A Fixed Dose Study of Adjunctive Treatment to Antidepressant Therapy for Adults With Major Depressive Disorder

The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist. Items were rated on a scale of 0 to 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 mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit and baseline score-by-visit.

Time frame: Randomization, 8 weeks

Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.

The ASEX scale was used to assess sexual functioning in both males and females. The ASEX total score for the male and female version was calculated as the sum of the responses (rated from 1 \[extremely\] to 6 \[no/never\]) to the 5 items of the ASEX scale. Total scores ranged from 5 to 30 with higher scores indicating greater sexual dysfunction. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit and baseline score-by-visit.

Time frame: Randomization, 8 weeks

Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.

Blood pressure (BP) measurements were collected when the participant was in a sitting position. Three measurements of sitting BP collected at approximately 1-minute intervals at every visit were averaged and used as the value for the visit. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline value, treatment-by-visit and baseline value-by-visit.

Time frame: Randomization, 8 weeks

Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.

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 (among the most extremely ill participants). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit and baseline score-by-visit.

Time frame: Randomization, 8 weeks

Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.

The FAsD is a participant-rated scale with a total of 13 items. Six of the 13 items ask how often participants experience different aspects of fatigue with responses from 1 (never) to 5 (always). Seven of the 13 items 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 was derived by taking the mean of Items 1 through 6, and the average score was the mean of Items 1 through 13 (derived by taking the mean of all applicable items for each participant). Item 12 applied only to participants with a spouse or significant other, and Item 13 applied to participants who had a job or who went to school. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit and baseline score-by-visit.

Time frame: Randomization, 8 weeks

Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.

The FAsD is a participant-rated scale with a total of 13 items. Six of the 13 items ask how often participants experience different aspects of fatigue with responses from 1 (never) to 5 (always). Seven of the 13 items ask how often fatigue impacts various aspects of the participant's lives with responses from 1 (not at all) to 5 (very much). The impact subscale score was derived by taking the mean of Items 7 through 13 (applicable items only). Item 12 applied only to participants with a spouse or significant other, and Item 13 applied to participants who had a job or who went to school. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline subscale score, treatment-by-visit and baseline subscale score-by-visit.

Time frame: Randomization, 8 weeks

Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.

The HADS is a 14-item questionnaire with 2 subscales: anxiety and depression. Each item was rated on a 4-point scale (0-3), giving maximum scores of 21 for anxiety and depression subscale. 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'. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline subscale score, treatment-by-visit, and baseline subscale score-by-visit.

Time frame: Randomization, 8 weeks

Population: All randomized participants with a baseline and at least one post-baseline value.

The HADS is a 14-item questionnaire with 2 subscales: anxiety and depression. Each item was rated on a 4-point scale (0-3), giving maximum scores of 21 for anxiety and depression subscale. 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'. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline subscale score, treatment-by-visit and baseline subscale score-by-visit.

Time frame: Randomization, 8 weeks

Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.

The 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 was scored on a 6-point scale ranging from 1 (greater than normal) to 6 (totally absent). Total scores ranged from 7 to 42. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit and baseline score-by-visit.

Time frame: Randomization, 8 weeks

Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.

The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had 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 were rated on a scale of 0 to 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 mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline item score, treatment-by-visit and baseline item score-by-visit.

Time frame: Randomization, 8 weeks

Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.

Pulse measurements were collected when the participant was in a sitting position. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline value, treatment-by-visit and baseline value-by-visit.

Time frame: Randomization, 8 weeks

Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.

The SDS was completed by the participant and used to assess the effect of the participant's symptoms on their work (Item 1), social (Item 2), and family life (Item 3). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. The Global Function Impairment Score is the sum of the 3 items, and scores ranged from 0 to 30 with higher values indicating disruption in the participant's work life (work/school impairment score), social life (social life/leisure activities impairment score), and family life (family life/home responsibilities impairment score). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit and baseline score-by-visit.

Time frame: Randomization, 8 weeks

Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.

The Sheehan Disability Scale (SDS) was 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 mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline item score, treatment-by-visit, and baseline item score-by-visit.

Time frame: Randomization, 8 weeks

Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.

The EQ-5D Visual Analog Scale is a generic, multidimensional, health-related, quality-of-life instrument. Overall health state score is self-reported using a visual analogue scale, marked on a scale of 0 to 100 with 0 representing the worst imaginable health state and 100 representing best imaginable health state. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit and baseline score-by-visit.

Time frame: Randomization, 8 weeks

Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.

The Q-LES-Q-SF is a self-administered 16-item questionnaire that measures degree of enjoyment and satisfaction experienced in various areas of daily life during the past week on a 5-point, Likert scale (1=very poor and 5=very good). The total raw score is the sum of items 1 to 14 and ranges from 14 to 70. The raw scores are converted to and expressed as the percentage of the maximum possible score. Higher scores indicate higher levels of enjoyment/satisfaction. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit and baseline score-by-visit.

Time frame: Randomization, 8 weeks

Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.

A MADRS total score of less than or equal to 10 for at least 2 consecutive measurements, including the participant's last measurement, was defined as remission criteria at last 2 consecutive visits. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist. Items were rated on a scale of 0 to 6 for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Percentage of participants was calculated by dividing the number of participants who meet criteria for remission at last 2 consecutive visits by the total number of participants analyzed, multiplied by 100%.

Time frame: Randomization up to 8 weeks

Population: All randomized participants with a baseline and at least one post-baseline value.

A MADRS total score of less than or equal to 10 was defined as remission criteria. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist. Items were rated on a scale of 0 to 6 for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Percentage of participants was calculated by dividing the number of participants who meet criteria for remission by the total number of participants analyzed, multiplied by 100%.

Time frame: Randomization up to 8 weeks

Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.

A greater than or equal to 50 percent improvement (that is, a decrease from baseline) in the MADRS total score was defined as response criteria. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist. Items were rated on a scale of 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Percentage of participants was calculated by dividing the number of participants meeting response criteria at last visit by the total number of participants analyzed, multiplied by 100%.

Time frame: Randomization up to 8 weeks

Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.

The C-SSRS captured occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal ideation was 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 was 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 TE if not present at baseline. Percentage of participants was calculated by dividing the number of participants with suicide-related TE events by the total number of participants at risk, multiplied by 100%. 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 8 weeks

Population: All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value.

A validated bioanalytical assay was used to determine plasma LY2216684 concentrations.

Time frame: 1 week, 4 weeks, and 8 weeks

Population: Participants exposed to LY2216684 with evaluable plasma concentration values. Samples with concentrations below the lower quantification limit (BQL) of the assay were treated as missing values for the analysis and samples with incomplete dosing information were not included in the pharmacokinetics assessment.

Treatment-emergent adverse events (TEAEs) were events that first occurred or worsened during the treatment phase. CYP2D6 functional phenotype was classified as poor metabolizer (PM) or non-poor metabolizer (non-PM). The percentage of participants who reported the TEAE is presented for each phenotype classification. Only TEAEs for which there was a statistically significant treatment-by-SSRI therapy interaction were included: tinnitus and influenza. A summary of serious and other non-serious adverse events regardless of causality is located in the Report of Adverse Events module.

Time frame: Through 8 weeks

Population: All randomized patients who do not discontinue from the study for the reason 'Lost to follow-up' at the first post-baseline visit.