A Study of Flexible or Fixed Dose LY2216684 as Adjunctive Treatment for Participants With Major Depressive Disorder Who Have Had a Partial Response to Selective Serotonin Reuptake Inhibitor (SSRI) Treatment

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01187407
• Collaborator: (none)
• Enrollment: 1,480
• Locations: 54
• Arms: 3
• Duration (Months): 29
• Patients Per Site: 27.4
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The purpose of this study is to assess if LY2216684 (flexible dose of 12 to 18 milligrams [mg] or fixed dose of 6 mg once daily) is superior to placebo once daily in the adjunctive treatment of participants with Major Depressive Disorder (MDD) who were identified as partial responders to an adequate course of treatment with a selective serotonin reuptake inhibitor (SSRI) during an 8-week, double-blind, acute adjunctive treatment phase.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder (MDD)	Drug: LY2216684; Drug: Placebo; Drug: SSRI	Phase 3

Detailed Description

Following the Confirmation (CF) Phase, participants were randomized to adjunctive LY2216684 or adjunctive placebo if they had <25% improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score over the past 3 weeks and a current MADRS total score ≥14. Participants who did not meet criteria received adjunctive placebo to preserve the blind.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1480 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Placebo-Controlled, Double-Blind Study of LY2216684 Flexible-Dose 12 mg to 18 mg Once Daily and LY2216684 Fixed-Dose 6 mg Once Daily as Adjunctive Treatment for Patients With Major Depressive Disorder Who Are Partial Responders to Selective Serotonin Reuptake Inhibitor Treatment
• Study Start Date: Mar 1, 2011
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Aug 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 12 or 18 mg flexible dose LY2216684 + SSRI LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI) Prior to entering the Adjunctive Treatment (AT) Phase, participants completed a 3-week Confirmation (CF) Phase where they received placebo (orally, QD) adjunctive to their SSRI. After the CF Phase, and after randomization criteria were met, participants were randomized to a 12 or 18 mg flexible dose of LY2216684. During the AT Phase, participants first received 6 mg LY2216684 QD for 3 days, followed by 12 mg QD for the next 11 days. Then, based on efficacy and tolerability, dosage could be increased to 18 mg QD over the next 6 weeks. Participants on 18 mg QD could have had their dose decreased back to 12 mg QD. Participants who completed the AT Phase or discontinued early had the option to enter the Discontinuation (DC) Phase. During the 1-week abrupt DC Phase, participants maintained their SSRI treatment.	Drug: LY2216684; Other Names: Edivoxetine ; Drug: Placebo; Drug: SSRI; Participants should have been on their SSRI for at least 6 weeks prior and were to continue on their stable dose throughout the study; Other Names: selective serotonin reuptake inhibitor
Experimental: 6 mg fixed dose LY2216684 + SSRI LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI Prior to entering the AT Phase, participants completed a 3-week CF Phase where they received placebo (orally, QD) adjunctive to their SSRI. After the CF Phase, and after randomization criteria were met, participants were randomized to 6 mg fixed dose of LY2216684. During the AT Phase, participants received a 6 mg fixed dose of LY2216684 adjunctive to their SSRI for 8 weeks. Participants who completed the AT Phase or discontinued early had the option to enter the DC Phase. During the 1-week abrupt DC Phase, participants maintained their SSRI treatment.	Drug: LY2216684; Other Names: Edivoxetine ; Drug: Placebo; Drug: SSRI; Participants should have been on their SSRI for at least 6 weeks prior and were to continue on their stable dose throughout the study; Other Names: selective serotonin reuptake inhibitor
Placebo Comparator: Placebo + SSRI Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI Prior to entering the AT Phase, participants completed a 3-week CF Phase where they received placebo (orally, QD) adjunctive to their SSRI. After the CF Phase, and after randomization criteria were met, participants were randomized to placebo. During the AT Phase, participants received placebo (administered orally, QD) adjunctive to their SSRI for 8 weeks. Participants who completed the AT Phase or discontinued early had the option to enter the DC Phase. During the 1-week abrupt DC Phase, participants maintained their SSRI treatment.	Drug: Placebo; Drug: SSRI; Participants should have been on their SSRI for at least 6 weeks prior and were to continue on their stable dose throughout the study; Other Names: selective serotonin reuptake inhibitor

Outcome Measures

Primary Outcome Measures

1. Change From Randomization to Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score [Randomization, 8 weeks]

   The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist (sadness [apparent], sadness [reported], inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Items were rated on a scale of 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit, and baseline score-by-visit.

Secondary Outcome Measures

1. Change From Randomization to Week 8 in the Sheehan Disability Scale (SDS) Global Functional Impairment Score [Randomization, 8 weeks]

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

2. Change From Randomization to Week 8 in the Fatigue Associated With Depression (FAsD) Impact Subscale Score [Randomization, 8 weeks]

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

3. Percentage of Participants Achieving a Montgomery-Asberg Depression Rating Scale (MADRS) Total Score of Less Than or Equal to 10 up to Week 8 [Randomization up to 8 weeks]

   A MADRS total score of less than or equal to 10 was defined as remission criteria. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist (sadness [apparent], sadness [reported], inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Items were rated on a scale of 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Percentage of participants was calculated by dividing the number of participants who meet criteria for remission by the total number of participants analyzed, multiplied by 100%.

4. Percentage of Participants Achieving a Montgomery-Asberg Depression Rating Scale (MADRS) Total Score of Less Than or Equal 10 for at Least 2 Consecutive Measurements, Including the Participant's Last Measurement [Randomization up to 8 weeks]

   A MADRS total score of less than or equal to 10 for at least 2 consecutive measurements, including the participant's last measurement was defined as remission criteria at last 2 consecutive visits. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist (sadness [apparent], sadness [reported], inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Items were rated on a scale of 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Percentage of participants was calculated by dividing the number of participants who meet criteria for remission at last 2 consecutive visits by the total number of participants analyzed, multiplied by 100%.

