Clinical trial NCT00590863: Combining Medications to Enhance Depression Outcomes
Official title: Combining Medications to Enhance Depression Outcomes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Major Depressive Disorder
Keywords: depression, medication, antidepressant, chronic, recurrent
Lead sponsor: National Institute of Mental Health (NIMH)
Sponsor class: NIH
First posted: 2008-01-11
Enrollment: 665
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Quick Inventory of Depressive Symptoms
timeFrame: Measured at Month 7
Secondary outcomes:
measure: Quality of Life Inventory
timeFrame: Measured at Month 7
Other outcomes:
Locations:
city: Tuscaloosa
country: United States
facility: Tuscalossa VA Mental Health Clinic
state: Alabama
city: Harbor City
country: United States
facility: Harbor UCLA Family Health Care Center
state: California
city: Los Angeles
country: United States
facility: UCLA Internal Medicine Clinic
state: California
city: San Diego
country: United States
facility: Veterans Affairs Medical Center/FIRM Primary Care Clinic
state: California
city: Chicago
country: United States
facility: Northwestern Psychiatric Outpatient Treatment Care Center
state: Illinois
city: Wichita
country: United States
facility: Clinical Research Institute
state: Kansas
city: Salem
country: United States
facility: MGH/Northshore Medical Center (Salem Psychiatric Facility)
state: Massachusetts
city: Ann Arbor
country: United States
facility: General Psychiatric Ambulatory Clinic
state: Michigan
city: New York
country: United States
facility: Irving Goldman Primary Care at North Shore Hospital
state: New York
city: Chapel Hill
country: United States
facility: UNC Chapel Hill Adult Diagnostic & Treatment Clinic
state: North Carolina
city: Tulsa
country: United States
facility: Laureate Psychiatric Clinic and Hospital
state: Oklahoma
city: Pittsburgh
country: United States
facility: Bellefield Clinic of WPIC
state: Pennsylvania
city: Nashville
country: United States
facility: Vine Hill Community Clinic
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern Family Medicine Clinic
state: Texas
city: Richmond
country: United States
facility: VCU Outpatient Psychiatry Clinic
state: Virginia
Study officials:
affiliation: University of Texas Southwestern Medical Center
name: Madhukar H. Trivedi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pittsburgh
name: Stephen R. Wisniewski, PhD
role: STUDY_DIRECTOR
affiliation: University of Texas Southwestern Medical Center
name: Diane Warden, PhD, MBA
role: STUDY_DIRECTOR
affiliation: University of Texas Southwestern Medical Center
name: Kathy Shores-Wilson, PhD
role: STUDY_DIRECTOR
affiliation: University of Texas Southwestern Medical Center
name: David W. Morris, PhD
role: STUDY_DIRECTOR
References:
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.