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

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01173601
• Collaborator: (none)
• Enrollment: 1,416
• Locations: 63
• Arms: 3
• Duration (Months): 35
• Patients Per Site: 22.5
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The primary purpose of this study is to assess whether at least 1 dose of LY2216684 (12 milligrams [mg] or 18 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	Drug: LY2216684; Drug: Placebo; Drug: SSRI	Phase 3

Detailed Description

Following the Confirmation Phase, participants were randomized to adjunctive LY2216684 or adjunctive placebo if they met the following randomization criteria: 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: 1416 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 Fixed-Dose 12 Milligrams (mg) and 18 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: Nov 1, 2010
• Actual Primary Completion Date: Oct 1, 2013
• Actual Study Completion Date: Oct 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 12 milligrams (mg) LY2216684 + SSRI LY2216684: 12 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 (administered orally, QD) adjunctive to their SSRI. After the CF Phase and after randomization criteria were met, participants were randomized to the LY2216684 12-mg treatment arm (AT Phase). Participants who completed the AT Phase or discontinued early entered a 2-week Discontinuation (DC) Phase. Participants were randomly assigned to either abrupt DC or tapered DC over the 2-week DC Phase. Participants maintained their SSRI treatment during the DC Phase.	Drug: LY2216684; Other Names: Edivoxetine ; 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: 18 milligrams (mg) LY2216684 + SSRI LY2216684: 12 milligrams (mg), administered orally, once daily (QD) for 1 week, followed by 18 mg, administered orally, once daily for 7 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 (administered orally, QD) adjunctive to their SSRI. After the CF Phase and after randomization criteria were met, participants were randomized to the LY2216684 18-mg treatment arm (AT Phase). Participants who completed the AT Phase or discontinued early entered a 2-week Discontinuation (DC) Phase. Participants were randomly assigned to either abrupt DC or tapered DC over the 2-week DC Phase. Participants maintained their SSRI treatment during the DC Phase.	Drug: LY2216684; Other Names: Edivoxetine ; 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: Tablet equivalent to LY2216684, administered orally, once daily (QD) for 11 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 (administered orally, QD) adjunctive to their SSRI. After the CF Phase and after randomization criteria were met, participants were randomized to the placebo treatment arm (AT Phase). Participants who completed the AT Phase or discontinued early had the option to enter the Discontinuation (DC) Phase. Participants who had received placebo were assigned to the abrupt DC over the 2-week DC Phase. Participants maintained their SSRI treatment during the DC Phase.	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. 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 Sheehan Disability Scale (SDS) Global Functional Impairment Scale [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 Function Impairment Score is the sum of the 3 items, and scores ranged from 0 to 30 with higher values indicating disruption in the participant's work life (work/school impairment score), social life (social life/leisure activities impairment score), and family life (family life/home responsibilities impairment score). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit and baseline score-by-visit.

2. Change From Randomization to Week 8 in 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. 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 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. 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. 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 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 (0-3), giving maximum scores of 21 for anxiety and depression subscale. Scores of 11 or more on either subscale were considered to be a significant 'case' of psychological morbidity, while scores of 8-10 represent 'borderline' and 0-7 represent 'normal'. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline subscale score, treatment-by-visit, and baseline subscale score-by-visit.

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. 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 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 (0-3), giving maximum scores of 21 for anxiety and depression subscale. Scores of 11 or more on either subscale were considered to be a significant 'case' of psychological morbidity, while scores of 8-10 represent 'borderline' and 0-7 represent 'normal'. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline subscale score, treatment-by-visit and baseline subscale score-by-visit.

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

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

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 the worst imaginable health state and 100 representing best imaginable health state. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit and baseline score-by-visit.

14. Percentage of 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 TE if not present at baseline. Percentage of participants was calculated by dividing the number of participants with suicide-related TE events by the total number of participants at risk, multiplied by 100%. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Event module.

15. Change From Randomization to Week 8 in 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]) to the 5 items of the ASEX scale. Total scores ranged from 5 to 30 with higher scores indicating greater sexual dysfunction. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit and baseline score-by-visit.

16. Change From Randomization to Week 8 in 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. 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. The Percentage of Participants Experiencing Treatment-Emergent Adverse Events as a Function of CYP2D6 Phenotype [Through 8 weeks]

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

18. Change From Randomization to Week 8 in Blood Pressure (BP) [Randomization, 8 weeks]

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

19. 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.

