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<b>Objective:</b>To review the pharmacology, pharmacokinetics, efficacy, safety, use requirements, and place in therapy of esketamine for treatment-resistant depression (TRD). <b>Data Sources:</b> A comprehensive PubMed search (1966 to October 2019) was conducted using the search terms <i>depression, treatment-resistant, suicide, intranasal, esketamine</i>, and <i>JNJ-54135419</i>. Additional data were obtained from references of identified articles, governmental sources, manufacturer product labeling, and Clinicaltrials.gov . <b>Study Selection and Data Extraction:</b> All English-language trials evaluating intranasal esketamine for TRD were included and discussed. <b>Data Synthesis:</b> Intranasal esketamine was approved by the US Food and Drug Administration, in conjunction with an oral antidepressant, for treating TRD in adults. Two short-term trials (TRANSFORM-1 and -2) found statistically significant reduction in the Montgomery-Asberg Depression Rating Scale score at day 28 for the fixed 56-mg dose (-4.1; 95% CI = -7.69 to -0.49; <i>P</i> = 0.027 [exploratory]) and flexible-dosed arms (-4.0; 95% CI = -7.31 to -0.64; <i>P</i> = 0.02), though the fixed-dose 84-mg arm (-3.2; 95% CI = -6.88 to 0.45; <i>P</i> = 0.088) of TRANSFORM-1 and TRANSFORM-3 did not (-3.6; 95% CI = -7.2 to 0.07; <i>P</i> = 0.059). Two long-term trials (SUSTAIN-1 and -2) suggested maintenance of response with continued use. Esketamine's adverse effects include dizziness, dysgeusia, somnolence, dissociation, suicidal thoughts and behaviors, and increased heart rate and blood pressure. <b>Relevance to Patient Care and Clinical Practice:</b> Although providing a novel antidepressant mechanism and formulation for TRD, esketamine's role in treatment will likely be limited by cost, administration, and diversion concerns. <b>Conclusion:</b> Intranasal esketamine significantly reduced depression symptoms in TRD, though with tolerability issues.