Selected RCTs included an intervention group using a combination of 2 antidepressants, regardless of dosage, and a control group of patients taking antidepressant monotherapy. Studies evaluated both patients being treated for the first time and those with a previously inadequate response to medical treatment. All participants were ages 18 years or older (mean age not reported) and had received a diagnosis of depressive disorder according to standard operationalized criteria; patients with multiple psychiatric comorbidities were not excluded.
Studies used various standardized questionnaires—most frequently, the Hamilton Depression Rating Scale (HDRS) and the Montgomery-Åsberg Depression Rating Scale (MADRS)—to determine the severity of depression at baseline and following treatment. The HDRS is a 17-item depression scale and the MADRS is a 10-item depression scale; for both, higher scores indicate worsening depression. Follow-up time ranged from 2 to 12 weeks.
The primary outcome was treatment efficacy measured as the standardized mean difference (SMD). Secondary outcomes included remission (normal-range scores) and response to treatment (eg, ≥ 50% reduction in scores), as defined by the study authors.
Combination therapy was determined to have superior efficacy relative to monotherapy (SMD = 0.31; 95% CI, 0.19-0.44; P < .001). Combinations with a presynaptic α2-autoreceptor antagonist (eg, mirtazapine, trazodone, or mianserin [the last of which is not approved by the US Food and Drug Administration for use in the United States]) and a monoamine reuptake inhibitor (eg, an SSRI, SNRI, or TCA) were superior to other combinations (SMD = 0.37; 95% CI, 0.19-0.55). Combinations that included bupropion were not superior to monotherapy (SMD = 0.10; 95% CI, –0.07 to 0.27).
Secondary outcomes revealed combination therapy to be superior to monotherapy with respect to remission (odds ratio [OR] = 1.52; 95% CI, 1.20-1.92) and response (OR = 1.40; 95% CI, 1.15-1.69). Subgroup analyses showed that combinations with presynaptic α2-autoreceptor antagonists led to improved remission (OR = 1.42; 95% CI, 1.01-2.01) and response (OR = 1.49; 95% CI, 1.18-1.87) compared with monotherapy, whereas combinations that included bupropion were not superior to monotherapy. For patients who dropped out of treatment for any reason, including adverse drug events, results for combination pharmacotherapy and monotherapy were similar.
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