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Combining Medications to Enhance Depression Outcomes (CO-MED)

Primary Purpose

Major Depressive Disorder

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
SSRI + placebo
Escitalopram + Bupropion SR
Venlafaxine XR + Mirtazapine
Sponsored by
National Institute of Mental Health (NIMH)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Major Depressive Disorder focused on measuring depression, medication, antidepressant, chronic, recurrent

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Seeking treatment at the primary or specialty care site, and be planning to continue living in the area of that clinic for the duration of the study
  • Meets clinical criteria for nonpsychotic MDD, recurrent (with the current episode being at least 2 months in duration), or chronic (current episode greater than 2 years) as defined by a clinical interview and confirmed by the MINI International Neuropsychiatric Interview (MINI)
  • Screening 17 item HRSD score of 16 or greater
  • Treatment with antidepressant medication combinations is clinically acceptable
  • Patient with and without current suicidal ideation may be included in the study as long as outpatient treatment is clinically appropriate

Exclusion Criteria:

  • Pregnant or breastfeeding
  • Plans to become pregnant over the ensuing 8 months following study entry or are sexually active and not using adequate birth control
  • History (lifetime) of psychotic depression, schizophrenia, bipolar (I, II, or NOS), schizoaffective, or other Axis I psychotic disorders
  • Current psychotic symptom(s)
  • History (within the last 2 years before study entry) of anorexia or bulimia
  • Current primary diagnosis of obsessive compulsive disorder
  • Current substance dependence that requires inpatient detoxification or inpatient treatment
  • Requiring immediate hospitalization for a psychiatric disorder
  • Definite history of intolerance or allergy (lifetime) to any protocol medication
  • History of clear nonresponse to an adequate trial of an FDA-approved monotherapy in the current MDE if recurrent, or during the last 2 years before study entry if chronic
  • History of clear nonresponse to an adequate trial of any study medication used as a monotherapy, or to one or more of the protocol combinations in the current or any prior MDE
  • Currently taking any of the study medications at any dose
  • Having taken Prozac (fluoxetine) or an MAOI in the 4 weeks before study entry
  • Presence of an unstable general medical condition (GMC) that will likely require hospitalization or to be deemed terminal (life expectancy less than 6 months after study entry)
  • Currently taking medications or have GMCs that contraindicate any study medications (e.g., seizure disorder)
  • Requiring medications for GMCs that contraindicate any study medication
  • Epilepsy or other conditions requiring an anticonvulsant
  • Lifetime history of having a seizure including febrile or withdrawal seizures
  • Receiving or have received vagus nerve stimulation (VNS), electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), or other somatic antidepressant treatments
  • Currently taking or having taken within the 7 days before study entry any of the following exclusionary medications: antipsychotic medications, anticonvulsant medications, mood stabilizers, or central nervous system stimulants (antidepressant medication used for the treatment of depression or other purposes such as smoking cessation or pain are excluded since these agents may interfere with the testing of the major hypotheses under study)
  • Uncontrolled narrow angle glaucoma
  • Taking thyroid medication for hypothyroidism may be included only if stable on the medication for 3 months
  • Using agents within the 7 days before study entry that are potential augmenting agents (e.g., T3 in the absence of thyroid disease, SAMe, St. John's Wort, lithium, buspirone)
  • Therapy that is depression-specific

Sites / Locations

  • Tuscalossa VA Mental Health Clinic
  • Harbor UCLA Family Health Care Center
  • UCLA Internal Medicine Clinic
  • Veterans Affairs Medical Center/FIRM Primary Care Clinic
  • Northwestern Psychiatric Outpatient Treatment Care Center
  • Clinical Research Institute
  • MGH/Northshore Medical Center (Salem Psychiatric Facility)
  • General Psychiatric Ambulatory Clinic
  • Irving Goldman Primary Care at North Shore Hospital
  • UNC Chapel Hill Adult Diagnostic & Treatment Clinic
  • Laureate Psychiatric Clinic and Hospital
  • Bellefield Clinic of WPIC
  • Vine Hill Community Clinic
  • UT Southwestern Family Medicine Clinic
  • VCU Outpatient Psychiatry Clinic

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Active Comparator

Arm Label

SSRI + placebo

Escitalopram + Bupropion SR

Venlafaxine XR + Mirtazapine

Arm Description

Participants will take escitalopram plus placebo.

Participants will take escitalopram + bupropion-SR.

Participants will take venlafaxine-XR + mirtazapine.

Outcomes

Primary Outcome Measures

Quick Inventory of Depressive Symptoms
Percentage of patients that achieve remission, as defined as QIDS total score below 6 for last 2 study visits. QIDS depression scores range from 0 (normal) to 27 (very severe).

