VAST-D: VA Augmentation and Switching Treatments for Improving Depression Outcomes

• Sponsor: VA Office of Research and Development (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT01421342
• Collaborator: (none)
• Enrollment: 1,522
• Locations: 35
• Arms: 3
• Duration (Months): 42
• Patients Per Site: 43.5
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

The overall purpose is to determine research based 'next-steps' for outpatients with major depressive disorder who have not had satisfactory outcomes to standard 'first-step' treatments. The primary objective is to compare the acute (up to 12 weeks) treatment effectiveness of augmenting an antidepressant with aripiprazole or with bupropion-slow release (SR) vs. switching treatment to bupropion-SR monotherapy on symptom remission in Veterans with Major Depressive Disorder (MDD) who have not achieved optimal response after an adequate trial on antidepressant (a selective serotonin reuptake inhibitor [SSRI] or serotonin and norepinephrine reuptake inhibitor [SNRI] or mirtazapine) monotherapy. The secondary objectives are to compare the acute (up to 12 weeks) and long term (up to 36 weeks) efficacy, safety, effects on functioning, suicidality, quality of life, anxiety and other associated symptoms, costs and cost-effectiveness of each of the three treatments.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: Switching: Bupropion-SR; Drug: Augmenting: Antidepressant + Bupropion-SR; Drug: Augmenting: Antidepressant + Aripiprazole	Phase 3

Detailed Description

The overall aim of VAST-D is to enhance treatment outcomes for representative outpatients diagnosed with nonpsychotic major depressive disorder (MDD) and treated in primary or psychiatric VA care settings. In particular, VAST-D is designed to determine the comparative effectiveness of different treatment options for participants with MDD who fail to have a satisfactory outcome to treatment with their initial antidepressants.

These options may be conceptualized as representing two overall treatment strategies: 1) Medication Switch - switching from the initial antidepressant to another antidepressant medication, specifically bupropion-SR and 2) Medication Augmentation - augmenting the initial antidepressant with a second antidepressant, specifically bupropion-SR or a second generation antipsychotic, specifically aripiprazole. VAST-D's primary goal is to determine which of these 3 treatment strategies is most likely to lead to remission. Other key objectives include comparisons of response, time to remission, time to response, relapse, anxiety symptoms, suicidal ideation and behaviors, side effects, tolerability, quality of life, health related costs and satisfaction with participation in the study.

VAST-D will enroll 1518 total patients of both genders and all ethnic/racial and socioeconomic backgrounds. All patients will meet Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV-TR (text revised) criteria for nonpsychotic MDD. The diagnostic criteria for eligibility will be established by clinical interview supplemented with the 9-item Patient Health Questionnaire (PHQ-9). Final determination for eligibility will be made by the study clinician. Only participants with a suboptimal outcome to a well documented, adequately delivered (dose and duration), trial with selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI) or mirtazapine will be eligible for the study. Failure to achieve an adequate outcome will be ascertained by a score on the 16-item Quick Inventory of Depressive Symptomatology - Clinician rated (QIDS-C16) scale >= 16 (considered severe depression) after at least 6 weeks of treatment or QIDS-C16 >= 11 (considered moderately severe depression) after at least 8 weeks of treatment. Otherwise, the inclusion criteria are broad and the exclusion criteria are few; participants with most comorbid general medical or psychiatric disorders are generally included to provide a broadly representative sample.

Participants will be randomized (1:1:1 ratio) to switch to bupropion-SR alone (n=506), current antidepressant plus bupropion-SR (n=506), or current antidepressant plus aripiprazole (n=506). Treatment will be guided by clinician-rated symptom measures (the PHQ-9) and global side effects measures (the Frequency, Intensity, and Burden of Side Effects Rating or FIBSER) obtained at each treatment visit. Acute treatment visits will occur at baseline and at weeks 1, 2, 4, 6, 8, 10, and 12 to ensure delivery of appropriate and yet vigorous and tolerable pharmacotherapy. Participants who tolerate the acute treatment and achieve adequate response at 12 weeks will enter the 24-week Continuation Treatment phase, during which the initial treatment will continue and visits will occur every four weeks subsequently until patients have been followed for 36 weeks post-randomization. The QIDS-C16 will be administered at baseline and at each follow-up visit by an independent evaluator (who will be blinded to treatment assignment) to measure symptoms of depression for the study outcomes of remission, response and relapse. Neither the participant nor the treating clinician will be blinded to treatment.

Primary hypotheses:

Primary hypothesis 1.a: Remission rate from major depressive disorder will be higher in patients whose treatment is augmented with bupropion-SR (antidepressant + bupropion-SR) compared to those switched to bupropion-SR monotherapy.

Primary Hypothesis 1.b: Remission rate from major depressive disorder will be higher in patients whose treatment is augmented with aripiprazole (antidepressant + aripiprazole) compared to those switched to bupropion-SR monotherapy.

Secondary hypotheses:

Secondary Hypothesis 2.a: Remission rate will be greater in patients whose treatment is augmented with bupropion-SR (antidepressant + bupropion-SR) than in those augmented with aripiprazole (antidepressant + aripiprazole).

Secondary Hypothesis 2.b: Relapse rate (within 36 weeks of the initiation of treatment) will be lower in patients whose antidepressant is augmented with bupropion-SR (antidepressant + bupropion-SR) than in those whose antidepressant is switched to bupropion-SR monotherapy.

Secondary Hypothesis 2.c: Relapse rate (within 36 weeks of the initiation of treatment) will be lower in patients whose treatment is augmented with aripiprazole (antidepressant + aripiprazole) vs. those switched to bupropion-SR monotherapy.

Secondary Hypothesis 2.d: Relapse rate (within 36 weeks of the initiation of treatment) will be lower in patients whose treatment is augmented with bupropion-SR (antidepressant + bupropion-SR) than in patients whose treatment was augmented with aripiprazole (antidepressant + aripiprazole).

