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

Tracking Information

• First Submitted Date: August 20, 2007
• First Posted Date: August 22, 2007
• Results First Submitted Date: October 6, 2016
• Results First Posted Date: October 4, 2017
• Last Update Posted Date: October 4, 2017
• Study Start Date: August 2007
• Actual Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 5, 2017)

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 [ Time Frame: 12 weeks ]

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.

• Original Primary Outcome Measures (submitted: August 20, 2007): Time to remission, defined by the week of onset of persistent HAM-D 17 <= 7, with no subsequent HAM-D 17 > 7 [ Time Frame: 12 weeks ]

Current Secondary Outcome Measures (submitted: September 5, 2017)

• Remission: Persistent Hamilton Rating Scale for Depression, 17 Items (HAM-D 17) <= 7, With no HAM-D 17 >7 Through Week 12 [ Time Frame: 12 weeks ]
  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.
• Severity of Depressive Symptoms as Measured by Hamilton Rating Scale for Depression (HAM-D 17) [ Time Frame: 12 weeks ]
  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
• Functioning, as Measured by the Social Adjustment Scale (SAS) Summary Score [ Time Frame: 12 weeks ]
  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
• Quality of Life, as Measured by the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) Short Form (SF) [ Time Frame: 12 weeks ]
  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.

Original Secondary Outcome Measures (submitted: August 20, 2007)

• Remission: persistent HAM-D 17 <= 7, with no HAM-D 17 >7 through week 12 [ Time Frame: 12 weeks ]
• Severity of depressive symptoms, measured by HAM-D 17, CGI, QIDS-SR 16 [ Time Frame: 12 weeks ]
• Functioning, as measured by the SAS functioning summary score [ Time Frame: 12 weeks ]
• Quality of Life, as measured by the Q-LES-Q short form [ Time Frame: 12 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Does Dual Therapy Hasten Antidepressant Response?
• Official Title: Combining Antidepressants to Hasten Remission From Depression
• Brief Summary: This study will utilize a randomized double-blind design to evaluate whether initial treatment with two anti-depressant medications (escitalopram and bupropion) results in more rapid remission and greater over-all remission rates than either monotherapy in 240 depressed subjects.
• Detailed Description: Depression is a major public health problem due to its prevalence and accompanying dysfunction and costs. Depression is undertreated, but even when treatment is adequate and effective, sources of delay in current pharmacologic strategies include: mechanistic delays, those related to the physiologic and behavioral effects of antidepressants; dosing delays in identifying the effective dose; and programmatic delays in identifying an effective agent using sequential monotherapy. This study will randomize 240 patients with Diagnostic and Statistical Manual, 4th Edition (DSM-IV) Major Depressive Disorder (MDD) to 12 week double blind treatment with combined escitalopram and bupropion or each antidepressant administered alone to evaluate whether combined escitalopram and bupropion result in more rapid remission and greater over-all remission than monotherapy. Preclinical and clinical studies suggest that bupropion might prevent one mechanistic delay inherent in escitalopram monotherapy. Rapid dose escalation may counter dosing delays. The simultaneous use of two known antidepressant medications may alleviate programmatic delays inherent in usual sequential monotherapy. Six months follow up and careful assessment of adverse events will address tolerability, acceptability, sustainability, and pharmacoeconomic concerns. If successful, this study might have a significant impact on clinical practice, public health, and depression's cost consequences.
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Major Depressive Disorder

Intervention

• Drug: escitalopram
  10mg/d increasing by 10 mg/week to a maximum of 40 mg/d if tolerated and not remitted
  Other Name: Lexapro
• Drug: bupropion extra long (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
  Other Name: Wellbutrin extra long (XL)
• Drug: escitalopram + bupropion
  same dosing schedule as for monotherapy
  Other Names:

  • Lexapro
  • Wellbutrin

Study Arms

• Experimental: escitalopram + bupropion
  escitalopram plus bupropion extra long (XL) as dual treatment (i.e., this is not a SINGLE treatment arm; all patients assigned this arm received both medications)
  Intervention: Drug: escitalopram + bupropion
• Active Comparator: escitalopram
  escitalopram monotherapy
  Intervention: Drug: escitalopram
• Active Comparator: bupropion
  bupropion extra long (XL) monotherapy
  Intervention: Drug: bupropion extra long (XL)

Publications *

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 26, 2012): 245
• Original Estimated Enrollment (submitted: August 20, 2007): 240
• Actual Study Completion Date: March 2012
• Actual Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Men and women ages 18-65
2. Major Depressive Disorder as primary diagnosis
3. Physically healthy
4. Signs informed consent
5. Montgomery Asberg Depression Rating Scale (MADRS) >= 22

Exclusion Criteria:

1. Bipolar Disorder (ie, Bipolar I, Bipolar II, Bipolar NOS)
2. Life-time history of psychosis
3. Current (ie, last 6 months) drug or alcohol abuse or dependence (except nicotine)
4. Currently taking effective antidepressant medication
5. Prior adequate treatment in current depressive episode with a selective serotonin re-uptake inhibitor (SSRI), bupropion (BUP) or bupropion (BUP) + a selective serotonin re-uptake inhibitor (SSRI) ("adequate" is defined as >= 4 weeks taking >= 2/3 Physician's Desk Reference (PDR) maximal dose
6. Most recent antidepressant was within 5 weeks for fluoxetine and 1 week for all others
7. Currently taking a medication contraindicated with either study medication
8. Life time history of anorexia or bulimia
9. Life time history of seizure or known increased seizure risk (e.g., history of significant brain trauma, taking pro-convulsant medication, known anatomical brain lesion)
10. Currently taking psychoactive medication deemed to be necessary (including but not limited anticonvulsants, antidepressants, antipsychotics, steroids, and B-blockers); occasional use of hypnotics (ie, less than three times per week) will be allowed
11. Unstable medical condition (ie, condition not adequately stabilized for >= 3 months)
12. Prior intolerance to escitalopram (ESC) or bupropion (BUP)
13. Inadequate understanding of English (for US site; Canadian site permits French fluency)
14. Currently pregnant or breast-feeding; fecund women not using adequate contraceptive methods

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT00519428
• Other Study ID Numbers: 5476; 5R01MH076961-04 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: New York State Psychiatric Institute
• Original Responsible Party: Not Provided
• Current Study Sponsor: New York State Psychiatric Institute
• Original Study Sponsor: Same as current

Collaborators

• University of Ottawa
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Jonathan W. Stewart, M.D.; New York State Psychiatric Institute
• Principal Investigator: Pierre Blier, M.D.; University of Ottawa, Institute of Mental Health Research

• PRS Account: New York State Psychiatric Institute
• Verification Date: September 2017