5. Change From Randomization to Week 8 in the Hospital and Anxiety and Depression Scale (HADS) Anxiety Subscale Score [Randomization, 8 weeks]

   The HADS is a 14-item questionnaire with 2 subscales: anxiety and depression. Each item was rated on a 4-point scale (0 to 3), giving maximum scores of 21 for anxiety and depression subscale. Scores of 11 or more on either subscale were considered to be a significant 'case' of psychological morbidity, while scores of 8 to 10 represent 'borderline' and scores of 0 to 7 represent 'normal'. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline subscale score, treatment-by-visit, and baseline subscale score-by-visit.

6. Percentage of Participants Who Have a Greater Than or Equal to 50 Percent Improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Randomization up to Week 8 [Randomization up to 8 weeks]

   A greater than or equal to 50 percent improvement (that is, a decrease from baseline) in the MADRS total score was defined as response criteria. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist (sadness [apparent], sadness [reported], inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Items were rated on a scale of 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Percentage of participants was calculated by dividing the number of participants meeting response criteria at last visit by the total number of participants analyzed, multiplied by 100%.

7. Change From Randomization to Week 8 in the Hospital Anxiety and Depression Scale (HADS) Depression Subscale Score [Randomization, 8 weeks]

   The HADS is a 14-item questionnaire with 2 subscales: anxiety and depression. Each item was rated on a 4-point scale (0 to 3), giving maximum scores of 21 for anxiety and depression subscale. Scores of 11 or more on either subscale were considered to be a significant 'case' of psychological morbidity, while scores of 8 to 10 represent 'borderline' and scores of 0 to 7 represent 'normal'. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline subscale score, treatment-by-visit, and baseline subscale score-by-visit.

8. Change From Randomization to Week 8 in Montgomery-Asberg Depression Rating Scale (MADRS) Individual Items [Randomization, 8 weeks]

   The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist (sadness [apparent], sadness [reported], inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Items were rated on a scale of 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline item score, treatment-by-visit and baseline item score-by-visit.

9. Change From Randomization to Week 8 in Clinical Global Impressions of Severity (CGI-S) [Randomization, 8 weeks]

   CGI-S measures severity of depression at the time of assessment compared with the start of treatment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit, and baseline score-by-visit

10. Change From Randomization to Week 8 in The Fatigue Associated With Depression (FAsD) Average Score and Experience Subscale Score [Randomization, 8 weeks]

    The FAsD is a participant-rated scale with a total of 13 items. Six of the 13 items ask how often participants experience different aspects of fatigue with responses from 1 (never) to 5 (always). Seven of the 13 items ask how often fatigue impacts various aspects of the participant's lives with responses from 1 (not at all) to 5 (very much). The experience subscale score was derived by taking the mean of Items 1 through 6, and the average score was the mean of Items 1 through 13 (derived by taking the mean of all applicable items for each participant). Item 12 applied only to participants with a spouse or significant other and Item 13 applied to participants who had a job or who went to school. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit, and baseline score-by-visit.

11. Change From Randomization to Week 8 in Sheehan Disability Scale (SDS) Items [Randomization, 8 weeks]

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

12. Change From Randomization to Week 8 in the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) [Randomization, 8 weeks]

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

13. Change From Randomization to Week 8 in the EuroQol Questionnaire-5 Dimension (EQ-5D) [Randomization, 8 weeks]

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

14. Percentage of Participants With Treatment-emergent (TE) Suicidal Ideation and Behaviors Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) [Randomization through 8 weeks]

    The C-SSRS captured occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal ideation was defined as a "yes" answer to any 1 of 5 suicidal ideation questions, which included a wish to be dead and 4 different categories of active suicidal ideation. Suicidal behavior was defined as a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation and behavior are defined as treatment-emergent (TE) if not present at baseline. Percentage of participants was calculated by dividing the number of participants with suicide-related TE events by the total number of participants analyzed, multiplied by 100%. A summary of serious and other non-serious adverse events, regardless of causality, is located in the Reported Adverse Event module.

15. Change From Randomization to Week 8 in the Arizona Sexual Experiences (ASEX) Scale [Randomization, 8 weeks]

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

16. Change From Randomization to Week 8 in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) [Randomization, 8 weeks]

    The CPFQ is a 7-item participant-rated questionnaire pertaining to a participant's cognitive and physical well-being. It assesses motivation, wakefulness, energy, focus, recall, word-finding difficulty, and mental acuity. Each item was scored on a 6-point scale ranging from 1 (greater than normal) to 6 (totally absent). Total scores ranged from 7 to 42. Higher scores indicate greater disease severity. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit, and baseline score-by-visit.

17. Change From Randomization to Week 8 in Blood Pressure [Randomization, 8 weeks]

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

18. Change From Randomization to Week 8 in Pulse Rate [Randomization, 8 weeks]

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

19. Pharmacokinetics: Plasma Concentrations of LY2216684 [Pre-randomization, 1 week, 4 weeks, and 8 weeks]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Clinical diagnosis of Major Depressive Disorder (MDD)

• Using a reliable method of birth control

• Are taking a selective serotonin reuptake inhibitor (SSRI) approved for MDD treatment within the participant's country and the SSRI prescribed, including dose, should be consistent with labeling guidelines within the participating country

• Have a partial response to SSRI treatment

• Meet inclusion scores on pre-defined psychiatric scales to assess diagnosis of depression, disease severity, and response to SSRI treatment

• Reliable and able to keep all scheduled appointments

Exclusion Criteria:

• Presence of another primary psychiatric illness:

• Have had or currently have any additional ongoing Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) Axis 1 condition other than major depression within 1 year of screening

• Have had any anxiety disorder that was considered a primary diagnosis within the past year (including panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, and social phobia, but excluding specific phobias)

• Have a current or previous diagnosis of a bipolar disorder, schizophrenia, or other psychotic disorder

• Have a history of substance abuse and/or dependence within the past 1 year (drug categories defined by DSM-IV-TR), not including caffeine and nicotine

• Have an Axis II disorder that, in the judgment of the investigator, would interfere with compliance with protocol

• Have any diagnosed medical condition that could be exacerbated by noradrenergic agents, including unstable hypertension, unstable heart disease, tachycardia, tachyarrhythmia, narrow-angle glaucoma, and history of urinary hesitation or retention

• Use of excluded concomitant or psychotropic medication other than SSRI

• Have initiated or discontinued hormone therapy within the previous 3 months of prior to enrollment