Secondary Hypothesis 2.e: The proportion of patients who develop akathisia, other akathisia-like side effects (e.g., tremor, irritability, motor restlessness) and extrapyramidal side effects will be greater in the patients whose antidepressant treatment is augmented with aripiprazole (antidepressant + aripiprazole) compared to patients whose treatment is augmented with bupropion-SR (antidepressant + bupropion-SR), or switched to bupropion-SR monotherapy.

Secondary Hypothesis 2.f: The relative costs (direct and indirect) of augmenting an antidepressant with aripiprazole (antidepressant + aripiprazole) will be greater than the costs of antidepressant augmentation with bupropion-SR (antidepressant + bupropion-SR), and the costs of antidepressant augmentation with bupropion-SR (antidepressant + bupropion-SR) will be greater than the costs of switching to bupropion-SR monotherapy, and augmentation and monotherapy with bupropion-SR will be more cost-effective than aripiprazole augmentation.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1522 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: CSP #576 - VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D)
• Study Start Date: Dec 1, 2012
• Actual Primary Completion Date: Aug 1, 2015
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Switching: Bupropion-SR Switching: Bupropion-SR	Drug: Switching: Bupropion-SR; Bupropion-SR (Dose: 150 mg - 400 mg taken per day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg (200 mg BID), maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.
Active Comparator: Augmenting: Antidepressant + Bupropion-SR Augmenting: Antidepressant + Bupropion-SR	Drug: Augmenting: Antidepressant + Bupropion-SR; Current antidepressant (either a SSRI or a SNRI or mirtazapine): Continue the dose prescribed at time of enrollment, or adjust depending on response or side effect profile for up to 36 weeks. And Bupropion-SR (Dose: 150 mg - 400 mg taken per day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg (200 mg BID), maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.
Active Comparator: Augmenting: Antidepressant + Aripiprazole Augmenting: Antidepressant + Aripiprazole	Drug: Augmenting: Antidepressant + Aripiprazole; Current antidepressant (either a SSRI or a SNRI or mirtazapine): Continue the dose prescribed at time of enrollment or adjust depending on response or side effect profile for up to 36 weeks. And Aripiprazole (Dose: 2 mg - 15 mg taken orally once per day for up to 36 weeks): Initiating with aripiprazole dose of 2 mg for one week, then increasing dose per protocol up to 15 mg, maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.

Outcome Measures

Primary Outcome Measures

1. Rate of Protocol Remission of Symptoms of Major Depressive Disorder [During acute phase (12 weeks)]

   Remission of symptoms of major depression during the acute treatment phase (12 weeks) defined as a sustained clinician-rated Quick Inventory of Depressive Symptoms (QIDS-C16) of <= 5 for two consecutive visits.

Secondary Outcome Measures

1. Rate of Protocol Relapse of Symptoms of Major Depression After Achieving Remission in the Acute Phase [Within 36 weeks after randomization (initiation of treatment)]

   Relapse in symptoms of major depression defined as a QIDS-C16 => 11 among those achieving remission in the acute phase.

2. Rate of Protocol Response as Reduction in Symptoms of Major Depression (>= 50% Reduction in QIDS-C) [During acute phase (up to 12 weeks)]

   Response measured as reduction in symptom score for major depression defined as: 1. a reduction in QIDS-C16 of 50% or greater

3. Rate of Protocol Response Measured as a Change in Clinical Global Impression (CGI) - Improvement Scale [During acute phase (up to 12 weeks)]

   Clinical assessment of a participant's level of depression and treatment response assessed by the Clinical Global Impression - Improvement (CGI -I) Scale, a 7-point clinician rating scale of improvement from baseline in severity of depression (Guy 1976). A secondary outcome measure of response was defined as achieving a score of 2 (much improved) or 1 (very much improved).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• DSM-IV diagnosis of single or recurrent, non-psychotic, major depressive disorder

• Currently taking a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) or mirtazapine for major depressive disorder

• Need for "next-step" treatment based on documented suboptimal outcome from current antidepressant treatment for major depressive episode (at least 6 weeks treatment with a QIDS-C16 >= 16 or at least 8 weeks with a QIDS-C16 >= 11; and at least 3 weeks at a stable "optimal" dose

• Age: 18 years of age or older

Exclusion Criteria:

• Prior inadequate response after an adequate treatment trial or clear cut intolerance to either of the study medications (aripiprazole or bupropion)

• Current treatment with bupropion, aripiprazole or any other antipsychotic agent

• Lifetime history of bipolar disorder, schizophrenia, schizoaffective disorder, or psychosis not otherwise specified

• Current diagnosis of Dementia

• Current diagnosis of an eating disorder or a seizure disorder

• High suicide risk currently requiring acute intervention (other than outpatient treatment of depression)

• Unstable, serious medical condition or one requiring acute medical treatment, or anticipation of hospitalization for extended care

• Requiring immediate hospitalization for psychiatric disorders

• Physiologic substance dependence requiring detoxification (excluding nicotine) in the past 30 days (substance abuse is not an exclusion criteria)

• Taking any concomitant medication that contraindicates any of treatment options or augmenting agents known to have an antidepressant effect

• Concurrent or recent participation (within the last 30 days) in another conflicting clinical trial with a mental health, investigational drug, or medical device intervention

• Female - pregnant or lactating or planning to become pregnant

• Patient was not able or willing to provide informed consent; or changed mind about participating prior to randomization

