Trial Outcomes & Findings for A Study in Prevention of Re-emergence of Depression Symptoms (NCT NCT01299272)

Last Updated: 2018-04-17

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1249 participants

Primary outcome timeframe

Randomization up to 44 weeks

Results posted on

2018-04-17

Participant Flow

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.

Participant milestones

Participant milestones
Measure	LY2216684 + SSRI (Acute Open-label Period) 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).	LY2216684 + SSRI (Stabilization Open-label Period) 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.	LY2216684 + SSRI (Double-blind Randomized Withdrawal Period) 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI (Double-blind Randomized Withdrawal Period) 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
Acute Open-label (OL) Period STARTED	1249	0	0	0
Acute Open-label (OL) Period Entered Discontinuation (DC) Period	271	0	0	0
Acute Open-label (OL) Period COMPLETED	835	0	0	0
Acute Open-label (OL) Period NOT COMPLETED	414	0	0	0
Stabilization Open-label (OL) Period STARTED	0	835	0	0
Stabilization Open-label (OL) Period Entered Discontinuation (DC) Period	0	164	0	0
Stabilization Open-label (OL) Period COMPLETED	0	586	0	0
Stabilization Open-label (OL) Period NOT COMPLETED	0	249	0	0
Double-blind (DB) Randomized Period STARTED	0	0	294	292
Double-blind (DB) Randomized Period Entered Taper Discontinuation Period	0	0	129	0
Double-blind (DB) Randomized Period Entered Abrupt Discontinuation Period	0	0	132	268
Double-blind (DB) Randomized Period COMPLETED	0	0	224	234
Double-blind (DB) Randomized Period NOT COMPLETED	0	0	70	58

Reasons for withdrawal

Reasons for withdrawal
Measure	LY2216684 + SSRI (Acute Open-label Period) 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).	LY2216684 + SSRI (Stabilization Open-label Period) 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.	LY2216684 + SSRI (Double-blind Randomized Withdrawal Period) 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI (Double-blind Randomized Withdrawal Period) 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
Acute Open-label (OL) Period Remission Criteria Not Met	140	0	0	0
Acute Open-label (OL) Period Adverse Event	140	0	0	0
Acute Open-label (OL) Period Withdrawal by Subject	56	0	0	0
Acute Open-label (OL) Period Protocol Violation	36	0	0	0
Acute Open-label (OL) Period Lost to Follow-up	14	0	0	0
Acute Open-label (OL) Period Sponsor Decision	13	0	0	0
Acute Open-label (OL) Period Lack of Efficacy	10	0	0	0
Acute Open-label (OL) Period Physician Decision	5	0	0	0
Stabilization Open-label (OL) Period Randomization Criteria Not Met	0	80	0	0
Stabilization Open-label (OL) Period Protocol Violation	0	44	0	0
Stabilization Open-label (OL) Period Adverse Event	0	42	0	0
Stabilization Open-label (OL) Period Withdrawal by Subject	0	42	0	0
Stabilization Open-label (OL) Period Sponsor Decision	0	12	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 Reemergence of Study Condition Symptoms	0	6	0	0
Stabilization Open-label (OL) Period Physician Decision	0	3	0	0
Double-blind (DB) Randomized Period Withdrawal by Subject	0	0	22	15
Double-blind (DB) Randomized Period Lack of Efficacy	0	0	20	10
Double-blind (DB) Randomized Period Adverse Event	0	0	8	9
Double-blind (DB) Randomized Period Protocol Violation	0	0	8	7
Double-blind (DB) Randomized Period Lost to Follow-up	0	0	5	5
Double-blind (DB) Randomized Period Reemergence of Study Condition Symptoms	0	0	4	10
Double-blind (DB) Randomized Period Physician Decision	0	0	2	1
Double-blind (DB) Randomized Period Sponsor Decision	0	0	1	1

