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

CO-MED was a 7-month single-blind, randomized, placebo-controlled trial that compared the efficacy of each of two medication combinations with escitalopram plus placebo in a 1:1:1 ratio as first-step treatment, including acute-phase (12 weeks) and long-term continuation (total 7 months) treatment. We planned a study group of 660 outpatients with nonpsychotic major depression from six primary and nine psychiatric care sites to allow detection of roughly a 15% difference in remission rates between each combination and escitalopram-placebo (with an expected remission rate of 35%). This difference was viewed as sufficiently large to affect practice since it approximates the benefit of a single antidepressant medication over placebo in successful antidepressant registration trials (8).

Clinical sites were selected on the basis of our prior experience and their performance in the Sequenced Treatment Alternatives to Relieve Depression trial to ensure 1) adequate patient flow, 2) committed administrative support, 3) adequate minority representation, and 4) adequate representation of both primary and psychiatric care sites.

Potential participants were screened at each clinical site with each site’s standard procedure (variable across sites). Most sites used two to nine questions from the Patient Health Questionnaire (19, 20). Patients identified by screening saw their study clinicians and clinical research coordinator to determine study eligibility following written informed consent.

Broad inclusion and minimal exclusion criteria ensured a reasonably representative participant group. The outpatient enrollees were 18–75 years old and met the DSM-IV-TR (21) criteria for either recurrent or chronic (current episode lasting at least 2 years) major depression according to a clinical interview and confirmed with a DSM-IV-based symptom checklist completed by the clinical research coordinator. Eligible participants had to have an index episode lasting at least 2 months and had to score at least 16 on the 17-Item Hamilton Depression Rating Scale (HAM-D) (22). Those with any psychotic illness or bipolar disorder and those in need of hospitalization were ineligible. (For a complete list of exclusion criteria, see http://clinicaltrials.gov/ct2/show/NCT00590863.)

The study protocol and all consent and study procedures were approved by the institutional review boards at the national coordinating center (University of Texas Southwestern Medical Center at Dallas), the University of Pittsburgh data coordinating center, and each participating regional center and relevant clinical site.

Sociodemographic and illness features were recorded at baseline. The anxiety subscale of the HAM-D was used to establish the presence of anxious features at baseline (23). This anxiety/somatization factor, derived from a factor analysis of the HAM-D conducted by Cleary and Guy (24), includes six items from the original 17-item version: item 10 (anxiety, psychic), item 11 (anxiety, somatic), item 12 (somatic symptoms, gastrointestinal), item 13 (somatic symptoms, general), item 15 (hypochondriasis), and item 17 (insight). A HAM-D anxiety/somatization factor score of 7 or higher indicated anxiety. The HAM-D administered at baseline by research outcome assessors (not located at any clinical site) was used to define anxious features. The self-report Psychiatric Diagnostic Screening Questionnaire (25) was used to establish the presence of current axis I disorders. The Self-Administered Comorbidity Questionnaire (26) established the presence, severity, and functional impact of a range of common concurrent general medical conditions.

A 12-week study period was chosen for the primary analysis to provide sufficient time for maximal dosing (if needed) and to allow most cases of depression that could remit to do so (27). Treatment visits were planned at baseline and weeks 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, and 28. No washout was required, but clinicians could choose a washout period if they thought it to be clinically advisable. Dose adjustments were based on measurement-based care following an operations manual to provide personally tailored but vigorous dosing (28). Dose adjustments were based on the score on the 16-item Quick Inventory of Depressive Symptomatology—Clinician-Rated (QIDS-C) (29), which was extracted from the 30-item Inventory of Depressive Symptomatology—Clinician-Rated (IDS-C) (30), and the score on the Frequency, Intensity, and Burden of Side Effects Rating Scale (31) obtained at each visit.

