Antidepressants
Clarissa Chan, PharmD
A meta-analysis of randomized clinical trials published February 2022 in JAMA Psychiatry compared antidepressant monotherapy against combined antidepressant therapy and found superior treatment outcomes were associated with combination therapies.
Non-monoamine oxidase inhibitor monotherapy is the first-line treatment for severe depression recommended by the National Institute for Health and Care Excellence, American Psychological Association, and American Psychiatric Association.
Although there are many available antidepressants, initial monotherapy response rate is only effective about 60% of the time, and only up to 40% of patients experience relief, even after a sufficient treatment trial.
The meta-analysis provides additional evidence to support the common prescribing practice of combining two antidepressants with different mechanisms of action to beneficially augment clinical efficacy when treating acute depression, often as a second-line treatment option, said Kelan Thomas, PharmD, MS, BCPS, BCPP, associate professor of clinical sciences at Touro University California College of Pharmacy in Vallejo, CA who was not part of the study.
Meta-analysis design
Henssler and colleagues conducted a systematic review and meta-analysis using MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials databases to evaluate the efficacy and tolerability of combining antidepressants versus monotherapy.
They examined 39 randomized controlled trials, and included 6,751 eligible adult patients. Antidepressant combinations with presynaptic a2-autoreceptor antagonists or bupropion were examined separately to assess the effectiveness of certain combinations.
Combined antidepressant therapy included monoamine reuptake inhibitors (e.g., selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], or tricyclic antidepressants), and presynaptic a2-autoreceptor antagonists (such as mianserin, mirtazapine, and trazodone).
While other medical and psychiatric conditions were included in the review, studies that examined bipolar depression were excluded. Although maintenance therapy trials were also excluded, first-line treatment trials were included in the analysis.
The primary outcome of standardized mean difference combination antibiotic therapy versus antibiotic monotherapy measured treatment efficacy and secondary outcomes measured adverse event–related dropouts.
Combination treatments provide better efficacy
The study found combination treatment to be superior to monotherapy.
While combinations of monoamine reuptake inhibitor with a presynaptic a2-autoreceptor antagonist were associated with superior outcomes over monotherapy, combinations with bupropion were not associated with consistently better outcomes in relation to monotherapy.
Adverse event–related dropout rates were similar between combination and monotherapy groups, indicating tolerability between both treatment options to be comparably insignificant.
Presynaptic a2-autoreceptor antagonist combinations work synergistically
“Mirtazapine–a primary presynaptic a2-autoreceptor antagonist analyzed [in the study]–augmentation is frequently used to target insomnia symptoms of major depressive disorder (MDD) and prevent SSRI/SNRI-related sexual dysfunction,” said Thomas. “But when combined with an SSRI/SNRIs, it also synergistically increases concentrations of monoamines in the synaptic cleft and that may explain the superior combination pharmacotherapy MDD outcomes demonstrated by this study.”
This study also suggests mirtazapine augmentation with SSRI/SNRI could even be considered first-line treatment for more severe MDD cases in addition to SSRI/SNRI partial responders, according to Thomas.
“Another noteworthy finding of the study was that while combinations with bupropion were not superior to monotherapy overall, among the nonresponder subgroup, bupropion augmentation was superior to monotherapy,” said Thomas.
Whether or not bupropion combinations help patients with treatment-resistant depression is inconclusive, said Christopher Baethge, MD, who was part of the meta-analysis. “More studies will likely help us get a clearer picture. So far, we do not have enough evidence to positively recommend bupropion combinations to that group of patients.” ■