20. Pharmacokinetics: Plasma Concentrations of LY2216684 [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)

• Women of child-bearing potential may participate but must test negative for pregnancy at the time of study entry; both women/men agree to use a reliable method of birth control

• Are taking a selective serotonin reuptake inhibitor (SSRI) approved for MDD treatment within the participant's country. 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 a DSM-IV-TR Axis II disorder that, in the judgment of the investigator, would interfere with compliance with protocol

• Have any diagnosed medical condition that could be exacerbated by noradrenergic agents including unstable hypertension, unstable heart disease, tachycardia, tachyarrhythmia, narrow-angle glaucoma, 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, transcranial magnetic stimulation, or psychosurgery

• Have received electroconvulsive therapy in the last year

• Enrollment in a clinical study for an investigational drug

• Serious or unstable medical condition

• History of seizure disorders

• Have initiated psychotherapy or other non-drug therapies (such as acupuncture or hypnosis) within 12 weeks prior to enrollment or any time during the study. Have no change in intensity of psychotherapy within the last 6 weeks prior to enrollment or at 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.	Irvine	California	United States	92618
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.	La Habra	California	United States	90631
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.	Redlands	California	United States	92374
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.	Denver	Colorado	United States	80212
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.	Jacksonville	Florida	United States	32256
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.	Atlanta	Georgia	United States	30328
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.	Marietta	Georgia	United States	30060
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.	Baltimore	Maryland	United States	21208
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.	Saint Louis	Missouri	United States	63109
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.	Berlin	New Jersey	United States	08009
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.	Jamaica	New York	United States	11432
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.	New York	New York	United States	10023
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.	Dayton	Ohio	United States	45417
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.	Middleburg Heights	Ohio	United States	44130
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.	Allentown	Pennsylvania	United States	18104
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.	Memphis	Tennessee	United States	38119
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.	Austin	Texas	United States	78731
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.	Dallas	Texas	United States	75230
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.	San Antonio	Texas	United States	78229
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.	Sugar Land	Texas	United States	77478
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.	Murray	Utah	United States	84123
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.	Milwaukee	Wisconsin	United States	53227
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.	Fukuoka		Japan	810-0001
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.	Fukushima		Japan	960-0102
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.	Hyogo		Japan	660-0882
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.	Kanagawa		Japan	238-0042
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.	Nagano		Japan	390-0303
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.	Saga		Japan	843-0023
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.	Tokyo		Japan	170-0002
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.	Daugavpils		Latvia	LV-5417
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.	Jelgava		Latvia	LV-3008
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.	Liepaja		Latvia	LV-3400
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.	Sigulda		Latvia	LV-2150
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.	Strenci		Latvia	LV-4730
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.	?Uromin		Poland	09-300
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.	Bialystok		Poland	15-879
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.	Bydgoszcz		Poland	85021
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.	Chelmno		Poland	86-200
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.	Gdansk		Poland	80-546
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.	Gorlice		Poland	38/300
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.	Katowice		Poland	40340
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.	Leszno		Poland	64-100
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.	Lublin		Poland	20-045
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.	Tuszyn		Poland	95-080
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.	Ekaterinburg		Russian Federation	620036
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.	Moscow		Russian Federation	107076
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.	Rostov-On-Don		Russian Federation	344007
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.	Bellville		South Africa	7530
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.	Cape Town		South Africa	7530
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.	Centurion		South Africa	0157
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.	George		South Africa	6529
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.	West Cape		South Africa	7500
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.	Chernihiv District		Ukraine	14000
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.	Dnipropetrovsk		Ukraine	49005
55	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.	Donetsk		Ukraine	83037
56	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.	Kherson		Ukraine	73488
57	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.	Kyiv		Ukraine	01030
58	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.	Lugansk		Ukraine	91045
59	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.	Odesa		Ukraine	65006
60	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.	Poltava		Ukraine	36013
61	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.	Simferopol		Ukraine	95006
62	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.	Uzhorod		Ukraine	88000
63	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.	Vinnytsya		Ukraine	21005

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: NCT01173601
• Other Study ID Numbers: 11316; H9P-MC-LNBM
• First Posted: Aug 2, 2010
• Last Update Posted: Apr 17, 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 was a double-blind adjunctive placebo lead-in Confirmation Phase during which participants continued their SSRI with adjunctive placebo. If randomization criteria were met, participants were randomized to receive LY2216684 12 mg, 18 mg, or placebo. If criteria were not met, participants continued on placebo to maintain the blind.