• History of treatment-resistant depression as shown by lack of response of the current depressive episode to 2 or more adequate courses of antidepressant therapy at a clinically appropriate dose for at least 4 weeks, or in the judgment of the investigator, the participant has treatment-resistant depression

• Have a lifetime history of vagal nerve stimulation (VNS) transcranial magnetic stimulation (TMS), or psychosurgery

• Have received electroconvulsive therapy (ECT) in the past year

• Enrollment in a clinical study for an investigational drug

• Serious or unstable medical condition

• History of seizure disorders

• Have initiated psychotherapy, change in intensity of psychotherapy or other nondrug therapies (such as acupuncture or hypnosis) within 6 weeks prior to enrollment or any time during the study

• Participants who, in the opinion of the investigator, are judged to be at serious risk for harm to self or others

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Birmingham	Alabama	United States	35216
2	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Phoenix	Arizona	United States	85032
3	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Chino	California	United States	91710
4	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Glendale	California	United States	91204
5	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Imperial	California	United States	92251
6	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	National City	California	United States	91950
7	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Sherman Oaks	California	United States	91403
8	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Colorado Springs	Colorado	United States	80907
9	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Clearwater	Florida	United States	33761
10	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Coral Gables	Florida	United States	33145
11	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Fort Lauderdale	Florida	United States	33319
12	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Tampa	Florida	United States	33613
13	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Atlanta	Georgia	United States	30308
14	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Hoffman Estates	Illinois	United States	60169
15	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Indianapolis	Indiana	United States	46260
16	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Prairie Village	Kansas	United States	66206
17	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Wichita	Kansas	United States	67205
18	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Baltimore	Maryland	United States	21285
19	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Haverhill	Massachusetts	United States	01830
20	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Weymouth	Massachusetts	United States	02190
21	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Flowood	Mississippi	United States	39232
22	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	O'Fallon	Missouri	United States	63368
23	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Brooklyn	New York	United States	11235
24	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	New York	New York	United States	10021
25	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Beachwood	Ohio	United States	44122
26	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Oklahoma City	Oklahoma	United States	73103
27	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Philadelphia	Pennsylvania	United States	19107
28	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Houston	Texas	United States	77096
29	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Rab		Croatia	51280
30	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Zagreb		Croatia	10090
31	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Horovice		Czechia	268 31
32	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Hostivice		Czechia	25201
33	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Kladno		Czechia	27201
34	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Olomouc		Czechia	77900
35	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Prague		Czechia	100 00
36	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Strakonice		Czechia	38601
37	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Usti Nad Labem		Czechia	400001
38	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Helsinki		Finland	00100
39	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Joensuu		Finland	80100
40	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Kuopio		Finland	70110
41	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Tampere		Finland	33200
42	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Turku		Finland	20100
43	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Chiba		Japan	270-0014
44	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Fukuoka		Japan	810-0035
45	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Fukushima		Japan	961-0021
46	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Hyogo		Japan	661-0002
47	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Kanagawa		Japan	247-0056
48	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Tokyo		Japan	100-0006
49	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	San Juan		Puerto Rico	00918
50	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Bratislava		Slovakia	85101
51	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Kosice		Slovakia	04001
52	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Michalovce		Slovakia	SK-071 01
53	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Rimavska Sobota		Slovakia	97901
54	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Roznava		Slovakia	04801

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT01187407
• Other Study ID Numbers: 12182; H9P-MC-LNBQ
• First Posted: Aug 24, 2010
• Last Update Posted: Apr 24, 2018
• Last Verified: Mar 1, 2018

• Additional relevant MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major; Serotonin; Serotonin Uptake Inhibitors

Study Results

Participant Flow

Pre-assignment Detail	The first 3 weeks of the study was a double-blind Confirmation Phase during which participants continued to receive their SSRI with adjunctive placebo. If randomization criteria were met, participants were randomized to adjunctive LY2216684 or adjunctive placebo. If criteria were not met, participants continued on placebo to maintain the blind.

Arm/Group Title	Placebo + SSRI (Pre-randomized Participants)	12 or 18 mg LY2216684 + SSRI (Randomized Participants)	6 mg LY2216684 + SSRI (Randomized Participants)	Placebo + SSRI (Randomized Participants)	Placebo + SSRI (Non-randomized Participants)
Arm/Group Description	Placebo: administered orally, once daily (QD) for 3 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, QD for 8 weeks, adjunctive to an SSRI	LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
Period Title: Confirmation (CF) Phase, 3 Weeks
STARTED	1480	0	0	0	0
Entered Discontinuation (DC) Phase	25	0	0	0	0
COMPLETED	1390	0	0	0	0
NOT COMPLETED	90	0	0	0	0
Period Title: Confirmation (CF) Phase, 3 Weeks
STARTED	0	232	226	231	701
Entered Discontinuation (DC) Phase	0	212	215	220	660
COMPLETED	0	196	191	202	626
NOT COMPLETED	0	36	35	29	75

Baseline Characteristics

Arm/Group Title	12 or 18 mg LY2216684 + SSRI (Randomized Participants)	6 mg LY2216684 + SSRI (Randomized Participants)	Placebo + SSRI (Randomized Participants)	Placebo + SSRI (Non-randomized Participants)	Total
Arm/Group Description	LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI	Total of all reporting groups
Overall Participants	232	226	231	701	1390
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.63 (12.00)	47.06 (12.76)	47.30 (12.10)	46.35 (12.42)	46.67 (12.35)
Sex: Female, Male (Count of Participants)
Female	149 64.2%	153 67.7%	156 67.5%	465 66.3%	923 66.4%
Male	83 35.8%	73 32.3%	75 32.5%	236 33.7%	467 33.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	11 4.7%	9 4%	14 6.1%	49 7%	83 6%
Not Hispanic or Latino	183 78.9%	181 80.1%	178 77.1%	562 80.2%	1104 79.4%
Unknown or Not Reported	38 16.4%	36 15.9%	39 16.9%	90 12.8%	203 14.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.4%	0 0%	3 1.3%	4 0.6%	8 0.6%
Asian	21 9.1%	26 11.5%	20 8.7%	54 7.7%	121 8.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	16 6.9%	25 11.1%	18 7.8%	63 9%	122 8.8%
White	192 82.8%	173 76.5%	186 80.5%	572 81.6%	1123 80.8%
More than one race	2 0.9%	2 0.9%	3 1.3%	8 1.1%	15 1.1%
Unknown or Not Reported	0 0%	0 0%	1 0.4%	0 0%	1 0.1%
Region of Enrollment (Count of Participants)
United States	103 44.4%	98 43.4%	104 45%	377 53.8%	682 49.1%
Czechia	44 19%	44 19.5%	46 19.9%	119 17%	253 18.2%
Slovakia	33 14.2%	35 15.5%	34 14.7%	39 5.6%	141 10.1%
Finland	18 7.8%	12 5.3%	17 7.4%	61 8.7%	108 7.8%
Croatia	9 3.9%	10 4.4%	7 3%	26 3.7%	52 3.7%
Japan	20 8.6%	23 10.2%	19 8.2%	53 7.6%	115 8.3%
Hungary	2 0.9%	2 0.9%	1 0.4%	3 0.4%	8 0.6%
Romania	3 1.3%	2 0.9%	3 1.3%	23 3.3%	31 2.2%