Treatment was randomly assigned, stratified by clinical site according to a web-based randomization system (32). Random block sizes of three and six were used to minimize the probability of identifying the next treatment assignment. Dosing schedules were based on prior reports (33–35). Doses were increased only in the context of acceptable side effects. Participants could exit the study if unacceptable or intolerable side effects occurred and could not be resolved with dose reduction or medication treatment of the side effects.

The first medication given in each treatment group was open label (both participant and study personnel were unblinded), while each second medication was given in a single-blind fashion (participant only) to ensure that the participants all took two types of pills. Specifically, in the escitalopram-placebo cell, placebo administration was blinded. For the bupropion-escitalopram combination, escitalopram was blinded. For venlafaxine-mirtazapine, mirtazapine was blinded. The participants remained blinded to the second medication throughout the 7-month study. The research coordinators and physicians were not blinded, to maximize safety and facilitate informed flexible dosing decisions.

Only protocol antidepressant medications were allowed. Treatments with possible antidepressant effects were proscribed, as were anxiolytics, sedative-hypnotics, and depression-targeted, empirically validated psychotherapies for depression. Other therapies (e.g., supportive, couples, occupational) were allowed, as were medications for any general medical condition. Given the inhibition of the 2D6 isoenzyme by sustained-release bupropion, we alerted clinicians about nonprotocol medications (e.g., type 1C antiarrhythmics, beta-blockers) for which serum or dose adjustments might be needed. Medications to treat antidepressant medication side effects were allowed; administration was based on clinician judgment.

Outcome measures were assessed at baseline and all treatment visits. The primary outcome, symptom remission, was based on the score on the 16-item Quick Inventory of Depressive Symptomatology—Self-Report (QIDS-SR) at 12 weeks (29). The designation of remission was based on the last two consecutive measurements during the 12-week acute-phase trial to ensure that a single “good week” was not falsely signaling remission. At least one of these ratings had to be less than 6, while the other had to be less than 8. If participants exited before 12 weeks, their last two consecutive scores were used to determine remission. Those without two post-baseline measures were considered not to have remission.

Physicians were advised that participants could exit the study if they had received a maximally tolerated dose(s) for 4 or more weeks by week 8 without obtaining at least a 30% reduction from the baseline score on the QIDS-C. They could enter continuation treatment (weeks 12–28) if they had received an acceptable benefit (defined as a QIDS-C score of 9 or less by week 12) or if they reached a score of 10–13 and the clinician and participant judged the benefit to be substantial enough to recommend treatment continuation. Thus, virtually all participants entering the continuation phase had at least a 40% reduction in the QIDS-C score. If a participant exited the study at any time, a study exit form was completed. Clinical research coordinators attempted to contact all participants who did not come for a final exit visit.

Secondary outcomes included attrition, anxiety as reflected in the score on the anxiety subscale of the IDS-C (30), functioning as measured by the Work and Social Adjustment Scale (36), quality of life as measured by the Quality of Life Inventory (37), side effect burden as measured by the Frequency, Intensity, and Burden of Side Effects Rating Scale (31), and specific side effects as measured by the Systematic Assessment for Treatment Emergent Events—Systematic Inquiry (38). Manic symptoms were assessed by using the Altman Self-Rating Mania Scale (39), and cognitive and executive dysfunction was assessed by means of the Cognitive and Physical Functioning Questionnaire (40).

Descriptive statistics, including measures of central tendency and dispersion, were computed for continuous data. Frequency distributions were estimated for categorical data.