• Patient was not referred to the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tuscaloosa VA Medical Center, Tuscaloosa, AL	Tuscaloosa	Alabama	United States	35404
2	Phoenix VA Health Care System, Phoenix, AZ	Phoenix	Arizona	United States	85012
3	Southern Arizona VA Health Care System, Tucson	Tucson	Arizona	United States	85723
4	VA Loma Linda Healthcare System, Loma Linda, CA	Loma Linda	California	United States	92357
5	VA Long Beach Healthcare System, Long Beach, CA	Long Beach	California	United States	90822
6	VA Palo Alto Health Care System, Palo Alto, CA	Palo Alto	California	United States	94304-1290
7	VA San Diego Healthcare System, San Diego, CA	San Diego	California	United States	92161
8	San Francisco VA Medical Center, San Francisco, CA	San Francisco	California	United States	94121
9	VA Eastern Colorado Health Care System, Denver, CO	Denver	Colorado	United States	80220
10	VA Connecticut Healthcare System West Haven Campus, West Haven, CT	West Haven	Connecticut	United States	06516
11	Washington DC VA Medical Center, Washington, DC	Washington	District of Columbia	United States	20422
12	Miami VA Healthcare System, Miami, FL	Miami	Florida	United States	33125
13	James A. Haley Veterans' Hospital, Tampa, FL	Tampa	Florida	United States	33612
14	Atlanta VA Medical and Rehab Center, Decatur, GA	Decatur	Georgia	United States	30033
15	Edward Hines Jr. VA Hospital, Hines, IL	Hines	Illinois	United States	60141-5000
16	Richard L. Roudebush VA Medical Center, Indianapolis, IN	Indianapolis	Indiana	United States	46202-2884
17	Baltimore VA Medical Center VA Maryland Health Care System, Baltimore, MD	Baltimore	Maryland	United States	21201
18	Minneapolis VA Health Care System, Minneapolis, MN	Minneapolis	Minnesota	United States	55417
19	Kansas City VA Medical Center, Kansas City, MO	Kansas City	Missouri	United States	64128
20	St. Louis VA Medical Center John Cochran Division, St. Louis, MO	Saint Louis	Missouri	United States	63106
21	Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE	Omaha	Nebraska	United States	68105-1873
22	New Mexico VA Health Care System, Albuquerque, NM	Albuquerque	New Mexico	United States	87108-5153
23	Asheville VA Medical Center, Asheville, NC	Asheville	North Carolina	United States	28805
24	Salisbury W.G. (Bill) Hefner VA Medical Center, Salisbury, NC	Salisbury	North Carolina	United States	28144
25	Cincinnati VA Medical Center, Cincinnati, OH	Cincinnati	Ohio	United States	45220
26	Louis Stokes VA Medical Center, Cleveland, OH	Cleveland	Ohio	United States	44106
27	Philadelphia VA Medical Center, Philadelphia, PA	Philadelphia	Pennsylvania	United States	19104
28	VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA	Pittsburgh	Pennsylvania	United States	15240
29	Memphis VA Medical Center, Memphis, TN	Memphis	Tennessee	United States	38104
30	Central Texas Veterans Health Care System, Temple, TX	Temple	Texas	United States	76504
31	Salem VA Medical Center, Salem, VA	Salem	Virginia	United States	24153
32	VA Puget Sound Health Care System American Lake Division, Tacoma, WA	Tacoma	Washington	United States	98493
33	Clarksburg Louis A. Johnson VA Medical Center, Clarksburg, WV	Clarksburg	West Virginia	United States	26301
34	William S. Middleton Memorial Veterans Hospital, Madison, WI	Madison	Wisconsin	United States	53705
35	Clement J. Zablocki VA Medical Center, Milwaukee, WI	Milwaukee	Wisconsin	United States	53295-1000

Sponsors and Collaborators

• VA Office of Research and Development

Investigators

• Study Chair: Somaia Mohamed, PhD, VA Connecticut Healthcare System West Haven Campus, West Haven, CT
• Study Chair: Sidney Zisook, MD, VA San Diego Healthcare System, San Diego, CA

Study Documents (Full-Text)

None provided.

More Information

Publications

• Mohamed S, Johnson GR, Vertrees JE, Guarino PD, Weingart K, Young IT, Yoon J, Gleason TC, Kirkwood KA, Kilbourne AM, Gerrity M, Marder S, Biswas K, Hicks P, Davis LL, Chen P, Kelada A, Huang GD, Lawrence DD, LeGwin M, Zisook S. The VA augmentation and switching treatments for improving depression outcomes (VAST-D) study: Rationale and design considerations. Psychiatry Res. 2015 Oct 30;229(3):760-70. doi: 10.1016/j.psychres.2015.08.005. Epub 2015 Aug 6.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT01421342
• Other Study ID Numbers: 576
• First Posted: Aug 22, 2011
• Last Update Posted: May 29, 2018
• Last Verified: Apr 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by VA Office of Research and Development: Mood Disorder; Depression; Depressive Disorder; Depressive Disorder, Major; Bupropion; Aripiprazole; Remission; Relapse; Cost-Effectiveness; Atypical Antipsychotic; Antidepressant; Augmentation; Veterans; Mental Health
• Additional relevant MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major; Aripiprazole; Bupropion; Antidepressive Agents

Study Results

Participant Flow

Arm/Group Title	Switching: Bupropion-SR	Augmenting: Antidepressant + Bupropion-SR	Augmenting: Antidepressant + Aripiprazole
Arm/Group Description	Switching: Bupropion-SR: Bupropion-SR (Dose: 150 mg - 400 mg taken per day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg (200 mg BID), maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.	Augmenting: Antidepressant + Bupropion-SR: Current antidepressant (either a SSRI or a SNRI or mirtazapine): Continue the dose prescribed at time of enrollment, or adjust depending on response or side effect profile for up to 36 weeks. And Bupropion-SR (Dose: 150 mg - 400 mg taken per day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg (200 mg BID), maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.	Augmenting: Antidepressant + Aripiprazole: Current antidepressant (either a SSRI or a SNRI or mirtazapine): Continue the dose prescribed at time of enrollment or adjust depending on response or side effect profile for up to 36 weeks. And Aripiprazole (Dose: 2 mg - 15 mg taken orally once per day for up to 36 weeks): Initiating with aripiprazole dose of 2 mg for one week, then increasing dose per protocol up to 15 mg, maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.
Period Title: Acute Treatment Phase (12 Weeks)
STARTED	511	506	505
COMPLETED	353	378	406
NOT COMPLETED	158	128	99
Period Title: Acute Treatment Phase (12 Weeks)
STARTED	353	378	406
COMPLETED	204	253	268
NOT COMPLETED	149	125	138
Period Title: Acute Treatment Phase (12 Weeks)
STARTED	204	253	268
COMPLETED	152	194	203
NOT COMPLETED	52	59	65