Baseline Characteristics

A Study in Prevention of Re-emergence of Depression Symptoms

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Enrolled Participants n=1249 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.
Age, Continuous	47.4 years STANDARD_DEVIATION 12.54 • n=5 Participants
Sex: Female, Male Female	917 Participants n=5 Participants
Sex: Female, Male Male	332 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	50 Participants n=5 Participants
Race (NIH/OMB) Asian	21 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	99 Participants n=5 Participants
Race (NIH/OMB) White	1066 Participants n=5 Participants
Race (NIH/OMB) More than one race	13 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	254 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	622 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	373 Participants n=5 Participants
Region of Enrollment United States	535 Participants n=5 Participants
Region of Enrollment Slovakia	65 Participants n=5 Participants
Region of Enrollment Greece	43 Participants n=5 Participants
Region of Enrollment Spain	43 Participants n=5 Participants
Region of Enrollment Turkey	30 Participants n=5 Participants
Region of Enrollment Russia	96 Participants n=5 Participants
Region of Enrollment Italy	44 Participants n=5 Participants
Region of Enrollment France	61 Participants n=5 Participants
Region of Enrollment Mexico	63 Participants n=5 Participants
Region of Enrollment Puerto Rico	77 Participants n=5 Participants
Region of Enrollment Argentina	62 Participants n=5 Participants
Region of Enrollment Belgium	11 Participants n=5 Participants
Region of Enrollment Croatia	9 Participants n=5 Participants
Region of Enrollment Romania	19 Participants n=5 Participants
Region of Enrollment Germany	73 Participants n=5 Participants
Region of Enrollment South Korea	18 Participants n=5 Participants

PRIMARY outcome

Timeframe: Randomization up to 44 weeks

Population: All randomized participants.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=294 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI n=292 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	8.24 percentage of participants

SECONDARY outcome

Timeframe: Week 44

Population: All randomized participants.

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).

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=294 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI n=292 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
Percentage of Participants With Re-emergence of Depressive Symptoms (Double-blind Randomized Withdrawal Period)	9.9 percentage of participants	8.2 percentage of participants

SECONDARY outcome

Timeframe: Randomization, Week 44

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

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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=290 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI n=292 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	0.34 units on a scale Standard Error 0.33
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	0.08 units on a scale Standard Error 0.05
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	0.05 units on a scale Standard Error 0.06
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	0.14 units on a scale Standard Error 0.06
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	-0.06 units on a scale Standard Error 0.07
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	-0.00 units on a scale Standard Error 0.04
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	0.08 units on a scale Standard Error 0.06
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	0.07 units on a scale Standard Error 0.06
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	-0.05 units on a scale Standard Error 0.05
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	-0.02 units on a scale Standard Error 0.04
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	0.01 units on a scale Standard Error 0.02

SECONDARY outcome

Timeframe: Randomization, Week 44

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

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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=286 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI n=285 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	0.15 units on a scale Standard Error 0.22
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	0.15 units on a scale Standard Error 0.23

SECONDARY outcome

Timeframe: Randomization, Week 44

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

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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=290 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI n=292 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	-0.00 units on a scale Standard Error 0.05

SECONDARY outcome

Timeframe: Randomization, Week 44

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 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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=286 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI n=286 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	0.05 units on a scale Standard Error 0.05
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	-0.01 units on a scale Standard Error 0.05
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	0.02 units on a scale Standard Error 0.05

SECONDARY outcome

Timeframe: Randomization, Week 44

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) 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

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=289 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI n=289 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	0.02 units on a scale Standard Error 0.17
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	-0.15 units on a scale Standard Error 0.14
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	-0.08 units on a scale Standard Error 0.14

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=278 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI n=285 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	0.01 units on a scale Standard Error 0.01
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	0.01 units on a scale Standard Error 0.02
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	0.61 units on a scale Standard Error 1.39

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=291 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI n=292 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	4 participants
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	0 participants

SECONDARY outcome

Timeframe: Randomization, Week 44

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

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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=280 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI n=277 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	-0.08 units on a scale Standard Error 0.33

SECONDARY outcome

Timeframe: Randomization, Week 44

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

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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=286 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI n=286 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	-0.05 units on a scale Standard Error 0.31

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=1214 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	—
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 0.70	—
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 8.30	—
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	—
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	—
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	—
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	—
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	—
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	—
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	—
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	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=812 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	—
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	—
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	—
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	—
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	—
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	—
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	—
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	—
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	—
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	—
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	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=1199 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	—
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 outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=781 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	—
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 outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=1214 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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 outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=812 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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 outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=1166 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	—
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	—
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 outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=781 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	—
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	—
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 outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=1197 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	—
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	—
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 outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=781 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	—
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	—
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 2.50	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=779 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	—
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	—
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 outcome

Timeframe: Baseline through Week 20

Population: All participants who have non-missing values at baseline and at least one post-baseline value.