Arm/Group Title	Placebo + SSRI (Pre-Randomized Participants)	12 mg LY2216684 + SSRI (Randomized Participants)	18 mg LY2216684 + SSRI (Randomized Participants)	Placebo + SSRI (Randomized Participants)	Placebo + SSRI (Non-Randomized Participants)
Arm/Group Description	Placebo: Administered orally, once daily for 3 weeks, adjunctive to selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a SSRI	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks
Period Title: Confirmation (CF) Phase, 3 Weeks
STARTED	1416	0	0	0	0
Entered Discontinuation Phase	21	0	0	0	0
COMPLETED	1328	0	0	0	0
NOT COMPLETED	88	0	0	0	0
Period Title: Confirmation (CF) Phase, 3 Weeks
STARTED	0	231	230	240	627
Entered Taper Discontinuation Phase	0	100	107	0	0
Entered Abrupt Discontinuation Phase	0	100	108	221	586
COMPLETED	0	196	197	210	559
NOT COMPLETED	0	35	33	30	68

Baseline Characteristics

Arm/Group Title	12 mg LY2216684 + SSRI (Randomized Participants)	18 mg LY2216684 + SSRI (Randomized Participants)	Placebo + SSRI (Randomized Participants)	Placebo + SSRI (Non-Randomized Participants)	Total
Arm/Group Description	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI	Total of all reporting groups
Overall Participants	231	230	240	627	1328
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.95 (12.38)	46.06 (12.82)	44.38 (10.60)	44.73 (11.89)	44.94 (11.92)
Sex: Female, Male (Count of Participants)
Female	145 62.8%	149 64.8%	155 64.6%	451 71.9%	900 67.8%
Male	86 37.2%	81 35.2%	85 35.4%	176 28.1%	428 32.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 3.9%	7 3%	7 2.9%	28 4.5%	51 3.8%
Not Hispanic or Latino	181 78.4%	172 74.8%	188 78.3%	520 82.9%	1061 79.9%
Unknown or Not Reported	41 17.7%	51 22.2%	45 18.8%	79 12.6%	216 16.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	2 0.3%	2 0.2%
Asian	47 20.3%	45 19.6%	56 23.3%	121 19.3%	269 20.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	14 6.1%	14 6.1%	19 7.9%	65 10.4%	112 8.4%
White	164 71%	170 73.9%	164 68.3%	429 68.4%	927 69.8%
More than one race	5 2.2%	1 0.4%	0 0%	9 1.4%	15 1.1%
Unknown or Not Reported	1 0.4%	0 0%	1 0.4%	1 0.2%	3 0.2%
Region of Enrollment (Count of Participants)
United States	73 31.6%	76 33%	74 30.8%	318 50.7%	541 40.7%
Poland	46 19.9%	52 22.6%	51 21.3%	63 10%	212 16%
Ukraine	33 14.3%	29 12.6%	29 12.1%	36 5.7%	127 9.6%
Russia	6 2.6%	6 2.6%	6 2.5%	15 2.4%	33 2.5%
South Africa	10 4.3%	9 3.9%	10 4.2%	44 7%	73 5.5%
Latvia	16 6.9%	14 6.1%	17 7.1%	34 5.4%	81 6.1%
Japan	47 20.3%	44 19.1%	53 22.1%	117 18.7%	261 19.7%

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. 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 mg LY2216684 + SSRI	18 mg LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI
Measure Participants	230	230	240
Least Squares Mean (Standard Error) [units on a scale]	-8.47 (0.52)	-8.70 (0.53)	-7.77 (0.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	12 mg LY2216684 + SSRI, Placebo + SSRI
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.338
	Comments	In order to test the primary outcome between each LY2216684 dose and placebo while controlling the overall Type I error at 0.05, the significance level was a priori partitioned equally between the 2 LY2216684 dose-placebo comparisons at 0.025.
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	18 mg LY2216684 + SSRI, Placebo + SSRI
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.201
	Comments	In order to test the primary outcome between each LY2216684 dose and placebo while controlling the overall Type I error at 0.05, the significance level was a priori partitioned equally between the 2 LY2216684 dose-placebo comparisons at 0.025.
	Method	Mixed Models Analysis
	Comments

2. Secondary Outcome

Title	Change From Randomization to Week 8 in Sheehan Disability Scale (SDS) Global Functional Impairment Scale
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 Function Impairment Score is the sum of the 3 items, and scores ranged from 0 to 30 with higher values indicating disruption in the participant's work life (work/school impairment score), social life (social life/leisure activities impairment score), and family life (family life/home responsibilities impairment score). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit and baseline score-by-visit.
Time Frame	Randomization, 8 weeks

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 mg LY2216684 + SSRI	18 mg LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI
Measure Participants	224	222	236
Least Squares Mean (Standard Error) [units on a scale]	-5.36 (0.44)	-5.27 (0.44)	-4.47 (0.43)

3. Secondary Outcome

Title	Change From Randomization to Week 8 in 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. 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 mg LY2216684 + SSRI	18 mg LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI
Measure Participants	224	221	236
Least Squares Mean (Standard Error) [units on a scale]	-0.74 (0.06)	-0.66 (0.06)	-0.53 (0.06)

4. Secondary Outcome

Title	Percentage of Participants Achieving a Montgomery-Asberg Depression Rating Scale (MADRS) Total Score of Less Than or Equal 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. 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.

