A Study of Olanzapine and Fluoxetine for Treatment-resistant Depression

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01687478
• Collaborator: (none)
• Enrollment: 176
• Locations: 11
• Arms: 2
• Duration (Months): 38
• Patients Per Site: 16
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the efficacy and safety of olanzapine and fluoxetine compared to placebo and fluoxetine as treatment for treatment-resistant depression (TRD) in Chinese participants.

Condition or Disease	Intervention/Treatment	Phase
Treatment Resistant Depression	Drug: Olanzapine; Drug: Fluoxetine; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 176 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Study to Assess the Short-Term Efficacy and Safety of Olanzapine and Fluoxetine Compared to Placebo and Fluoxetine for Nonpsychotic Treatment-Resistant Depression
• Study Start Date: Sep 1, 2012
• Actual Primary Completion Date: Nov 1, 2015
• Actual Study Completion Date: Nov 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Olanzapine + Fluoxetine Olanzapine starting dose is 5 milligram (mg) (1 tablet). May titrate up to 10 mg (2 tablets), or 15 mg (3 tablets) administered once daily by mouth for 8 weeks. Fluoxetine starting dose is 20 mg. May titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.	Drug: Olanzapine; Administered Orally; Other Names: LY170053 Zyprexa ; Drug: Fluoxetine; Administered Orally; Other Names: LY110140 Prozac
Placebo Comparator: Placebo + Fluoxetine Placebo matches the Olanzapine tablet for blinding. Fluoxetine starting dose is 20 mg, then may titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.	Drug: Fluoxetine; Administered Orally; Other Names: LY110140 Prozac ; Drug: Placebo; Administered Orally

Outcome Measures

Primary Outcome Measures

1. Mean Change From Baseline to 8 Week Endpoint in Montgomery-Äsberg Depression Rating Scale (MADRS) [Baseline, 8 Weeks]

   The MADRS total score is the sum of the 10 items; therefore the possible MADRS total score ranges from 0 to 60. A higher MADRS total score indicates a greater severity of depressive symptoms. Least square means (LSM) change from baseline, standard error was derived using mixed model repeated measures (MMRM) methodology with factors for treatment, Pooled Investigator, Visit, (Baseline + Treatment)*Visit.

Secondary Outcome Measures

1. Mean Change From Baseline to 8 Week Endpoint in Clinical Global Impressions-Severity of Depression (CGI-S) Scale [Baseline, 8 Weeks]

   CGI-S scale measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). The LS mean (LSM) change from baseline, standard error was derived using MMRM methodology with factors for treatment , Pooled Investigator , Visit , (Baseline + Treatment)*Visit.

2. Mean Change From Baseline to 8 Week Endpoint in the Simpson-Angus Scale (SAS) [Baseline, 8 Weeks]

   SAS scale consists of 10 items including 7 items that address bradykinesia-rigidity and additional single items for tremor, glabellar tap,and salivation. Each item represents a specific physical condition and is rated on a 5-point category rating scale ranging from 0 (complete absence of the condition) to 4 (the condition is present to an extreme degree).The total score is obtained by adding the scores for the 10 individual items making the maximum possible score is 40. Higher scores are indicative of more severe Parkinsonian-type symptoms.

3. Mean Change From Baseline to 8 Week Endpoint in the Short-Form 36 Health Survey (SF-36) [Baseline, 8 Weeks]

   SF-36, version 2 is a generic participant-rated questionnaire and consists of 36 questions covering the following 8 health domains (subscales): general health, role limitations because of physical problems, role limitations due to emotional problems, physical functioning, bodily pain, mental health, social functioning, and vitality. Each subscale is scored by summing the individual items and transforming the scores into a 0 to 100 scale, with higher scores indicating better health status or functioning. Two summary scores, the physical component summary (PCS) and the mental component summary (MCS) were constructed based on the eight SF-36 subscales. Both PCS and MCS range from 0-100 with higher scores indicating better health or functioning.

4. Mean Change From Baseline to 8 Week Endpoint in the Sheehan Disability Scale (SDS) [Baseline, 8 Weeks]

   SDS consists of 3 items (work/school, social life/leisure activities, and family life/home responsibilities). Total scores range from 0 to 30 with higher values indicating greater disruption. Individual Item scores range from 0 to 10 with higher values indicating greater disruption.

