Trial Outcomes & Findings for A Study Comparing the Efficacy and Safety of Duloxetine and Placebo for the Treatment of Depression in Elderly Patients (NCT NCT00406848)

Last Updated: 2010-09-29

Results Overview

The Maier subscale (Items 1,2,7,8,9,10) represents symptoms of depression. Total subscale scores range from 0 (normal) to 24 (severe).

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

370 participants

Primary outcome timeframe

baseline (Week 1), Week 13

Results posted on

2010-09-29

Participant Flow

This study had a double-blind one-week placebo lead-in period before randomization, so baseline is defined as Week 1. 370 total patients were randomized and make up the safety analysis population. 299 of these patients were randomized under protocol amendments c, d and e, and make up the efficacy analysis population.

Participant milestones

Participant milestones
Measure	Duloxetine Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Overall Study STARTED	249	121
Overall Study COMPLETED	156	67
Overall Study NOT COMPLETED	93	54

Reasons for withdrawal

Reasons for withdrawal
Measure	Duloxetine Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.
Overall Study Withdrawal by Subject	27	22
Overall Study Adverse Event	38	7
Overall Study Lack of Efficacy	9	14
Overall Study Protocol Violation	10	6
Overall Study Lost to Follow-up	6	2
Overall Study Physician Decision	2	2
Overall Study Sponsor Decision	1	1

Baseline Characteristics

A Study Comparing the Efficacy and Safety of Duloxetine and Placebo for the Treatment of Depression in Elderly Patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Duloxetine n=249 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=121 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Total n=370 Participants Total of all reporting groups
Age Continuous	72.89 years STANDARD_DEVIATION 6.10 • n=5 Participants	73.02 years STANDARD_DEVIATION 5.64 • n=7 Participants	72.93 years STANDARD_DEVIATION 5.95 • n=5 Participants
Sex: Female, Male Female	163 Participants n=5 Participants	71 Participants n=7 Participants	234 Participants n=5 Participants
Sex: Female, Male Male	86 Participants n=5 Participants	50 Participants n=7 Participants	136 Participants n=5 Participants
Race/Ethnicity, Customized African	5 Participants n=5 Participants	6 Participants n=7 Participants	11 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	198 Participants n=5 Participants	92 Participants n=7 Participants	290 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic	46 Participants n=5 Participants	22 Participants n=7 Participants	68 Participants n=5 Participants
Race/Ethnicity, Customized Native American	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment France	13 participants n=5 Participants	8 participants n=7 Participants	21 participants n=5 Participants
Region of Enrollment United States	195 participants n=5 Participants	94 participants n=7 Participants	289 participants n=5 Participants
Region of Enrollment Mexico	17 participants n=5 Participants	8 participants n=7 Participants	25 participants n=5 Participants
Region of Enrollment Puerto Rico	24 participants n=5 Participants	11 participants n=7 Participants	35 participants n=5 Participants
17 item Hamilton Depression Rating Scale Total Score(HAMD-17)	19.42 units on a scale STANDARD_DEVIATION 5.56 • n=5 Participants	19.32 units on a scale STANDARD_DEVIATION 5.78 • n=7 Participants	19.39 units on a scale STANDARD_DEVIATION 5.62 • n=5 Participants
17 item Hamilton Depression Rating Scale (HAMD-17) - Maier subscale	9.96 Units on a scale STANDARD_DEVIATION 3.11 • n=5 Participants	10.08 Units on a scale STANDARD_DEVIATION 3.36 • n=7 Participants	10.00 Units on a scale STANDARD_DEVIATION 3.19 • n=5 Participants
Geriatric Depression Scale (GDS) Total Score	18.54 units on a scale STANDARD_DEVIATION 6.91 • n=5 Participants	17.64 units on a scale STANDARD_DEVIATION 6.66 • n=7 Participants	18.26 units on a scale STANDARD_DEVIATION 6.83 • n=5 Participants
Numerical Rating Scale (NRS) Overall Pain Score	3.79 units on a scale STANDARD_DEVIATION 2.96 • n=5 Participants	3.59 units on a scale STANDARD_DEVIATION 2.67 • n=7 Participants	3.73 units on a scale STANDARD_DEVIATION 2.87 • n=5 Participants
Brief Pain Inventory (BPI) 24-hour Average Pain Score	3.48 units on a scale STANDARD_DEVIATION 2.70 • n=5 Participants	3.48 units on a scale STANDARD_DEVIATION 2.57 • n=7 Participants	3.48 units on a scale STANDARD_DEVIATION 2.66 • n=5 Participants
Mini Mental State Exam (MMSE) Total Score	28.55 units on a scale STANDARD_DEVIATION 1.83 • n=5 Participants	28.42 units on a scale STANDARD_DEVIATION 1.72 • n=7 Participants	28.51 units on a scale STANDARD_DEVIATION 1.79 • n=5 Participants
Montgomery-Asberg Depression Rating Scale (MADRS) Total Score	29.25 units on a scale STANDARD_DEVIATION 5.57 • n=5 Participants	28.46 units on a scale STANDARD_DEVIATION 5.40 • n=7 Participants	29.00 units on a scale STANDARD_DEVIATION 5.52 • n=5 Participants

PRIMARY outcome

Timeframe: baseline (Week 1), Week 13

Population: All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

The Maier subscale (Items 1,2,7,8,9,10) represents symptoms of depression. Total subscale scores range from 0 (normal) to 24 (severe).

Outcome measures

Outcome measures
Measure	Duloxetine n=201 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=95 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Change From Baseline to 13 Weeks in Hamilton Depression Rating Scale (HAMD-17) Maier Subscale	-4.34 units on a scale Standard Error 0.29	-3.90 units on a scale Standard Error 0.44	—

SECONDARY outcome

Timeframe: baseline (Week 1), Week 13, Week 25

Population: All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

The 30-item Geriatric Depression Scale (GDS) is a self-administered test of 30 questions to measure the severity of depression. The yes/no questions result in a range of scores from 0 (normal) to 30 (severe depression).

Outcome measures

Outcome measures
Measure	Duloxetine n=200 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=90 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Change From Baseline on the 30-item Geriatric Depression Scale (GDS) Week 13 change	-6.01 units on a scale Standard Error 0.53	-4.53 units on a scale Standard Error 0.79	—
Change From Baseline on the 30-item Geriatric Depression Scale (GDS) Week 25 change	-7.02 units on a scale Standard Error 0.58	-3.66 units on a scale Standard Error 1.00	—

SECONDARY outcome

Timeframe: baseline (Week 1), Week 13, Week 25

Population: Randomized patients with non-missing data at baseline and post-baseline visit.

Total Score assess depression severity (scores 0-52). Core, Maier and Bech subscales assess symptoms of depression (scores:0-20=Core; 0-24=Maier; 0-22=Bech). Anxiety/Somatization subscale assesses severity of anxiety (0-18). Retardation subscale assesses dysfunction in mood and work (0-14). Sleep subscale assesses insomnia (0-6). Individual item scores may range from 0-4 or 0-2. Higher numbers indicate more severe symptoms.