Baseline Characteristics

Arm/Group Title	Switching: Bupropion-SR	Augmenting: Antidepressant + Bupropion-SR	Augmenting: Antidepressant + Aripiprazole	Total
Arm/Group Description	Switching: Bupropion-SR: Bupropion-SR (Dose: 150 mg - 400 mg taken per day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg (200 mg BID), maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.	Augmenting: Antidepressant + Bupropion-SR: Current antidepressant (either a SSRI or a SNRI or mirtazapine): Continue the dose prescribed at time of enrollment, or adjust depending on response or side effect profile for up to 36 weeks. And Bupropion-SR (Dose: 150 mg - 400 mg taken per day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg (200 mg BID), maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.	Augmenting: Antidepressant + Aripiprazole: Current antidepressant (either a SSRI or a SNRI or mirtazapine): Continue the dose prescribed at time of enrollment or adjust depending on response or side effect profile for up to 36 weeks. And Aripiprazole (Dose: 2 mg - 15 mg taken orally once per day for up to 36 weeks): Initiating with aripiprazole dose of 2 mg for one week, then increasing dose per protocol up to 15 mg, maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.	Total of all reporting groups
Overall Participants	511	506	505	1522
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.5 (12.2)	54.4 (12.2)	54.2 (12.3)	54.4 (12.2)
Sex: Female, Male (Count of Participants)
Female	68 13.3%	81 16%	77 15.2%	226 14.8%
Male	443 86.7%	425 84%	428 84.8%	1296 85.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	2 0.4%	1 0.2%	3 0.2%
Not Hispanic or Latino	454 88.8%	449 88.7%	459 90.9%	1362 89.5%
Unknown or Not Reported	57 11.2%	55 10.9%	45 8.9%	157 10.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	8 1.6%	8 1.6%	6 1.2%	22 1.4%
Asian	2 0.4%	1 0.2%	4 0.8%	7 0.5%
Native Hawaiian or Other Pacific Islander	2 0.4%	2 0.4%	1 0.2%	5 0.3%
Black or African American	129 25.2%	115 22.7%	126 25%	370 24.3%
White	341 66.7%	343 67.8%	338 66.9%	1022 67.1%
More than one race	10 2%	20 4%	13 2.6%	43 2.8%
Unknown or Not Reported	19 3.7%	17 3.4%	17 3.4%	53 3.5%
QIDS-C16 Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	16.6 (3.3)	16.6 (3.2)	16.9 (3.3)	16.7 (3.3)
Patient Health Questionnaire (PHQ-9) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	15.9 (5.2)	16.3 (5.2)	16.3 (5.2)	16.2 (5.2)
CGI - Severity Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	4.5 (1.0)	4.6 (0.9)	4.6 (1.0)	4.6 (1.0)
Beck Anxiety Inventory (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	18.6 (11.1)	19.0 (11.4)	19.7 (11.3)	19.1 (11.3)
Arizona Sexual Experiences Scale (Female) (participants) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [participants]	4.2 (1.1) 0.8%	4.2 (1.1) 0.8%	4.2 (1.2) 0.8%	4.2 (1.1) 0.3%
Arizona Sexual Experiences Scale (male) (participants) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [participants]	4.1 (1.1) 0.8%	4.1 (1.1) 0.8%	4.1 (1.2) 0.8%	4.1 (1.1) 0.3%
PTSD (Count of Participants)
Count of Participants [Participants]	248 48.5%	244 48.2%	225 44.6%	717 47.1%
EuroQol Health State Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	54.7 (20.5)	52.7 (19.8)	54.0 (20.8)	53.8 (20.4)
Quality of Life Enjoyment and Satisfaction Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	41.4 (13.8)	40.3 (14.8)	40.1 (14.8)	40.6 (14.5)
Cumulative Illness Rating Scale (CIRS) Severity Index (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	11.4 (5.5)	11.1 (4.9)	11.0 (5.1)	11.2 (5.2)

Outcome Measures

1. Primary Outcome

Title	Rate of Protocol Remission of Symptoms of Major Depressive Disorder
Description	Remission of symptoms of major depression during the acute treatment phase (12 weeks) defined as a sustained clinician-rated Quick Inventory of Depressive Symptoms (QIDS-C16) of <= 5 for two consecutive visits.
Time Frame	During acute phase (12 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Switching: Bupropion-SR	Augmenting: Antidepressant + Bupropion-SR	Augmenting: Antidepressant + Aripiprazole
Arm/Group Description	Switching: Bupropion-SR: Bupropion-SR (Dose: 150 mg - 400 mg taken per day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg (200 mg BID), maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.	Augmenting: Antidepressant + Bupropion-SR: Current antidepressant (either a SSRI or a SNRI or mirtazapine): Continue the dose prescribed at time of enrollment, or adjust depending on response or side effect profile for up to 36 weeks. And Bupropion-SR (Dose: 150 mg - 400 mg taken per day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg (200 mg BID), maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.	Augmenting: Antidepressant + Aripiprazole: Current antidepressant (either a SSRI or a SNRI or mirtazapine): Continue the dose prescribed at time of enrollment or adjust depending on response or side effect profile for up to 36 weeks. And Aripiprazole (Dose: 2 mg - 15 mg taken orally once per day for up to 36 weeks): Initiating with aripiprazole dose of 2 mg for one week, then increasing dose per protocol up to 15 mg, maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.
Measure Participants	511	506	505
Count of Participants [Participants]	114 22.3%	136 26.9%	146 28.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching: Bupropion-SR, Augmenting: Antidepressant + Bupropion-SR
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.076
	Comments	Co-primary hypothesis: After ordering results from largest p-value to smallest (Hochberg approach) the comparison of Augmenting Antidepressant+Bupropion with Switching to Bupropion-SR was performed at the 0.05 significance level.
	Method	Regression, Logistic
	Comments	Stratified by participating medical center
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.31
	Confidence Interval	(2-Sided) 95%; 0.97 to 1.75
	Parameter Dispersion	Type: Value:
	Estimation Comments	Represents relative odds of remission for Augmentation Antidepressant + Bupropion-SR / Switching to Bupropion-SR

