In a recent systematic review and meta-analysis, the investigators looked at randomized clinical trials (RCTs) that compared combinations of antidepressants with antidepressant monotherapy in adult patients with acute depression. In total, the 39 RCTs included 6,751 patients, and the publication dates ranged from 1977 to 2020. The primary outcome criterion was treatment efficacy measured as the standardized mean difference (SMD) between combination and monotherapy, on an intention-to treat basis, if possible.

Of 39 studies included, 38 trial reports provided data on the primary outcome. Results showed that combination treatment was statistically significantly associated with superior treatment outcomes relative to monotherapy (SMD = 0.31; 95% CI, 0.19-0.44). When looking at combinations using presynaptic α2-autoreceptor antagonists or bupropion separately, the data showed that combination of a monoamine reuptake inhibitor with an antagonist of presynaptic α2-autoreceptors was associated with superior outcomes relative to monotherapy: among all 18 RCTs (SMD = 0.37; 95% CI, 0.19-0.55), among nonresponder populations (SMD = 0.24; 95% CI, 0.03-0.45), and additionally when applied as a firstline treatment (SMD = 0.64; 95% CI, 0.12-1.15). The numbers of dropouts and dropouts due to adverse events did not differ between treatments.

These two mechanisms, monoamine transport blockade and α2 antagonism, are synergistic, so that blocking them simultaneously gives a much more powerful disinhibitory signal to these two neurotransmitters than if only one mechanism is blocked. For this reason, the α2 antagonist, such as mirtazapine, combined with an serotonin norepinephrine reuptake inhibitors (SNRIs) is sometimes called “California rocket fuel” (Figure 1) because of the potentially powerful drugs for depression action blasting the patient out of the depths of depression. This combination exploits the pharmacologic synergy attained by adding the enhanced serotonin and norepinephrine release from inhibition of both dual serotonin and norepinephrine reuptake by an SNRI to the disinhibition of both serotonin and norepinephrine release by the α2 antagonist actions of mirtazapine. It may thus be a safe treatment alternative when compared with other second-step strategies in treatment-resistant depression, such as augmenting monotherapy with lithium or atypical.

References:

Henssler J et al. JAMA Psychiatry. Epub ahead of print. Abstract

Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Fifth edition. Cambridge University Press; 2021.