Outcome measures

Outcome measures
Measure	Duloxetine n=201 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=95 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 14: Genital Symptoms Week 25 Change	-0.41 units on a scale Standard Error 0.06	-0.47 units on a scale Standard Error 0.12	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 15: Hypochondriasis Week 13 Change	-0.47 units on a scale Standard Error 0.06	-0.32 units on a scale Standard Error 0.08	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Total - Week 13 Change	-7.42 units on a scale Standard Error 0.52	-7.15 units on a scale Standard Error 0.77	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Total - Week 25 Change	-8.98 units on a scale Standard Error 0.57	-7.00 units on a scale Standard Error 1.01	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Maier subscale Week 25 Change	-5.31 units on a scale Standard Error 0.29	-4.17 units on a scale Standard Error 0.54	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Bech subscale Week 13 Change	-4.35 units on a scale Standard Error 0.30	-3.98 units on a scale Standard Error 0.46	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Bech subscale Week 25 Change	-5.36 units on a scale Standard Error 0.31	-4.07 units on a scale Standard Error 0.58	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Core Mood subscale Week 13 Change	-3.29 units on a scale Standard Error 0.24	-3.02 units on a scale Standard Error 0.36	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Core Mood subscale Week 25 Change	-4.08 units on a scale Standard Error 0.23	-3.00 units on a scale Standard Error 0.43	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Anxiety/Somatization subscale Week 13	-2.38 units on a scale Standard Error 0.20	-2.26 units on a scale Standard Error 0.30	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Anxiety/Somatization subscale Week 25	-2.90 units on a scale Standard Error 0.22	-2.44 units on a scale Standard Error 0.38	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Sleep subscale Week 13 Change	-1.14 units on a scale Standard Error 0.12	-1.14 units on a scale Standard Error 0.18	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Sleep subscale Week 25 Change	-1.37 units on a scale Standard Error 0.13	-1.35 units on a scale Standard Error 0.24	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Retardation subscale Week 13 Change	-2.70 units on a scale Standard Error 0.21	-2.73 units on a scale Standard Error 0.31	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Retardation subscale Week 25 Change	-3.42 units on a scale Standard Error 0.20	-2.77 units on a scale Standard Error 0.38	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 1: Depressed Mood - Week 13 Change	-1.13 units on a scale Standard Error 0.09	-1.02 units on a scale Standard Error 0.13	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 1: Depressed Mood Week 25 Change	-1.36 units on a scale Standard Error 0.09	-1.02 units on a scale Standard Error 0.16	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 2: Feelings of Guilt Week 13 Change	-0.70 units on a scale Standard Error 0.06	-0.60 units on a scale Standard Error 0.09	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 2: Feelings of Guilt Week 25 Change	-0.91 units on a scale Standard Error 0.06	-0.65 units on a scale Standard Error 0.12	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 3: Suicide Week 13 Change	-0.16 units on a scale Standard Error 0.04	-0.18 units on a scale Standard Error 0.05	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 3: Suicide Week 25 Change	-0.19 units on a scale Standard Error 0.04	-0.11 units on a scale Standard Error 0.07	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 4: Insomnia Early Week 13 Change	-0.37 units on a scale Standard Error 0.06	-0.29 units on a scale Standard Error 0.09	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 4: Insomnia Early Week 25 Change	-0.42 units on a scale Standard Error 0.06	-0.41 units on a scale Standard Error 0.12	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 5: Insomnia Middle Week 13 Change	-0.40 units on a scale Standard Error 0.06	-0.47 units on a scale Standard Error 0.09	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 5: Insomnia Middle Week 25 Change	-0.49 units on a scale Standard Error 0.06	-0.46 units on a scale Standard Error 0.11	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 6: Insomnia Late Week 13 Change	-0.36 units on a scale Standard Error 0.06	-0.41 units on a scale Standard Error 0.08	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 6: Insomnia Late Week 25 Change	-0.45 units on a scale Standard Error 0.05	-0.53 units on a scale Standard Error 0.10	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 7: Work and Activities Week 13 Change	-0.82 units on a scale Standard Error 0.08	-0.81 units on a scale Standard Error 0.12	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 7: Work and Activities Week 25 Change	-1.12 units on a scale Standard Error 0.09	-0.87 units on a scale Standard Error 0.16	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 8: Retardation Week 13 Change	-0.48 units on a scale Standard Error 0.05	-0.51 units on a scale Standard Error 0.08	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 8: Retardation Week 25 Change	-0.57 units on a scale Standard Error 0.05	-0.54 units on a scale Standard Error 0.09	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 9: Agitation Week 13 Change	-0.39 units on a scale Standard Error 0.06	-0.32 units on a scale Standard Error 0.08	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 9: Agitation Week 25 Change	-0.45 units on a scale Standard Error 0.06	-0.53 units on a scale Standard Error 0.11	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 10: Anxiety/Psychic Week 13 Change	-0.81 units on a scale Standard Error 0.07	-0.75 units on a scale Standard Error 0.11	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 10: Anxiety/Psychic Week 25 Change	-0.98 units on a scale Standard Error 0.08	-0.85 units on a scale Standard Error 0.14	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 11: Anxiety (Somatic) Week 13 Change	-0.49 units on a scale Standard Error 0.06	-0.55 units on a scale Standard Error 0.09	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 11: Anxiety (Somatic) Week 25 Change	-0.70 units on a scale Standard Error 0.06	-0.60 units on a scale Standard Error 0.11	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 12: Somatic Symptom/Gastrointestinal Week 13	-0.16 units on a scale Standard Error 0.04	-0.20 units on a scale Standard Error 0.06	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 12: Somatic Symptom/Gastrointestinal Week 25	-0.23 units on a scale Standard Error 0.04	-0.26 units on a scale Standard Error 0.07	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 13: Somatic Symptoms/General Week 13 Change	-0.41 units on a scale Standard Error 0.06	-0.40 units on a scale Standard Error 0.09	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 13: Somatic Symptoms/General Week 25 Change	-0.52 units on a scale Standard Error 0.07	-0.59 units on a scale Standard Error 0.13	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 14: Genital Symptoms Week 13 Change	-0.29 units on a scale Standard Error 0.06	-0.46 units on a scale Standard Error 0.08	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 15: Hypochondriasis Week 25 Change	-0.49 units on a scale Standard Error 0.06	-0.39 units on a scale Standard Error 0.11	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 16: Loss of Weight Week 13 Change	-0.02 units on a scale Standard Error 0.03	-0.09 units on a scale Standard Error 0.04	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 16: Loss of Weight Week 25 Change	-0.13 units on a scale Standard Error 0.02	-0.01 units on a scale Standard Error 0.04	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 17: Insight Week 13 Change	-0.09 units on a scale Standard Error 0.02	-0.10 units on a scale Standard Error 0.03	—
Change From Baseline in the HAMD-17 Total Score, Subscales, and Individual Items Item 17: Insight Week 25 Change	-0.07 units on a scale Standard Error 0.03	-0.11 units on a scale Standard Error 0.05	—

SECONDARY outcome

Timeframe: baseline (Week 1), Week 13, Week 25

Population: All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

The Brief Pain Inventory (severity and interference scales) (BPI) is a self-reported scale that measures the severity of pain and the interference of pain on function. Severity scores: 0 (no pain) to 10 (severe pain) on each question assessing worst pain, least pain, and average pain in past 24 hours, and pain right now. Interference scores: 0 (does not interfere) to 10 (completely interferes) on each question assessing interference of pain in past 24 hours for general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life.