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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=1216 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	—
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 outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=1115 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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 outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=1167 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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 outcome

Timeframe: Randomization, Week 44

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

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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=291 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI n=292 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	-4.19 millimeters of mercury (mmHg) Standard Error 0.75
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	-4.18 millimeters of mercury (mmHg) Standard Error 0.55

SECONDARY outcome

Timeframe: 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.

Blood pressure measurements were taken 3 times at each visit in a sitting position. The average of the 3 values was used for analysis.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=1214 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
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	—
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 outcome

Timeframe: Randomization, Week 44

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

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.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=291 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI n=292 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
Change From Randomization in Pulse Rate at Week 44 (Double-blind Randomized Withdrawal Period)	-2.54 beats per minute (bpm) Standard Error 0.74	-10.76 beats per minute (bpm) Standard Error 0.74

SECONDARY outcome

Timeframe: 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.

Pulse measurements were collected when the participant was in a sitting position.

Outcome measures

Outcome measures
Measure	LY2216684 + SSRI n=1214 Participants 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 12 weeks. At 20 weeks, participants meeting criteria for randomization continued at their current dose of LY2216684 and SSRI, orally, QD, for an additional 24 weeks.	Placebo + SSRI 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 12 weeks. At 20 weeks, participants meeting criteria for randomization were switched from LY2216684 to Placebo and continued at their current SSRI dose, orally, QD, for an additional 24 weeks.
Change From Baseline in Pulse Rate up to Week 20 (Open-label Period)	10.80 beats per minute (bpm) Standard Deviation 12.47	—

Adverse Events

LY2216684 + SSRI (Acute Open-label Period)

Serious events: 19 serious events

Other events: 505 other events

Deaths: 0 deaths

LY2216684 + SSRI (Stabilization Open-label Period)

Serious events: 15 serious events

Other events: 112 other events

Deaths: 0 deaths

LY2216684 + SSRI (Double-blind Randomized Withdrawal Period)

Serious events: 2 serious events

Other events: 37 other events

Deaths: 0 deaths

Placebo + SSRI (Double-blind Randomized Withdrawal Period)

Serious events: 6 serious events

Other events: 21 other events

Deaths: 0 deaths

LY2216684 + SSRI (Randomized Tapered Discontinuation Period)

Serious events: 2 serious events

Other events: 9 other events

Deaths: 0 deaths

LY2216684 + SSRI (Randomized Abrupt Discontinuation Period)

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Placebo + SSRI (Abrupt Discontinuation Period)

Serious events: 2 serious events

Other events: 16 other events

Deaths: 0 deaths

LY2216684 + SSRI (Nonrandomized Abrupt Discontinuation Period)

