Combining Medications to Enhance Depression Outcomes (CO-MED): Acute and Long-term Outcomes of a Single-blind Randomized Study

Major depressive disorder (MDD) is a chronic and disabling condition that affects up to 12% of men and 25% of women. MDD is recurrent, with many patients not achieving complete recovery between depressive episodes. The aim of treatment for MDD is remission, which is associated with improved functioning and prognosis.

- Brayden Kameg, DNP, PMHNP-BC, CARN, CNE

What do the results of this study mean for a practicing PMHNP?

"The overall aim of CO-MED was to identify effects on remission rates for outpatients with chronic or recurrent nonpsychotic major depressive disorder (MDD) by using combinations of medications for initial pharmacotherapy. Studying if such combinations could offer higher remission rates or greater longer-term benefits was important because data such as these can help guide clinical practice."

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Why was the research needed?

Initial antidepressant pharmacotherapy has been shown to result in approximately 50% response rates in patients with MDD.1 Per American Psychiatric Association (APA) guidelines, if adequate improvement in symptoms is not achieved after 4 to 8 weeks of initiating first-line antidepressant therapy, and the current therapy is judged to be adequate in dose and administered for an adequate duration, a second-line treatment plan should be considered.2 The APA recommends using combinations of medications as one management strategy for the treatment of MDD.2

Combinations of antidepressant therapies have the potential to help improve response rates.1 However, current treatment guidelines do not recommend this approach as first-line therapy for patients with MDD.1 The authors of this study wanted to understand if combination therapy as initial therapy would change remission rates (primary outcome), side effect burden, adverse events, quality of life, functioning, or attrition (secondary outcomes).1 They also recognized the need to assess the possibility of adverse events or side effects when combining antidepressant therapies, as this had not previously been evaluated.

What did the researchers do?

Rush et al designed a 7-month single-blind, randomized, placebo-controlled trial to compare the efficacy of 3 medication combinations as a first-step treatment for MDD.1

  • Selective serotonin reuptake inhibitor (SSRI) + placebo
  • SSRI + norepinephrine–dopamine reuptake inhibitor (NDRI)
  • Serotonin and norepinephrine reuptake inhibitor (SNRI) + tetracyclic antidepressant (TeCA)

The authors chose to assess acute response at 12 weeks and longer-term response at 7 months.1

A total of 665 patients, aged 18 to 75 years, were recruited from primary care and psychiatric clinics. These patients met the DSM-4-TR criteria for major depression, had an index episode of at least 2 months in duration, and scored at least 16 on the 17-item Hamilton Depression Rating Scale (HAM-D-17).1 Patients with psychosis or bipolar disorder or who required inpatient treatment were not eligible.1 The anxiety subscale of the HAM-D was used to identify patients with anxious features. Two self-report questionnaires were used to identify any axis I disorders or general medical conditions.1 Participants were randomly assigned (1:1:1) to 1 of the 3 treatment groups. Participants were blinded to only 1 of the 2 medications (placebo, SSRI, and TeCA, respectively).1 To maximize safety and inform dosing decisions, research coordinators and physicians were not blinded.1 Participants were not allowed to be on other antidepressants, treatments with possible antidepressant effects, anxiolytics, sedative-hypnotics, or depression-targeted psychotherapy for the duration of the study.1

Treatment visits occurred at baseline and weeks 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, and 28. Outcome measures were assessed at each of these visits. The primary outcome, symptom remission, was assessed based on the score on the 16-item Quick Inventory of Depressive Symptomatology – Self-Report (QIDS-SR) at 12 weeks.1 A patient was estimated to have remitted if 1 score was < 6 and 1 score was < 8 on their last 2 consecutive QIDS-SR questionnaires.1

Participants who underwent treatment at the maximum tolerated dose for at least 4 weeks by week 8 without achieving at least a 30% reduction from baseline on the 16-item Quick Inventory of Depressive Symptomatology – Clinician-Rated (QIDS-C) could exit the study.1 Patients could enter continuation treatment through 7 months if they experienced a benefit (QIDS-C score of 9 or less by week 12) or if they reached a QIDS-C score of 10 to 13 and both the patient and clinician felt that the patient had experienced a substantial benefit.1 

What were the key findings of the study?

The study had 4 key findings1:

1. Remission and response rates were not different at 12 weeks.

  • Treatment groups did not differ in remission or response rates.
  • Treatment groups did not differ in change in QIDS-SR score.

2. Remission and response rates were not different at 7 months.

  • Attrition rates over the 7-month period did not differ among treatment groups.
  • Treatment groups did not differ in remission or response rates.
  • Treatment groups did not differ in change in QIDS-SR score.

3. The effects of the 3 treatments on quality of life and on work and social adjustment were not different.

4. Extended-release SNRI plus TeCA was associated with a greater side effect burden at 12 weeks and 7 months than SSRI plus placebo and a greater number of worsening adverse events than SSRI plus placebo at 7 months. 

Why are these results important?

Based on the results of this study, there is no clinical benefit to beginning the management of MDD with a combination of pharmacotherapies as opposed to the currently recommended monotherapy. Additionally, both combination therapies evaluated had more side effects than seen in the monotherapy group.1

A previous study by Blier et al noted improved rates of response and remission in patients on combination regimens as compared to SSRI monotherapy.3 CO-MED’s findings are not in agreement with these prior results. Rush et al point out that the 2 studies differ in terms of length of treatment, primary outcome, and clinical scales used.1 This study included more chronically ill individuals than Blier et al did, while Blier et al included more melancholic patients than this study did.1 However, subsequent statistical sub-analyses did not reveal the proportion of patients with melancholia or chronic illness as a potential source of the difference in findings between these 2 studies.1

Rush et al also used lower doses than some prior studies, including Blier et al. However, a sub-analysis of patients who advanced to higher doses suggest that underdosing is not the cause of the differences in findings between CO-MED and the 2010 study by Blier et al.1 Rush et al recognize several limitations, including that the participant population may not be reflective of the general population with MDD, the doses used may have been too low to achieve remission, and that this was a single-blind trial.1 

What's next?

Especially in this case, where different studies have come to different conclusions regarding the benefits of combination therapy as compared to monotherapy for initial treatment of MDD in adults, further studies with greater populations of participants may be helpful.

An improved understanding of treatment regimens that could potentially lead to greater numbers of patients achieving remission from this chronic and debilitating condition could benefit significant numbers of patients with MDD.


  1. Rush AJ, Trivedi MH, Stewart JW, et al. Combining medications to enhance depression outcomes (CO-MED): acute and long-term outcomes of a single-blind randomized study. Am J Psychiatry. 2011;168(7):689-701. doi:10.1176/appi.ajp.2011.10111645

  2. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Major Depressive Disorder. 3rd ed. American Psychiatric Association; 2010.
  3. Blier P, Ward HE, Tremblay P, Laberge L, Hébert C, Bergeron R. Combination of antidepressant medications from treatment initiation for major depressive disorder: a double-blind randomized study. Am J Psychiatry. 2010;167(3):281-288. doi:10.1176/appi.ajp.2009.09020186

This summary was prepared independently of the study’s authors.

This resource is intended for educational purposes only and is intended for US healthcare professionals. Healthcare professionals should use independent medical judgment. All decisions regarding patient care must be handled by a healthcare professional and be made based on the unique needs of each patient.

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