Outcome measures

Outcome measures
Measure	Duloxetine n=191 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=87 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Worst Pain - Week 13	-0.66 units on a scale Standard Error 0.14	-0.18 units on a scale Standard Error 0.19	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Worst Pain - Week 25	-0.74 units on a scale Standard Error 0.14	-0.36 units on a scale Standard Error 0.20	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Least Pain - Week 13	-0.47 units on a scale Standard Error 0.11	-0.00 units on a scale Standard Error 0.15	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Least Pain - Week 25	-0.54 units on a scale Standard Error 0.11	-0.26 units on a scale Standard Error 0.16	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Average Pain - Week 13	-0.83 units on a scale Standard Error 0.13	-0.14 units on a scale Standard Error 0.18	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Average Pain - Week 25	-0.87 units on a scale Standard Error 0.12	-0.37 units on a scale Standard Error 0.18	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Pain Right Now - Week 13	-0.78 units on a scale Standard Error 0.13	-0.26 units on a scale Standard Error 0.18	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Pain Right Now - Week 25	-0.86 units on a scale Standard Error 0.13	-0.46 units on a scale Standard Error 0.18	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Interference with General Activity - Week13	-0.58 units on a scale Standard Error 0.13	-0.03 units on a scale Standard Error 0.19	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Interference with General Activity - Week 25	-0.65 units on a scale Standard Error 0.13	-0.23 units on a scale Standard Error 0.19	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Interference with Mood - Week 13	-0.82 units on a scale Standard Error 0.14	-0.03 units on a scale Standard Error 0.19	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Interference with Mood - Week 25	-0.95 units on a scale Standard Error 0.13	-0.25 units on a scale Standard Error 0.19	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Interference with Walking Ability - Week 13	-0.74 units on a scale Standard Error 0.14	-0.19 units on a scale Standard Error 0.20	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Interference with Walking Ability - Week 25	-0.75 units on a scale Standard Error 0.15	-0.24 units on a scale Standard Error 0.21	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Interference with Normal Work - Week 13	-0.72 units on a scale Standard Error 0.15	-0.01 units on a scale Standard Error 0.21	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Interference with Normal Work - Week 25	-0.79 units on a scale Standard Error 0.15	-0.19 units on a scale Standard Error 0.21	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Int. with Relations with other people- Week 13	-0.60 units on a scale Standard Error 0.13	-0.03 units on a scale Standard Error 0.19	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Int. with Relations with other people-Week 25	-0.73 units on a scale Standard Error 0.13	-0.18 units on a scale Standard Error 0.19	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Interference with Sleep - Week 13	-0.77 units on a scale Standard Error 0.15	-0.17 units on a scale Standard Error 0.21	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Interference with Sleep - Week 25	-0.94 units on a scale Standard Error 0.14	-0.26 units on a scale Standard Error 0.21	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Interference with Enjoyment of Life- Week 13	-0.93 units on a scale Standard Error 0.15	0.03 units on a scale Standard Error 0.21	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Interference with Enjoyment of Life- Week 25	-1.04 units on a scale Standard Error 0.15	-0.08 units on a scale Standard Error 0.21	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Average Interference Score - Week 13	-0.76 units on a scale Standard Error 0.12	-0.07 units on a scale Standard Error 0.17	—
Change From Baseline in the Brief Pain Inventory (BPI) Severity and Interference Scores Average Interference Score - Week 25	-0.86 units on a scale Standard Error 0.12	-0.19 units on a scale Standard Error 0.18	—

SECONDARY outcome

Timeframe: baseline (Week 1), Week 13, Week 25

Population: All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

Numeric Rating Scales (Semantic Differential Scales) for Pain are 6 self-administered scales that assesses experience of overall pain, back pain, headache, shoulder pain, time in pain while awake, and pain interference with daily activities, during the past week. Each item is scored on a numeric 11-point semantic differential scale (0-10) from 0 = no pain to 10 = pain as severe as you can imagine; or 0 = none of the time to 10 = all of the time; or 0 = no interference to 10 = unable to do any activities at all.

Outcome measures

Outcome measures
Measure	Duloxetine n=191 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=87 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Change From Baseline in the Numeric Rating Scales (NRS) for Pain Item Scores Overall Pain - Week 13	-0.65 units on a scale Standard Error 0.13	-0.05 units on a scale Standard Error 0.18	—
Change From Baseline in the Numeric Rating Scales (NRS) for Pain Item Scores Overall Pain - Week 25	-0.67 units on a scale Standard Error 0.13	-0.40 units on a scale Standard Error 0.19	—
Change From Baseline in the Numeric Rating Scales (NRS) for Pain Item Scores Headaches - Week 13	-0.32 units on a scale Standard Error 0.12	0.01 units on a scale Standard Error 0.16	—
Change From Baseline in the Numeric Rating Scales (NRS) for Pain Item Scores Headaches - Week 25	-0.28 units on a scale Standard Error 0.12	0.01 units on a scale Standard Error 0.18	—
Change From Baseline in the Numeric Rating Scales (NRS) for Pain Item Scores Back Pain - Week 13	-0.63 units on a scale Standard Error 0.14	0.00 units on a scale Standard Error 0.20	—
Change From Baseline in the Numeric Rating Scales (NRS) for Pain Item Scores Back Pain - Week 25	-0.75 units on a scale Standard Error 0.14	-0.15 units on a scale Standard Error 0.21	—
Change From Baseline in the Numeric Rating Scales (NRS) for Pain Item Scores Shoulder Pain - Week 13	-0.54 units on a scale Standard Error 0.12	-0.22 units on a scale Standard Error 0.17	—
Change From Baseline in the Numeric Rating Scales (NRS) for Pain Item Scores Shoulder Pain - Week 25	-0.55 units on a scale Standard Error 0.13	-0.30 units on a scale Standard Error 0.18	—
Change From Baseline in the Numeric Rating Scales (NRS) for Pain Item Scores Pain Interference with Daily Activities - Week 13	-0.84 units on a scale Standard Error 0.14	-0.20 units on a scale Standard Error 0.20	—
Change From Baseline in the Numeric Rating Scales (NRS) for Pain Item Scores Pain Interference with Daily Activities - Week 25	-0.91 units on a scale Standard Error 0.15	-0.34 units on a scale Standard Error 0.21	—
Change From Baseline in the Numeric Rating Scales (NRS) for Pain Item Scores Time in Pain While Awake - Week 13	-0.75 units on a scale Standard Error 0.14	-0.04 units on a scale Standard Error 0.19	—
Change From Baseline in the Numeric Rating Scales (NRS) for Pain Item Scores Time in Pain While Awake - Week 25	-0.80 units on a scale Standard Error 0.13	-0.33 units on a scale Standard Error 0.20	—

SECONDARY outcome

Timeframe: Week 13, Week 25

Population: All participants randomized under protocol amendment c,d,e, and have at least one post-randomization observation.