Arm/Group Title	12 mg LY2216684 + SSRI	18 mg LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI
Measure Participants	230	230	240
Number [percentage of participants]	27.83 12%	26.96 11.7%	26.67 11.1%

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. 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 with a baseline and at least one post-baseline value.

Arm/Group Title	12 mg LY2216684 + SSRI	18 mg LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI
Measure Participants	230	230	240
Number [percentage of participants]	16.96 7.3%	19.13 8.3%	19.58 8.2%

6. Secondary Outcome

Title	Change From Randomization to Week 8 in 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 (0-3), giving maximum scores of 21 for anxiety and depression subscale. Scores of 11 or more on either subscale were considered to be a significant 'case' of psychological morbidity, while scores of 8-10 represent 'borderline' and 0-7 represent 'normal'. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline subscale score, treatment-by-visit, and baseline subscale score-by-visit.
Time Frame	Randomization, 8 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	12 mg LY2216684 + SSRI	18 mg LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI
Measure Participants	230	230	239
Least Squares Mean (Standard Error) [units on a scale]	-1.97 (0.22)	-2.05 (0.22)	-1.85 (0.22)

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. 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.

Arm/Group Title	12 mg LY2216684 + SSRI	18 mg LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI
Measure Participants	230	230	240
Number [percentage of participants]	30.43 13.2%	34.35 14.9%	27.08 11.3%

8. Secondary Outcome

Title	Change From Randomization to Week 8 in 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 (0-3), giving maximum scores of 21 for anxiety and depression subscale. Scores of 11 or more on either subscale were considered to be a significant 'case' of psychological morbidity, while scores of 8-10 represent 'borderline' and 0-7 represent 'normal'. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline subscale score, treatment-by-visit and baseline subscale score-by-visit.
Time Frame	Randomization, 8 weeks

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 mg LY2216684 + SSRI	18 mg LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI
Measure Participants	230	230	239
Least Squares Mean (Standard Error) [units on a scale]	-3.19 (0.26)	-3.38 (0.27)	-2.76 (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 mg LY2216684 + SSRI	18 mg LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI
Measure Participants	230	230	240
Apparent sadness	-1.18 (0.08)	-1.04 (0.08)	-1.01 (0.08)
Reported sadness	-1.21 (0.08)	-1.20 (0.08)	-1.00 (0.08)
Inner tension	-0.71 (0.07)	-0.74 (0.07)	-0.65 (0.07)
Reduced sleep	-0.97 (0.09)	-0.94 (0.09)	-0.83 (0.08)
Reduced appetite	-0.82 (0.08)	-0.74 (0.08)	-0.75 (0.08)
Concentration difficulties	-0.88 (0.08)	-1.01 (0.08)	-0.94 (0.08)
Lassitude	-1.04 (0.08)	-1.12 (0.08)	-0.89 (0.08)
Inability to feel	-1.05 (0.08)	-1.07 (0.08)	-0.90 (0.08)
Pessimistic thoughts	-0.77 (0.07)	-0.74 (0.07)	-0.74 (0.07)
Suicidal thoughts	-0.09 (0.03)	-0.13 (0.03)	-0.15 (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 mg LY2216684 + SSRI	18 mg LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI
Measure Participants	230	230	240
Least Squares Mean (Standard Error) [units on a scale]	-1.01 (0.07)	-1.08 (0.07)	-0.95 (0.07)

11. Secondary Outcome

Title	Change From Randomization to Week 8 in 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 mg LY2216684 + SSRI	18 mg LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI
Measure Participants	224	221	236
Average score	-0.69 (0.05)	-0.67 (0.05)	-0.57 (0.05)
Experience score	-0.66 (0.06)	-0.67 (0.06)	-0.60 (0.05)

