Does Dual Therapy Hasten Antidepressant Response?

• ClinicalTrials.gov Identifier: NCT00519428
• Recruitment Status: Completed
• First Posted: August 22, 2007
• Results First Posted: October 4, 2017
• Last Update Posted: October 4, 2017
• Sponsor: New York State Psychiatric Institute
• Collaborators: University of Ottawa; National Institute of Mental Health (NIMH)
• Information provided by (Responsible Party): New York State Psychiatric Institute

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Major Depressive Disorder
• Interventions: Drug: escitalopram; Drug: bupropion extra long (XL); Drug: escitalopram + bupropion
• Enrollment: 245

Participant Flow

Recruitment Details	Recruitment dates: August, 2007 to August 2011 Locations: 4 outpatient research clinics in two countries (US and Canada)
Pre-assignment Details	All patients had to be psychoactive drug-free for at least two weeks (five weeks for fluoxetine) prior to randomization and had to continue to meet study entry criteria at point of randomization

Arm/Group Title	Escitalopram + Bupropion	Escitalopram	Bupropion
Arm/Group Description	escitalopram plus bupropion	escitalopram monotherapy	bupropion monotherapy
Period Title: Overall Study
Started	78	84	83
Completed	57	69	58
Not Completed	21	15	25
Reason Not Completed
Adverse Event	5	2	10
Lost to Follow-up	7	7	6
Withdrawal by Subject	8	3	7
unstated	1	3	2

Baseline Characteristics

Arm/Group Title		Escitalopram + Bupropion	Escitalopram	Bupropion	Total
Arm/Group Description		escitalopram plus bupropion XL	escitalopram monotherapy	bupropion XL monotherapy	Total of all reporting groups
Overall Number of Baseline Participants		78	84	83	245
Baseline Analysis Population Description		[Not Specified]
Age, Continuous [1]; Mean (Standard Deviation); Unit of measure: Years
Age	Number Analyzed	78 participants	84 participants	83 participants	245 participants
		40 (10)	41 (11)	40 (11)	40 (11)
		[1] Measure Description: Patient's report of their age
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	78 participants	84 participants	83 participants	245 participants
	Female	52 66.7%	62 73.8%	49 59.0%	163 66.5%
	Male	26 33.3%	22 26.2%	34 41.0%	82 33.5%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	78 participants	84 participants	83 participants	245 participants
United States		37	42	41	120
Canada		41	42	42	125

Outcome Measures

1. Primary Outcome

Title	Time to Remission, Defined by the Week of Onset of Persistent Hamilton Rating Scale for Depression (HAM-D 17) <= 7, With no Subsequent HAM-D 17 > 7
Description	Life Table Survival Analysis run twice, once comparing Dual Therapy (i.e., Bupropion + Escitalopram) to Bupropion alone (i.e., Bupropion + Placebo) and once comparing Dual Therapy to Escitalopram alone (i.e., Escitalopram + Placebo). Because both analyses must significantly favor Dual Therapy, each individual analysis must reach a critical alpha = .0916 in order to reach an over-all alpha = .05.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

age 18-65 with Major Depressive Disorder (MDD), non-bipolar, non-psychotic, non-substance abusing, without intolerance to study drugs or adequate selective serotonin re-uptake inhibitor (SSRI) and/or bupropion treatment in current episode; physically healthy without contraindications to bupropion or escitalopram.

Arm/Group Title	Escitalopram + Bupropion	Escitalopram	Bupropion
Arm/Group Description:	escitalopram plus bupropion XL	escitalopram monotherapy	bupropion XL monotherapy
Overall Number of Participants Analyzed	78	84	83
Mean (Standard Deviation); Unit of Measure: weeks
	8 (7)	9 (7)	10 (7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Escitalopram + Bupropion, Escitalopram, Bupropion
	Comments	Hypothesis: Dual Treatment (escitalopram + bupropion) will result in greater improvement over 12 weeks than either monotherapy (i.e., two analyses: 1) dual treatment will outperform escitalopram monotherapy; 2) dual treatment will outperform bupropion monotherapy). Therefore each analysis will be done twice and it will be required that both analyses be significant to declare the over-all study significant.
	Type of Statistical Test	Superiority
	Comments	Hypothesis: Dual Treatment (escitalopram + bupropion) will result in greater improvement over 12 weeks than either monotherapy (i.e., two analyses: 1) dual treatment will outperform escitalopram monotherapy; 2) dual treatment will outperform bupropion monotherapy).
Statistical Test of Hypothesis	P-Value	.05
	Comments	Each individual test will require the calculated "p" to be < .0916 to declare that comparison to be significant. Since the hypothesis requires both comparisons to be significant, this produces an over-all alpha of .05.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	.05
	Parameter Dispersion	Type: Standard Deviation; Value: 4
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Remission: Persistent Hamilton Rating Scale for Depression, 17 Items (HAM-D 17) <= 7, With no HAM-D 17 >7 Through Week 12
Description	Chi square comparison of rates of persistent remission (i.e., no subsequent Hamilton Rating Scale for Depression, 17 items [HAMD-D 17] > 7 once HAMD-D 17 <= 7); Dual rate vs. Escitalopram only rate and Dual rate vs. Bupropion only rate.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