The PGI-Improvement scale is a patient-rated instrument that measures perceived improvement in symptoms. It is a 7-point scale where a score of 1 indicates that the patient is "very much improved," a score of 4 indicates that the patient has experienced "no change," and a score of 7 indicates that the patient is "very much worse."

Outcome measures

Outcome measures
Measure	Duloxetine n=178 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=84 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Patient's Global Impression of Improvement (PGI-I) at 13 Weeks and 25 Weeks Week 13	2.74 units on a scale Standard Error 0.13	3.02 units on a scale Standard Error 0.19	—
Patient's Global Impression of Improvement (PGI-I) at 13 Weeks and 25 Weeks Week 25	2.38 units on a scale Standard Error 0.12	2.85 units on a scale Standard Error 0.23	—

SECONDARY outcome

Timeframe: baseline (Week 1), Week 13, Week 25

Population: All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

Measures severity of illness at the time of assessment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill patients).

Outcome measures

Outcome measures
Measure	Duloxetine n=203 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=94 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Change From Baseline in the Clinical Global Impression-Severity (CGI-S) Week 13 Change	-1.25 units on a scale Standard Error 0.09	-1.04 units on a scale Standard Error 0.13	—
Change From Baseline in the Clinical Global Impression-Severity (CGI-S) Week 25 Change	-1.65 units on a scale Standard Error 0.09	-1.17 units on a scale Standard Error 0.16	—

SECONDARY outcome

Timeframe: baseline (Week 1), Week 9, Week 25

Population: All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

Mini-Mental State Examination (MMSE)is a widely used rating measure of cognitive ability. Scores range from 0 to 30. The MMSE will be used to categorize patients as with or without dementia. Higher number indicates better cognitive ability. Patients with a MMSE score of 20 to 23 will be categorized as having mild dementia, while those with a score of ≥ 24 will be categorized as having no dementia.

Outcome measures

Outcome measures
Measure	Duloxetine n=159 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=69 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Change From Baseline in the Mini-Mental State Exam (MMSE) Week 9 Change (n=159, n=69)	0.12 units on a scale Standard Error 0.13	0.24 units on a scale Standard Error 0.18	—
Change From Baseline in the Mini-Mental State Exam (MMSE) Week 25 Change (n=161, n=71)	0.29 units on a scale Standard Error 0.13	0.35 units on a scale Standard Error 0.18	—

SECONDARY outcome

Timeframe: baseline (Week 1), Week 13, Week 25

Population: All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF) measures the degree of enjoyment and satisfaction experienced in various areas of daily life. The short version is a self-administered 16 item scale evaluating satisfaction of general activities on a 5-point Likert scale that indicates the degree of enjoyment or satisfaction achieved during the past week (1 = very poor and 5 = very good).

Outcome measures

Outcome measures
Measure	Duloxetine n=167 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=82 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Change From Baseline in the Quality of Life, Enjoyment, and Satisfaction Questionnaire (Q-LES-Q-SF) Week 13 Change	6.58 units on a scale Standard Error 0.71	5.27 units on a scale Standard Error 0.98	—
Change From Baseline in the Quality of Life, Enjoyment, and Satisfaction Questionnaire (Q-LES-Q-SF) Week 25 Change (n=168, n=82)	7.44 units on a scale Standard Error 0.78	4.79 units on a scale Standard Error 1.08	—

SECONDARY outcome

Timeframe: Week 13, Week 25

Population: All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

Remission (visitwise binary outcome, yes/no) is defined as HAMD-17 Total Score ≤7 and ≤10. HAMD-17 measures depression severity. The total score can range from 0 (normal) to 52 (severe depression). The visitwise probability of patients meeting criteria for remission (either Total Score ≤7 or ≤10) was analyzed using a categorical, pseudo-likelihood-based repeated measures approach. This analysis included the fixed, categorical effects of treatment, investigator, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline score.

Outcome measures

Outcome measures
Measure	Duloxetine n=201 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=95 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Probability of Remission as Measured by the HAMD-17 Total Score ≤7 and ≤10 Remission (HAMD17 ≤ 7) - Week 13	0.37 probability of remission Standard Error 0.26	0.33 probability of remission Standard Error 0.42	—
Probability of Remission as Measured by the HAMD-17 Total Score ≤7 and ≤10 Remission (HAMD17 ≤ 7) - Week 25	0.54 probability of remission Standard Error 0.22	0.49 probability of remission Standard Error 0.46	—
Probability of Remission as Measured by the HAMD-17 Total Score ≤7 and ≤10 Remission (HAMD17 ≤ 10) - Week 13	0.54 probability of remission Standard Error 0.19	0.53 probability of remission Standard Error 0.31	—
Probability of Remission as Measured by the HAMD-17 Total Score ≤7 and ≤10 Remission (HAMD17 ≤ 10) - Week 25	0.70 probability of remission Standard Error 0.21	0.72 probability of remission Standard Error 0.47	—

SECONDARY outcome

Timeframe: Week 13, Week 25

Population: All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

Response (visitwise binary outcome, yes/no) is defined as ≥ 50% reduction from baseline in the HAMD-17 total score. HAMD-17 measures depression severity. The total score can range from 0 (normal) to 52 (severe depression). The visitwise probability of patients meeting criteria for response was analyzed using a categorical, pseudo-likelihood-based repeated measures approach. This analysis included the fixed, categorical effects of treatment, investigator, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline score.

Outcome measures

Outcome measures
Measure	Duloxetine n=201 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=95 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Probability of Response at Endpoint as Measured by ≥50% Improvement in the HAMD-17 Total Score Week 13	0.44 probability of response Standard Error 0.19	0.48 probability of response Standard Error 0.29	—
Probability of Response at Endpoint as Measured by ≥50% Improvement in the HAMD-17 Total Score Week 25	0.61 probability of response Standard Error 0.20	0.72 probability of response Standard Error 0.46	—

SECONDARY outcome

Timeframe: Week 13, Week 25

Population: Randomized patients with non-missing data at baseline and post-baseline visit.

Remission defined as HAMD-17 Total Score ≤7 and ≤10. HAMD-17 measures depression severity. Total score ranges: 0 (normal) to 52 (severe depression). Visitwise probability of patients achieving remission was analyzed using a categorical, pseudo-likelihood-based repeated measures approach. CIRS-G evaluates 14 organ-specific categories using a rating strategy of 0=no problems; 1=current mild problem/past significant problem; 2=moderate disability/morbidity; 3=severe/constant significant disability; and 4=extremely severe/immediate treatment required/end organ failure. Total score ranges: 0 to 56.