5. Percentage of Participants Who Achieve a Response Based on a ≥50% Reduction From Baseline in MADRS Total Score [Baseline,8 Weeks]

   The MADRS total score is the sum of the 10 items; therefore the possible MADRS total score ranges from 0 to 60. A higher MADRS total score indicates a greater severity of depressive symptoms.

6. Percentage of Participants Who Achieve Remission Based on MADRS Total Score ≤10 at 8 Weeks [Baseline, 8 Weeks]

   The MADRS consists of 10 items with each item rated on a scale ranging from 0 to 6. Fixed descriptors appear along the scale for each item at points 0, 2, 4, and 6, to standardize the gradation of response along the scale. The MADRS total score is the sum of the 10 items; therefore the possible MADRS total score ranges from 0 to 60. A higher MADRS total score indicates a greater severity of depressive symptoms.

7. Mean Change From Baseline to 8 Week Endpoint in the Barnes Akathisia Scale (BAS) [Baseline, 8 Weeks]

   BAS is used to rate observable, restless movements of drug induced akathisia and the subjective awareness of restlessness and any distress associated with the akathisia. The BAS consists of the following 3 items: an objective assessment of akathisia symptoms; a subjective assessment of the patient's awareness of inner restlessness; and a global clinical assessment of akathisia. The first two items are rated on a 4-point scale ranging from 0 (no abnormal movements or the absence of inner restlessness) to 3 (severe akathisia or the awareness of intense compulsion to move most of the time). The last item, the global clinical assessment of akathisia, is rated on a 5-point scale, ranging from 0 (no evidence of akathisia) to 5 (severe akathisia). Total BAS score ranges from 0 to 14 with a higher score representing worse results.

8. Mean Change From Baseline to 8 Week Endpoint in the Abnormal Involuntary Movement Scale (AIMS) [Baseline, 8 Weeks]

   AIMS is a 12-item scale. Items 1 to 8 are rated on a 5-point scale ranging from 0 (no dyskinetic movements) to 4 (severe dyskinetic movements). Item 9 assesses the participant's incapacitation due to abnormal movements, and item 10 assesses the participant's awareness of the abnormal movements and associated distress. Items 9 and 10 are rated on 5-point scales ranging from 0 (none or no awareness) to 4 (severe or aware, severe distress). Items 11 and 12 are yes/no questions regarding the dental status of the participant. The total score is the sum of the scores for the 12 items and the possible total score ranges from 0 to 42. A higher total score is indicative of more severe dyskinetic movements.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Have single or recurrent unipolar major depressive disorder (MDD) without psychotic features by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision (DSM-IV-TR) clinical assessment

• Have a total score ≥22 on the 17-item Hamilton Depression Rating Scale (HAM-D17) at screening and randomization

• Have treatment-resistant depression (TRD), defined as having failed to achieve a satisfactory antidepressant response, in the opinion of the investigator, to separate treatment courses of at least 2 different antidepressants, other than fluoxetine, of adequate dosage and duration (≥6 weeks) within the current major depressive episode

Exclusion Criteria:

• Have a diagnosis of Parkinson's disease or a related disorder

• Have a current or lifetime diagnosis of any of the following conditions, according to DSM-IV-TR criteria: Schizophrenia; Schizophreniform Disorder; Schizoaffective Disorder; Delusional Disorder; Psychotic Disorder Not Otherwise Specified; Bipolar Disorder I or II; Delirium of any type; Dementia of any type; Amnestic Disorder; any Substance-Induced Disorder; or any Psychotic Disorder due to a General Medical Condition

• Have a current diagnosis of post-partum depression or MDD with a seasonal pattern as defined in the DSM-IV-TR

• Have paranoid, schizoid, schizotypal, antisocial, or borderline personality disorder (Axis II) as a comorbid or primary diagnosis, based on DSM-IV-TR criteria

• Have DSM-IV-TR substance dependence/abuse or are not willing to avoid use of the substance (not including dependence on nicotine or caffeine) within 30 days of screening