age 18-65 with MDD, non-bipolar, non-psychotic, non-substance abusing, without intolerance to study drugs or adequate SSRI/bupropion treatment in current episode; physically healthy without contraindications to bupropion or escitalopram.

Arm/Group Title	Escitalopram + Bupropion	Escitalopram	Bupropion
Arm/Group Description:	escitalopram plus bupropion XL	escitalopram monotherapy	bupropion XL monotherapy
Overall Number of Participants Analyzed	78	84	83
Measure Type: Number; Unit of Measure: percentage of participants
	52	46	34

3. Secondary Outcome

Title	Severity of Depressive Symptoms as Measured by Hamilton Rating Scale for Depression (HAM-D 17)
Description	Last summary score rating on the 17-item Hamilton Rating Scale for Depression Eight items are scored on a 5-point scale, ranging from 0 = not present to 4 = severe. Nine are scored from 0-2. Range 0-58. 0-7 = Normal 8-13 = Mild Depression 14-18 = Moderate Depression 19-22 = Severe Depression ≥ 23 = Very Severe Depression
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

age 18-65 with MDD, non-bipolar, non-psychotic, non-substance abusing, without intolerance to study drugs or adequate SSRI/bupropion treatment in current episode; physically healthy without contraindications to bupropion or escitalopram.

Arm/Group Title	Escitalopram + Bupropion	Escitalopram	Bupropion
Arm/Group Description:	escitalopram plus bupropion XL	escitalopram monotherapy	bupropion XL monotherapy
Overall Number of Participants Analyzed	78	83	84
Mean (Standard Deviation); Unit of Measure: units on Hamilton Rating Scale for Depre
	10 (8)	9 (7)	12 (8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Escitalopram + Bupropion, Escitalopram, Bupropion
	Comments	To test the hypothesis that escitalopram + bupropion would have superior efficacy relative to each monotherapy, the group receiving both medications was separately compared to each monotherapy group, covarying for baseline score and country
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	.0916
	Comments	escitalopram + bupropion vs. escitalopram: F(1,159) = 1.93, ns escitalopram + bupropion vs. bupropion: F (1,157) = 1.99, ns
	Method	ANCOVA
	Comments	adjusting for baseline score and country
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	10
	Parameter Dispersion	Type: Standard Deviation; Value: 8
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Functioning, as Measured by the Social Adjustment Scale (SAS) Summary Score
Description	Social adjustment was measured using the Social Adjustment Scale (SAS). The SAS is a self-report scale that assesses depressive symptoms and functioning in nine social and work-related domains generating a total score that is indicative of a subject's overall level of social adjustment. Subjects rate their own social functioning over times on a 5-point scale on items covering work for pay, housework, extended family, parenting, marital status, social activity and leisure, family unit and student status (sub-scales). Mean values of all the sub-scales are used, with a range from 0-5. Higher score = worse outcome … worse functioning
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients; latest available Total SAS score used if week 12 score not available.

