The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine was first developed as a shorter-acting, less psychoactive anesthetic than phencyclidine (Mion, 2017). Due to its broad safety profile, ketamine was soon approved for human anesthesia and used extensively as a battlefield medication during the Vietnam War. As an anesthetic, ketamine was also found to prevent shock, decrease hyperalgesia, and have neuroprotective effects, including anti-inflammatory actions (Hirota & Lambert, 2022). However, from the earliest days of its use as an anesthetic, reports emerged of patients experiencing sensations of floating and other dissociative effects after administration, which led to the coining of the term “dissociative anesthetic” (Domino & Warner, 2010). In addition to these psychotomimetic effects, some patients experienced increases in intracranial pressure (Shapiro, Wyte, & Harris, 1972), lowering of seizure thresholds (Krystal et al., 2003), hypertension (Broughton Pipkin & Waldron, 1983), and tachycardia that led ketamine to be used less frequently (Pai & Heining, 2007). The US Controlled Substances Act subsequently classified ketamine as a Class III substance in parallel with rising social concerns about its potential for misuse (Mion, 2017).

Despite these concerns, researchers in the early 1990s began investigating the potential antidepressant-like actions of another NMDAR antagonist, MK-801 (Nowak, Trullas, Layer, Skolnick, & Paul, 1993). In parallel, other investigators found that stress increased the probability of glutamate release in specific brain regions (Moghaddam, 2002), sparking a newfound interest in the effects of glutamatergic modulation in depression. Building on this work, Berman and colleagues conducted a small, proof-of-concept clinical study that led to a paradigm shift in psychiatry, finding that subanesthetic-dose ketamine induced rapid and robust antidepressant effects, an outcome previously unheard of with traditional monoaminergic-based therapeutics (Berman et al., 2000).

These rapid-acting effects were subsequently replicated in participants with treatment-resistant depression (TRD) and bipolar depression, with remission rates significantly higher than those of traditional antidepressants (Zarate Jr. et al., 2006; Zarate Jr. et al., 2012). Over the past two decades, multiple randomized, placebo-controlled trials have validated these initial observations (Alnefeesi et al., 2022; Marcantoni et al., 2020; McIntyre et al., 2020). In addition to ketamine's actions as a rapid-acting antidepressant, it appears to uniquely target symptoms that are often resistant to traditional antidepressants, such as anhedonia and suicidal ideation. For instance, multiple meta-analyses have shown that acute intravenous ketamine led to significant short-term reductions in suicidal ideation (Wilkinson et al., 2018; Witt et al., 2020), which could be extremely useful in emergency medicine settings. Intranasal esketamine, the (S)-enantiomer of ketamine, has similarly been shown to reduce suicidal ideation in participants with depression (Canuso et al., 2018). Notably, anhedonia often does not respond to monoaminergic-based antidepressants despite being one of the core symptoms of depression (Rizvi, Pizzagalli, Sproule, & Kennedy, 2016; Treadway & Zald, 2011); ketamine, however, has proven quite successful at clinically resolving anhedonia symptoms (Nogo et al., 2022). Ketamine also appears to have broad therapeutic properties, demonstrating treatment efficacy in obsessive compulsive disorder (OCD), social anxiety disorders, and post-traumatic stress disorder (PTSD), which are often comorbid with major depressive disorder (MDD) and impact further treatment resistance (Bandeira et al., 2022; Belzer & Schneier, 2004; Feder et al., 2021; Glue et al., 2020; Whittaker, Dadabayev, Joshi, & Glue, 2021). However, these results are preliminary, as most of these studies were small and require replication. Notably, one recent, randomized, controlled trial found no significant improvement in PTSD symptoms after ketamine administration (Abdallah et al., 2022).

Collectively, this evidence led the Food and Drug Administration (FDA) to approve intranasal esketamine (Spravato)—the (S)-enantiomer of ketamine—for adults with TRD in 2019 and for adults with MDD and acute suicidal ideation or behavior in 2020. The European Union also approved esketamine for the same indications in 2019 and 2021, respectively. In addition, off-label use of intravenous ketamine has demonstrated robust short-term efficacy in TRD and treatment-resistant bipolar disorder, but few studies have explored ketamine's real-world efficacy or explored optimal dosing and routes of administration (McIntyre et al., 2020). A recent real-world effectiveness meta-analysis found robust efficacy on average, although certain populations—including those with TRD—experienced more variable results (Alnefeesi et al., 2022). The longer-term effects of ketamine have also been called into question, given that the effectiveness of acute doses generally peaks at 24 h and lasts up to two weeks after administration (Kishimoto et al., 2016; Murrough et al., 2013).

The discovery of ketamine's rapid and potent therapeutic effects led researchers to explore whether other agents could either be developed or repurposed with antidepressant effects similar to those of ketamine but lacking its undesirable side effects; that question seems most likely to be answered by exploring ketamine's own pharmacology. This review seeks to briefly summarize recent research conducted on ketamine's enantiomer-specific actions, with a focus on the prophylactic, immediate, and sustained antidepressant effects of ketamine's enantiomers in clinical and preclinical research.