• Are actively suicidal in the judgment of the investigator

• Have uncorrected narrow-angle glaucoma

• Have had one or more seizures without a clear and resolved etiology

• Have leukopenia

• Have any acute, serious, or unstable medical conditions

• Have an increased serum prolactin concentration at screening

• Have a rate-corrected cardiac QT interval, calculated using Bazett's formula (QTc Bazett's [Rate-corrected cardiac QT interval on electrocardiogram calculated using Bazett's formula(QTcB)]), on Electrocardiogram (ECG) >450 milliseconds (male) or >470 milliseconds (female) at screening

• Have a history of allergic reaction to olanzapine, fluoxetine, or olanzapine in combination with fluoxetine

• Have had treatment with olanzapine, fluoxetine, or olanzapine in combination with fluoxetine withdrawn due to clinically significant and/or intolerable adverse effects within 6 months of screening

• Have received treatment with remoxipride within 6 months of randomization

• Have received treatment with depot antipsychotics within one dosing interval before randomization

• Have received electroconvulsive therapy (ECT) or vagus nerve stimulation (VNS) treatment within the current MDD episode, or has a history of failure to respond to adequate treatment courses of ECT or VNS, or is expected to require ECT or VNS at any time during the study

• Have received previous treatment with clozapine

• Have received treatment with a monoamine oxidase inhibitor (MAOI) within 14 days of screening, or are expected to need MAOI treatment at any time during the study or up until 5 weeks after study discontinuation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Baoding		China	071000
2	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Beijing		China	100088
3	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Changsha		China	410011
4	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Guang Zhou		China	510080
5	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Hangzhou		China	310009
6	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Kunming		China	650032
7	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Nanjing		China	210029
8	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Shanghai		China	200030
9	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Wuhan		China	430022
10	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Xi'An		China	710061
11	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Xinxiang		China	453002

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT01687478
• Other Study ID Numbers: 13702; F1D-CR-HGNB
• First Posted: Sep 19, 2012
• Last Update Posted: Oct 9, 2019
• Last Verified: Sep 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant; Olanzapine; Fluoxetine

Study Results

Participant Flow

Arm/Group Title	Olanzapine + Fluoxetine	Placebo + Fluoxetine
Arm/Group Description	Olanzapine starting dose is 5 milligram (mg). May titrate up to 10 mg, or 15 mg administered once daily by mouth for 8 weeks. Fluoxetine starting dose is 20 mg. May titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.	Placebo matches the Olanzapine tablet for blinding. Fluoxetine starting dose is 20 mg, then may titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.
Period Title: Overall Study
STARTED	88	88
Safety Analysis Set	88	87
COMPLETED	56	49
NOT COMPLETED	32	39

Baseline Characteristics

Arm/Group Title	Olanzapine + Fluoxetine	Placebo + Fluoxetine	Total
Arm/Group Description	Olanzapine starting dose is 5 milligram (mg). May titrate up to 10 mg, or 15 mg administered once daily by mouth for 8 weeks. Fluoxetine starting dose is 20 mg. May titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.	Placebo matches the Olanzapine tablet for blinding. Fluoxetine starting dose is 20 mg, then may titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.	Total of all reporting groups
Overall Participants	88	88	176
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	38.63 (12.18)	41.45 (12.44)	40.04 (12.36)
Sex: Female, Male (Count of Participants)
Female	41 46.6%	36 40.9%	77 43.8%
Male	47 53.4%	52 59.1%	99 56.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	88 100%	88 100%	176 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	88 100%	88 100%	176 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
China	88 100%	88 100%	176 100%
Montgomery-Äsberg Depression Rating Scale (MADRS) Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	32.1 (5.3)	31.8 (4.8)	32.0 (5.0)
17 Item Hamilton Rating Scale for Depression (HAM-D17) Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	24.6 (2.6)	25.0 (2.6)	24.8 (2.6)
Clinical Global Impressions-Severity of Depression (CGI-S) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	4.9 (0.6)	4.9 (0.7)	4.9 (0.7)
Age of First Major Depressive Disorder (MDD) Episode (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29.92 (12.61)	34.07 (12.69)	30.00 (12.79)
Years Since the First MDD Episode (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	8.71 (6.21)	7.38 (7.86)	8.05 (7.10)
Years Since the Most Recent MDD Episode (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	3.66 (5.12)	3.23 (4.15)	3.45 (4.65)
Number of Previous Lifetime MDD Episodes (Number of MDD Episodes) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Number of MDD Episodes]	1.4 (1.4)	1.3 (2.1)	1.3 (1.8)
Number of Previous MDD Episodes Within the Last 36 Months (Number of MDD Episodes) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Number of MDD Episodes]	0.5 (0.8)	0.5 (1.1)	0.5 (0.9)