12. Secondary Outcome

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

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 mg LY2216684 + SSRI	18 mg LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI
Measure Participants	224	222	236
Work impairment score	-1.77 (0.19)	-1.74 (0.20)	-1.44 (0.19)
Social life impairment score	-1.85 (0.16)	-1.81 (0.16)	-1.64 (0.16)
Family life impairment score	-1.72 (0.16)	-1.71 (0.16)	-1.43 (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 that measures degree of enjoyment and satisfaction experienced in various areas of daily life during the past week on a 5-point, Likert scale (1=very poor and 5=very good). The total raw score is the sum of items 1 to 14 and ranges from 14 to 70. The raw scores are converted to and expressed as the percentage of the maximum possible score. Higher scores indicate higher levels of enjoyment/satisfaction. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit and baseline score-by-visit.
Time Frame	Randomization, 8 weeks

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 mg LY2216684 + SSRI	18 mg LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI
Measure Participants	224	222	236
Least Squares Mean (Standard Error) [percentage of maximum possible score]	10.51 (0.98)	9.93 (0.98)	8.47 (0.95)

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 the worst imaginable health state and 100 representing best imaginable health state. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit and baseline score-by-visit.
Time Frame	Randomization, 8 weeks

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 mg LY2216684 + SSRI	18 mg LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI
Measure Participants	224	222	236
Least Squares Mean (Standard Error) [units on a scale]	12.201 (1.218)	12.762 (1.225)	9.756 (1.188)

15. Secondary Outcome

Title	Percentage of 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 TE if not present at baseline. Percentage of participants was calculated by dividing the number of participants with suicide-related TE events by the total number of participants at risk, multiplied by 100%. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Event module.
Time Frame	Randomization through 8 weeks

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 mg LY2216684 + SSRI	18 mg LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI
Measure Participants	230	230	240
TE of suicidal ideation	3.91 1.7%	3.91 1.7%	3.33 1.4%
TE of suicidal behavior	0.00 0%	0.47 0.2%	0.44 0.2%

16. Secondary Outcome

Title	Change From Randomization to Week 8 in 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]) to the 5 items of the ASEX scale. Total scores ranged from 5 to 30 with higher scores indicating greater sexual dysfunction. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit and baseline score-by-visit.
Time Frame	Randomization, 8 weeks

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 mg LY2216684 + SSRI	18 mg LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI
Measure Participants	222	220	233
Least Squares Mean (Standard Error) [units on a scale]	-1.32 (0.26)	-1.27 (0.26)	-0.79 (0.25)

17. Secondary Outcome

Title	Change From Randomization to Week 8 in 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. 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 mg LY2216684 + SSRI	18 mg LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI
Measure Participants	224	222	236
Least Squares Mean (Standard Error) [units on a scale]	-4.70 (0.37)	-4.41 (0.38)	-3.79 (0.36)

18. Secondary Outcome

Title	The Percentage of Participants Experiencing Treatment-Emergent Adverse Events as a Function of CYP2D6 Phenotype
Description	Treatment-emergent adverse events (TEAEs) were events that first occurred or worsened during the treatment phase. CYP2D6 functional phenotype was classified as poor metabolizer (PM) or non-poor metabolizer (non-PM). The percentage of participants who reported the TEAE is presented for each phenotype classification. Only TEAEs for which there was a statistically significant treatment-by-SSRI therapy interaction were included: tinnitus and influenza. A summary of serious and other non-serious adverse events regardless of causality is located in the Report of Adverse Events module.
Time Frame	Through 8 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	12 mg LY2216684 + SSRI	18 mg LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI
Measure Participants	144	140	157
Tinnitus non-PM	0.00 0%	0.00 0%	1.27 0.5%
Tinnitus PM	0.00 0%	3.61 1.6%	0.00 0%
Influenza non-PM	1.39 0.6%	0.00 0%	0.64 0.3%
Influenza PM	0.00 0%	2.41 1%	0.00 0%

19. Secondary Outcome

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

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 mg LY2216684 + SSRI	18 mg LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI
Measure Participants	230	230	240
Sitting systolic BP	2.11 (0.57)	3.18 (0.57)	0.02 (0.55)
Sitting diastolic BP	3.57 (0.43)	4.00 (0.43)	0.66 (0.42)

20. 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 mg LY2216684 + SSRI	18 mg LY2216684 + SSRI	Placebo + SSRI
Arm/Group Description	LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI)	LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI	Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI
Measure Participants	230	230	240
Least Squares Mean (Standard Error) [beats per minute (bpm)]	8.66 (0.64)	9.12 (0.64)	-1.41 (0.62)

21. Secondary Outcome

Title	Pharmacokinetics: Plasma Concentrations of LY2216684
Description	A validated bioanalytical assay was used to determine plasma LY2216684 concentrations.
Time Frame	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 pharmacokinetics assessment.

