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Introduction: Major depressive disorder (MDD) is the leading cause of disability worldwide with a heterogeneous symptom profile. Levomilnacipran extended release (ER) (Fetzima), a SNRI, has been approved by the Food and Drug Administration for treatment of MDD. While categorized as a SNRI, in contradistinction to other approved SNRIs, levomilnacipran exhibits differential affinity for the norepinephrine reuptake transporter when compared to the serotonin reuptake transporter. Areas covered: Completed clinical trials which focused on levomilnacipran ER administered in those with MDD were included in this drug evaluation. Expert opinion: Levomilnacipran ER, like all other first-line antidepressants exhibits significant efficacy in reducing total symptom severity. Levomilnacipran ER is particularly effective at improving measures of motivation, energy, and interest. Head to head comparative trials are not available with other antidepressants, and consequently, there are no claims of superior efficacy when compared to alternative antidepressants. Notwithstanding, it would be a viable and testable hypothesis that differential efficacy in favor of levomilnacipran may be obtained across select dimensions of depressive symptoms (e.g., fatigue and lack of motivation). Unfortunately, rigorous studies evaluating levomilnacipran for cognitive function in MDD have not been conducted. Levomilnacipran ER is generally well tolerated with minimal propensity for metabolic and weight disturbance.