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline to 8 Week Endpoint in Montgomery-Äsberg Depression Rating Scale (MADRS)
Description	The MADRS total score is the sum of the 10 items; therefore the possible MADRS total score ranges from 0 to 60. A higher MADRS total score indicates a greater severity of depressive symptoms. Least square means (LSM) change from baseline, standard error was derived using mixed model repeated measures (MMRM) methodology with factors for treatment, Pooled Investigator, Visit, (Baseline + Treatment)*Visit.
Time Frame	Baseline, 8 Weeks

Outcome Measure Data

Analysis Population Description

Participants in the full analysis set (FAS) population: all randomized participants who had a baseline and at least one post-baseline MADRS total score measurement.

Arm/Group Title	Olanzapine + Fluoxetine	Placebo + Fluoxetine
Arm/Group Description	Olanzapine starting dose is 5 milligram (mg). May titrate up to 10 mg, or 15 mg administered once daily by mouth for 8 weeks. Fluoxetine starting dose is 20 mg. May titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.	Placebo matches the Olanzapine tablet for blinding. Fluoxetine starting dose is 20 mg, then may titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.
Measure Participants	87	86
Least Squares Mean (Standard Error) [Units on a scale]	-15.92 (1.20)	-14.30 (1.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine + Fluoxetine, Placebo + Fluoxetine
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.62
	Confidence Interval	(2-Sided) 95%; -5.04 to 1.80
	Parameter Dispersion	Type: Value:
	Estimation Comments	The Confidence Interval is based on the treatment difference LS Mean changes from baseline between Olanzapine + Fluoxetine and Placebo + Fluoxetine.

2. Secondary Outcome

Title	Mean Change From Baseline to 8 Week Endpoint in Clinical Global Impressions-Severity of Depression (CGI-S) Scale
Description	CGI-S scale measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). The LS mean (LSM) change from baseline, standard error was derived using MMRM methodology with factors for treatment , Pooled Investigator , Visit , (Baseline + Treatment)*Visit.
Time Frame	Baseline, 8 Weeks

Outcome Measure Data

Analysis Population Description

Participants in the FAS population: all randomized participants who had a baseline and at least one post-baseline MADRS total score measurement.

Arm/Group Title	Olanzapine + Fluoxetine	Placebo + Fluoxetine
Arm/Group Description	Olanzapine starting dose is 5 milligram (mg). May titrate up to 10 mg, or 15 mg administered once daily by mouth for 8 weeks. Fluoxetine starting dose is 20 mg. May titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.	Placebo matches the Olanzapine tablet for blinding. Fluoxetine starting dose is 20 mg, then may titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.
Measure Participants	87	86
Least Squares Mean (Standard Error) [Units on a scale]	-1.43 (0.15)	-1.63 (0.16)

3. Secondary Outcome

Title	Mean Change From Baseline to 8 Week Endpoint in the Simpson-Angus Scale (SAS)
Description	SAS scale consists of 10 items including 7 items that address bradykinesia-rigidity and additional single items for tremor, glabellar tap,and salivation. Each item represents a specific physical condition and is rated on a 5-point category rating scale ranging from 0 (complete absence of the condition) to 4 (the condition is present to an extreme degree).The total score is obtained by adding the scores for the 10 individual items making the maximum possible score is 40. Higher scores are indicative of more severe Parkinsonian-type symptoms.
Time Frame	Baseline, 8 Weeks

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug.

