The introduction of safe general anesthetic drugs in the mid-nineteenth century revolutionized medicine, because these drugs allowed complex and prolonged surgeries to be performed painlessly.¹ General anesthetic drugs are now addressing a second unmet clinical need: the treatment of depression.² The discovery of the rapid and sustained antidepressant properties of ketamine, and possibly nitrous oxide, propofol, and isoflurane, has offered hope for the development of new treatments for common, debilitating, and sometimes lethal mood disorders. In this article, we summarize emerging evidence that supports the effectiveness of general anesthetic drugs for the treatment of major depressive disorder, treatment-resistant depression, and bipolar depression. We also provide a brief overview of the mechanisms that potentially underlie the antidepressant properties of anesthetic drugs. Most importantly, we highlight the emerging overlap between the specialties of anesthesiology and psychiatry and offer suggestions to foster strong partnerships between the two medical disciplines for the benefit of our patients.

Major Depressive Disorder

Few clinical problems are as pressing as the need to develop new treatments for depression. Major depressive disorder, also referred to as clinical depression, is characterized by at least 2 weeks of pervasive changes in mood and cognition as well as a loss of interest or pleasure in normally enjoyable activities (anhedonia).³ Major depressive disorder affects more than 300 million people worldwide,⁴ and has an estimated lifetime prevalence of 11%.⁵ It is the single largest contributor to global disability and is associated with substantial healthcare costs and reduced quality of life.^4,6 Depression is also among the strongest risk factors for suicide.⁷

Since the very first generation of antidepressant drugs was introduced into clinical practice in the 1950s, dozens of drugs that target the monoamine system have been developed and approved as antidepressants, including selective serotonin reuptake inhibitors.⁸ However, these drugs typically require weeks or months to take effect, and are associated with adverse effects that reduce drug adherence.⁹ In addition, as is the case with many chronic, multifactorial illnesses, response rates to classical antidepressants are suboptimal.¹⁰ The likelihood of experiencing a treatment response declines with each successive drug that is tried.⁹ Approximately one third of patients with major depressive disorder do not respond to conventional therapies despite several courses of treatment,⁹ and develop what is known as treatment-resistant depression.¹¹

Given the worldwide prevalence of depression, and the limitations of drugs acting on monoaminergic circuits, the first study showing ketamine’s potential as a novel antidepressant was met with considerable excitement (but also skepticism). A cohort study published by Bermanet al. in 2000 showed that symptoms of depression in seven patients with major depressive disorder or bipolar disorder significantly improved over 72 h after a single intravenous treatment with ketamine, relative to placebo.¹² More recently, a limited number of studies have investigated the use of nitrous oxide as an antidepressant, with preliminary results showing similar promise.¹³ Other drugs of interest include propofol¹⁴ and the inhaled anesthetic isoflurane.^15,16

Ketamine is rapidly changing clinical practice but is also prompting a conceptual trend away from an exclusive focus on the monoamine hypothesis of depression. Contemporary hypotheses of the pathogenesis of depression now focus on an imbalance between excitatory glutamate neurotransmission and inhibitory γ-aminobutyric acid (GABA) neurotransmission.^17,18 The invention of techniques such as spectrophotofluorimetry (in the 1950s), advanced brain imaging methods like magnetic resonance imaging (in the 1970s),¹⁹ genetic technologies (in the 1980s), and more recently optogenetics and chemogenetics have provided insights into the biologic underpinnings of psychiatric disorders²⁰ and the molecular basis for general anesthesia. As a result, hypotheses concerning mood disorders and general anesthetics are now aligned on the same excitatory and inhibitory neurotransmitter systems, their primary receptors, and intracellular signaling pathways.^17,21 Dysregulation of glutamatergic and GABA-mediated (GABAergic) neurotransmission contributes, at least in part, to the general anesthetic state (e.g., in terms of loss of consciousness, analgesia, lack of memory), perioperative disorders (e.g., postoperative delirium and depression), and psychiatric disorders (e.g., mood, anxiety, and psychosis).^22–25 Thus, close collaborations between anesthesiology and psychiatry will advance our shared goal of using anesthetic drugs to optimally modify network synchrony and neuroplasticity in surgical and nonsurgical patients.²