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Switching: Bupropion-SR, Augmenting: Antidepressant + Aripiprazole
	Comments	Co-primary hypothesis: After ordering results form largest p-value to smallest (Hochberg approach) the comparison of Augmentation Antidepressant + Aripiprazole with Switching to Bupropion-SR was performed at the 0.025 significance level.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments	Co-primary hypothesis: Second ordered test after ordering largest p-value to smallest (Hochberg approach) the comparison of Augmentation Antidepressant + Aripiprazole with Switching to Bupropion-SR was performed at the 0.025 significance level.
	Method	Regression, Logistic
	Comments	Stratified by participating medical center
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.42
	Confidence Interval	(2-Sided) 95%; 1.06 to 1.89
	Parameter Dispersion	Type: Value:
	Estimation Comments	Represents relative odds of remission for Augmentation Antidepressant + Aripiprazole / Switching to Bupropion-SR

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Augmenting: Antidepressant + Bupropion-SR, Augmenting: Antidepressant + Aripiprazole
	Comments	If either if the first two hypothesis tests for the co-primary hypotheses were significant, perform the test of Augmentation Antidepressant + Aripiprazole vs. Augmentation Antidepressant + Bupropion-SR at the 0.05 significance level.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.46
	Comments	Following the gate-keeping strategy of the analysis plan, complete the comparison of Augmentation Antidepressant + Aripiprazole vs. Augmentation Antidepressant + Bupropion-SR was evaluated at the 0.05 significance level.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.11
	Confidence Interval	(2-Sided) 95%; 0.84 to 1.48
	Parameter Dispersion	Type: Value:
	Estimation Comments	Represents relative odds of remission for Augmentation Antidepressant + Aripiprazole / Augmentation Antidepressant + Bupropion-SR

2. Secondary Outcome

Title	Rate of Protocol Relapse of Symptoms of Major Depression After Achieving Remission in the Acute Phase
Description	Relapse in symptoms of major depression defined as a QIDS-C16 => 11 among those achieving remission in the acute phase.
Time Frame	Within 36 weeks after randomization (initiation of treatment)

Outcome Measure Data

Analysis Population Description

The Analysis Population is the cohort of participants who met the criteria for protocol remission during the Acute Phase (first 12 Weeks of follow-up)

Arm/Group Title	Switching: Bupropion-SR	Augmenting: Antidepressant + Bupropion-SR	Augmenting: Antidepressant + Aripiprazole
Arm/Group Description	Switching: Bupropion-SR: Bupropion-SR (Dose: 150 mg - 400 mg taken per day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg (200 mg BID), maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.	Augmenting: Antidepressant + Bupropion-SR: Current antidepressant (either a SSRI or a SNRI or mirtazapine): Continue the dose prescribed at time of enrollment, or adjust depending on response or side effect profile for up to 36 weeks. And Bupropion-SR (Dose: 150 mg - 400 mg taken per day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg (200 mg BID), maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.	Augmenting: Antidepressant + Aripiprazole: Current antidepressant (either a SSRI or a SNRI or mirtazapine): Continue the dose prescribed at time of enrollment or adjust depending on response or side effect profile for up to 36 weeks. And Aripiprazole (Dose: 2 mg - 15 mg taken orally once per day for up to 36 weeks): Initiating with aripiprazole dose of 2 mg for one week, then increasing dose per protocol up to 15 mg, maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.
Measure Participants	114	136	146
Count of Participants [Participants]	26 5.1%	35 6.9%	37 7.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching: Bupropion-SR, Augmenting: Antidepressant + Bupropion-SR
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.70
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.36
	Confidence Interval	(2-Sided) 95%; 0.78 to 2.39
	Parameter Dispersion	Type: Value:
	Estimation Comments	Represents relative odds of relapse for Augmentation Antidepressant + Bupropion-SR / Switching to Bupropion-SR

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Switching: Bupropion-SR, Augmenting: Antidepressant + Aripiprazole
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.68
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; 0.65 to 1.94
	Parameter Dispersion	Type: Value:
	Estimation Comments	Represents relative odds of relapse for Augmentation Antidepressant + Aripiprazole / Switching to Bupropion-SR

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Augmenting: Antidepressant + Bupropion-SR, Augmenting: Antidepressant + Aripiprazole
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.87
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.58 to 1.59
	Parameter Dispersion	Type: Value:
	Estimation Comments	Represents relative odds of relapse for Augmentation Antidepressant + Aripiprazole / Augmentation Antidepressant + Bupropion-SR

3. Secondary Outcome

Title	Rate of Protocol Response as Reduction in Symptoms of Major Depression (>= 50% Reduction in QIDS-C)
Description	Response measured as reduction in symptom score for major depression defined as: 1. a reduction in QIDS-C16 of 50% or greater
Time Frame	During acute phase (up to 12 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Switching: Bupropion-SR	Augmenting: Antidepressant + Bupropion-SR	Augmenting: Antidepressant + Aripiprazole
Arm/Group Description	Switching: Bupropion-SR: Bupropion-SR (Dose: 150 mg - 400 mg taken per day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg (200 mg BID), maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.	Augmenting: Antidepressant + Bupropion-SR: Current antidepressant (either a SSRI or a SNRI or mirtazapine): Continue the dose prescribed at time of enrollment, or adjust depending on response or side effect profile for up to 36 weeks. And Bupropion-SR (Dose: 150 mg - 400 mg taken per day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg (200 mg BID), maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.	Augmenting: Antidepressant + Aripiprazole: Current antidepressant (either a SSRI or a SNRI or mirtazapine): Continue the dose prescribed at time of enrollment or adjust depending on response or side effect profile for up to 36 weeks. And Aripiprazole (Dose: 2 mg - 15 mg taken orally once per day for up to 36 weeks): Initiating with aripiprazole dose of 2 mg for one week, then increasing dose per protocol up to 15 mg, maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.
Measure Participants	511	506	505
Count of Participants [Participants]	319 62.4%	332 65.6%	375 74.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching: Bupropion-SR, Augmenting: Antidepressant + Bupropion-SR
	Comments	After ordering results form largest p-value to smallest (Hochberg approach) the comparison of Augmentation Antidepressant + Bupropion with Switching to Bupropion was performed at the 0.05 significance level.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.28
	Comments
	Method	Regression, Logistic
	Comments	Stratified by participating medical center
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.16
	Confidence Interval	(2-Sided) 95%; 0.89 to 1.50
	Parameter Dispersion	Type: Value:
	Estimation Comments	Represents relative odds of response for Augmentation Antidepressant + Bupropion / Switching to Bupropion