Arm/Group Title	LY2216684 + SSRI
Arm/Group Description	LY2216684: fixed doses of 12 milligrams (mg) administered orally, once daily for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI) or 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI
Measure Participants	442
12 mg dose	37.8 (20.7)
18 mg dose	55.3 (30.4)

Adverse Events

Time Frame	Adverse event data was collected over the 3-week double blind adjunctive placebo lead-in confirmation phase, the 8 week double-blind placebo-controlled adjunctive active treatment phase, and the 2-week discontinuation (DC) phase.
Adverse Event Reporting Description	During the 2-week DC phase, participants who received LY2216684 were randomly assigned to either abrupt DC or tapered DC over the 2-week period. Participants who had received placebo either during the adjunctive treatment phase or the lead-in confirmation phase remained on placebo during the 2-week DC phase.
Arm/Group Title	Placebo + SSRI (Pre-randomized) CF Phase		12 mg LY2216684 + SSRI (Randomized) AT Phase		18 mg LY2216684 + SSRI (Randomized) AT Phase		Placebo + SSRI (Randomized) AT Phase		Placebo + SSRI (Non-randomized) AT Phase		Placebo + SSRI (Pre-randomized) Discontinuation Phase		12 mg LY2216684 + SSRI (Abrupt Discontinuation Phase)		12 mg LY2216684 + SSRI (Taper Discontinuation Phase)		18 mg LY2216684 + SSRI (Abrupt Discontinuation Phase)		18 mg LY2216684 + SSRI (Taper Discontinuation Phase)		Placebo + SSRI (Randomized) Discontinuation Phase		Placebo + SSRI (Non-randomized) Discontinuation Phase
Arm/Group Description	Placebo: Administered orally, once daily for 3 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 Confirmation (CF) Phase.		LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a SSRI, during the adjunctive treatment phase. 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: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI, during the adjunctive treatment phase. 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 SSRI, during the adjunctive treatment phase 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 SSRI, during the adjunctive treatment phase. 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.		Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI, during the adjunctive treatment phase. 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.		LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a SSRI 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.		LY2216684: 12 milligrams (mg), administered orally, once daily for 8 weeks, adjunctive to a SSRI Includes all randomized participants who tapered discontinuation of 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.		LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI, during the adjunctive treatment phase 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.		LY2216684: 12 mg, administered orally, once daily for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a SSRI, during the adjunctive treatment phase Includes all randomized participants who tapered discontinuation of 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.		Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI, during the adjunctive treatment phase. Includes all randomized participants who 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.		