Ketamine was initially used as an anesthetic which could induce cognitive impairment and psychomimetic effects. In initial randomized controlled trials (RCTs) that mostly included a small sample size and were investigator-initiated, ketamine reportedly exerted antidepressant effects 1 to 2 h after a single intravenous infusion in patients with major depressive episodes, particularly treatment-resistant depression (TRD). Interest in ketamine was reported in systematic reviews and meta-analyses, however, many were primarily focused on the rapid onset of ketamine effects without equal attention to its safety and tolerability. Furthermore, several meta-analyses were based on many duplicated RCTs. The initial trends emphasized the clinical utility of ketamine as an antidepressant. The development of esketamine nasal spray by a pharmaceutical company led to an RCT with a large sample size and segmented therapeutic strategy, which provided results applicable to patients with TRD in the real-world clinical environment. However, possible effects of ketamine on cognitive function have not yet been investigated in RCTs. In numerous studies, chronic, recreational use of ketamine reportedly substantially impaired cognitive function in most domains. Although results of several human and animal studies indicated the therapeutic use of ketamine for treatment of depression did not induce cognitive impairment, this issue should be further investigated. Based on the current knowledge about ketamine, future antidepressants are expected to be glutamatergic drugs without ketamine-like adverse events (e.g., psychomimetic symptoms and cognitive impairment), but having only ketamine-like therapeutic properties (e.g., rapid antidepressants effects without time lag). Copyright © 2020. Published by Elsevier Inc.