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Switching: Bupropion-SR, Augmenting: Antidepressant + Aripiprazole
	Comments	After ordering results form largest p-value to smallest (Hochberg approach) the comparison of Augmentation Antidepressant + Aripiprazole with Switching to Bupropion-SR was performed at the 0.025 significance level.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Logistic
	Comments	Stratified by participating medical center (site)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.74
	Confidence Interval	(2-Sided) 95%; 1.33 to 2.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	Represents relative odds of response for Augmentation Antidepressant + Aripiprazole / Switching to Bupropion-SR

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Augmenting: Antidepressant + Bupropion-SR, Augmenting: Antidepressant + Aripiprazole
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	Following the gate-keeping strategy of the analysis plan, complete the comparison of Augmentation Antidepressant + Aripiprazole with Augmentation Antidepressant + Bupropion-SR at the 0.05 significance level.
	Method	Regression, Logistic
	Comments	Stratified by participating medical center
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.55
	Confidence Interval	(2-Sided) 95%; 1.17 to 2.05
	Parameter Dispersion	Type: Value:
	Estimation Comments	Represents relative odds of response for Augmentation Antidepressant + Aripiprazole / Augmentation Antidepressant + Bupropion-SR

4. Secondary Outcome

Title	Rate of Protocol Response Measured as a Change in Clinical Global Impression (CGI) - Improvement Scale
Description	Clinical assessment of a participant's level of depression and treatment response assessed by the Clinical Global Impression - Improvement (CGI -I) Scale, a 7-point clinician rating scale of improvement from baseline in severity of depression (Guy 1976). A secondary outcome measure of response was defined as achieving a score of 2 (much improved) or 1 (very much improved).
Time Frame	During acute phase (up to 12 weeks)

Outcome Measure Data

Analysis Population Description

Whole randomized cohort by intent-to-treat

Arm/Group Title	Switching: Bupropion-SR	Augmenting: Antidepressant + Bupropion-SR	Augmenting: Antidepressant + Aripiprazole
Arm/Group Description	Switching: Bupropion-SR: Bupropion-SR (Dose: 150 mg - 400 mg taken per day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg (200 mg BID), maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.	Augmenting: Antidepressant + Bupropion-SR: Current antidepressant (either a SSRI or a SNRI or mirtazapine): Continue the dose prescribed at time of enrollment, or adjust depending on response or side effect profile for up to 36 weeks. And Bupropion-SR (Dose: 150 mg - 400 mg taken per day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg (200 mg BID), maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.	Augmenting: Antidepressant + Aripiprazole: Current antidepressant (either a SSRI or a SNRI or mirtazapine): Continue the dose prescribed at time of enrollment or adjust depending on response or side effect profile for up to 36 weeks. And Aripiprazole (Dose: 2 mg - 15 mg taken orally once per day for up to 36 weeks): Initiating with aripiprazole dose of 2 mg for one week, then increasing dose per protocol up to 15 mg, maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.
Measure Participants	511	506	505
Count of Participants [Participants]	356 69.7%	376 74.3%	400 79.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Switching: Bupropion-SR, Augmenting: Antidepressant + Bupropion-SR
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments	After ordering results form largest p-value to smallest (Hochberg approach) the comparison of Augmentation Antidepressant + Bupropion with Switching to Bupropion was performed at the 0.05 significance level.
	Method	Regression, Logistic
	Comments	Stratified by participating medical center
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.26
	Confidence Interval	(2-Sided) 95%; 0.95 to 1.68
	Parameter Dispersion	Type: Value:
	Estimation Comments	Represents relative odds of response for Augmentation Antidepressant + Bupropion / Switching to Bupropion

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Switching: Bupropion-SR, Augmenting: Antidepressant + Aripiprazole
	Comments	After ordering results form largest p-value to smallest (Hochberg approach) the comparison of Augmentation Antidepressant + Aripiprazole with Switching to Bupropion-SR was performed at the 0.025 significance level.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments	Stratified by participating medical center
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.70
	Confidence Interval	(2-Sided) 95%; 1.26 to 2.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	Represents relative odds of response for Augmentation Antidepressant + Aripiprazole / Switching to Bupropion-SR

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Augmenting: Antidepressant + Bupropion-SR, Augmenting: Antidepressant + Aripiprazole
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.043
	Comments	Following the gate-keeping strategy of the analysis plan, complete the comparison of Augmentation Antidepressant + Aripiprazole with Augmentation Antidepressant + Bupropion-SR at the 0.05 significance level.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.37
	Confidence Interval	(2-Sided) 95%; 1.01 to 1.86
	Parameter Dispersion	Type: Value:
	Estimation Comments	Represents relative odds of response for Augmentation Antidepressant + Aripiprazole / Augmentation Antidepressant + Bupropion-SR