Repurposing Anesthetic Drugs as Psychotropics

Part of the excitement related to the use of ketamine and possibly other anesthetic drugs as novel psychotropics^26,27 stems from the many advantages of repurposing safe and widely available drugs compared withde novo drug development. The design and commercialization of a new drug that targets the central nervous system is encumbered by high failure rates, prohibitive costs, and long timelines for development.²⁸ In fact, the mean cost of developing a new “nervous system” therapy and bringing it to market is more than $1 billion,²⁹ and the average timeline to bring a drug to the North American market is 10 to 15 yr.³⁰ In contrast, anesthetic drugs are safe for use in humans (when administered by skilled providers), relatively inexpensive, and readily available. The repurposing of existing anesthetics for new therapeutic indications therefore comes at much lower costs and with fewer uncertainties regarding safety.

Given that ketamine has been widely available for decades, it is important to consider the reasons its value as an antidepressant drug has only recently been appreciated. The lack of familiarity of psychiatrists with the clinical properties of anesthetic drugs, as well as doubt about its effectiveness and concerns related to addiction,³¹ duration of drug action, and serious adverse effects (including reduced level of consciousness, suppression of airway reflexes, and the well-known psychomimetic effects of these agents), have likely hampered discovery. In addition, the lack of financial incentives to study and market drugs that cannot be patented may have contributed. Shared knowledge between anesthesiologists and psychiatrists of both the clinical and mechanistic properties of anesthetic drugs is paramount to avoiding missed opportunities and facilitating clinical uptake and future studies.

Modifying Excitatory and Inhibitory Neurotransmission

To date, anesthetic drugs that have been identified as having antidepressant properties primarily target glutamatergic neurotransmission (e.g., ketamine and nitrous oxide) and GABAergic neurotransmission (e.g., propofol and isoflurane); however, it is appreciated that all general anesthetic drugs act at multiple target sites.³² Currently, it remains unclear whether the antidepressant properties of general anesthetic agents result from a single common pathway or multiple different mechanisms. All anesthetics modify the balance between excitation and inhibition in the central nervous system, and regional changes in excitation and inhibition balance have been described in the context of major depressive disorder.³³ However, not all general anesthetic drugs have been shown to elicit antidepressant effects, and it is unlikely that alterations in excitation and inhibition balance alone are sufficient to produce a therapeutic effect. Furthermore, depression is a heterogenous condition for which most treatments have pleiotropic effects, and so the mechanisms of benefit may also differ across individual patients. A brief overview of the antidepressant properties of several general anesthetic drugs and our current understandings of their mechanisms of action are provided in the following sections. More comprehensive reviews of the mechanisms underlying ketamine’s antidepressant properties,³⁴ the role of glutamate³⁵ and GABA signaling in depression,³⁶ and the mechanisms of general anesthesia have been previously undertaken by others.^21,32

Glutamate-mediated Neurotransmission

Ketamine’s efficacy as an antidepressant has contributed to a growing focus on alterations in excitatory glutamatergic neurotransmitter in the mammalian brain during depression.³⁷ Glutamate binds to several classes of heteromeric ionotropic receptors, including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors,N-methyl-d-aspartate (NMDA) receptors, and kainate receptors, as well as metabotropic G protein–coupled receptors.³⁵ AMPA receptors are tetrameric cation-selective ion channels composed of four subunits (GluR1, GluR2, GluR3, and GluR4) in various combinations.³⁸ Glutamate binding leads to channel opening and an influx of sodium and in some cases calcium, generating excitatory postsynaptic potentials and facilitating most fast synaptic transmission in the central nervous system.³⁹

In contrast, NMDA receptors are assembled from GluN1, GluN2A to D, or GluN3A and B subunits.⁴⁰ These receptors are coagonized by glutamate and either glycine or D-serine and are blocked by magnesium under hyperpolarizing conditions.^40,41 An initial membrane depolarization (usually resulting from the activation of AMPA receptors) and NMDA channel opening relieves the magnesium blockade, allowing an influx of calcium, sodium, and potassium across the plasma membrane and the generation of more sustained cell depolarization as compared to the activation of AMPA receptors alone. NMDA receptor opening also leads to the activation of second messenger systems and altered gene expression.⁴² Finally, kainate receptors are composed of five subunits (GluK1 to 5), and perform a variety of functions including the generation of excitatory postsynaptic potentials (via calcium and sodium flux).⁴³ Several anesthetics including ketamine and nitrous oxide are known to modulate glutamate-mediated neurotransmission through noncompetitive and possibly allosteric inhibition of NMDA receptors.³²