Secondary Outcome Measures

Quality of Life Inventory
The Quality of Life Inventory (QOLI) is a 32-item comprehensive self-report of satisfaction in 16 areas of life, such as love, work, and health. Each area is rated in terms of satisfaction and the relationship of that area to overall quality of life. It yields an overall raw score and satisfaction ratings for the 16 individual areas of life. The QOLI raw score is an average of weighted satisfaction ratings computed only over areas of life judged to be Important or Extremely Important to the respondent. Higher scores indicate higher reported quality of life.

Full Information

First Posted
December 26, 2007
Last Updated
April 21, 2014
Sponsor
National Institute of Mental Health (NIMH)
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1. Study Identification

Unique Protocol Identification Number
NCT00590863
Brief Title
Combining Medications to Enhance Depression Outcomes
Acronym
CO-MED
Official Title
Combining Medications to Enhance Depression Outcomes
Study Type
Interventional

2. Study Status

Record Verification Date
April 2009
Overall Recruitment Status
Completed
Study Start Date
March 2008 (undefined)
Primary Completion Date
September 2009 (Actual)
Study Completion Date
September 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Mental Health (NIMH)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study will compare whether a combination of antidepressant medications is better than one antidepressant medication alone when given as initial treatment for people with chronic or recurrent major depressive disorder.
Detailed Description
The overall aim of Combining Medications to Enhance Depression Outcomes (CO-MED) is to enhance remission rates for outpatients with chronic or recurrent nonpsychotic major depressive disorder (MDD) as defined by DSM-IV TR, treated in primary or psychiatric care settings. Current evidence indicates that remission, the goal of treatment, is found in only about one-third of representative depressed outpatients treated for up to 14 weeks with an initial SSRI. In addition, even for those who do respond or remit, over one-third relapse in the subsequent 12 months. Combinations of antidepressants are used in practice at the second or subsequent steps when relapse occurs in the longer term, or, in some cases, even acutely as a first step when speed of effect is a clinical priority. Whether such combinations could potentially offer higher remission rates, lower attrition, or greater longer-term benefit if used as initial treatments as compared to monotherapy remains to be examined. CO-MED will test whether two different medications when given in combination as the first treatment step, compared to one medication, will enhance remission rates, increase speed of remission, be tolerable, and provide better sustained benefits in the longer term. Results of this study will inform practitioners in managing the treatment of patients with chronic or recurrent MDD.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Major Depressive Disorder
Keywords
depression, medication, antidepressant, chronic, recurrent

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
Participant
Allocation
Randomized
Enrollment
665 (Actual)

8. Arms, Groups, and Interventions

Arm Title
SSRI + placebo
Arm Type
Active Comparator
Arm Description
Participants will take escitalopram plus placebo.
Arm Title
Escitalopram + Bupropion SR
Arm Type
Active Comparator
Arm Description
Participants will take escitalopram + bupropion-SR.
Arm Title
Venlafaxine XR + Mirtazapine
Arm Type
Active Comparator
Arm Description
Participants will take venlafaxine-XR + mirtazapine.
Intervention Type
Drug
Intervention Name(s)
SSRI + placebo
Other Intervention Name(s)
escitalopram, placebo
Intervention Description
Participants will take escitalopram (10 - 20 mg/day)+ placebo (1 to 3 pills per day). Medications taken orally. Participants will take escitalopram plus placebo for up to 28 weeks. Dosages were adjusted as need at each clinic visit.
Intervention Type
Drug
Intervention Name(s)
Escitalopram + Bupropion SR
Other Intervention Name(s)
escitalopram, bupropion-SR
Intervention Description
Participant will take Burpopion SR (150 to 450 mg/day) + Escitalopram (10 to 20 mg/day) for up to 28 weeks. Medications taken orally. Bupropion SR was blinded, and escitalopram was given open label. Dosages were adjusted as need at each clinic visit.
Intervention Type
Drug
Intervention Name(s)
Venlafaxine XR + Mirtazapine
Other Intervention Name(s)
venlafaxine-XR, mirtazapine
Intervention Description
Participants will take Venlafaxine XR (75 to 225 mg/day) + Mirtazapine (15 to 45 mg/day) for up to 28 weeks. Medications taken orally. Venlafaxine XR was blinded, and mirtazapine was given open label. Dosages were adjusted as need at each clinic visit.
Primary Outcome Measure Information:
Title
Quick Inventory of Depressive Symptoms
Description
Percentage of patients that achieve remission, as defined as QIDS total score below 6 for last 2 study visits. QIDS depression scores range from 0 (normal) to 27 (very severe).
Time Frame
Measured at Month 7
Secondary Outcome Measure Information:
Title
Quality of Life Inventory
Description
The Quality of Life Inventory (QOLI) is a 32-item comprehensive self-report of satisfaction in 16 areas of life, such as love, work, and health. Each area is rated in terms of satisfaction and the relationship of that area to overall quality of life. It yields an overall raw score and satisfaction ratings for the 16 individual areas of life. The QOLI raw score is an average of weighted satisfaction ratings computed only over areas of life judged to be Important or Extremely Important to the respondent. Higher scores indicate higher reported quality of life.
Time Frame
Measured at Month 7