Outcome Measures

1. Primary Outcome

Title	Change From Randomization to Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
Description	The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist (sadness [apparent], sadness [reported], inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Items were rated on a scale of 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit, and baseline score-by-visit.
Time Frame	Randomization, 8 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	12 or 18 mg Flexible Dose LY2216684 + SSRI	6 mg Fixed Dose LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
Measure Participants	231	220	228
Least Squares Mean (Standard Error) [units on a scale]	-9.36 (0.55)	-9.59 (0.55)	-9.36 (0.54)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	12 or 18 mg Flexible Dose LY2216684 + SSRI, Placebo + SSRI
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.997
	Comments	Primary comparison.
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	6 mg Fixed Dose LY2216684 + SSRI, Placebo + SSRI
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.769
	Comments	Secondary comparison.
	Method	Mixed Models Analysis
	Comments

2. Secondary Outcome

Title	Change From Randomization to Week 8 in the Sheehan Disability Scale (SDS) Global Functional Impairment Score
Description	The SDS was completed by the participant and used to assess the effect of the participant's symptoms on their work (Item 1), social (Item 2), and family life (Item 3). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. The Global Functional Impairment Score is the sum of the 3 items, and scores ranged from 0 to 30 with higher values indicating greater disruption in the participant's work life (work/school impairment score), social life (social life/leisure activities impairment score), and family life (family life/home responsibilities impairment score). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit, and baseline score-by-visit.
Time Frame	Randomization, 8 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	12 or 18 mg Flexible Dose LY2216684 + SSRI	6 mg Fixed Dose LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
Measure Participants	225	210	221
Least Squares Mean (Standard Error) [units on a scale]	-5.30 (0.43)	-6.29 (0.44)	-4.30 (0.43)

3. Secondary Outcome

Title	Change From Randomization to Week 8 in the Fatigue Associated With Depression (FAsD) Impact Subscale Score
Description	The FAsD is a participant-rated scale with a total of 13 items. Six of the 13 items ask how often participants experience different aspects of fatigue with responses from 1 (never) to 5 (always). Seven of the 13 items ask how often fatigue impacts various aspects of the participant's lives with responses from 1 (not at all) to 5 (very much). The impact subscale score was derived by taking the mean of Items 7 through 13 (applicable items only). Item 12 applied only to participants with a spouse or significant other and Item 13 applied to participants who had a job or who went to school. The FAsD impact subscale score ranges from 1 to 5. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline subscale score, treatment-by-visit, and baseline subscale score-by-visit.
Time Frame	Randomization, 8 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	12 or 18 mg Flexible Dose LY2216684 + SSRI	6 mg Fixed Dose LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
Measure Participants	225	210	221
Least Squares Mean (Standard Error) [units on a scale]	-0.71 (0.06)	-0.67 (0.06)	-0.56 (0.06)

4. Secondary Outcome

Title	Percentage of Participants Achieving a Montgomery-Asberg Depression Rating Scale (MADRS) Total Score of Less Than or Equal to 10 up to Week 8
Description	A MADRS total score of less than or equal to 10 was defined as remission criteria. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist (sadness [apparent], sadness [reported], inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Items were rated on a scale of 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Percentage of participants was calculated by dividing the number of participants who meet criteria for remission by the total number of participants analyzed, multiplied by 100%.
Time Frame	Randomization up to 8 weeks

Outcome Measure Data

Analysis Population Description

All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value. Last observation carried forward (LOCF) methodology was used.

Arm/Group Title	12 or 18 mg Flexible Dose LY2216684 + SSRI	6 mg Fixed Dose LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
Measure Participants	231	221	228
Number [percentage of participants]	26.84 11.6%	29.41 13%	26.32 11.4%

5. Secondary Outcome

Title	Percentage of Participants Achieving a Montgomery-Asberg Depression Rating Scale (MADRS) Total Score of Less Than or Equal 10 for at Least 2 Consecutive Measurements, Including the Participant's Last Measurement
Description	A MADRS total score of less than or equal to 10 for at least 2 consecutive measurements, including the participant's last measurement was defined as remission criteria at last 2 consecutive visits. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist (sadness [apparent], sadness [reported], inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Items were rated on a scale of 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Percentage of participants was calculated by dividing the number of participants who meet criteria for remission at last 2 consecutive visits by the total number of participants analyzed, multiplied by 100%.
Time Frame	Randomization up to 8 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	12 or 18 mg Flexible Dose LY2216684 + SSRI	6 mg Fixed Dose LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
Measure Participants	231	221	228
Number [percentage of participants]	17.75 7.7%	19.00 8.4%	14.47 6.3%

6. Secondary Outcome

Title	Change From Randomization to Week 8 in the Hospital and Anxiety and Depression Scale (HADS) Anxiety Subscale Score
Description	The HADS is a 14-item questionnaire with 2 subscales: anxiety and depression. Each item was rated on a 4-point scale (0 to 3), giving maximum scores of 21 for anxiety and depression subscale. Scores of 11 or more on either subscale were considered to be a significant 'case' of psychological morbidity, while scores of 8 to 10 represent 'borderline' and scores of 0 to 7 represent 'normal'. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline subscale score, treatment-by-visit, and baseline subscale score-by-visit.
Time Frame	Randomization, 8 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	12 or 18 mg Flexible Dose LY2216684 + SSRI	6 mg Fixed Dose LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
Measure Participants	231	220	228
Least Squares Mean (Standard Error) [units on a scale]	-2.24 (0.24)	-2.64 (0.24)	-2.05 (0.24)