Outcome analyses were conducted with the full group, on the basis of the intention-to-treat principle. Each combination therapy was compared to the monotherapy. To control for the overall type I error rate, a type I error rate of 0.025 was planned for the comparison of each combination treatment with monotherapy. The analytic approach for the two comparisons was identical. A chi-square test was used to compare the remission rates across the treatment groups. Fisher’s exact test was used when the expected cell frequencies were less than 5. For binary outcomes (e.g., remission), bivariate logistic regression models were fit to estimate the effect of treatment on outcome. Multivariable logistic regression models were then fit to control for the effect of regional center and baseline characteristics that were not balanced across treatment groups. A similar approach was used for discrete outcomes with more than two levels, except a polytomous logistic regression model was used. For continuous outcomes, a t test was used to compare the means when distributions were normal, and the nonparametric Kruskal-Wallis test was used when distributions were nonnormal. Linear regression models were used to compare the means after controlling for regional center and baseline characteristics not balanced across treatment groups. A general linear model with a negative binomial distribution and log link was estimated for outcomes with severely nonnormal distributions (the last number of worsening adverse events indicated by the Systematic Assessment for Treatment Emergent Effects and the score on the IDS-C anxiety subscale).

Figure 1 contains a chart specifying how the study group was formed. From March 2008 through February 2009, the study enrolled 665 participants. They were moderately to severely ill, as indicated by a mean HAM-D score of 23.8 (SD=4.8) and a score on the QIDS-SR of 15.5 (SD=4.3). About half of the participants were unemployed, and two-thirds were female (Table 1). Over three-quarters had recurrent major depression (Table 2). More than one-half of the participants were in a chronic current major depressive episode. About one-third had both recurrent and chronic depression. Almost one in 10 had made a prior suicide attempt, and for over 40% the illness had begun before age 18. Most (75%) had anxious features. Concurrent comorbid axis I and axis III disorders were common (Table 3).

During the first 12 weeks, the participants were in treatment for an average of 10 weeks (Table 4). Of the 665 participants, 86.0% (N=572) completed at least 4 weeks of treatment. Overall, 78.3% (N=521) completed week 8 and 72.2% (N=480) completed at least 12 weeks of treatment. For the escitalopram-placebo group, the escitalopram dose was close to the maximum target dose of 20 mg/day. For bupropion-escitalopram, the comparable mean exit escitalopram dose during acute treatment was significantly lower, at 12.5 mg/day (SD=8.3) (χ²=31.15, df=1, p<0.0001). Also of note, while the venlafaxine dose was close to 200 mg/day by 12 weeks, the mean mirtazapine dose was only 20.0 mg/day (SD=15.7) (Table 4).

As shown in Table 5 and Figure 2, the treatment groups did not differ in either remission or response rates, nor did they differ in the percentage of change in QIDS-SR score (baseline to exit or 12 weeks) or in effects on quality of life. The venlafaxine-mirtazapine combination was associated with more side effect burden than escitalopram-placebo. Patients taking venlafaxine-mirtazapine had more adverse symptoms (ear aches, blurred vision, irritability, etc.) present at baseline that became worse during treatment, as measured by the Systematic Assessment for Treatment Emergent Events (mean number of effects=5.7, SD=5.8), than the monotherapy group (Table 5).

Overall, while 72.2% of the 665 participants (N=480) completed at least 12 weeks of treatment, 65.6% completed 16 weeks or more, 61.4% completed 20 weeks, 55.6% completed 24 weeks, and 58.0% completed 28 weeks. Attrition rates over the 7-month period did not differ among treatment groups. Average drug doses were basically unchanged from 12 weeks to 7 months of treatment, regardless of treatment group (Table 4).

At 7 months (or study exit, if earlier), the three groups were not different in terms of remission rate (range: 41.8%–46.6%), response rate (range: 57.4%–59.4%), or attrition rate. Nor did the groups differ in the percentage of change in QIDS-SR (baseline to exit or 7 months), quality of life, or work and social adjustment.

Table 6 compares the side effect frequency, intensity, and burden in the escitalopram monotherapy group and each of the combination groups. Overall, there were modestly more side effects with escitalopram-bupropion than with escitalopram-placebo in both the 12-week and 7-month comparisons. On the other hand, the venlafaxine-mirtazapine group had greater side effect frequency and intensity at 12 weeks and greater side effect frequency, intensity, and burden at 7 months as compared to escitalopram-placebo.