Placebo: Administered orally, once daily for 8 weeks, adjunctive to a SSRI, during the adjunctive treatment phase. Includes all non-randomized participants who 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 mg LY2216684 + SSRI (Randomized) AT Phase		18 mg LY2216684 + SSRI (Randomized) AT Phase		Placebo + SSRI (Randomized) AT Phase		Placebo + SSRI (Non-randomized) AT Phase		Placebo + SSRI (Pre-randomized) Discontinuation Phase		12 mg LY2216684 + SSRI (Abrupt Discontinuation Phase)		12 mg LY2216684 + SSRI (Taper Discontinuation Phase)		18 mg LY2216684 + SSRI (Abrupt Discontinuation Phase)		18 mg LY2216684 + SSRI (Taper Discontinuation Phase)		Placebo + SSRI (Randomized) Discontinuation Phase		Placebo + SSRI (Non-randomized) Discontinuation 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	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo + SSRI (Pre-randomized) CF Phase		12 mg LY2216684 + SSRI (Randomized) AT Phase		18 mg LY2216684 + SSRI (Randomized) AT Phase		Placebo + SSRI (Randomized) AT Phase		Placebo + SSRI (Non-randomized) AT Phase		Placebo + SSRI (Pre-randomized) Discontinuation Phase		12 mg LY2216684 + SSRI (Abrupt Discontinuation Phase)		12 mg LY2216684 + SSRI (Taper Discontinuation Phase)		18 mg LY2216684 + SSRI (Abrupt Discontinuation Phase)		18 mg LY2216684 + SSRI (Taper Discontinuation Phase)		Placebo + SSRI (Randomized) Discontinuation Phase		Placebo + SSRI (Non-randomized) Discontinuation 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	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/1413 (0.1%)		3/231 (1.3%)		2/230 (0.9%)		1/240 (0.4%)		5/627 (0.8%)		1/20 (5%)		1/108 (0.9%)		1/100 (1%)		0/108 (0%)		1/107 (0.9%)		0/221 (0%)		1/585 (0.2%)
Gastrointestinal disorders
Gastritis	0/1413 (0%)	0	1/231 (0.4%)	1	0/230 (0%)	0	0/240 (0%)	0	0/627 (0%)	0	0/20 (0%)	0	0/108 (0%)	0	0/100 (0%)	0	0/108 (0%)	0	0/107 (0%)	0	0/221 (0%)	0	0/585 (0%)	0
Oesophageal achalasia	1/1413 (0.1%)	1	1/231 (0.4%)	1	0/230 (0%)	0	0/240 (0%)	0	0/627 (0%)	0	0/20 (0%)	0	1/108 (0.9%)	1	0/100 (0%)	0	0/108 (0%)	0	0/107 (0%)	0	0/221 (0%)	0	0/585 (0%)	0
Hepatobiliary disorders
Cholecystitis	0/1413 (0%)	0	0/231 (0%)	0	0/230 (0%)	0	0/240 (0%)	0	0/627 (0%)	0	0/20 (0%)	0	0/108 (0%)	0	1/100 (1%)	1	0/108 (0%)	0	0/107 (0%)	0	0/221 (0%)	0	0/585 (0%)	0
Cholelithiasis	0/1413 (0%)	0	0/231 (0%)	0	0/230 (0%)	0	0/240 (0%)	0	1/627 (0.2%)	1	0/20 (0%)	0	0/108 (0%)	0	0/100 (0%)	0	0/108 (0%)	0	0/107 (0%)	0	0/221 (0%)	0	0/585 (0%)	0
Infections and infestations
Sialoadenitis	0/1413 (0%)	0	0/231 (0%)	0	0/230 (0%)	0	0/240 (0%)	0	1/627 (0.2%)	1	0/20 (0%)	0	0/108 (0%)	0	0/100 (0%)	0	0/108 (0%)	0	0/107 (0%)	0	0/221 (0%)	0	0/585 (0%)	0
Investigations
Blood pressure increased	0/1413 (0%)	0	0/231 (0%)	0	0/230 (0%)	0	0/240 (0%)	0	1/627 (0.2%)	1	0/20 (0%)	0	0/108 (0%)	0	0/100 (0%)	0	0/108 (0%)	0	0/107 (0%)	0	0/221 (0%)	0	0/585 (0%)	0
Electrocardiogram qt prolonged	0/1413 (0%)	0	0/231 (0%)	0	0/230 (0%)	0	0/240 (0%)	0	1/627 (0.2%)	1	0/20 (0%)	0	0/108 (0%)	0	0/100 (0%)	0	0/108 (0%)	0	0/107 (0%)	0	0/221 (0%)	0	0/585 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer metastatic	0/1413 (0%)	0	0/231 (0%)	0	0/230 (0%)	0	0/240 (0%)	0	1/627 (0.2%)	1	0/20 (0%)	0	0/108 (0%)	0	0/100 (0%)	0	0/108 (0%)	0	0/107 (0%)	0	0/221 (0%)	0	1/585 (0.2%)	1
Oesophageal carcinoma	1/1413 (0.1%)	1	0/231 (0%)	0	0/230 (0%)	0	0/240 (0%)	0	0/627 (0%)	0	1/20 (5%)	1	0/108 (0%)	0	0/100 (0%)	0	0/108 (0%)	0	0/107 (0%)	0	0/221 (0%)	0	0/585 (0%)	0