Arm/Group Title	Escitalopram + Bupropion	Escitalopram	Bupropion
Arm/Group Description:	escitalopram plus bupropion XL as dual treatment (i.e., this is not a SINGLE treatment arm; all patients assigned this arm received both medications) escitalopram + bupropion: same dosing schedule as for monotherapy	escitalopram monotherapy escitalopram: 10mg/d increasing by 10 mg/week to a maximum of 40 mg/d if tolerated and not remitted	bupropion XL monotherapy bupropion XL: 150mg/d increasing to 300 mg/d after 1 week and 450 mg/d after 3 weeks, all increases if tolerated and not remitted
Overall Number of Participants Analyzed	78	83	84
Mean (Standard Deviation); Unit of Measure: units on the SAS scale
	2.65 (.69)	2.63 (.69)	2.74 (.71)

5. Secondary Outcome

Title	Quality of Life, as Measured by the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) Short Form (SF)
Description	The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) intends to measure quality of life in 16 domains. A summary score is computed by adding the scores and dividing by 16 (or the number of answered items if some are not answered). The minimum raw score on the Q-LES-Q-SF is 14, and the maximum score is 70. Higher score means more satisfaction.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

All Randomized Subjects

Arm/Group Title	Escitalopram + Bupropion	Escitalopram	Bupropion
Arm/Group Description:	escitalopram plus bupropion XL	escitalopram monotherapy	bupropion XL monotherapy
Overall Number of Participants Analyzed	78	83	84
Mean (Standard Deviation); Unit of Measure: units on the Q-LES-Q scale
	3.0 (.82)	3.0 (.76)	3.1 (.74)

Adverse Events

Time Frame	12 weeks
Adverse Event Reporting Description	A modified Systematic Assessment for Treatment Emergent Events (SAFTEE) at each visit specifically asked about 17 items (too much energy, muscle tightness, insomnia, tremor, poor concentration, word finding, spacy, dizzy, headache, dry mouth, decreased appetite, nausea, low energy, sleepy, sweating, decreased libido, anger/irritability) a pilot study showed occurred in at least 10% of patients treated with escitalopram plus bupropion. A General Inquiry then asked re additional symptoms.
Arm/Group Title	Escitalopram + Bupropion		Escitalopram		Bupropion
Arm/Group Description	escitalopram plus bupropion XL escitalopram + bupropion: same dosing schedule as for monotherapy		escitalopram monotherapy escitalopram: 10mg/d increasing by 10 mg/week to a maximum of 40 mg/d if tolerated and not remitted		bupropion XL monotherapy bupropion XL: 150mg/d increasing to 300 mg/d after 1 week and 450 mg/d after 3 weeks, all increases if tolerated and not remitted
All-Cause Mortality
	Escitalopram + Bupropion		Escitalopram		Bupropion
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--		--/--
Serious Adverse Events
	Escitalopram + Bupropion		Escitalopram		Bupropion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/78 (0.00%)		0/84 (0.00%)		0/83 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Escitalopram + Bupropion		Escitalopram		Bupropion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	71/78 (91.03%)		80/84 (95.24%)		71/83 (85.54%)
Cardiac disorders
dizzy † 8 [1]	19/78 (24.36%)	19	20/84 (23.81%)	20	19/83 (22.89%)	19
Gastrointestinal disorders
dry mouth † 10 [2]	27/78 (34.62%)	27	18/84 (21.43%)	18	28/83 (33.73%)	28
decreased appetite † 11 [3]	17/78 (21.79%)	17	21/84 (25.00%)	21	21/83 (25.30%)	21
nausea, vomiting † 12 [4]	25/78 (32.05%)	25	32/84 (38.10%)	32	28/83 (33.73%)	28
General disorders
Too much energy † 1 [5]	5/78 (6.41%)	5	4/84 (4.76%)	4	7/83 (8.43%)	7
insomnia † 3 [6]	24/78 (30.77%)	24	27/84 (32.14%)	27	31/83 (37.35%)	31
lethargy † 13 [7]	10/78 (12.82%)	10	15/84 (17.86%)	15	10/83 (12.05%)	10
sweating † 15 [8]	19/78 (24.36%)	19	13/84 (15.48%)	13	5/83 (6.02%)	5
sexual dysfunction † 16 [9]	20/78 (25.64%)	20	18/84 (21.43%)	28	9/83 (10.84%)	9
Musculoskeletal and connective tissue disorders
muscle tightness † 2 [10]	13/78 (16.67%)	13	14/84 (16.67%)	14	18/83 (21.69%)	18
Nervous system disorders
tremor † 4 [11]	23/78 (29.49%)	23	14/84 (16.67%)	14	18/83 (21.69%)	18
trouble thinking † 5 [12]	12/78 (15.38%)	12	13/84 (15.48%)	13	5/83 (6.02%)	5
trouble finding words † 6 [13]	5/78 (6.41%)	5	6/84 (7.14%)	6	7/83 (8.43%)	7
spacey † 7 [14]	13/78 (16.67%)	13	12/84 (14.29%)	12	5/83 (6.02%)	5
headache † 9 [15]	28/78 (35.90%)	28	28/84 (33.33%)	28	26/83 (31.33%)	26
daytime sleepiness † 14 [16]	13/78 (16.67%)	13	17/84 (20.24%)	17	9/83 (10.84%)	9
Psychiatric disorders
anger, irritability † 17 [17]	4/78 (5.13%)	4	5/84 (5.95%)	5	14/83 (16.87%)	14
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, Too much energy; 2 Term from vocabulary, muscle tightness; 3 Term from vocabulary, insomnia; 4 Term from vocabulary, tremor; 5 Term from vocabulary, cognitive disturbanc; 6 Term from vocabulary, trouble finding word; 7 Term from vocabulary, spacey; 8 Term from vocabulary, dizzy; 9 Term from vocabulary, headache; 10 Term from vocabulary, dry mouth; 11 Term from vocabulary, decreased appetite; 12 Term from vocabulary, nausea, vomiting; 13 Term from vocabulary, lethargy; 14 Term from vocabulary, daytime sleepiness; 15 Term from vocabulary, sweating; 16 Term from vocabulary, sexual dysfunction; 17 Term from vocabulary, anger, irritability; [1] feeling dizzy, lightheaded or faint; [2] dry mouth; [3] anorexia; [4] nausea, vomiting, queasy stomach; [5] A feeling of being too "revved up"; [6] trouble falling asleep, staying asleep or waking too early; [7] low energy, lack of "get up and go"; [8] sweating too much, excessive perspiration; [9] delayed orgasm, anorgasmia, erectile dysfunction, poor libido, low sex drive; [10] a feeling of tenseness or tightness in the muscles; [11] involuntary shaking or trembling; [12] trouble thinking or concentrating, cognitive disturbance; [13] word finding difficulty; [14] feeling "spacey", "out of it", "fuzzy headed", "cotton in my head"; [15] pain inside the head; [16] daytime sleepiness, feeling sleepy or groggy during the day; [17] anger, irritability, feeling like "flying off the handle", too touchy