7. Secondary Outcome

Title	Percentage of Participants Who Have a Greater Than or Equal to 50 Percent Improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Randomization up to Week 8
Description	A greater than or equal to 50 percent improvement (that is, a decrease from baseline) in the MADRS total score was defined as response criteria. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist (sadness [apparent], sadness [reported], inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Items were rated on a scale of 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Percentage of participants was calculated by dividing the number of participants meeting response criteria at last visit by the total number of participants analyzed, multiplied by 100%.
Time Frame	Randomization up to 8 weeks

Outcome Measure Data

Analysis Population Description

All randomized participants who have non-missing values at the time of randomization and at least one post-randomization value. Last observation carried forward (LOCF) methodology was used.

Arm/Group Title	12 or 18 mg Flexible Dose LY2216684 + SSRI	6 mg Fixed Dose LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
Measure Participants	231	221	228
Number [percentage of participants]	30.74 13.3%	34.84 15.4%	32.46 14.1%

8. Secondary Outcome

Title	Change From Randomization to Week 8 in the Hospital Anxiety and Depression Scale (HADS) Depression Subscale Score
Description	The HADS is a 14-item questionnaire with 2 subscales: anxiety and depression. Each item was rated on a 4-point scale (0 to 3), giving maximum scores of 21 for anxiety and depression subscale. Scores of 11 or more on either subscale were considered to be a significant 'case' of psychological morbidity, while scores of 8 to 10 represent 'borderline' and scores of 0 to 7 represent 'normal'. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline subscale score, treatment-by-visit, and baseline subscale score-by-visit.
Time Frame	Randomization, 8 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	12 or 18 mg Flexible Dose LY2216684 + SSRI	6 mg Fixed Dose LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
Measure Participants	231	220	228
Least Squares Mean (Standard Error) [units on a scale]	-3.40 (0.26)	-3.62 (0.27)	-2.55 (0.26)

9. Secondary Outcome

Title	Change From Randomization to Week 8 in Montgomery-Asberg Depression Rating Scale (MADRS) Individual Items
Description	The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist (sadness [apparent], sadness [reported], inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Items were rated on a scale of 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline item score, treatment-by-visit and baseline item score-by-visit.
Time Frame	Randomization, 8 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	12 or 18 mg Flexible Dose LY2216684 + SSRI	6 mg Fixed Dose LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
Measure Participants	231	220	228
Apparent sadness	-1.34 (0.08)	-1.25 (0.08)	-1.26 (0.08)
Reported sadness	-1.41 (0.09)	-1.31 (0.09)	-1.26 (0.09)
Inner tension	-0.96 (0.08)	-0.91 (0.08)	-0.87 (0.08)
Reduced sleep	-0.82 (0.09)	-0.96 (0.09)	-0.92 (0.09)
Reduced appetite	-0.57 (0.08)	-0.67 (0.08)	-0.71 (0.08)
Concentration difficulties	-1.13 (0.08)	-1.14 (0.08)	-0.98 (0.08)
Lassitude	-1.15 (0.09)	-1.07 (0.09)	-1.16 (0.09)
Inability to feel	-1.11 (0.09)	-1.30 (0.09)	-1.14 (0.09)
Pessimistic thoughts	-0.84 (0.07)	-0.82 (0.07)	-0.91 (0.07)
Suicidal thoughts	-0.17 (0.03)	-0.19 (0.03)	-0.17 (0.03)

10. Secondary Outcome

Title	Change From Randomization to Week 8 in Clinical Global Impressions of Severity (CGI-S)
Description	CGI-S measures severity of depression at the time of assessment compared with the start of treatment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit, and baseline score-by-visit
Time Frame	Randomization, 8 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	12 or 18 mg Flexible Dose LY2216684 + SSRI	6 mg Fixed Dose LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
Measure Participants	231	220	228
Least Squares Mean (Standard Error) [units on a scale]	-1.20 (0.08)	-1.21 (0.08)	-1.14 (0.07)

11. Secondary Outcome

Title	Change From Randomization to Week 8 in The Fatigue Associated With Depression (FAsD) Average Score and Experience Subscale Score
Description	The FAsD is a participant-rated scale with a total of 13 items. Six of the 13 items ask how often participants experience different aspects of fatigue with responses from 1 (never) to 5 (always). Seven of the 13 items ask how often fatigue impacts various aspects of the participant's lives with responses from 1 (not at all) to 5 (very much). The experience subscale score was derived by taking the mean of Items 1 through 6, and the average score was the mean of Items 1 through 13 (derived by taking the mean of all applicable items for each participant). Item 12 applied only to participants with a spouse or significant other and Item 13 applied to participants who had a job or who went to school. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit, and baseline score-by-visit.
Time Frame	Randomization, 8 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	12 or 18 mg Flexible Dose LY2216684 + SSRI	6 mg Fixed Dose LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
Measure Participants	225	210	221
FAsD average score	-0.67 (0.05)	-0.68 (0.06)	-0.53 (0.05)
FAsD experience score	-0.63 (0.06)	-0.67 (0.06)	-0.50 (0.06)

12. Secondary Outcome

Title	Change From Randomization to Week 8 in Sheehan Disability Scale (SDS) Items
Description	The SDS was completed by the participant and used to assess the effect of the participant's symptoms on their work (work/school impairment score), social life (social life/leisure activities impairment score), and family life (family life/home responsibilities impairment score). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline item score, treatment-by-visit, and baseline item score-by-visit.
Time Frame	Randomization, 8 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	12 or 18 mg Flexible Dose LY2216684 + SSRI	6 mg Fixed Dose LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
Measure Participants	225	210	221
Work impairment score	-1.81 (0.19)	-1.93 (0.20)	-1.32 (0.19)
Social life impairment score	-1.79 (0.16)	-2.11 (0.16)	-1.52 (0.16)
Family life impairment score	-1.75 (0.15)	-2.16 (0.15)	-1.47 (0.15)