Arm/Group Title	Olanzapine + Fluoxetine	Placebo + Fluoxetine
Arm/Group Description	Olanzapine starting dose is 5 milligram (mg). May titrate up to 10 mg, or 15 mg administered once daily by mouth for 8 weeks. Fluoxetine starting dose is 20 mg. May titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.	Placebo matches the Olanzapine tablet for blinding. Fluoxetine starting dose is 20 mg, then may titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.
Measure Participants	88	87
Mean (Standard Deviation) [units on a scale]	0.03 (1.71)	-0.14 (1.72)

4. Secondary Outcome

Title	Mean Change From Baseline to 8 Week Endpoint in the Short-Form 36 Health Survey (SF-36)
Description	SF-36, version 2 is a generic participant-rated questionnaire and consists of 36 questions covering the following 8 health domains (subscales): general health, role limitations because of physical problems, role limitations due to emotional problems, physical functioning, bodily pain, mental health, social functioning, and vitality. Each subscale is scored by summing the individual items and transforming the scores into a 0 to 100 scale, with higher scores indicating better health status or functioning. Two summary scores, the physical component summary (PCS) and the mental component summary (MCS) were constructed based on the eight SF-36 subscales. Both PCS and MCS range from 0-100 with higher scores indicating better health or functioning.
Time Frame	Baseline, 8 Weeks

Outcome Measure Data

Analysis Population Description

All randomized participants.

Arm/Group Title	Olanzapine + Fluoxetine	Placebo + Fluoxetine
Arm/Group Description	Olanzapine starting dose is 5 milligram (mg). May titrate up to 10 mg, or 15 mg administered once daily by mouth for 8 weeks. Fluoxetine starting dose is 20 mg. May titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.	Placebo matches the Olanzapine tablet for blinding. Fluoxetine starting dose is 20 mg, then may titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.
Measure Participants	88	88
Physical Functioning	2.20 (7.51)	0.70 (7.47)
Role-Physical	3.99 (11.79)	3.93 (11.23)
Bodily Pain	6.81 (12.05)	0.02 (11.30)
General Health	5.82 (11.49)	2.84 (9.44)
Vitality	7.43 (13.54)	5.04 (9.83)
Social Functioning	6.13 (13.55)	4.56 (11.78)
Role-Emotional	6.61 (12.39)	6.71 (12.12)
Mental Health	8.98 (13.46)	8.43 (11.99)
Mental Component Score	8.87 (14.29)	8.73 (12.54)
Physical Component Score	2.87 (7.59)	-0.65 (7.22)

5. Secondary Outcome

Title	Mean Change From Baseline to 8 Week Endpoint in the Sheehan Disability Scale (SDS)
Description	SDS consists of 3 items (work/school, social life/leisure activities, and family life/home responsibilities). Total scores range from 0 to 30 with higher values indicating greater disruption. Individual Item scores range from 0 to 10 with higher values indicating greater disruption.
Time Frame	Baseline, 8 Weeks

Outcome Measure Data

Analysis Population Description

All randomized participants.

Arm/Group Title	Olanzapine + Fluoxetine	Placebo + Fluoxetine
Arm/Group Description	Olanzapine starting dose is 5 milligram (mg). May titrate up to 10 mg, or 15 mg administered once daily by mouth for 8 weeks. Fluoxetine starting dose is 20 mg. May titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.	Placebo matches the Olanzapine tablet for blinding. Fluoxetine starting dose is 20 mg, then may titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.
Measure Participants	88	88
Work/School (n=68,65)	-1.34 (2.71)	-1.55 (2.89)
Social Life (n=79,79)	-1.70 (2.66)	-1.49 (2.85)
Family Life (n=79,78)	-1.63 (3.00)	-1.53 (2.66)
SDS Total Score (68,64)	-4.57 (7.75)	-4.41 (7.89)

6. Secondary Outcome

Title	Percentage of Participants Who Achieve a Response Based on a ≥50% Reduction From Baseline in MADRS Total Score
Description	The MADRS total score is the sum of the 10 items; therefore the possible MADRS total score ranges from 0 to 60. A higher MADRS total score indicates a greater severity of depressive symptoms.
Time Frame	Baseline,8 Weeks

Outcome Measure Data

Analysis Population Description

All randomized participants who had a baseline and at least one post-baseline MADRS total score measurement.