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Seeking treatment at the primary or specialty care site, and be planning to continue living in the area of that clinic for the duration of the study Meets clinical criteria for nonpsychotic MDD, recurrent (with the current episode being at least 2 months in duration), or chronic (current episode greater than 2 years) as defined by a clinical interview and confirmed by the MINI International Neuropsychiatric Interview (MINI) Screening 17 item HRSD score of 16 or greater Treatment with antidepressant medication combinations is clinically acceptable Patient with and without current suicidal ideation may be included in the study as long as outpatient treatment is clinically appropriate Exclusion Criteria: Pregnant or breastfeeding Plans to become pregnant over the ensuing 8 months following study entry or are sexually active and not using adequate birth control History (lifetime) of psychotic depression, schizophrenia, bipolar (I, II, or NOS), schizoaffective, or other Axis I psychotic disorders Current psychotic symptom(s) History (within the last 2 years before study entry) of anorexia or bulimia Current primary diagnosis of obsessive compulsive disorder Current substance dependence that requires inpatient detoxification or inpatient treatment Requiring immediate hospitalization for a psychiatric disorder Definite history of intolerance or allergy (lifetime) to any protocol medication History of clear nonresponse to an adequate trial of an FDA-approved monotherapy in the current MDE if recurrent, or during the last 2 years before study entry if chronic History of clear nonresponse to an adequate trial of any study medication used as a monotherapy, or to one or more of the protocol combinations in the current or any prior MDE Currently taking any of the study medications at any dose Having taken Prozac (fluoxetine) or an MAOI in the 4 weeks before study entry Presence of an unstable general medical condition (GMC) that will likely require hospitalization or to be deemed terminal (life expectancy less than 6 months after study entry) Currently taking medications or have GMCs that contraindicate any study medications (e.g., seizure disorder) Requiring medications for GMCs that contraindicate any study medication Epilepsy or other conditions requiring an anticonvulsant Lifetime history of having a seizure including febrile or withdrawal seizures Receiving or have received vagus nerve stimulation (VNS), electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), or other somatic antidepressant treatments Currently taking or having taken within the 7 days before study entry any of the following exclusionary medications: antipsychotic medications, anticonvulsant medications, mood stabilizers, or central nervous system stimulants (antidepressant medication used for the treatment of depression or other purposes such as smoking cessation or pain are excluded since these agents may interfere with the testing of the major hypotheses under study) Uncontrolled narrow angle glaucoma Taking thyroid medication for hypothyroidism may be included only if stable on the medication for 3 months Using agents within the 7 days before study entry that are potential augmenting agents (e.g., T3 in the absence of thyroid disease, SAMe, St. John's Wort, lithium, buspirone) Therapy that is depression-specific
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Madhukar H. Trivedi, MD
Organizational Affiliation
University of Texas Southwestern Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Stephen R. Wisniewski, PhD
Organizational Affiliation
University of Pittsburgh
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Diane Warden, PhD, MBA
Organizational Affiliation
University of Texas Southwestern Medical Center
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Kathy Shores-Wilson, PhD
Organizational Affiliation
University of Texas Southwestern Medical Center
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
David W. Morris, PhD
Organizational Affiliation
University of Texas Southwestern Medical Center
Official's Role
Study Director
Facility Information:
Facility Name
Tuscalossa VA Mental Health Clinic
City
Tuscaloosa
State/Province
Alabama
ZIP/Postal Code