13. Secondary Outcome

Title	Change From Randomization to Week 8 in the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF)
Description	The Q-LES-Q-SF is a self-administered 16 item questionnaire measuring degree of enjoyment and satisfaction experienced in various areas of daily life during the past week on a 5-point Likert scale (1=very poor and 5=very good). The total raw score is the sum of Items 1 to 14 and ranges from 14 to 70. The raw scores are converted to and expressed as the percentage of the maximum possible score. Higher scores indicate higher levels of enjoyment/satisfaction. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit, and baseline score-by-visit.
Time Frame	Randomization, 8 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	12 or 18 mg Flexible Dose LY2216684 + SSRI	6 mg Fixed Dose LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
Measure Participants	224	210	221
Least Squares Mean (Standard Error) [percentage of maximum possible score]	10.54 (1.00)	10.05 (1.02)	8.74 (0.99)

14. Secondary Outcome

Title	Change From Randomization to Week 8 in the EuroQol Questionnaire-5 Dimension (EQ-5D)
Description	The EQ-5D Visual Analog Scale is a generic, multidimensional, health-related, quality-of-life instrument. Overall health state score is self-reported using a visual analogue scale, marked on a scale of 0 to 100 with 0 representing worst imaginable health state and 100 representing best imaginable health state. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit, and baseline score-by-visit.
Time Frame	Randomization, 8 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	12 or 18 mg Flexible Dose LY2216684 + SSRI	6 mg Fixed Dose LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
Measure Participants	225	210	221
Least Squares Mean (Standard Error) [units on a scale]	11.457 (1.218)	11.895 (1.239)	9.530 (1.207)

15. Secondary Outcome

Title	Percentage of Participants With Treatment-emergent (TE) Suicidal Ideation and Behaviors Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS)
Description	The C-SSRS captured occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal ideation was defined as a "yes" answer to any 1 of 5 suicidal ideation questions, which included a wish to be dead and 4 different categories of active suicidal ideation. Suicidal behavior was defined as a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation and behavior are defined as treatment-emergent (TE) if not present at baseline. Percentage of participants was calculated by dividing the number of participants with suicide-related TE events by the total number of participants analyzed, multiplied by 100%. A summary of serious and other non-serious adverse events, regardless of causality, is located in the Reported Adverse Event module.
Time Frame	Randomization through 8 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	12 or 18 mg Flexible Dose LY2216684 + SSRI	6 mg Fixed Dose LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI)	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
Measure Participants	232	221	228
TE suicidal ideation	5.17 2.2%	3.62 1.6%	4.39 1.9%
TE suicidal behavior	0.00 0%	0.00 0%	0.00 0%

16. Secondary Outcome

Title	Change From Randomization to Week 8 in the Arizona Sexual Experiences (ASEX) Scale
Description	The ASEX scale was used to assess sexual functioning in both males and females. The ASEX total score for the male and female version was calculated as the sum of the responses (rated from 1 [extremely] to 6 [no/never]) of the 5 items of the ASEX scale. Total scores ranged from 5 to 30, with higher scores indicating greater sexual dysfunction. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit, and baseline score-by-visit.
Time Frame	Randomization, 8 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	12 or 18 mg Flexible Dose LY2216684 + SSRI	6 mg Fixed Dose LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
Measure Participants	224	209	220
Least Squares Mean (Standard Error) [units on a scale]	-1.62 (0.29)	-1.29 (0.29)	-0.97 (0.29)

17. Secondary Outcome

Title	Change From Randomization to Week 8 in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ)
Description	The CPFQ is a 7-item participant-rated questionnaire pertaining to a participant's cognitive and physical well-being. It assesses motivation, wakefulness, energy, focus, recall, word-finding difficulty, and mental acuity. Each item was scored on a 6-point scale ranging from 1 (greater than normal) to 6 (totally absent). Total scores ranged from 7 to 42. Higher scores indicate greater disease severity. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit, and baseline score-by-visit.
Time Frame	Randomization, 8 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	12 or 18 mg Flexible Dose LY2216684 + SSRI	6 mg Fixed Dose LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
Measure Participants	225	210	221
Least Squares Mean (Standard Error) [units on a scale]	-4.74 (0.38)	-4.67 (0.39)	-3.64 (0.38)

18. Secondary Outcome

Title	Change From Randomization to Week 8 in Blood Pressure
Description	Blood pressure measurements were collected when the participant was in a sitting position. Three measurements of sitting blood pressure collected at approximately 1-minute intervals at every visit were averaged and used as the value for the visit. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline value, treatment-by-visit, and baseline value-by-visit.
Time Frame	Randomization, 8 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	12 or 18 mg Flexible Dose LY2216684 + SSRI	6 mg Fixed Dose LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
Measure Participants	232	220	228
Systolic blood pressure	1.64 (0.62)	2.93 (0.63)	0.78 (0.62)
Diastolic blood pressure	3.46 (0.49)	4.47 (0.50)	1.01 (0.49)

19. Secondary Outcome

Title	Change From Randomization to Week 8 in Pulse Rate
Description	Pulse measurements were collected when the participant was in a sitting position. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline value, treatment-by-visit, and baseline value-by-visit.
Time Frame	Randomization, 8 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	12 or 18 mg Flexible Dose LY2216684 + SSRI	6 mg Fixed Dose LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI	Placebo: administered orally, QD for 8 weeks, adjunctive to an SSRI
Measure Participants	232	220	228
Least Squares Mean (Standard Error) [beats per minute (bpm)]	9.26 (0.65)	7.32 (0.66)	-1.03 (0.65)

20. Secondary Outcome

Title	Pharmacokinetics: Plasma Concentrations of LY2216684
Description	A validated bioanalytical assay was used to determine plasma LY2216684 concentrations.
Time Frame	Pre-randomization, 1 week, 4 weeks, and 8 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2216684
Arm/Group Description	LY2216684: flexible dose of 12 or 18 milligrams (mg) or fixed dose of 6 mg, administered orally, once daily (QD)
Measure Participants	400
6-mg dose	17.0 (10.2)
12-mg dose	32.2 (21.1)
18-mg dose	52.4 (34.6)