Arm/Group Title	Olanzapine + Fluoxetine	Placebo + Fluoxetine
Arm/Group Description	Olanzapine starting dose is 5 milligram (mg). May titrate up to 10 mg, or 15 mg administered once daily by mouth for 8 weeks. Fluoxetine starting dose is 20 mg. May titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.	Placebo matches the Olanzapine tablet for blinding. Fluoxetine starting dose is 20 mg, then may titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.
Measure Participants	87	86
Number [Percent of participants]	65.5 74.4%	61.2 69.5%

7. Secondary Outcome

Title	Percentage of Participants Who Achieve Remission Based on MADRS Total Score ≤10 at 8 Weeks
Description	The MADRS consists of 10 items with each item rated on a scale ranging from 0 to 6. Fixed descriptors appear along the scale for each item at points 0, 2, 4, and 6, to standardize the gradation of response along the scale. The MADRS total score is the sum of the 10 items; therefore the possible MADRS total score ranges from 0 to 60. A higher MADRS total score indicates a greater severity of depressive symptoms.
Time Frame	Baseline, 8 Weeks

Outcome Measure Data

Analysis Population Description

All randomized participants who had a baseline and at least one post-baseline MADRS total score measurement.

Arm/Group Title	Olanzapine + Fluoxetine	Placebo + Fluoxetine
Arm/Group Description	Olanzapine starting dose is 5 milligram (mg). May titrate up to 10 mg, or 15 mg administered once daily by mouth for 8 weeks. Fluoxetine starting dose is 20 mg. May titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.	Placebo matches the Olanzapine tablet for blinding. Fluoxetine starting dose is 20 mg, then may titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.
Measure Participants	87	86
Number [Percent of participants]	37.9 43.1%	38.8 44.1%

8. Secondary Outcome

Title	Mean Change From Baseline to 8 Week Endpoint in the Barnes Akathisia Scale (BAS)
Description	BAS is used to rate observable, restless movements of drug induced akathisia and the subjective awareness of restlessness and any distress associated with the akathisia. The BAS consists of the following 3 items: an objective assessment of akathisia symptoms; a subjective assessment of the patient's awareness of inner restlessness; and a global clinical assessment of akathisia. The first two items are rated on a 4-point scale ranging from 0 (no abnormal movements or the absence of inner restlessness) to 3 (severe akathisia or the awareness of intense compulsion to move most of the time). The last item, the global clinical assessment of akathisia, is rated on a 5-point scale, ranging from 0 (no evidence of akathisia) to 5 (severe akathisia). Total BAS score ranges from 0 to 14 with a higher score representing worse results.
Time Frame	Baseline, 8 Weeks

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug.

Arm/Group Title	Olanzapine + Fluoxetine	Placebo + Fluoxetine
Arm/Group Description	Olanzapine starting dose is 5 milligram (mg). May titrate up to 10 mg, or 15 mg administered once daily by mouth for 8 weeks. Fluoxetine starting dose is 20 mg. May titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.	Placebo matches the Olanzapine tablet for blinding. Fluoxetine starting dose is 20 mg, then may titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.
Measure Participants	88	87
Mean (Standard Deviation) [units on a scale]	-0.01 (2.24)	-0.04 (2.13)

9. Secondary Outcome

Title	Mean Change From Baseline to 8 Week Endpoint in the Abnormal Involuntary Movement Scale (AIMS)
Description	AIMS is a 12-item scale. Items 1 to 8 are rated on a 5-point scale ranging from 0 (no dyskinetic movements) to 4 (severe dyskinetic movements). Item 9 assesses the participant's incapacitation due to abnormal movements, and item 10 assesses the participant's awareness of the abnormal movements and associated distress. Items 9 and 10 are rated on 5-point scales ranging from 0 (none or no awareness) to 4 (severe or aware, severe distress). Items 11 and 12 are yes/no questions regarding the dental status of the participant. The total score is the sum of the scores for the 12 items and the possible total score ranges from 0 to 42. A higher total score is indicative of more severe dyskinetic movements.
Time Frame	Baseline, 8 Weeks

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug.

Arm/Group Title	Olanzapine + Fluoxetine	Placebo + Fluoxetine
Arm/Group Description	Olanzapine starting dose is 5 milligram (mg). May titrate up to 10 mg, or 15 mg administered once daily by mouth for 8 weeks. Fluoxetine starting dose is 20 mg. May titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.	Placebo matches the Olanzapine tablet for blinding. Fluoxetine starting dose is 20 mg, then may titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.
Measure Participants	88	87
Mean (Standard Deviation) [units on a scale]	-0.16 (1.47)	-0.31 (3.28)

