Major depressive disorder (MDD) is the third-highest cause of disability worldwide, but researchers have yet to identify a pharmacological therapy that treats it in all contexts [1, 2]. Around 30% of patients with MDD do not respond to the common first-line treatment, selective serotonin reuptake inhibitors . Consequently, physicians require a secondary approach in those instances, which are generally termed treatment-resistant depression (TRD) . One contender is ketamine delivered in sub-anesthetic doses . Numerous studies indicate that ketamine is a fast-acting, long-lasting treatment for chronic depression [2, 3]. Furthermore, it is successful in various contexts, including non-chronic pain and chronic pain-induced depression . However, several details concerning its administration–such as ideal dosage, mechanism, side effects, and efficacy in extreme cases–warrant further investigation.
In terms of dosage, ketamine for chronic depression is most widely administered intravenously at 0.5 mg/kg over 40 minutes . Despite this practice, several studies have found other dosages, administration routes, and durations to be effective as well . For instance, some patients have responded to doses “as low as 0.1 mg/kg,” while “others may require 0.75 mg/kg” . One study found ketamine at 0.5 mg/kg to be an effective treatment for patients suffering from MDD with suicidal ideation . Administration durations spanning from 2 to 100 minutes have been utilized safely and effectively . Additionally, intramuscular, intranasal, sublingual, subcutaneous, transmucosal, and oral administration routes also appear successful in many cases . As no definitive set of standards exists for ketamine in the context of depression, physicians should consult the literature on this subject before establishing a therapeutic plan for their patients.
The mechanism through which ketamine treats MDD is unclear, although recent progress has been made in clarifying it. A 2021 study by Aguilar-Valles et al. investigated the metabolic pathway of ketamine in rodents . Past studies suggested that ketamine achieves its antidepressant effects once converted into the metabolite (2R,6R)-HNK, which is thought to inhibit N-methyl-D-aspartate (NMDA) receptors . NMDA receptor blockade triggers antidepressant responses at rapid rates . The Aguilar-Valles et al. investigation demonstrated how rodents with deletions of 4E-BP2, a gene involved in protein synthesis, did not experience the antidepressant effects of ketamine . This finding supports the hypothesis that ketamine operates through the 4E-binding proteins–specifically, 4E-BP2–which, in turn, may affect NMDA signaling . While clinicians require further research to corroborate these findings, this study could still be a promising advance in our understanding of ketamine and depression.
Another area that justifies additional investigation is the side effects of ketamine. As a recreational drug, ketamine is associated with “substantially impaired cognitive function in most domains” . In the context of MDD, ketamine has not been shown to have the same deleterious effects, but this does not mean that similar outcomes are not impossible . In addition, acute cardiovascular, neurological, psychotomimetic, and psychiatric side effects were observed in a systematic review of 60 short-term studies . Among them, psychiatric (38%) and psychotomimetic/dissociative (72%) side effects were especially common . A minority of patients also reported a variety of negative occurrences, including suicidal attempts, ectopic pregnancy, and rashes . Given this wide variety of potential side effects, physicians should be cautious when prescribing ketamine to MDD patients.
Despite the lack of clarity surrounding it, ketamine’s widely demonstrated efficacy still represents a signification advance in the care of MDD patients. Because of its success, the future of antidepressant treatment may involve glutamatergic drugs . Hopefully, those drugs will have the fast-acting, long-lasting effects of ketamine without risking its adverse effects . While those drugs are being developed, ketamine appears to be a promising choice for many patients suffering from depression.
 A. Corriger and G. Pickering, “Ketamine and depression: a narrative review,” Drug Design, Development and Therapy, vol. 13, p. 3051-3067, August 2019. [Online]. Available: https://doi.org/10.2147/DDDT.S221437.
 A. Aguilar-Valles et al., “Antidepressant actions of ketamine engage cell-specific translation via eIF4E,” Nature, vol. 590, p. 315-319, February 2021. [Online]. Available: https://doi.org/10.1038/s41586-020-03047-0.
 D. F. Ionescu et al., “Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: A randomized, double blind, placebo controlled trial,” Journal of Affective Disorders, vol. 243, p. 516-524, January 2019. [Online]. Available: https://doi.org/10.1016/j.jad.2018.09.037.
 M. Humo et al., “Ketamine induces rapid and sustained antidepressant-like effects in chronic pain induced depression: Role of MAPK signaling pathway,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 100, p. 1-8, June 2020. [Online]. Available: https://doi.org/10.1016/j.pnpbp.2020.109898.
 C. Andrarde, “Ketamine for Depression, 4: In What Dose, at What Rate, by What Route, for How Long, and at What Frequency?” Journal of Clinical Psychiatry, vol. 78, no. 7, p. e852-e857, July/August 2017. [Online]. Available: https://doi.org/10.1016/j.jad.2018.09.037.
 A. E. Autry et al., “NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses,” Nature, vol. 475, p. 91-95, June 2011. [Online]. Available: https://doi.org/10.1038/nature10130.
 K.-S. Na and Y.-K. Kim, “Increased use of ketamine for the treatment of depression: Benefits and concerns,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 104, p. 1-8, January 2021. [Online]. Available: https://doi.org/10.1016/j.pnpbp.2020.110060.
 B. Short et al., “Side-effects associated with ketamine use in depression: a systematic review,” The Lancet Psychiatry, vol. 5, no. 1, p. 65-78, January 2018. [Online]. Available: https://doi.org/10.1016/S2215-0366(17)30272-9.