Psychiatric disorders
Depression	0/1413 (0%)	0	0/231 (0%)	0	1/230 (0.4%)	1	0/240 (0%)	0	0/627 (0%)	0	0/20 (0%)	0	0/108 (0%)	0	0/100 (0%)	0	0/108 (0%)	0	0/107 (0%)	0	0/221 (0%)	0	0/585 (0%)	0
Suicidal ideation	0/1413 (0%)	0	1/231 (0.4%)	1	0/230 (0%)	0	0/240 (0%)	0	0/627 (0%)	0	0/20 (0%)	0	0/108 (0%)	0	0/100 (0%)	0	0/108 (0%)	0	0/107 (0%)	0	0/221 (0%)	0	0/585 (0%)	0
Suicide attempt	0/1413 (0%)	0	0/231 (0%)	0	0/230 (0%)	0	1/240 (0.4%)	1	0/627 (0%)	0	0/20 (0%)	0	0/108 (0%)	0	0/100 (0%)	0	0/108 (0%)	0	0/107 (0%)	0	0/221 (0%)	0	0/585 (0%)	0
Vascular disorders
Arteriosclerosis	0/1413 (0%)	0	0/231 (0%)	0	1/230 (0.4%)	1	0/240 (0%)	0	0/627 (0%)	0	0/20 (0%)	0	0/108 (0%)	0	0/100 (0%)	0	0/108 (0%)	0	1/107 (0.9%)	1	0/221 (0%)	0	0/585 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo + SSRI (Pre-randomized) CF Phase		12 mg LY2216684 + SSRI (Randomized) AT Phase		18 mg LY2216684 + SSRI (Randomized) AT Phase		Placebo + SSRI (Randomized) AT Phase		Placebo + SSRI (Non-randomized) AT Phase		Placebo + SSRI (Pre-randomized) Discontinuation Phase		12 mg LY2216684 + SSRI (Abrupt Discontinuation Phase)		12 mg LY2216684 + SSRI (Taper Discontinuation Phase)		18 mg LY2216684 + SSRI (Abrupt Discontinuation Phase)		18 mg LY2216684 + SSRI (Taper Discontinuation Phase)		Placebo + SSRI (Randomized) Discontinuation Phase		Placebo + SSRI (Non-randomized) Discontinuation 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	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	240/1413 (17%)		71/231 (30.7%)		73/230 (31.7%)		36/240 (15%)		100/627 (15.9%)		3/20 (15%)		17/108 (15.7%)		15/100 (15%)		18/108 (16.7%)		19/107 (17.8%)		39/221 (17.6%)		106/585 (18.1%)
Cardiac disorders
Tachycardia	4/1413 (0.3%)	4	16/231 (6.9%)	16	23/230 (10%)	24	0/240 (0%)	0	3/627 (0.5%)	4	0/20 (0%)	0	0/108 (0%)	0	0/100 (0%)	0	0/108 (0%)	0	1/107 (0.9%)	1	0/221 (0%)	0	0/585 (0%)	0
Gastrointestinal disorders
Nausea	55/1413 (3.9%)	57	11/231 (4.8%)	11	17/230 (7.4%)	21	1/240 (0.4%)	1	13/627 (2.1%)	13	0/20 (0%)	0	2/108 (1.9%)	2	1/100 (1%)	1	5/108 (4.6%)	7	6/107 (5.6%)	6	4/221 (1.8%)	4	19/585 (3.2%)	21
Infections and infestations
Nasopharyngitis	43/1413 (3%)	45	18/231 (7.8%)	18	10/230 (4.3%)	10	15/240 (6.3%)	15	34/627 (5.4%)	37	0/20 (0%)	0	3/108 (2.8%)	3	2/100 (2%)	2	3/108 (2.8%)	3	2/107 (1.9%)	2	11/221 (5%)	11	10/585 (1.7%)	10
Nervous system disorders
Dizziness	45/1413 (3.2%)	48	8/231 (3.5%)	9	12/230 (5.2%)	13	5/240 (2.1%)	10	13/627 (2.1%)	16	0/20 (0%)	0	3/108 (2.8%)	3	5/100 (5%)	5	3/108 (2.8%)	4	8/107 (7.5%)	11	7/221 (3.2%)	9	34/585 (5.8%)	42
Headache	116/1413 (8.2%)	136	22/231 (9.5%)	28	18/230 (7.8%)	18	14/240 (5.8%)	16	39/627 (6.2%)	47	3/20 (15%)	3	13/108 (12%)	29	7/100 (7%)	9	10/108 (9.3%)	14	10/107 (9.3%)	18	26/221 (11.8%)	36	69/585 (11.8%)	108
Reproductive system and breast disorders
Erectile dysfunction	3/447 (0.7%)	3	2/86 (2.3%)	2	1/81 (1.2%)	1	0/85 (0%)	0	2/176 (1.1%)	2	1/6 (16.7%)	1	0/37 (0%)	0	0/41 (0%)	0	0/38 (0%)	0	0/37 (0%)	0	0/81 (0%)	0	0/168 (0%)	0
Skin and subcutaneous tissue disorders
Hyperhidrosis	17/1413 (1.2%)	17	19/231 (8.2%)	20	16/230 (7%)	16	2/240 (0.8%)	2	6/627 (1%)	6	0/20 (0%)	0	0/108 (0%)	0	1/100 (1%)	1	1/108 (0.9%)	3	4/107 (3.7%)	7	1/221 (0.5%)	1	3/585 (0.5%)	3

Limitations/Caveats

[Not Specified]

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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.