Limitations and Caveats

Sample size may have limited demonstration of differences.

More Information

Certain Agreements

Principal Investigators are NOT 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.

Results Point of Contact

• Name/Title: Jonathan W. Stewart, M.D.
• Organization: NYSPInstitute
• Phone: 212-543-5745
• EMail: jws6@columbia.edu

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Weissman MM, Wickramaratne P, Pilowsky DJ, Poh E, Batten LA, Hernandez M, Flament MF, Stewart JA, McGrath P, Blier P, Stewart JW. Treatment of maternal depression in a medication clinical trial and its effect on children. Am J Psychiatry. 2015 May;172(5):450-9. doi: 10.1176/appi.ajp.2014.13121679. Epub 2015 Jan 23.

Gerra ML, Marchesi C, Amat JA, Blier P, Hellerstein DJ, Stewart JW. Does negative affectivity predict differential response to an SSRI versus a non-SSRI antidepressant? J Clin Psychiatry. 2014 Sep;75(9):e939-44. doi: 10.4088/JCP.14m09025.

Stewart JW, McGrath PJ, Blondeau C, Deliyannides DA, Hellerstein D, Norris S, Amat J, Pilowsky DJ, Tessier P, Laberge L, O'Shea D, Chen Y, Withers A, Bergeron R, Blier P. Combination antidepressant therapy for major depressive disorder: speed and probability of remission. J Psychiatr Res. 2014 May;52:7-14. doi: 10.1016/j.jpsychires.2013.12.001. Epub 2013 Dec 17.

• Responsible Party: New York State Psychiatric Institute
• ClinicalTrials.gov Identifier: NCT00519428
• Other Study ID Numbers: 5476; 5R01MH076961-04 ( U.S. NIH Grant/Contract )
• First Submitted: August 20, 2007
• First Posted: August 22, 2007
• Results First Submitted: October 6, 2016
• Results First Posted: October 4, 2017
• Last Update Posted: October 4, 2017