Adverse Events

Time Frame	Serious adverse events were collected from the time of enrollment to withdrawal (up to 36 weeks after randomization) with one month of surveillance after withdrawal. Non-serious adverse events were collected from the time of randomization to withdrawal (up to 36 weeks after randomization).
Adverse Event Reporting Description	A non-serious adverse events was reported if it was among the symptoms prompted for at each scheduled follow-up or if it was a symptom assessed as possibly related to s study medication.
Arm/Group Title	Switching: Bupropion-SR		Augmenting: Antidepressant + Bupropion-SR		Augmenting: Antidepressant + Aripiprazole
Arm/Group Description	Switching: Bupropion-SR Switching: Bupropion-SR: Bupropion-SR (Dose: 150 mg - 400 mg taken per day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg (200 mg BID), maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.		Augmenting: Antidepressant + Bupropion-SR Augmenting: Antidepressant + Bupropion-SR: Current antidepressant (either a SSRI or a SNRI or mirtazapine): Continue the dose prescribed at time of enrollment, or adjust depending on response or side effect profile for up to 36 weeks. And Bupropion-SR (Dose: 150 mg - 400 mg taken per day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg (200 mg BID), maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.		Augmenting: Antidepressant + Aripiprazole Augmenting: Antidepressant + Aripiprazole: Current antidepressant (either a SSRI or a SNRI or mirtazapine): Continue the dose prescribed at time of enrollment or adjust depending on response or side effect profile for up to 36 weeks. And Aripiprazole (Dose: 2 mg - 15 mg taken orally once per day for up to 36 weeks): Initiating with aripiprazole dose of 2 mg for one week, then increasing dose per protocol up to 15 mg, maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.
All Cause Mortality
	Switching: Bupropion-SR		Augmenting: Antidepressant + Bupropion-SR		Augmenting: Antidepressant + Aripiprazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/511 (0.6%)		1/506 (0.2%)		4/505 (0.8%)
Serious Adverse Events
	Switching: Bupropion-SR		Augmenting: Antidepressant + Bupropion-SR		Augmenting: Antidepressant + Aripiprazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	52/511 (10.2%)		57/506 (11.3%)		56/505 (11.1%)
Blood and lymphatic system disorders
Haemorrhagic disorder	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Cardiac disorders
Cardiac disorders (total)	7/511 (1.4%)	7	4/506 (0.8%)	4	8/505 (1.6%)	8
Acute myocardial infarction	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Angina pectoris	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Atrial fibrillation	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Cardiac failure acute	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Cardiac failure congestive	1/511 (0.2%)	1	1/506 (0.2%)	1	2/505 (0.4%)	2
Cardiomyopathy	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Coronary artery disease	2/511 (0.4%)	2	0/506 (0%)	0	0/505 (0%)	0
Coronary artery occlusion	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Coronary artery stenosis	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Intracardiac thrombus	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Myocardial infarction	1/511 (0.2%)	1	0/506 (0%)	0	1/505 (0.2%)	1
Nodal rhythm	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Sinus bradycardia	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Sinus node dysfunction	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Endocrine disorders
Hyperaldosteronism	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Gastrointestinal disorders
Gastrointestinal disorders (total)	3/511 (0.6%)	3	2/506 (0.4%)	3	2/505 (0.4%)	2
Abdominal hernia	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Diverticulum intestinal haemorrhagic	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Gastric perforation	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Gastrooesophageal reflux disease	1/511 (0.2%)	1	0/506 (0%)	0	1/505 (0.2%)	1
Large intestine polyp	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Oesophagitis ulcerative	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Pancreatic pseudocyst	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
General disorders
General disorders and administration site conditions (total)	4/511 (0.8%)	6	2/506 (0.4%)	2	5/505 (1%)	6
Adverse drug reaction	1/511 (0.2%)	1	1/506 (0.2%)	1	0/505 (0%)	0
Asthenia	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Chest pain	1/511 (0.2%)	1	0/506 (0%)	0	3/505 (0.6%)	4
Device malfunction	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Hernia obstructive	1/511 (0.2%)	3	0/506 (0%)	0	0/505 (0%)	0
Non-cardiac chest pain	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Sudden death	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Hepatobiliary disorders
Biliary colic	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Cholecystitis	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Cholecystitis acute	0/511 (0%)	0	1/506 (0.2%)	1	1/505 (0.2%)	1
Gallbladder disorder	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Infections and infestations
Infections and infestations (total)	6/511 (1.2%)	6	10/506 (2%)	11	12/505 (2.4%)	14
Abscess	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Arthritis bacterial	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Bronchitis	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Cellulitis of male external genital organ	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Diverticulitis	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Eczema infected	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Erysipelas	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Infectious colitis	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Infective tenosynovitis	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Perirectal abscess	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Pneumonia	2/511 (0.4%)	2	4/506 (0.8%)	4	3/505 (0.6%)	3
Pneumonia staphylococcal	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Postoperative wound infection	0/511 (0%)	0	1/506 (0.2%)	1	1/505 (0.2%)	1
Pyelonephritis	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Sinusitis	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Tooth abscess	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Urinary tract infection	1/511 (0.2%)	1	0/506 (0%)	0	3/505 (0.6%)	3
Urinary tract infection bacterial	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Injury, poisoning and procedural complications
Accident at work	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Back injury	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Cardiac valve replacement complication	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Fall	0/511 (0%)	0	2/506 (0.4%)	2	0/505 (0%)	0
Injury	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Joint injury	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Post procedural haemorrhage	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Procedural complication	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Road traffic accident	1/511 (0.2%)	1	1/506 (0.2%)	1	3/505 (0.6%)	3