Ketamine

Ketamine was initially synthesized as a derivative of phencyclidine by Parke-Davis (Detroit, Michigan) in 1956.⁴⁴ It was first trialed in humans in 1966 by Guenter Corssen and Edward Domino,⁴⁵ and was approved for clinical use as an anesthetic drug by the U.S. Food and Drug Administration (Silver Spring, Maryland) in 1970.⁴⁴ Ketamine is a racemic preparation composed of the enantiomers (S)-ketamine (esketamine) and (R)-ketamine (arketamine).⁴⁶ The drug quickly found application as a field anesthetic during the Vietnam War because its cardiorespiratory effects are relatively limited,⁴⁷ and it has since been widely used in operating rooms and emergency departments as a sedative and anesthetic agent. More recently, ketamine has been employed at subanesthetic doses (with low doses having the advantages of reduced cognitive effects, fewer requirements for monitoring, and shorter recovery time)⁴⁸ to treat both acute and chronic pain.⁴⁹ During the past 2 decades, however, ketamine has become better known as the prototypical anesthetic drug repurposed as a fast-acting therapy for major depressive disorder and treatment-resistant depression.⁵⁰

Early patient experiences hinted at the antidepressant properties of ketamine. Edward Domino recalled in a memoir that, shortly after ketamine became available, one patient seen in a substance use clinic said, “Oh, doctor, my antidepressants don’t work as well [as ketamine].”⁵¹ Moreover, preclinical studies of ketamine’s actions on NMDA receptors predicted that ketamine would have antidepressant effects.⁵² Despite such important early insights, ketamine was not rigorously investigated as an antidepressant until the twenty-first century.²⁶

In a landmark study published in 2000, Bermanet al. reported significant improvement in depressive symptoms 72 h after a single low-dose treatment (0.5 mg/kg) with ketamine.¹² This small (n = 7) placebo-controlled trial of ketamine for patients with depression was met with tremendous excitement (as well as doubt). The ketamine dose administered in this study has since become the most common antidepressant dose used in clinical practice and trials. Subsequently, Zarateet al. undertook a larger (n = 18), hypothesis-driven clinical trial of patients with treatment-resistant depression and found that a single intravenous infusion of ketamine significantly improved symptoms: an unprecedented 71% of patients met the criteria for a positive treatment response 1 day after ketamine infusion, with a significant improvement recognizable in the first 2 h, and 29% experienced a degree of improvement that was considered consistent with remission (fig. 1).⁵³ Since then, several major trials and meta-analyses have confirmed the antidepressant properties of ketamine for the treatment of major depressive disorder,^54,55 treatment-resistant depression,^56,57 and bipolar depression.^58–60

After these early reports, enthusiasm for the use of ketamine to treat both depression and suicidal ideation has burgeoned. As evidence, a brief search in PubMed using the key words “ketamine” and “depression” yielded more than 4,000 articles published on the topic since the report by Bermanet al. in 2000, with an inflection point around the year 2010 (fig. 2). A recent systematic review and meta-analysis identified 49 randomized clinical trials (comprising more than 3,000 patients with major depressive disorder) that collectively showed a rapid reduction in depression severity after just a single dose, reaching peak effect approximately 1 day after treatment.⁵⁴ Interest in ketamine continues to grow year on year, and this is compounded by reports of its therapeutic efficacy for comorbid conditions including chronic pain,⁶¹ obsessive-compulsive disorder,⁶² anxiety disorders,⁶³ and possibly posttraumatic stress disorder.⁶⁴