Adverse Events

Arm/Group Title	Placebo + SSRI (Pre-randomized) - CF Phase		12 or 18 mg LY2216684 + SSRI (Randomized) - AT Phase		6 mg LY2216684 + SSRI (Randomized) - AT Phase		Placebo + SSRI (Randomized) - AT Phase		Placebo + SSRI (Non-randomized) - AT Phase		Placebo + SSRI (Pre-randomized) - DC Phase		12 or 18 mg LY2216684 + SSRI (Randomized) - DC Phase		6 mg LY2216684 + SSRI (Randomized) - DC Phase		Placebo + SSRI (Randomized) - DC Phase		Placebo + SSRI (Non-randomized) - DC Phase
Arm/Group Description	Placebo: administered orally, once daily for 3 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI) Includes all enrolled who did not discontinue for the reason 'Lost to Follow-up' at the first post-baseline visit during the Confirmation (CF) Phase.		LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily for 8 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 Adjunctive Treatment (AT) Phase.		LY2216684: fixed dose of 6 milligrams (mg), administered orally, once daily for 8 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 Adjunctive Treatment (AT) Phase.		Placebo: administered orally, once daily for 8 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 Adjunctive Treatment (AT) Phase.		Placebo: administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI) Includes all non-randomized participants who did not discontinue for the reason 'Lost to Follow-up' at the first post-randomization visit during the Adjunctive Treatment (AT) Phase.		No study drug was administered. Participants were to maintain their selective serotonin reuptake inhibitor (SSRI) treatment at a stable dose for 1 week. Includes all enrolled participants who abruptly discontinued placebo after early withdrawal during the Confirmation (CF) Phase and who did not discontinue for the reason 'Lost to Follow-up' at the Discontinuation (DC) Phase visit.		No study drug was administered. Participants were to maintain their selective serotonin reuptake inhibitor (SSRI) treatment at a stable dose for 1 week. Includes all randomized participants who abruptly discontinued LY2216684 either at the end of the study or after early withdrawal from the study and who did not discontinue for the reason 'Lost to Follow-up' at the Discontinuation (DC) Phase visit.		No study drug was administered. Participants were to maintain their selective serotonin reuptake inhibitor (SSRI) treatment at a stable dose for 1 week. Includes all randomized participants who abruptly discontinued LY2216684 either at the end of the study or after early withdrawal from the study and who did not discontinue for the reason 'Lost to Follow-up' at the Discontinuation (DC) Phase visit.		No study drug was administered. Participants were to maintain their selective serotonin reuptake inhibitor (SSRI) treatment at a stable dose for 1 week. Includes all randomized participants who abruptly discontinued placebo either at the end of the study or after early withdrawal from the study and who did not discontinue for the reason 'Lost to Follow-up' at the Discontinuation (DC) Phase visit.		No study drug was administered. Participants were to maintain their selective serotonin reuptake inhibitor (SSRI) treatment at a stable dose for 1 week. Includes all non-randomized participants who abruptly discontinued placebo either at the end of the study or after early withdrawal from the study and who did not discontinue for the reason 'Lost to Follow-up' at the Discontinuation (DC) Phase visit.
All Cause Mortality
	Placebo + SSRI (Pre-randomized) - CF Phase		12 or 18 mg LY2216684 + SSRI (Randomized) - AT Phase		6 mg LY2216684 + SSRI (Randomized) - AT Phase		Placebo + SSRI (Randomized) - AT Phase		Placebo + SSRI (Non-randomized) - AT Phase		Placebo + SSRI (Pre-randomized) - DC Phase		12 or 18 mg LY2216684 + SSRI (Randomized) - DC Phase		6 mg LY2216684 + SSRI (Randomized) - DC Phase		Placebo + SSRI (Randomized) - DC Phase		Placebo + SSRI (Non-randomized) - DC Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo + SSRI (Pre-randomized) - CF Phase		12 or 18 mg LY2216684 + SSRI (Randomized) - AT Phase		6 mg LY2216684 + SSRI (Randomized) - AT Phase		Placebo + SSRI (Randomized) - AT Phase		Placebo + SSRI (Non-randomized) - AT Phase		Placebo + SSRI (Pre-randomized) - DC Phase		12 or 18 mg LY2216684 + SSRI (Randomized) - DC Phase		6 mg LY2216684 + SSRI (Randomized) - DC Phase		Placebo + SSRI (Randomized) - DC Phase		Placebo + SSRI (Non-randomized) - DC Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/1476 (0.5%)		2/232 (0.9%)		1/223 (0.4%)		2/231 (0.9%)		5/699 (0.7%)		3/25 (12%)		0/212 (0%)		2/213 (0.9%)		1/220 (0.5%)		2/659 (0.3%)