Outcome measures

Outcome measures
Measure	Duloxetine n=201 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=95 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Probability of Remission as Measured by the HAMD-17 Total Score ≤7 and ≤10 by Medical Comorbidity Severity as Assessed by the Cumulative Illness Rating Scale-Geriatric Version (CIRS-G) Remission HAMD-17 ≤ 7 Week 13 (CIRS-G ≥ 6)	0.44 probability of remission Standard Error 0.07	0.44 probability of remission Standard Error 0.10	—
Probability of Remission as Measured by the HAMD-17 Total Score ≤7 and ≤10 by Medical Comorbidity Severity as Assessed by the Cumulative Illness Rating Scale-Geriatric Version (CIRS-G) Remission HAMD-17 ≤ 7 Week 13 (CIRS-G < 6)	0.33 probability of remission Standard Error 0.07	0.20 probability of remission Standard Error 0.10	—
Probability of Remission as Measured by the HAMD-17 Total Score ≤7 and ≤10 by Medical Comorbidity Severity as Assessed by the Cumulative Illness Rating Scale-Geriatric Version (CIRS-G) Remission HAMD-17 ≤ 10 Week 13 (CIRS-G ≥ 6)	0.53 probability of remission Standard Error 0.07	0.52 probability of remission Standard Error 0.10	—
Probability of Remission as Measured by the HAMD-17 Total Score ≤7 and ≤10 by Medical Comorbidity Severity as Assessed by the Cumulative Illness Rating Scale-Geriatric Version (CIRS-G) Remission HAMD-17 ≤ 10 Week 13 (CIRS-G <6)	0.53 probability of remission Standard Error 0.07	0.57 probability of remission Standard Error 0.14	—
Probability of Remission as Measured by the HAMD-17 Total Score ≤7 and ≤10 by Medical Comorbidity Severity as Assessed by the Cumulative Illness Rating Scale-Geriatric Version (CIRS-G) Remission HAMD-17 ≤ 7 Week 25 (CIRS-G ≥ 6)	0.52 probability of remission Standard Error 0.08	0.42 probability of remission Standard Error 0.13	—
Probability of Remission as Measured by the HAMD-17 Total Score ≤7 and ≤10 by Medical Comorbidity Severity as Assessed by the Cumulative Illness Rating Scale-Geriatric Version (CIRS-G) Remission HAMD-17 ≤ 7 Week 25 (CIRS-G <6)	0.53 probability of remission Standard Error 0.08	0.45 probability of remission Standard Error 0.25	—
Probability of Remission as Measured by the HAMD-17 Total Score ≤7 and ≤10 by Medical Comorbidity Severity as Assessed by the Cumulative Illness Rating Scale-Geriatric Version (CIRS-G) Remission HAMD-17 ≤ 10 Week 25 (CIRS-G ≥ 6)	0.71 probability of remission Standard Error 0.06	0.65 probability of remission Standard Error 0.12	—
Probability of Remission as Measured by the HAMD-17 Total Score ≤7 and ≤10 by Medical Comorbidity Severity as Assessed by the Cumulative Illness Rating Scale-Geriatric Version (CIRS-G) Remission HAMD-17 ≤ 10 Week 25 (CIRS-G <6)	0.63 probability of remission Standard Error 0.08	0.72 probability of remission Standard Error 0.25	—

SECONDARY outcome

Timeframe: Week 3

Population: All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

Patients are considered to have met onset (visitwise binary outcome, yes/no) criteria at a particular visit if they had at least 20% reduction from baseline in the HAMD-17 Maier subscale at that visit and at all subsequent visits in the acute phase. Maier subscale measures core symptoms of depression and scores range from 0 (normal) to 24 (severe). The visitwise probability of patients meeting onset criteria was analyzed using a categorical, pseudo-likelihood-based repeated measures approach.

Outcome measures

Outcome measures
Measure	Duloxetine n=201 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=95 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Probability of Efficacy Onset as Measured by at Least 20% Sustained Reduction From Baseline in the HAMD-17 Maier Subscale at Week 3	0.43 Probability of onset Standard Error 0.04	0.30 Probability of onset Standard Error 0.05	—

SECONDARY outcome

Timeframe: baseline (Week 1), Week 13, Week 25

Population: All randomized patients with a baseline and at least one non-missing post-baseline value.

Outcome measures

Outcome measures
Measure	Duloxetine n=246 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=118 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Change From Baseline in Supine Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Systolic BP Week 13 Change	0.19 mmHg Standard Error 0.94	-0.58 mmHg Standard Error 1.39	—
Change From Baseline in Supine Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Diastolic BP Week 13 Change	1.89 mmHg Standard Error 0.62	-1.58 mmHg Standard Error 0.92	—
Change From Baseline in Supine Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Systolic BP Week 25 Change	2.22 mmHg Standard Error 1.09	0.54 mmHg Standard Error 1.99	—
Change From Baseline in Supine Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Diastolic BP Week 25 Change	2.44 mmHg Standard Error 0.68	0.65 mmHg Standard Error 1.23	—

SECONDARY outcome

Timeframe: baseline (Week 1), Week 13, Week 25

Population: All randomized patients with a baseline and at least one non-missing post-baseline value.

Outcome measures

Outcome measures
Measure	Duloxetine n=246 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=118 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Change From Baseline in Pulse Rate Week 13 Change	0.03 beats per minute (bpm) Standard Error 0.60	-1.56 beats per minute (bpm) Standard Error 0.88	—
Change From Baseline in Pulse Rate Week 25 Change	2.10 beats per minute (bpm) Standard Error 0.69	-0.87 beats per minute (bpm) Standard Error 1.28	—

SECONDARY outcome

Timeframe: baseline (Week 1), Week 13, Week 25

Population: All randomized patients with a baseline and at least one non-missing post-baseline value.

Outcome measures

Outcome measures
Measure	Duloxetine n=248 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=121 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Change From Baseline in Weight Week 13 Change	-0.86 kilograms (kg) Standard Error 0.17	0.06 kilograms (kg) Standard Error 0.26	—
Change From Baseline in Weight Week 25 Change	-0.69 kilograms (kg) Standard Error 0.22	-0.03 kilograms (kg) Standard Error 0.38	—

SECONDARY outcome

Timeframe: Baseline (Week 1) through Week 25

Population: All randomized patients with a normal baseline and at least one post-baseline value in each treatment group.

A patient has a treatment-emergent elevated supine systolic blood pressure if the value is ≥140 with an increase ≥10 from baseline. A patient has a treatment-emergent elevated supine diastolic blood pressure if the value is ≥90 with an increase ≥10 from baseline. A patient has a treatment-emergent elevated supine pulse if the value is ≥100 with an increase ≥10 from baseline. A patient has abnormal weight change if the gain or loss is ≥7% compared to baseline.

Outcome measures

Outcome measures
Measure	Duloxetine n=248 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=121 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Number of Participants With Abnormal Vital Signs and Weight at Any Time During the Study Diastolic Blood Pressure - High (n=210, n=98)	22 Participants	5 Participants	—
Number of Participants With Abnormal Vital Signs and Weight at Any Time During the Study Pulse - High (n=243, n=115)	10 Participants	4 Participants	—
Number of Participants With Abnormal Vital Signs and Weight at Any Time During the Study Systolic Blood Pressure - High (n=119, n=58)	28 Participants	7 Participants	—
Number of Participants With Abnormal Vital Signs and Weight at Any Time During the Study Weight Change (gain)	11 Participants	2 Participants	—
Number of Participants With Abnormal Vital Signs and Weight at Any Time During the Study Weight Change (loss)	15 Participants	6 Participants	—

SECONDARY outcome

Timeframe: baseline (Week 1) through Week 25

Population: All randomized patients with a normal baseline and at least one post-baseline value in each treatment group.