Serious events: 8 serious events

Other events: 32 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	LY2216684 + SSRI (Acute Open-label Period) n=1244 participants at risk 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). Includes all enrolled participants who did not discontinue for the reason 'Lost to Follow-up' at the first post-baseline visit during the Acute Open-label Period.	LY2216684 + SSRI (Stabilization Open-label Period) n=831 participants at risk Same, stable dose of LY2216684 as in the Acute Open-label Period, orally, once daily (QD) for 12 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI). Includes all participants who completed the Acute Open-label Period and did not discontinue for the reason 'Lost to Follow-up' at the first post-baseline visit during the Stabilization Open-label Period.	LY2216684 + SSRI (Double-blind Randomized Withdrawal Period) n=294 participants at risk Same, stable dose of LY2216684 as in the Stabilization Open-label Period, orally, once daily (QD) for 24 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI). Includes randomized participants who did not discontinue for the reason 'Lost to Follow-up' at the first post-randomization visit during the Double-blind Randomized Withdrawal Period.	Placebo + SSRI (Double-blind Randomized Withdrawal Period) n=292 participants at risk Placebo, orally, once daily (QD) for 24 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI). Includes randomized participants who did not discontinue for the reason 'Lost to Follow-up' at the first post-randomization visit during the Double-blind Randomized Withdrawal Period.	LY2216684 + SSRI (Randomized Tapered Discontinuation Period) n=128 participants at risk 12 milligrams (mg) LY2216684 for 4 days, 6 mg LY2216684 for 4 days, then placebo for 6 days, orally, once daily (QD), adjunctive to a selective serotonin reuptake inhibitor (SSRI). Includes all randomized participants who tapered discontinuation of LY2216684 after completion of or early withdrawal from the Double-blind Randomized Withdrawal Period and who did not discontinue for the reason 'Lost to Follow-up' at the Discontinuation Period visit.	LY2216684 + SSRI (Randomized Abrupt Discontinuation Period) n=132 participants at risk Placebo, orally, once daily (QD) for 2 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI). Includes all randomized participants who abruptly discontinued LY2216684 after completion of or early withdrawal from the Double-blind Randomized Withdrawal Period and who did not discontinue for the reason 'Lost to Follow-up' at the Discontinuation Period visit.	Placebo + SSRI (Abrupt Discontinuation Period) n=267 participants at risk Placebo, orally, once daily (QD) for 2 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI). Includes all randomized participants who discontinued placebo after completion of or early withdrawal from the Double-blind Randomized Withdrawal Period and who did not discontinue for the reason 'Lost to Follow-up' at the Discontinuation Period visit.	LY2216684 + SSRI (Nonrandomized Abrupt Discontinuation Period) n=434 participants at risk Placebo, orally, once daily (QD) for 2 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI). Includes all non-randomized participants who discontinued early from either Open-label Period and who did not discontinue for the reason 'Lost to Follow-up' at the Discontinuation Period visit.
Cardiac disorders Myocardial infarction	0.08% 1/1244 • Number of events 1	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Cardiac disorders Tachycardia	0.08% 1/1244 • Number of events 1	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Cardiac disorders Ventricular extrasystoles	0.00% 0/1244	0.12% 1/831 • Number of events 1	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Gastrointestinal disorders Abdominal pain upper	0.08% 1/1244 • Number of events 1	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Gastrointestinal disorders Colitis ischaemic	0.00% 0/1244	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.23% 1/434 • Number of events 1
Gastrointestinal disorders Intestinal obstruction	0.00% 0/1244	0.12% 1/831 • Number of events 1	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Gastrointestinal disorders Nausea	0.24% 3/1244 • Number of events 3	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Gastrointestinal disorders Oesophageal spasm	0.08% 1/1244 • Number of events 1	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Gastrointestinal disorders Vomiting	0.24% 3/1244 • Number of events 3	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
General disorders Chest pain	0.00% 0/1244	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.23% 1/434 • Number of events 1
Infections and infestations Diverticulitis	0.08% 1/1244 • Number of events 1	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Infections and infestations Gastroenteritis	0.08% 1/1244 • Number of events 1	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Infections and infestations Pneumonia	0.00% 0/1244	0.12% 1/831 • Number of events 1	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Injury, poisoning and procedural complications Intentional overdose	0.08% 1/1244 • Number of events 1	0.12% 1/831 • Number of events 1	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Injury, poisoning and procedural complications Poisoning	0.00% 0/1244	0.12% 1/831 • Number of events 1	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Injury, poisoning and procedural complications Road traffic accident	0.00% 0/1244	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.23% 1/434 • Number of events 1
