the criteria by the total number of participants analyzed, multiplied by 100. The MADRS is a rating scale for severity of depressive mood symptoms and has a 10-item checklist with items rated on a scale of 0-6, for a total score range of 0 (low severity) to 60 (high severity). CGI-S measures severity of depression at the time of assessment compared with the start of treatment. Scores range from 1 (normal, not at all ill) to 7 (extremely ill).
Time frame: Week 44
Population: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2216684 + SSRI | Percentage of Participants With Re-emergence of Depressive Symptoms (Double-blind Randomized Withdrawal Period) | 9.9 percentage of participants |
| Placebo + SSRI | Percentage of Participants With Re-emergence of Depressive Symptoms (Double-blind Randomized Withdrawal Period) | 8.2 percentage of participants |