Sustained Hypertension is defined as supine systolic BP \>= 140 (or diastolic BP \>= 90) mm Hg and increase from baseline (highest value in baseline visit interval) \>= 10 mm Hg for 3 or more consecutive visits in postbaseline visit interval. Orthostatic Hypotension is defined as standing diastolic BP at least 10 mm Hg less than the supine diastolic BP or the standing systolic BP at least 20 mm Hg less than the supine systolic BP at any time in postbaseline visit interval and a patient does not meet this criterion at any visit in baseline interval.

Outcome measures

Outcome measures
Measure	Duloxetine n=246 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=118 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Number of Participants Experiencing Sustained Hypertension (SH) or Orthostatic Hypotension (OH) Sustained Hypertension	5 Participants	1 Participants	—
Number of Participants Experiencing Sustained Hypertension (SH) or Orthostatic Hypotension (OH) Orthostatic Hypotension (n=183, n=90)	57 Participants	21 Participants	—

SECONDARY outcome

Timeframe: baseline (Week 1) through Week 25

Population: All randomized patients.

Adverse Events and Serious Adverse Events leading to study discontinuation.

Outcome measures

Outcome measures
Measure	Duloxetine n=249 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=86 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue n=35 Participants Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Total Discontinued due to Adverse Events	38 participants	7 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Diarrhoea	3 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Fatigue	3 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Headache	1 participants	2 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Nausea	3 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Constipation	2 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Dizziness	2 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Hypertension	1 participants	1 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Memory impairment	2 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Urinary Tract Infection	2 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Vomiting	1 participants	1 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Alopecia	1 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Anxiety	1 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Blood pressure increased	0 participants	1 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Chills	1 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Depression	1 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Erectile dysfunction	1 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Faecal incontinence	1 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Gastrooesophageal reflux disease	1 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Hip fracture	1 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Insomnia	1 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Intracranial aneurysm	1 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Lethargy	1 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Oesophageal adenocarcinoma metastatic	1 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Palpitations	1 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Paranasal sinus hypersecretion	1 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Pneumoperitoneum	1 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Presyncope	0 participants	1 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Rash pruritic	0 participants	1 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Renal failure acute	1 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Suicidal ideation	1 participants	0 participants	0 participants
Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation Tremor	1 participants	0 participants	0 participants

SECONDARY outcome

Timeframe: baseline (Week 1), Week 13, Week 25

Population: All randomized patients with a baseline and at least one post-baseline value in each treatment group.

Results are reported for laboratory analytes that exhibited statistically significantly different changes from baseline to endpoint between treatment groups. Statistical significance was considered at the 0.05 level.

Outcome measures

Outcome measures
Measure	Duloxetine n=227 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=108 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Change From Baseline in Laboratory Values - Platelet Count Platelet Count Week 13 Change	7.92 billions per liter (bill/L) Standard Deviation 45.75	-4.66 billions per liter (bill/L) Standard Deviation 42.95	—
Change From Baseline in Laboratory Values - Platelet Count Platelet Count Week 25 Change	10.58 billions per liter (bill/L) Standard Deviation 51.66	-6.11 billions per liter (bill/L) Standard Deviation 39.87	—

SECONDARY outcome

Timeframe: baseline (Week 1), Week 13, Week 25

Population: All randomized patients with a baseline and at least one post-baseline value in each treatment group.

Outcome measures

Outcome measures
Measure	Duloxetine n=230 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=112 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Change From Baseline in Laboratory Values - Uric Acid Week 13 Change	-11.63 micromole/liter Standard Deviation 63.05	9.30 micromole/liter Standard Deviation 47.39	—
Change From Baseline in Laboratory Values - Uric Acid Week 25 Change	-9.93 micromole/liter Standard Deviation 59.64	10.26 micromole/liter Standard Deviation 48.29	—

SECONDARY outcome

Timeframe: baseline (Week 1), Week 25

Population: All randomized patients with a baseline and at least one post-baseline value in each treatment group.

Outcome measures

Outcome measures
Measure	Duloxetine n=228 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=109 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Change From Baseline in Laboratory Values - Erythrocyte Count Erythrocyte Count	-0.04 Trillion/Liter Standard Deviation 0.29	0.01 Trillion/Liter Standard Deviation 0.25	—

SECONDARY outcome

Timeframe: baseline (Week 1), Week 25

Population: All randomized patients with a baseline and at least one post-baseline value in each treatment group.

Outcome measures

Outcome measures
Measure	Duloxetine n=228 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=109 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Change From Baseline in Laboratory Values - Hemoglobin, Mean Cell Hemoglobin Concentration (MCHC) Hemoglobin Week 25 Change	-0.11 Micromole/liter (Fe) Standard Deviation 0.56	0.01 Micromole/liter (Fe) Standard Deviation 0.46	—
Change From Baseline in Laboratory Values - Hemoglobin, Mean Cell Hemoglobin Concentration (MCHC) Mean Cell Hemoglobin Concentration Week 25 Change	-0.20 Micromole/liter (Fe) Standard Deviation 0.81	-0.02 Micromole/liter (Fe) Standard Deviation 0.81	—

SECONDARY outcome

Timeframe: baseline (Week 1), Week 25

Population: All randomized patients with a baseline and at least one post-baseline value in each treatment group.

Outcome measures

Outcome measures
Measure	Duloxetine n=230 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=112 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Change From Baseline in Laboratory Values - Chloride and Fasting Glucose Chloride Week 25 Change	-0.63 millimole/liter Standard Deviation 2.83	0.01 millimole/liter Standard Deviation 2.77	—
Change From Baseline in Laboratory Values - Chloride and Fasting Glucose Fasting Glucose Week 25 Change (n=155, n=67)	0.37 millimole/liter Standard Deviation 1.88	-0.11 millimole/liter Standard Deviation 1.06	—

SECONDARY outcome

Timeframe: baseline (Week 1) through Week 13

Population: All randomized patients with a normal baseline and at least one post-baseline value in each treatment group.

The number of participants with abnormal laboratory values at any time during the study period. Results are reported for laboratory analytes that exhibited statistically significantly different proportions of participants who had abnormal values between treatment groups. Statistical significance was considered at the 0.05 level. The lower limit of normal for leukocyte count is 3.8 Billion/Liter. Participants who had a value below that number were considered to have abnormally low leukocyte count.

Outcome measures

Outcome measures
Measure	Duloxetine n=225 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=109 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Number of Participants With Abnormal Laboratory Values - Low Leukocyte Count Leukocyte Count (Low)	11 participants	0 participants	—

SECONDARY outcome

Timeframe: baseline (Week 1), Week 25

Population: Participants with a baseline and at least one non-missing post baseline value.