Investigations
Electrocardiogram QT prolonged	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Metabolism and nutrition disorders
Diabetic ketoacidosis	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Hyperglycaemia	0/511 (0%)	0	1/506 (0.2%)	1	2/505 (0.4%)	2
Hypokalaemia	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Musculoskeletal and connective tissue disorders
Arthritis	1/511 (0.2%)	1	1/506 (0.2%)	1	1/505 (0.2%)	1
Arthropathy	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Back pain	0/511 (0%)	0	1/506 (0.2%)	1	1/505 (0.2%)	1
Cervical spinal stenosis	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Intervertebral disc degeneration	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Lumbar spinal stenosis	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Musculoskeletal chest pain	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Osteoarthritis	0/511 (0%)	0	2/506 (0.4%)	2	3/505 (0.6%)	3
Rhabdomyolysis	1/511 (0.2%)	1	1/506 (0.2%)	1	0/505 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung adenocarcinoma stage I	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Lung neoplasm malignant	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Parathyroid tumour benign	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Prostate cancer	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Prostate cancer stage I	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Nervous system disorders
Nervous system disorders (total)	7/511 (1.4%)	7	3/506 (0.6%)	4	3/505 (0.6%)	4
Carpal tunnel syndrome	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Diabetic neuropathy	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Drug withdrawal headache	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Guillain-Barre syndrome	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Lacunar infarction	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Seizure	2/511 (0.4%)	2	2/506 (0.4%)	3	0/505 (0%)	0
Serotonin syndrome	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Syncope	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Transient ischaemic attack	2/511 (0.4%)	2	0/506 (0%)	0	1/505 (0.2%)	1
Psychiatric disorders
Psychiatric disorders (total)	15/511 (2.9%)	15	14/506 (2.8%)	17	13/505 (2.6%)	16
Aggression	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Alcohol abuse	1/511 (0.2%)	1	0/506 (0%)	0	2/505 (0.4%)	2
Alcoholism	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Anxiety	0/511 (0%)	0	1/506 (0.2%)	1	1/505 (0.2%)	1
Completed suicide	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Delirium	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Drug abuse	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Homicidal ideation	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Self-injurious ideation	0/511 (0%)	0	1/506 (0.2%)	1	1/505 (0.2%)	1
Somatisation disorder	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Substance abuse	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Substance-induced psychotic disorder	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Suicidal ideation	8/511 (1.6%)	8	10/506 (2%)	11	5/505 (1%)	5
Suicide attempt	3/511 (0.6%)	3	1/506 (0.2%)	1	3/505 (0.6%)	3
Renal and urinary disorders
Bladder perforation	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Chronic kidney disease	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	2
Nephrolithiasis	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Renal failure	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Urinary incontinence	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/511 (0.2%)	1	2/506 (0.4%)	3	3/505 (0.6%)	3
Dyspnoea exertional	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Haemoptysis	0/511 (0%)	0	0/506 (0%)	0	0/505 (0%)	0
Oropharyngeal pain	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Pulmonary embolism	0/511 (0%)	0	1/506 (0.2%)	1	0/505 (0%)	0
Skin and subcutaneous tissue disorders
Angioedema	0/511 (0%)	0	2/506 (0.4%)	2	0/505 (0%)	0
Surgical and medical procedures
Alcohol detoxification	1/511 (0.2%)	1	1/506 (0.2%)	1	0/505 (0%)	0
Drug detoxification	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Vascular disorders
Arterial occlusive disease	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Arteriosclerosis	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Peripheral arterial occlusive disease	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Other (Not Including Serious) Adverse Events
	Switching: Bupropion-SR		Augmenting: Antidepressant + Bupropion-SR		Augmenting: Antidepressant + Aripiprazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	383/511 (75%)		369/506 (72.9%)		374/505 (74.1%)
Blood and lymphatic system disorders
Blood and lymphatic system disorders	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Cardiac disorders
Cardiac disorders	4/511 (0.8%)	4	2/506 (0.4%)	2	3/505 (0.6%)	3
Congenital, familial and genetic disorders
Congenital, familial and genetic disorders	0/511 (0%)	0	1/506 (0.2%)	1	0/0 (NaN)	0
Ear and labyrinth disorders
Ear and labyrinth disorders	4/511 (0.8%)	4	11/506 (2.2%)	12	1/505 (0.2%)	1
Eye disorders
Eye disorders	5/511 (1%)	5	10/506 (2%)	10	12/505 (2.4%)	14
Gastrointestinal disorders
Gastrointestinal disorders	189/511 (37%)	305	157/506 (31%)	288	147/505 (29.1%)	230
General disorders
General disorders and administration site conditions	82/511 (16%)	100	73/506 (14.4%)	97	105/505 (20.8%)	115
Hepatobiliary disorders
Hepatobiliary disorders	1/511 (0.2%)	1	0/506 (0%)	0	0/505 (0%)	0
Infections and infestations
Infections and infestations	20/511 (3.9%)	21	10/506 (2%)	13	11/505 (2.2%)	12
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications	2/511 (0.4%)	2	11/506 (2.2%)	12	9/505 (1.8%)	10
Investigations
Investigations	25/511 (4.9%)	28	38/506 (7.5%)	41	72/505 (14.3%)	81
Metabolism and nutrition disorders
Metabolism and nutrition disorders	114/511 (22.3%)	134	95/506 (18.8%)	111	113/505 (22.4%)	142
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders	20/511 (3.9%)	21	10/506 (2%)	10	17/505 (3.4%)	20
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	2/511 (0.4%)	2	1/506 (0.2%)	1	0/505 (0%)	0
Nervous system disorders
Nervous system disorders	218/511 (42.7%)	383	235/506 (46.4%)	426	239/505 (47.3%)	433
Psychiatric disorders
Psychiatric disorders	224/511 (43.8%)	393	200/506 (39.5%)	349	176/176 (100%)	270
Renal and urinary disorders
Renal and urinary disorders	8/511 (1.6%)	8	9/506 (1.8%)	10	6/505 (1.2%)	6
Reproductive system and breast disorders
Reproductive system and breast disorders	1/511 (0.2%)	2	9/506 (1.8%)	9	7/505 (1.4%)	7
Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders	10/511 (2%)	11	5/506 (1%)	5	10/505 (2%)	12
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders	50/511 (9.8%)	63	48/506 (9.5%)	58	38/505 (7.5%)	45
Social circumstances
Social circumstances	0/511 (0%)	0	0/506 (0%)	0	1/505 (0.2%)	1
Vascular disorders
Vascular disorders	7/511 (1.4%)	8	3/506 (0.6%)	3	3/505 (0.6%)	3

Limitations/Caveats

[Not Specified]

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.