Cardiac disorders
Atrial fibrillation	2/1476 (0.1%)	2	0/232 (0%)	0	0/223 (0%)	0	0/231 (0%)	0	0/699 (0%)	0	1/25 (4%)	1	0/212 (0%)	0	0/213 (0%)	0	0/220 (0%)	0	0/659 (0%)	0
General disorders
Inflammation	0/1476 (0%)	0	1/232 (0.4%)	1	0/223 (0%)	0	0/231 (0%)	0	0/699 (0%)	0	0/25 (0%)	0	0/212 (0%)	0	0/213 (0%)	0	0/220 (0%)	0	0/659 (0%)	0
Infections and infestations
Appendicitis	0/1476 (0%)	0	1/232 (0.4%)	1	0/223 (0%)	0	0/231 (0%)	0	0/699 (0%)	0	0/25 (0%)	0	0/212 (0%)	0	0/213 (0%)	0	0/220 (0%)	0	0/659 (0%)	0
Diverticulitis	0/1476 (0%)	0	0/232 (0%)	0	0/223 (0%)	0	0/231 (0%)	0	1/699 (0.1%)	1	0/25 (0%)	0	0/212 (0%)	0	0/213 (0%)	0	0/220 (0%)	0	0/659 (0%)	0
Mastitis	0/1476 (0%)	0	0/232 (0%)	0	0/223 (0%)	0	0/231 (0%)	0	1/699 (0.1%)	1	0/25 (0%)	0	0/212 (0%)	0	0/213 (0%)	0	0/220 (0%)	0	1/659 (0.2%)	1
Pneumonia	0/1476 (0%)	0	0/232 (0%)	0	0/223 (0%)	0	0/231 (0%)	0	1/699 (0.1%)	1	0/25 (0%)	0	0/212 (0%)	0	0/213 (0%)	0	0/220 (0%)	0	1/659 (0.2%)	1
Injury, poisoning and procedural complications
Accidental overdose	0/1476 (0%)	0	0/232 (0%)	0	0/223 (0%)	0	0/231 (0%)	0	1/699 (0.1%)	1	0/25 (0%)	0	0/212 (0%)	0	0/213 (0%)	0	0/220 (0%)	0	0/659 (0%)	0
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/1476 (0.1%)	1	0/232 (0%)	0	0/223 (0%)	0	1/231 (0.4%)	1	0/699 (0%)	0	0/25 (0%)	0	0/212 (0%)	0	0/213 (0%)	0	1/220 (0.5%)	1	0/659 (0%)	0
Nervous system disorders
Syncope	0/1476 (0%)	0	0/232 (0%)	0	0/223 (0%)	0	0/231 (0%)	0	0/699 (0%)	0	0/25 (0%)	0	0/212 (0%)	0	1/213 (0.5%)	1	0/220 (0%)	0	0/659 (0%)	0
Psychiatric disorders
Mania	1/1476 (0.1%)	1	0/232 (0%)	0	0/223 (0%)	0	0/231 (0%)	0	0/699 (0%)	0	1/25 (4%)	1	0/212 (0%)	0	0/213 (0%)	0	0/220 (0%)	0	0/659 (0%)	0
Suicidal ideation	2/1476 (0.1%)	2	0/232 (0%)	0	0/223 (0%)	0	0/231 (0%)	0	0/699 (0%)	0	1/25 (4%)	1	0/212 (0%)	0	0/213 (0%)	0	0/220 (0%)	0	0/659 (0%)	0
Suicide attempt	0/1476 (0%)	0	0/232 (0%)	0	0/223 (0%)	0	0/231 (0%)	0	1/699 (0.1%)	1	0/25 (0%)	0	0/212 (0%)	0	0/213 (0%)	0	0/220 (0%)	0	0/659 (0%)	0
Reproductive system and breast disorders
Cervical dysplasia	1/979 (0.1%)	1	0/149 (0%)	0	1/152 (0.7%)	1	0/156 (0%)	0	0/464 (0%)	0	0/16 (0%)	0	0/133 (0%)	0	1/148 (0.7%)	1	0/145 (0%)	0	0/441 (0%)	0
Fibrocystic breast disease	0/1476 (0%)	0	0/232 (0%)	0	0/223 (0%)	0	0/231 (0%)	0	1/699 (0.1%)	1	0/25 (0%)	0	0/212 (0%)	0	0/213 (0%)	0	0/220 (0%)	0	1/659 (0.2%)	1
Metrorrhagia	0/979 (0%)	0	0/149 (0%)	0	0/152 (0%)	0	1/156 (0.6%)	1	0/464 (0%)	0	0/16 (0%)	0	0/133 (0%)	0	0/148 (0%)	0	0/145 (0%)	0	0/441 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/1476 (0%)	0	0/232 (0%)	0	0/223 (0%)	0	0/231 (0%)	0	1/699 (0.1%)	1	0/25 (0%)	0	0/212 (0%)	0	0/213 (0%)	0	0/220 (0%)	0	0/659 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo + SSRI (Pre-randomized) - CF Phase		12 or 18 mg LY2216684 + SSRI (Randomized) - AT Phase		6 mg LY2216684 + SSRI (Randomized) - AT Phase		Placebo + SSRI (Randomized) - AT Phase		Placebo + SSRI (Non-randomized) - AT Phase		Placebo + SSRI (Pre-randomized) - DC Phase		12 or 18 mg LY2216684 + SSRI (Randomized) - DC Phase		6 mg LY2216684 + SSRI (Randomized) - DC Phase		Placebo + SSRI (Randomized) - DC Phase		Placebo + SSRI (Non-randomized) - DC Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	231/1476 (15.7%)		57/232 (24.6%)		39/223 (17.5%)		38/231 (16.5%)		115/699 (16.5%)		0/25 (0%)		18/212 (8.5%)		22/213 (10.3%)		17/220 (7.7%)		64/659 (9.7%)
Cardiac disorders
Tachycardia	6/1476 (0.4%)	6	12/232 (5.2%)	12	5/223 (2.2%)	5	0/231 (0%)	0	2/699 (0.3%)	2	0/25 (0%)	0	0/212 (0%)	0	0/213 (0%)	0	0/220 (0%)	0	0/659 (0%)	0
Gastrointestinal disorders
Nausea	77/1476 (5.2%)	80	12/232 (5.2%)	17	12/223 (5.4%)	13	9/231 (3.9%)	10	25/699 (3.6%)	41	0/25 (0%)	0	2/212 (0.9%)	2	4/213 (1.9%)	4	2/220 (0.9%)	2	13/659 (2%)	13
Infections and infestations
Nasopharyngitis	35/1476 (2.4%)	35	12/232 (5.2%)	12	7/223 (3.1%)	7	7/231 (3%)	7	27/699 (3.9%)	27	0/25 (0%)	0	1/212 (0.5%)	1	1/213 (0.5%)	1	2/220 (0.9%)	2	5/659 (0.8%)	5
Nervous system disorders
Headache	112/1476 (7.6%)	127	14/232 (6%)	15	15/223 (6.7%)	18	22/231 (9.5%)	33	61/699 (8.7%)	81	0/25 (0%)	0	13/212 (6.1%)	14	19/213 (8.9%)	19	14/220 (6.4%)	14	47/659 (7.1%)	54
Skin and subcutaneous tissue disorders
Hyperhidrosis	34/1476 (2.3%)	35	18/232 (7.8%)	19	7/223 (3.1%)	8	4/231 (1.7%)	4	11/699 (1.6%)	11	0/25 (0%)	0	4/212 (1.9%)	4	0/213 (0%)	0	0/220 (0%)	0	7/659 (1.1%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.