The Electrocardiogram measures include the following time intervals: QT interval, QT Interval Corrected for Heart Rate Using Fridericia's Formula (QTcF), QT Interval Corrected for Heart Rate Using Bazett's Formula (QTcB), PR interval and QRS interval.

Outcome measures

Outcome measures
Measure	Duloxetine n=194 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=68 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Change From Baseline in Electrocardiograms QT Interval Week 25 Change	-11.80 millisecond (msec) Standard Error 2.19	-10.95 millisecond (msec) Standard Error 3.43	—
Change From Baseline in Electrocardiograms QTcF Interval Week 25 Change	-5.02 millisecond (msec) Standard Error 1.48	-5.91 millisecond (msec) Standard Error 2.33	—
Change From Baseline in Electrocardiograms QTcB Interval Week 25 Change	-1.38 millisecond (msec) Standard Error 1.61	-3.78 millisecond (msec) Standard Error 2.55	—
Change From Baseline in Electrocardiograms PR Interval Week 25 Change	-5.91 millisecond (msec) Standard Error 1.45	-1.34 millisecond (msec) Standard Error 2.32	—
Change From Baseline in Electrocardiograms QRS Interval Week 25 Change	-1.11 millisecond (msec) Standard Error 0.80	-3.25 millisecond (msec) Standard Error 1.26	—

SECONDARY outcome

Timeframe: Baseline (Week 1) through Week 25

Population: All participants randomized under protocol amendment c,d,e, and that have non-missing successful treatment values.

Successful treatment outcome defined as: Participant completed the study and being in remission (HAMD-17 Total score ≤7 and ≤10) at least for the last two visits (4 weeks)of the study. The HAMD-17 is used to assess the severity of depression. The total score ranges from 0 (not at all depressed) to 52 (severely depressed).

Outcome measures

Outcome measures
Measure	Duloxetine n=204 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=95 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Number of Participants With Successful Treatment Outcome Successful Treatment Outcome (with HAMD17 ≤ 7)	55 participants	17 participants	—
Number of Participants With Successful Treatment Outcome Successful Treatment Outcome (with HAMD17 ≤ 10)	74 participants	21 participants	—

SECONDARY outcome

Timeframe: baseline (Week 1), Week 9, Week 25

Population: All participants randomized under protocol amendment c,d,e, and have a baseline observation and at least one post-randomization observation.

The cognitive assessment battery is composed of four tests: Verbal Learning (score 0-15)and Delayed Recall(score 0-15) test, SDST(Score 0-133),2DCT(score 0-40),Trail Making(Part B)(score 0-180).They are designed to challenge the patient's abilities in the following areas: verbal learning and memory; attention to visually presented material; and working memory and executive function. Composite Cognitive score(0-51)is derived from normalized individual test scores. For Trail Making Test,lower number indicates better cognition. For all other test scores,higher number indicates better cognition.

Outcome measures

Outcome measures
Measure	Duloxetine n=183 Participants Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=90 Participants Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity.	Placebo Rescue Participants who were randomized to placebo at baseline and for whom rescue treatment was required during the continuation phase. Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which they were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally until completing or discontinuing from the study.
Change From Baseline on Cognitive Test Scores: Verbal Learning and Recall Test (VLRT), Symbol Digit Substitution Test (SDST), Trail Making Test (Part B), 2-Digit Cancellation Test (2DCT), and the Composite Cognitive Score Derived From the Above Scores Composite Cognitive Score Week 9	-0.38 units on a scale Standard Error 0.38	0.01 units on a scale Standard Error 0.51	—
Change From Baseline on Cognitive Test Scores: Verbal Learning and Recall Test (VLRT), Symbol Digit Substitution Test (SDST), Trail Making Test (Part B), 2-Digit Cancellation Test (2DCT), and the Composite Cognitive Score Derived From the Above Scores Composite Cognitive Score Week 25	0.96 units on a scale Standard Error 0.40	0.31 units on a scale Standard Error 0.54	—
Change From Baseline on Cognitive Test Scores: Verbal Learning and Recall Test (VLRT), Symbol Digit Substitution Test (SDST), Trail Making Test (Part B), 2-Digit Cancellation Test (2DCT), and the Composite Cognitive Score Derived From the Above Scores Learning Trials Score Week 9	-0.06 units on a scale Standard Error 0.12	-0.04 units on a scale Standard Error 0.17	—
Change From Baseline on Cognitive Test Scores: Verbal Learning and Recall Test (VLRT), Symbol Digit Substitution Test (SDST), Trail Making Test (Part B), 2-Digit Cancellation Test (2DCT), and the Composite Cognitive Score Derived From the Above Scores Learning Trials Score Week 25	0.34 units on a scale Standard Error 0.13	0.06 units on a scale Standard Error 0.18	—
Change From Baseline on Cognitive Test Scores: Verbal Learning and Recall Test (VLRT), Symbol Digit Substitution Test (SDST), Trail Making Test (Part B), 2-Digit Cancellation Test (2DCT), and the Composite Cognitive Score Derived From the Above Scores Delayed Recall Score Week 9	-0.65 units on a scale Standard Error 0.21	-0.59 units on a scale Standard Error 0.28	—
Change From Baseline on Cognitive Test Scores: Verbal Learning and Recall Test (VLRT), Symbol Digit Substitution Test (SDST), Trail Making Test (Part B), 2-Digit Cancellation Test (2DCT), and the Composite Cognitive Score Derived From the Above Scores Delayed Recall Score Week 25	0.12 units on a scale Standard Error 0.22	-0.36 units on a scale Standard Error 0.29	—
Change From Baseline on Cognitive Test Scores: Verbal Learning and Recall Test (VLRT), Symbol Digit Substitution Test (SDST), Trail Making Test (Part B), 2-Digit Cancellation Test (2DCT), and the Composite Cognitive Score Derived From the Above Scores SDST Score Week 9	1.98 units on a scale Standard Error 0.76	3.99 units on a scale Standard Error 1.04	—
Change From Baseline on Cognitive Test Scores: Verbal Learning and Recall Test (VLRT), Symbol Digit Substitution Test (SDST), Trail Making Test (Part B), 2-Digit Cancellation Test (2DCT), and the Composite Cognitive Score Derived From the Above Scores SDST Score Week 25	5.60 units on a scale Standard Error 0.84	3.61 units on a scale Standard Error 1.15	—
Change From Baseline on Cognitive Test Scores: Verbal Learning and Recall Test (VLRT), Symbol Digit Substitution Test (SDST), Trail Making Test (Part B), 2-Digit Cancellation Test (2DCT), and the Composite Cognitive Score Derived From the Above Scores 2DCT Score Week 9	0.30 units on a scale Standard Error 0.46	0.94 units on a scale Standard Error 0.63	—
Change From Baseline on Cognitive Test Scores: Verbal Learning and Recall Test (VLRT), Symbol Digit Substitution Test (SDST), Trail Making Test (Part B), 2-Digit Cancellation Test (2DCT), and the Composite Cognitive Score Derived From the Above Scores 2DCT Score Week 25	0.87 units on a scale Standard Error 0.51	1.01 units on a scale Standard Error 0.70	—
Change From Baseline on Cognitive Test Scores: Verbal Learning and Recall Test (VLRT), Symbol Digit Substitution Test (SDST), Trail Making Test (Part B), 2-Digit Cancellation Test (2DCT), and the Composite Cognitive Score Derived From the Above Scores Trail Making Test (Part B) Week 9	-5.60 units on a scale Standard Error 2.90	-3.09 units on a scale Standard Error 4.00	—
Change From Baseline on Cognitive Test Scores: Verbal Learning and Recall Test (VLRT), Symbol Digit Substitution Test (SDST), Trail Making Test (Part B), 2-Digit Cancellation Test (2DCT), and the Composite Cognitive Score Derived From the Above Scores Trail Making Test (Part B) Week 25	-1.59 units on a scale Standard Error 2.82	-6.86 units on a scale Standard Error 3.86	—