Injury, poisoning and procedural complications Tendon rupture	0.00% 0/1244	0.00% 0/831	0.34% 1/294 • Number of events 1	0.00% 0/292	0.78% 1/128 • Number of events 1	0.00% 0/132	0.00% 0/267	0.00% 0/434
Investigations Blood creatine phosphokinase increased	0.08% 1/1244 • Number of events 1	0.12% 1/831 • Number of events 1	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Investigations Blood glucose increased	0.08% 1/1244 • Number of events 1	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Metabolism and nutrition disorders Dehydration	0.08% 1/1244 • Number of events 1	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.23% 1/434 • Number of events 1
Metabolism and nutrition disorders Ketosis	0.08% 1/1244 • Number of events 1	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/1244	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.23% 1/434 • Number of events 1
Musculoskeletal and connective tissue disorders Intervertebral disc disorder	0.08% 1/1244 • Number of events 1	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.23% 1/434 • Number of events 1
Musculoskeletal and connective tissue disorders Osteoarthritis	0.08% 1/1244 • Number of events 1	0.12% 1/831 • Number of events 1	0.00% 0/294	0.34% 1/292 • Number of events 1	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Angiomyolipoma	0.00% 0/1244	0.00% 0/831	0.00% 0/294	0.34% 1/292 • Number of events 1	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.08% 1/1244 • Number of events 1	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.23% 1/434 • Number of events 1
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cholesteatoma	0.08% 1/1244 • Number of events 1	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.23% 1/434 • Number of events 1
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to liver	0.08% 1/1244 • Number of events 1	0.12% 1/831 • Number of events 1	0.00% 0/294	0.34% 1/292 • Number of events 1	0.00% 0/128	0.00% 0/132	0.37% 1/267 • Number of events 1	0.00% 0/434
Nervous system disorders Convulsion	0.08% 1/1244 • Number of events 1	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Nervous system disorders Dizziness	0.00% 0/1244	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.23% 1/434 • Number of events 1
Nervous system disorders Encephalopathy	0.08% 1/1244 • Number of events 1	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Nervous system disorders Headache	0.00% 0/1244	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.23% 1/434 • Number of events 1
Nervous system disorders Hypoaesthesia	0.08% 1/1244 • Number of events 1	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Nervous system disorders Syncope	0.08% 1/1244 • Number of events 1	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.23% 1/434 • Number of events 1
Pregnancy, puerperium and perinatal conditions Abortion	0.00% 0/914	0.16% 1/641 • Number of events 1	0.00% 0/223	0.00% 0/226	0.00% 0/95	0.00% 0/105	0.00% 0/212	0.00% 0/307
Pregnancy, puerperium and perinatal conditions Blighted ovum	0.11% 1/914 • Number of events 1	0.00% 0/641	0.00% 0/223	0.00% 0/226	0.00% 0/95	0.00% 0/105	0.00% 0/212	0.33% 1/307 • Number of events 1
Psychiatric disorders Alcohol abuse	0.00% 0/1244	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.23% 1/434 • Number of events 1
Psychiatric disorders Depression	0.00% 0/1244	0.12% 1/831 • Number of events 1	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.23% 1/434 • Number of events 1
Psychiatric disorders Major depression	0.00% 0/1244	0.00% 0/831	0.00% 0/294	0.34% 1/292 • Number of events 1	0.78% 1/128 • Number of events 1	0.00% 0/132	0.00% 0/267	0.00% 0/434
Psychiatric disorders Self injurious behaviour	0.08% 1/1244 • Number of events 1	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Psychiatric disorders Suicidal behaviour	0.00% 0/1244	0.12% 1/831 • Number of events 2	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Psychiatric disorders Suicidal ideation	0.00% 0/1244	0.12% 1/831 • Number of events 1	0.00% 0/294	0.34% 1/292 • Number of events 1	0.00% 0/128	0.00% 0/132	0.37% 1/267 • Number of events 1	0.00% 0/434
Psychiatric disorders Suicide attempt	0.08% 1/1244 • Number of events 1	0.24% 2/831 • Number of events 2	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Renal and urinary disorders Nephrolithiasis	0.08% 1/1244 • Number of events 1	0.12% 1/831 • Number of events 1	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Reproductive system and breast disorders Vaginal polyp	0.00% 0/914	0.16% 1/641 • Number of events 1	0.45% 1/223 • Number of events 1	0.00% 0/226	0.00% 0/95	0.00% 0/105	0.00% 0/212	0.00% 0/307
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/1244	0.00% 0/831	0.00% 0/294	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.23% 1/434 • Number of events 1
Surgical and medical procedures Hysterectomy	0.00% 0/914	0.16% 1/641 • Number of events 1	0.00% 0/223	0.00% 0/226	0.00% 0/95	0.00% 0/105	0.00% 0/212	0.00% 0/307
Vascular disorders Hypertension	0.16% 2/1244 • Number of events 2	0.00% 0/831	0.00% 0/294	0.34% 1/292 • Number of events 1	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434

