The New Frontier of Repurposing Anesthetic Drugs for Depression

Anesthesiologists now find themselves – perhaps unexpectedly – at a new frontier of brain health: the treatment of neuropsychiatric disorders. Historically, our involvement with mental health has been limited to providing anesthesia care for electroconvulsive therapy, and our focus on brain health has revolved around perioperative neurocognitive disorders. However, mental health is now increasingly recognized as a critical dimension of brain health (Nature Mental Health 2023;1:441-3). The discovery of the antidepressant properties of general anesthetic drugs like ketamine has transformed our relationships with patients and psychiatrists and is presently kindling new opportunities to promote brain health.

Globally, anesthesiologists are now working closely with psychiatrists to provide ketamine therapy to alleviate suicidality and treatment-resistant depression. As experts on the safe use of anesthetic drugs, we are important collaborators in research to determine optimum dosing, best practices related to monitoring, and the molecular mechanisms of ketamine’s properties. The promise of ketamine has also inspired efforts to explore the repurposing of other general anesthetic drugs as antidepressants. This research is important because depression is one of the most prevalent disorders worldwide, with a lifetime risk of approximately 12% (JAMA Psychiatry 2014;71:573-81). It is the leading cause of global disability and a significant risk factor for suicide (Arch Gen Psychiatry 1992;49:831-4; Neurosci Biobehav Rev 2013;37:2372-4). Despite the availability of multiple treatment options, depression is frequently a chronic disorder. Treatment-resistant depression (TRD), which is most commonly defined as depression that does not remit following two or more antidepressant trials, occurs in about one-third of cases (J Affect Disord 2014;156:1-7; J Clin Psychiatry 2021;82:20m13699). Thus, the discovery of ketamine’s neuropsychiatric properties heralds an exciting new era of anesthesia psychopharmacology.

It might seem like the successes of ketamine as an antidepressant emerged overnight; however, the discovery of ketamine’s therapeutic effectiveness as a psychoactive drug has been a protracted, 60-year journey. The delays were likely due, in part, to stigma surrounding mental illness and the obstacles to interdisciplinary collaboration. The phencyclidine derivative CI-581, or ketamine, was first synthesized in 1956 by chemists at Parke-Davis (Front Hum Neurosci 2016;10:612). Drs. Guenter Corssen and Edward Domino first reported ketamine’s general anesthetic properties in 1966 (Anesth Analg 1966;45:29-40). Dr. Domino later recalled an earlier encounter with a patient who was self-medicating with ketamine; her experience was foretelling. She confided that ketamine improved her mood more rapidly and robustly than her prescribed antidepressant drugs (Anesthesiology 2010;113:678-84). However, it took several decades before ketamine’s valuable antidepressant properties were rigorously explored.

In the year 2000, Drs. Robert Berman and John Krystal reported the first placebo-controlled trial of ketamine for depression in a cohort of seven patients (Biol Psychiatry 2000;47:351-4). Soon after, Dr. Carlos Zarate Jr. led pioneering evaluations of ketamine’s use and mechanisms as an antidepressant (Biol Psychiatry 2008;63:349-52; Arch Gen Psychiatry 2006;63:856-64). Only this year, the ELEKT-D trial revealed that ketamine, administered intravenously at a subanesthetic dose, was noninferior to electroconvulsive therapy in patients with treatment-resistant major depression without psychosis (N Engl J Med 2023;388:2315-25). In this pragmatic, multicenter, randomized clinical trial, 195 patients received ketamine with a response rate of 55.4%, whereas 170 patients were treated with electroconvulsive therapy with a response rate of 41.2%. In hindsight, many more patients might have benefited from ketamine treatments had better conditions existed earlier for pivotal trials. Hopefully, the protracted interval between recognizing therapeutic potential and widespread adoption will be shorter for other drugs showing psychotropic promise.

Nitrous oxide has recently emerged as a novel antidepressant with impressive effects in patients with treatment-resistant depression (Biol Psychiatry 2015;78:10-8; Sci Transl Med 2021;13:eabe1376). A trial led by anesthesiologist Dr. Peter Nagele showed that inhalation of 50% nitrous oxide for one hour reduced depressive symptoms in patients with severe treatment-resistant depression (Biol Psychiatry 2015;78:10-8). A second trial found that one hour of 25% nitrous oxide had similar efficacy, although a trend toward greater efficacy was observed with the higher concentration (Sci Transl Med 2021;13:eabe1376). Importantly, the lower concentration had superior tolerability (e.g., fewer gastrointestinal and neuropsychiatric side effects). The antidepressant effects persisted for up to four weeks in some patients. Unlike many traditional antidepressants, nitrous oxide acts rapidly and has a relatively limited adverse effect profile and a low potential for abuse when used under medical supervision. Efforts to identify the antidepressant mechanisms of nitrous oxide, and their possible association with cerebral hemodynamics, have begun (Bipolar Disord 2023;25:221-32). More work is required to better understand the therapeutic potential of nitrous oxide; however, initial findings are a cause for optimism.

Other anesthetic drugs are also being studied for use in neuropsychiatric care, including propofol. In 2018, an open-label pilot trial suggested that propofol provides a rapid and durable antidepressant effect, similar to electroconvulsive therapy (Int J Neuropsychopharmacol 2018;21:1079-89). Propofol primarily targets GABA_A receptors, and emerging data from animal studies suggest that GABA_A receptor dysregulation is a common feature in various neuropsychiatric disorders (Neuropharmacology 2012;62:42-53). Disruption of slow-wave sleep has also been implicated in depression and, similar to propofol, other GABAergic drugs that promote slow wave sleep may have antidepressant properties (Am J Geriatr Psychiatry 2023;31:643-52). In fact, several modulators of GABA receptor-mediated inhibition are currently being tested as novel psychotropics (Neuropsychopharmacol September 2023).

Repurposing ketamine, nitrous oxide, propofol, and other general anesthetic drugs for neuropsychiatric disorders represents an exciting avenue of ongoing research. The strategy of repurposing, where new clinical uses are identified for an existing drug that has been approved for other indications, offers many advantages over the de novo synthesis of new compounds. The synthesis and evaluation of new compounds is extremely costly and is encumbered by numerous regulatory and legal hurdles. In contrast, general anesthetic drugs are readily available, extensively studied, and their safety is thoroughly understood; thus, the early stages of drug development can be expedited.

Research related to brain health often progresses slowly. We recognize the decades that passed between the first reports of perioperative neurocognitive disorders and clinical trials that identified their true incidence and potential preventative strategies. A key inflection point that accelerated progress was the formation of strong partnerships between anesthesiologists, neurologists, and geriatricians. A glance backward at the history of ketamine’s adoption for depression motivates efforts to improve the discovery pipeline in neuropsychiatry. Anesthesiologists have an in-depth understanding of the clinical properties of anesthetic drugs and are thus uniquely positioned to collaborate with psychiatrists to tackle outstanding questions. It is the right time to expand the concept of anesthesia-related brain health to include neuropsychiatric disorders. By rising to this occasion, we will accelerate the pace of discovery and address a significant unmet need in brain health.