35404
Country
United States
Facility Name
Harbor UCLA Family Health Care Center
City
Harbor City
State/Province
California
ZIP/Postal Code
90710
Country
United States
Facility Name
UCLA Internal Medicine Clinic
City
Los Angeles
State/Province
California
ZIP/Postal Code
90024
Country
United States
Facility Name
Veterans Affairs Medical Center/FIRM Primary Care Clinic
City
San Diego
State/Province
California
ZIP/Postal Code
92161
Country
United States
Facility Name
Northwestern Psychiatric Outpatient Treatment Care Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Clinical Research Institute
City
Wichita
State/Province
Kansas
ZIP/Postal Code
67214
Country
United States
Facility Name
MGH/Northshore Medical Center (Salem Psychiatric Facility)
City
Salem
State/Province
Massachusetts
ZIP/Postal Code
01970
Country
United States
Facility Name
General Psychiatric Ambulatory Clinic
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48105
Country
United States
Facility Name
Irving Goldman Primary Care at North Shore Hospital
City
New York
State/Province
New York
ZIP/Postal Code
11040
Country
United States
Facility Name
UNC Chapel Hill Adult Diagnostic & Treatment Clinic
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599-7160
Country
United States
Facility Name
Laureate Psychiatric Clinic and Hospital
City
Tulsa
State/Province
Oklahoma
ZIP/Postal Code
74135
Country
United States
Facility Name
Bellefield Clinic of WPIC
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Facility Name
Vine Hill Community Clinic
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37212
Country
United States
Facility Name
UT Southwestern Family Medicine Clinic
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Facility Name
VCU Outpatient Psychiatry Clinic
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
21536692
Citation
Rush AJ, Trivedi MH, Stewart JW, Nierenberg AA, Fava M, Kurian BT, Warden D, Morris DW, Luther JF, Husain MM, Cook IA, Shelton RC, Lesser IM, Kornstein SG, Wisniewski SR. Combining medications to enhance depression outcomes (CO-MED): acute and long-term outcomes of a single-blind randomized study. Am J Psychiatry. 2011 Jul;168(7):689-701. doi: 10.1176/appi.ajp.2011.10111645. Epub 2011 May 2.
Results Reference
result
PubMed Identifier
35815954
Citation
Olgiati P, Fanelli G, Atti AR, De Ronchi D, Serretti A. Clinical correlates and prognostic impact of binge-eating symptoms in major depressive disorder. Int Clin Psychopharmacol. 2022 Nov 1;37(6):247-254. doi: 10.1097/YIC.0000000000000422. Epub 2022 Jul 12.
Results Reference
derived
PubMed Identifier
35695646
Citation
Olgiati P, Serretti A. Persistence of suicidal ideation within acute phase treatment of major depressive disorder: analysis of clinical predictors. Int Clin Psychopharmacol. 2022 Sep 1;37(5):193-200. doi: 10.1097/YIC.0000000000000416. Epub 2022 Jul 7.
Results Reference
derived
PubMed Identifier
35191860
Citation
Olgiati P, Fanelli G, Serretti A. Obsessive-compulsive symptoms in major depressive disorder correlate with clinical severity and mixed features. Int Clin Psychopharmacol. 2022 Jul 1;37(4):166-172. doi: 10.1097/YIC.0000000000000396. Epub 2022 Feb 21.
Results Reference
derived
PubMed Identifier
34686642
Citation
Olgiati P, Serretti A. Post-traumatic stress disorder and childhood emotional abuse are markers of subthreshold bipolarity and worse treatment outcome in major depressive disorder. Int Clin Psychopharmacol. 2022 Jan 1;37(1):1-8. doi: 10.1097/YIC.0000000000000380.
Results Reference
derived
PubMed Identifier
32950785
Citation
Medeiros GC, Prueitt WL, Minhajuddin A, Patel SS, Czysz AH, Furman JL, Mason BL, Rush AJ, Jha MK, Trivedi MH. Childhood maltreatment and impact on clinical features of major depression in adults. Psychiatry Res. 2020 Nov;293:113412. doi: 10.1016/j.psychres.2020.113412. Epub 2020 Aug 18.
Results Reference
derived
PubMed Identifier
30922100
Citation
Jha MK, Minhajuddin A, South C, Rush AJ, Trivedi MH. Irritability and Its Clinical Utility in Major Depressive Disorder: Prediction of Individual-Level Acute-Phase Outcomes Using Early Changes in Irritability and Depression Severity. Am J Psychiatry. 2019 May 1;176(5):358-366. doi: 10.1176/appi.ajp.2018.18030355. Epub 2019 Mar 29.
Results Reference
derived