Other adverse events

Other adverse events
Measure	LY2216684 + SSRI (Acute Open-label Period) n=1244 participants at risk 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). Includes all enrolled participants who did not discontinue for the reason 'Lost to Follow-up' at the first post-baseline visit during the Acute Open-label Period.	LY2216684 + SSRI (Stabilization Open-label Period) n=831 participants at risk Same, stable dose of LY2216684 as in the Acute Open-label Period, orally, once daily (QD) for 12 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI). Includes all participants who completed the Acute Open-label Period and did not discontinue for the reason 'Lost to Follow-up' at the first post-baseline visit during the Stabilization Open-label Period.	LY2216684 + SSRI (Double-blind Randomized Withdrawal Period) n=294 participants at risk Same, stable dose of LY2216684 as in the Stabilization Open-label Period, orally, once daily (QD) for 24 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI). Includes randomized participants who did not discontinue for the reason 'Lost to Follow-up' at the first post-randomization visit during the Double-blind Randomized Withdrawal Period.	Placebo + SSRI (Double-blind Randomized Withdrawal Period) n=292 participants at risk Placebo, orally, once daily (QD) for 24 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI). Includes randomized participants who did not discontinue for the reason 'Lost to Follow-up' at the first post-randomization visit during the Double-blind Randomized Withdrawal Period.	LY2216684 + SSRI (Randomized Tapered Discontinuation Period) n=128 participants at risk 12 milligrams (mg) LY2216684 for 4 days, 6 mg LY2216684 for 4 days, then placebo for 6 days, orally, once daily (QD), adjunctive to a selective serotonin reuptake inhibitor (SSRI). Includes all randomized participants who tapered discontinuation of LY2216684 after completion of or early withdrawal from the Double-blind Randomized Withdrawal Period and who did not discontinue for the reason 'Lost to Follow-up' at the Discontinuation Period visit.	LY2216684 + SSRI (Randomized Abrupt Discontinuation Period) n=132 participants at risk Placebo, orally, once daily (QD) for 2 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI). Includes all randomized participants who abruptly discontinued LY2216684 after completion of or early withdrawal from the Double-blind Randomized Withdrawal Period and who did not discontinue for the reason 'Lost to Follow-up' at the Discontinuation Period visit.	Placebo + SSRI (Abrupt Discontinuation Period) n=267 participants at risk Placebo, orally, once daily (QD) for 2 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI). Includes all randomized participants who discontinued placebo after completion of or early withdrawal from the Double-blind Randomized Withdrawal Period and who did not discontinue for the reason 'Lost to Follow-up' at the Discontinuation Period visit.	LY2216684 + SSRI (Nonrandomized Abrupt Discontinuation Period) n=434 participants at risk Placebo, orally, once daily (QD) for 2 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI). Includes all non-randomized participants who discontinued early from either Open-label Period and who did not discontinue for the reason 'Lost to Follow-up' at the Discontinuation Period visit.
Gastrointestinal disorders Constipation	10.6% 132/1244 • Number of events 134	1.7% 14/831 • Number of events 14	1.4% 4/294 • Number of events 5	0.68% 2/292 • Number of events 2	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.00% 0/434
Gastrointestinal disorders Dry mouth	6.4% 80/1244 • Number of events 81	1.2% 10/831 • Number of events 10	1.0% 3/294 • Number of events 3	0.00% 0/292	0.00% 0/128	0.00% 0/132	0.00% 0/267	0.23% 1/434 • Number of events 1
Gastrointestinal disorders Nausea	11.8% 147/1244 • Number of events 155	2.2% 18/831 • Number of events 21	2.4% 7/294 • Number of events 7	1.7% 5/292 • Number of events 5	2.3% 3/128 • Number of events 3	0.76% 1/132 • Number of events 1	1.9% 5/267 • Number of events 6	1.8% 8/434 • Number of events 10
Nervous system disorders Dizziness	6.7% 83/1244 • Number of events 86	0.96% 8/831 • Number of events 8	1.0% 3/294 • Number of events 3	1.4% 4/292 • Number of events 4	0.78% 1/128 • Number of events 1	0.76% 1/132 • Number of events 1	1.5% 4/267 • Number of events 4	0.92% 4/434 • Number of events 4
Nervous system disorders Headache	8.9% 111/1244 • Number of events 128	6.4% 53/831 • Number of events 54	6.1% 18/294 • Number of events 24	4.5% 13/292 • Number of events 13	5.5% 7/128 • Number of events 10	3.0% 4/132 • Number of events 5	4.1% 11/267 • Number of events 16	5.5% 24/434 • Number of events 30
Skin and subcutaneous tissue disorders Hyperhidrosis	17.3% 215/1244 • Number of events 228	2.8% 23/831 • Number of events 24	2.7% 8/294 • Number of events 8	0.34% 1/292 • Number of events 1	0.00% 0/128	0.00% 0/132	0.00% 0/267	1.2% 5/434 • Number of events 5

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 800-545-5979

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60