Adverse Events

Duloxetine

Serious events: 13 serious events

Other events: 199 other events

Deaths: 0 deaths

Placebo

Serious events: 4 serious events

Other events: 77 other events

Deaths: 0 deaths

Rescued Placebo

Serious events: 1 serious events

Other events: 17 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Duloxetine n=249 participants at risk Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=121 participants at risk Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity. Results are for the randomized placebo patients who reported events while they were on placebo.	Rescued Placebo n=35 participants at risk Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally for the remainder of the study. Results are for the randomized placebo patients who were rescued to duloxetine and reported events while they were on duloxetine.
Gastrointestinal disorders Constipation	14.9% 37/249 • Number of events 37 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	4.1% 5/121 • Number of events 6 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	8.6% 3/35 • Number of events 3 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Gastrointestinal disorders Diarrhoea	12.4% 31/249 • Number of events 33 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	2.5% 3/121 • Number of events 3 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Gastrointestinal disorders Dry mouth	13.7% 34/249 • Number of events 35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	5.8% 7/121 • Number of events 7 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	2.9% 1/35 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Gastrointestinal disorders Nausea	11.2% 28/249 • Number of events 29 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	5.8% 7/121 • Number of events 7 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
General disorders Fatigue	5.6% 14/249 • Number of events 17 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	2.5% 3/121 • Number of events 3 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	2.9% 1/35 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Infections and infestations Upper respiratory tract infection	5.2% 13/249 • Number of events 14 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/121 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Injury, poisoning and procedural complications Contusion	4.8% 12/249 • Number of events 16 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	3.3% 4/121 • Number of events 4 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	5.7% 2/35 • Number of events 2 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Injury, poisoning and procedural complications Fall	23.7% 59/249 • Number of events 80 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	14.0% 17/121 • Number of events 21 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	17.1% 6/35 • Number of events 11 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Musculoskeletal and connective tissue disorders Back pain	5.2% 13/249 • Number of events 14 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	6.6% 8/121 • Number of events 9 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Musculoskeletal and connective tissue disorders Pain in extremity	4.0% 10/249 • Number of events 11 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	1.7% 2/121 • Number of events 3 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	5.7% 2/35 • Number of events 2 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Nervous system disorders Dizziness	10.4% 26/249 • Number of events 30 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	5.0% 6/121 • Number of events 7 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	5.7% 2/35 • Number of events 2 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Nervous system disorders Headache	12.9% 32/249 • Number of events 37 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	10.7% 13/121 • Number of events 13 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Skin and subcutaneous tissue disorders Hyperhidrosis	6.0% 15/249 • Number of events 15 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	1.7% 2/121 • Number of events 2 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Vascular disorders Orthostatic hypotension	2.0% 5/249 • Number of events 5 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	1.7% 2/121 • Number of events 2 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	5.7% 2/35 • Number of events 2 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 800-545-5979

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	Duloxetine n=249 participants at risk Participants received placebo for 1 week (double-blind placebo lead-in) then started with duloxetine 30 milligrams (mg) orally once daily (QD) for 1 week, followed by duloxetine 60 mg QD orally for 11 weeks. This double-blind acute treatment phase was followed by a double-blind 12 week continuation phase during which participants either remained on 60 mg QD or were eligible for dose escalation to 120 mg QD orally based on depression symptom severity.	Placebo n=121 participants at risk Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants either remained on placebo or were eligible for receiving duloxetine 60 milligrams (mg) orally once daily (QD), beginning with duloxetine 30 mg QD orally for 1 week followed by duloxetine 60 mg QD orally for the remainder of the study based on depression symptom severity. Results are for the randomized placebo patients who reported events while they were on placebo.	Rescued Placebo n=35 participants at risk Participants received placebo for 13 weeks (The first week was placebo lead-in). This double-blind acute phase was followed by a double-blind 12 week continuation phase during which participants were rescued to duloxetine 60 milligrams (mg) orally once daily (QD) beginning with duloxetine 30 mg QD orally for one week followed by duloxetine 60 mg QD orally for the remainder of the study. Results are for the randomized placebo patients who were rescued to duloxetine and reported events while they were on duloxetine.
Cardiac disorders Arrhythmia	0.40% 1/249 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/121 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Cardiac disorders Atrial flutter	0.40% 1/249 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/121 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Cardiac disorders Coronary artery occlusion	0.40% 1/249 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/121 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Gastrointestinal disorders Pneumoperitoneum	0.40% 1/249 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/121 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
General disorders Chest pain	0.80% 2/249 • Number of events 2 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/121 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Infections and infestations Abscess intestinal	0.40% 1/249 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/121 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Infections and infestations Influenza	0.00% 0/249 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.83% 1/121 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Injury, poisoning and procedural complications Ankle fracture	0.40% 1/249 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/121 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Injury, poisoning and procedural complications Head injury	0.40% 1/249 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/121 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Injury, poisoning and procedural complications Hip fracture	0.40% 1/249 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/121 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Metabolism and nutrition disorders Diabetes mellitus	0.40% 1/249 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/121 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Musculoskeletal and connective tissue disorders Spinal osteoarthritis	0.40% 1/249 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/121 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Oesophageal adenocarcinoma metastatic	0.40% 1/249 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/121 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Nervous system disorders Intracranial aneurysm	0.40% 1/249 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/121 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Nervous system disorders Presyncope	0.00% 0/249 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.83% 1/121 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Renal and urinary disorders Renal failure acute	0.40% 1/249 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/121 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Reproductive system and breast disorders Prostatitis	0.40% 1/249 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/121 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/249 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.83% 1/121 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.40% 1/249 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/121 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	0.40% 1/249 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/121 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/249 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/121 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	2.9% 1/35 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Surgical and medical procedures Toe amputation	0.00% 0/249 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.83% 1/121 • Number of events 1 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.
Vascular disorders Orthostatic hypotension	0.40% 1/249 • Number of events 2 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/121 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.	0.00% 0/35 • Baseline (Week 1) through Week 25. The event of fall was collected using a solicited Falls Assessment questionnaire at each visit.