Some antidepressant combination therapies may outperform monotherapy

Combination therapy that included an antagonist of presynaptic alpha2-autoreceptors appeared effective and safe for patients with depression who did not respond to monotherapy, according to a report published in JAMA Psychiatry.

“This systematic review and meta-analysis of randomized clinical trials (RCTs) comparing combinations of two antidepressants with antidepressant monotherapy in adults with acute depression addresses a number of questions,” Jonathan Henssler, MD, of the department of psychiatry and psychotherapy at the University of Cologne Medical School in Germany, and colleagues wrote. “What is the efficacy of combination therapy, relative to monotherapy, both as first-line treatment and as treatment for nonresponders? Are combination treatments that include mirtazapine or bupropion particularly effective? What is the comparative tolerability of combination therapies?”

Henssler and colleagues conducted systematic searches for these RCTs in four databases from inception through January 2020. Efficacy measured as standardized mean difference (SMD) served as the primary outcome. Secondary outcomes included response, remission, change from baseline in rating scale scores, number of dropouts and number of dropouts because of adverse events. They included 39 RCTs with a total of 6,751 patients.

Results showed a statistically significant association between combination treatment and superior treatment outcomes compared with monotherapy (SMD = 0.31; 95% CI, 0.19-0.44). Combination therapy featuring a reuptake inhibitor and an antagonist of presynaptic alpha2-autoreceptiors exhibited superiority to other combinations (SMD = 0.37; 95% CI, 0.19-0.55). Bupropion combinations did not appear superior to monotherapy (SMD = 0.1; 95% CI, 0.07 to 0.27). Treatments did not differ on numbers of dropouts and dropouts because of adverse events. Although studies were heterogeneous and there was evidence of publication bias, results remained robust across prespecified secondary outcomes and sensitivity and subgroup analyses, including those restricted to studies with low bias risk.

“For clinical practice, physicians should be aware that combinations of reuptake inhibitors (selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor or tricyclic antidepressant) with alpha2-autoreceptor antagonists are a potent treatment option, associated with superior outcomes relative to monotherapy,” Henssler and colleagues wrote. “Clinicians can inform patients that on average this advantage does not come at the cost of lower tolerability and that there is reason to believe in a synergistic therapeutic effect.

“While we did not find an association of outcome and severity of depression, we believe combination treatment particularly suggests itself in severe cases of depression and for patients resistant to standard treatment,” they added. “Research should focus on the dearth of methodologically rigorous data on bupropion combinations for nonresponder populations.”