PubMed Identifier
30794033
Citation
Sies A, Demyttenaere K, Van Mechelen I. Studying treatment-effect heterogeneity in precision medicine through induced subgroups. J Biopharm Stat. 2019;29(3):491-507. doi: 10.1080/10543406.2019.1579220. Epub 2019 Feb 22.
Results Reference
derived
PubMed Identifier
30370613
Citation
De La Garza N, Rush AJ, Killian MO, Grannemann BD, Carmody TJ, Trivedi MH. The Concise Health Risk Tracking Self-Report (CHRT-SR) assessment of suicidality in depressed outpatients: A psychometric evaluation. Depress Anxiety. 2019 Apr;36(4):313-320. doi: 10.1002/da.22855. Epub 2018 Oct 29.
Results Reference
derived
PubMed Identifier
28628884
Citation
Gadad BS, Jha MK, Grannemann BD, Mayes TL, Trivedi MH. Proteomics profiling reveals inflammatory biomarkers of antidepressant treatment response: Findings from the CO-MED trial. J Psychiatr Res. 2017 Nov;94:1-6. doi: 10.1016/j.jpsychires.2017.05.012. Epub 2017 May 26.
Results Reference
derived
PubMed Identifier
28187400
Citation
Jha MK, Minhajuddin A, Gadad BS, Greer T, Grannemann B, Soyombo A, Mayes TL, Rush AJ, Trivedi MH. Can C-reactive protein inform antidepressant medication selection in depressed outpatients? Findings from the CO-MED trial. Psychoneuroendocrinology. 2017 Apr;78:105-113. doi: 10.1016/j.psyneuen.2017.01.023. Epub 2017 Jan 24.
Results Reference
derived
PubMed Identifier
26803397
Citation
Chekroud AM, Zotti RJ, Shehzad Z, Gueorguieva R, Johnson MK, Trivedi MH, Cannon TD, Krystal JH, Corlett PR. Cross-trial prediction of treatment outcome in depression: a machine learning approach. Lancet Psychiatry. 2016 Mar;3(3):243-50. doi: 10.1016/S2215-0366(15)00471-X. Epub 2016 Jan 21.
Results Reference
derived
PubMed Identifier
24638046
Citation
Warden D, Trivedi MH, Carmody T, Toups M, Zisook S, Lesser I, Myers A, Kurian KR, Morris D, Rush AJ. Adherence to antidepressant combinations and monotherapy for major depressive disorder: a CO-MED report of measurement-based care. J Psychiatr Pract. 2014 Mar;20(2):118-32. doi: 10.1097/01.pra.0000445246.46424.fe.
Results Reference
derived
PubMed Identifier
24163386
Citation
Toups MS, Myers AK, Wisniewski SR, Kurian B, Morris DW, Rush AJ, Fava M, Trivedi MH. Relationship between obesity and depression: characteristics and treatment outcomes with antidepressant medication. Psychosom Med. 2013 Nov-Dec;75(9):863-72. doi: 10.1097/PSY.0000000000000000. Epub 2013 Oct 25.
Results Reference
derived
PubMed Identifier
22687487
Citation
Sung SC, Haley CL, Wisniewski SR, Fava M, Nierenberg AA, Warden D, Morris DW, Kurian BT, Trivedi MH, Rush AJ; CO-MED Study Team. The impact of chronic depression on acute and long-term outcomes in a randomized trial comparing selective serotonin reuptake inhibitor monotherapy versus each of 2 different antidepressant medication combinations. J Clin Psychiatry. 2012 Jul;73(7):967-76. doi: 10.4088/JCP.11m07043. Epub 2012 May 29.
Results Reference
derived
PubMed Identifier
22230827
Citation
Morris DW, Budhwar N, Husain M, Wisniewski SR, Kurian BT, Luther JF, Kerber K, Rush AJ, Trivedi MH. Depression treatment in patients with general medical conditions: results from the CO-MED trial. Ann Fam Med. 2012 Jan-Feb;10(1):23-33. doi: 10.1370/afm.1316.
Results Reference
derived
PubMed Identifier
22129562
Citation
Chan HN, Rush AJ, Nierenberg AA, Trivedi M, Wisniewski SR, Balasubramani GK, Friedman ES, Gaynes BN, Davis L, Morris D, Fava M. Correlates and outcomes of depressed out-patients with greater and fewer anxious symptoms: a CO-MED report. Int J Neuropsychopharmacol. 2012 Nov;15(10):1387-99. doi: 10.1017/S1461145711001660. Epub 2011 Dec 1.
Results Reference
derived
PubMed Identifier
22075098
Citation
Zisook S, Lesser IM, Lebowitz B, Rush AJ, Kallenberg G, Wisniewski SR, Nierenberg AA, Fava M, Luther JF, Morris DW, Trivedi MH. Effect of antidepressant medication treatment on suicidal ideation and behavior in a randomized trial: an exploratory report from the Combining Medications to Enhance Depression Outcomes Study. J Clin Psychiatry. 2011 Oct;72(10):1322-32. doi: 10.4088/JCP.10m06724.
Results Reference
derived

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Combining Medications to Enhance Depression Outcomes

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