Adverse Events

Adverse Event Reporting Description	All participants in the safety analysis set.
Arm/Group Title	Olanzapine + Fluoxetine		Placebo + Fluoxetine
Arm/Group Description	Olanzapine starting dose is 5 milligram (mg). May titrate up to 10 mg, or 15 mg administered once daily by mouth for 8 weeks. Fluoxetine starting dose is 20 mg. May titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.		Placebo matches the Olanzapine tablet for blinding. Fluoxetine starting dose is 20 mg, then may titrate up to 40 mg or 50 mg administered once daily by mouth for 8 weeks.
All Cause Mortality
	Olanzapine + Fluoxetine		Placebo + Fluoxetine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Olanzapine + Fluoxetine		Placebo + Fluoxetine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/88 (1.1%)		1/87 (1.1%)
Psychiatric disorders
Restlessness	1/88 (1.1%)	1	0/87 (0%)	0
Suicide attempt	0/88 (0%)	0	1/87 (1.1%)	1
Other (Not Including Serious) Adverse Events
	Olanzapine + Fluoxetine		Placebo + Fluoxetine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	55/88 (62.5%)		45/87 (51.7%)
Cardiac disorders
Angina pectoris	1/88 (1.1%)	1	0/87 (0%)	0
Cardiovascular insufficiency	1/88 (1.1%)	1	0/87 (0%)	0
Palpitations	1/88 (1.1%)	1	2/87 (2.3%)	2
Sinus bradycardia	0/88 (0%)	0	1/87 (1.1%)	1
Supraventricular extrasystoles	0/88 (0%)	0	1/87 (1.1%)	1
Tachycardia	1/88 (1.1%)	1	0/87 (0%)	0
Ear and labyrinth disorders
Tinnitus	1/88 (1.1%)	1	0/87 (0%)	0
Eye disorders
Vision blurred	2/88 (2.3%)	2	2/87 (2.3%)	2
Gastrointestinal disorders
Abdominal pain upper	1/88 (1.1%)	1	1/87 (1.1%)	1
Diarrhoea	0/88 (0%)	0	2/87 (2.3%)	2
Dry mouth	1/88 (1.1%)	1	1/87 (1.1%)	1
Haematochezia	1/88 (1.1%)	1	0/87 (0%)	0
Nausea	0/88 (0%)	0	4/87 (4.6%)	4
Retching	0/88 (0%)	0	1/87 (1.1%)	1
Salivary hypersecretion	1/88 (1.1%)	1	0/87 (0%)	0
Tongue disorder	1/88 (1.1%)	1	0/87 (0%)	0
General disorders
Asthenia	2/88 (2.3%)	2	3/87 (3.4%)	3
Chest discomfort	1/88 (1.1%)	1	2/87 (2.3%)	2
Chest pain	1/88 (1.1%)	1	0/87 (0%)	0
Discomfort	0/88 (0%)	0	2/87 (2.3%)	2
Fatigue	3/88 (3.4%)	3	1/87 (1.1%)	1
Gait disturbance	1/88 (1.1%)	1	0/87 (0%)	0
Hunger	1/88 (1.1%)	1	0/87 (0%)	0
Oedema	1/88 (1.1%)	1	0/87 (0%)	0
Sensation of foreign body	0/88 (0%)	0	1/87 (1.1%)	1
Thirst	2/88 (2.3%)	2	0/87 (0%)	0
Hepatobiliary disorders
Hepatic function abnormal	6/88 (6.8%)	6	1/87 (1.1%)	1
Liver disorder	1/88 (1.1%)	1	0/87 (0%)	0
Liver injury	1/88 (1.1%)	1	0/87 (0%)	0
Immune system disorders
Hypersensitivity	0/88 (0%)	0	1/87 (1.1%)	1
Infections and infestations
Nasopharyngitis	1/88 (1.1%)	1	1/87 (1.1%)	1
Upper respiratory tract infection	1/88 (1.1%)	1	1/87 (1.1%)	1
Injury, poisoning and procedural complications
Overdose	0/88 (0%)	0	1/87 (1.1%)	1
Skin injury	0/88 (0%)	0	1/87 (1.1%)	1
Investigations
Alanine aminotransferase increased	7/88 (8%)	7	1/87 (1.1%)	1
Aspartate aminotransferase increased	5/88 (5.7%)	5	0/87 (0%)	0
Blood bilirubin increased	1/88 (1.1%)	1	2/87 (2.3%)	2
Blood cholesterol increased	5/88 (5.7%)	5	1/87 (1.1%)	1
Blood creatine phosphokinase increased	1/88 (1.1%)	1	1/87 (1.1%)	1
Blood glucose increased	2/88 (2.3%)	2	1/87 (1.1%)	1
Blood pressure increased	2/88 (2.3%)	2	0/87 (0%)	0
Blood prolactin increased	9/88 (10.2%)	9	2/87 (2.3%)	2
Blood triglycerides increased	7/88 (8%)	7	3/87 (3.4%)	3
Electrocardiogram abnormal	1/88 (1.1%)	1	1/87 (1.1%)	1
Electrocardiogram t wave abnormal	1/88 (1.1%)	1	0/87 (0%)	0
Gamma-glutamyltransferase increased	3/88 (3.4%)	3	0/87 (0%)	0
High density lipoprotein decreased	1/88 (1.1%)	1	1/87 (1.1%)	1
Lipids increased	3/88 (3.4%)	3	0/87 (0%)	0
Low density lipoprotein increased	3/88 (3.4%)	3	1/87 (1.1%)	1
Transaminases increased	3/88 (3.4%)	3	0/87 (0%)	0
Weight decreased	1/88 (1.1%)	1	4/87 (4.6%)	4
Weight increased	8/88 (9.1%)	8	2/87 (2.3%)	2
White blood cell count decreased	0/88 (0%)	0	2/87 (2.3%)	2
Metabolism and nutrition disorders
Decreased appetite	1/88 (1.1%)	1	1/87 (1.1%)	1
Diabetes mellitus	1/88 (1.1%)	1	0/87 (0%)	0
Dyslipidaemia	2/88 (2.3%)	2	0/87 (0%)	0
Hyperlipidaemia	4/88 (4.5%)	4	1/87 (1.1%)	1
Increased appetite	6/88 (6.8%)	6	1/87 (1.1%)	1
Musculoskeletal and connective tissue disorders
Joint swelling	1/88 (1.1%)	1	0/87 (0%)	0
Pain in extremity	1/88 (1.1%)	1	0/87 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma	0/41 (0%)	0	1/35 (2.9%)	1
Nervous system disorders
Akathisia	1/88 (1.1%)	1	0/87 (0%)	0
Dizziness	3/88 (3.4%)	3	5/87 (5.7%)	5
Extrapyramidal disorder	1/88 (1.1%)	1	1/87 (1.1%)	1
Headache	2/88 (2.3%)	2	3/87 (3.4%)	3
Hypokinesia	0/88 (0%)	0	1/87 (1.1%)	1
Somnolence	15/88 (17%)	17	3/87 (3.4%)	4
Syncope	1/88 (1.1%)	1	0/87 (0%)	0
Tremor	1/88 (1.1%)	2	0/87 (0%)	0
Psychiatric disorders
Dysphoria	0/88 (0%)	0	1/87 (1.1%)	1
Fear	1/88 (1.1%)	1	0/87 (0%)	0
Initial insomnia	0/88 (0%)	0	2/87 (2.3%)	2
Insomnia	1/88 (1.1%)	1	0/87 (0%)	0
Mental disorder	1/88 (1.1%)	1	0/87 (0%)	0
Nervousness	2/88 (2.3%)	2	2/87 (2.3%)	3
Restlessness	2/88 (2.3%)	2	3/87 (3.4%)	3
Sleep disorder	0/88 (0%)	0	1/87 (1.1%)	1
Somatic delusion	0/88 (0%)	0	1/87 (1.1%)	1
Suicidal ideation	1/88 (1.1%)	1	1/87 (1.1%)	1
Renal and urinary disorders
Urine odour abnormal	1/88 (1.1%)	1	0/87 (0%)	0
Respiratory, thoracic and mediastinal disorders
Hiccups	0/88 (0%)	0	1/87 (1.1%)	1
Respiratory tract congestion	0/88 (0%)	0	1/87 (1.1%)	1
Skin and subcutaneous tissue disorders
Hyperhidrosis	2/88 (2.3%)	2	3/87 (3.4%)	3
Vascular disorders
Hypertension	1/88 (1.1%)	1	1/87 (1.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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