The efficacy of ketamine in pioneering studies of its antidepressant effect has been translated into real-world effectiveness. In 2023, the landmark ELEctroconvulsive therapyversus Ketamine in patients with Treatment-resistant Depression (ELEKT-D) study compared ketamine to electroconvulsive therapy in patients with treatment-resistant depression without psychosis.⁶⁵ In the trial, 195 patients received ketamine (0.5 mg/kg), which was infused over 40 min twice weekly, and 170 patients received electroconvulsive therapy three times weekly. Electroconvulsive therapy was initially administered as a right-sided unilateral ultrabrief pulse protocol, which is widely used in real-world practice as it is associated with fewer adverse cognitive effects compared to bilateral pulses.⁶⁶ After the initial treatments, subsequent modification to the settings and location of electrode placement was based on the discretion of the treating physician.⁶⁵ ELEKT-D reported that ketamine was noninferior—and, in fact, numerically superior—to electroconvulsive therapy: 55.4% and 41.2% of subjects met the criteria for a positive response on the basis of depression scores, respectively.⁶⁵ The trial also attributed greater memory impairment at the end of treatment to electroconvulsive therapy (although no differences were detected in follow-up) and, importantly, reported that more patients randomized to receive electroconvulsive therapy elected to withdraw from the trial before receiving their assigned intervention.⁶⁵ It should be noted that several smaller trials that predated the ELEKT-D study reported conflicting results and overall favored electroconvulsive therapy over ketamine for mixed populations with unipolar/bipolar major depressive disorder or treatment-resistant depression (pooled standard mean difference, –0.69).⁶⁷ However, these earlier trials have been criticized as they were likely underpowered and lacked robust longer-term follow-up.⁶⁷ The findings of the ELEKT-D study have the potential to substantially disrupt treatment strategies for patients who have trialed conventional antidepressants without success, and for whom electroconvulsive therapy has traditionally been considered to be the most effective available treatment.^68,69

Current areas of ongoing study in the repurposing of ketamine for depression include optimizing drug dosing and patient selection, mitigating side effects, determining stereoselectivity, and exploring synergies with concurrent treatments. Esketamine, administered as a nasal spray, was approved by the U.S. Food and Drug Administration in 2019 for the treatment of adults with treatment-resistant depression and in 2020 for adults with major depressive disorder and acute suicidal ideation or behavior.⁷⁰ Interestingly, the greatest effect size for symptomatic improvement in the context of major depressive disorder is observed with a high dose (0.5 mg/kg or greater) of the racemic formulation of intravenous ketamine; a recent meta-analysis has reported a standard mean difference in depression scores of –0.73 (95% CI, –0.91 to –0.56).⁵⁴ Finally, a comparison of the effectiveness of ketamine when administered either intravenously as a racemic mixture or intranasally as esketamine, for patients with treatment-resistant depression, demonstrated effect sizes of 1.666 and 1.244 (on differing depression scales and compared to baseline scores), response rates of 36% and 25%, and comparable remission rates (13% and 12%), respectively.⁷¹ Overall, the efficacy of ketamine as a novel antidepressant has been demonstrated across various formulations and doses.

Ongoing mechanistic research supports the concept that ketamine promotes glutamate homeostasis, restores synaptic efficacy, and increases synaptic density.⁷² Synaptic modification is an important characteristic of depression in humans and animal models that is not accounted for in the traditional monoamine model. Ketamine acts as a noncompetitive inhibitor of NMDA receptors by either sterically occluding the open channel pore or stabilizing a closed receptor statevia a hydrophobic pathway.^73,74 Importantly, the relatively low doses of ketamine used to treat depression appear to block only a subset of NMDA receptors, leaving unblocked receptors available to contribute to the drug’s synaptic effects.⁷⁵ The drug is thought to promote synaptic plasticityvia disinhibition by transiently and preferentially inhibiting NMDA receptors on GABAergic interneurons,^76,77 thereby reducing GABA release⁷⁸ and increasing excitability of principal neurons. The change in neuronal excitability in turn increases expression of brain-derived neurotrophic factor (BDNF), activates the mammalian target for rapamycin (mTOR), and drives the growth of dendritic spines.^72,79,80 A reduction in dendritic spine density has been implicated in depression, and restoration of dendritic spines by ketamine appears to be an important factor in its actions on network activity and the recovery of gamma frequency oscillations (electrical correlates of neural circuit function), as well as the drug’s antidepressant efficacy.⁸¹

The effects of ketamine might also depend on inhibitory actions on NMDA receptors in specific brain regions. Ketamine suppresses burst firing activity in the lateral habenula,⁸² a region of the thalamus that contributes to learning from aversive or desired experiences (an antireward center). Also, a dose-dependent increase in gamma- and high-frequency oscillations occurs in the hippocampus after treatment with ketamine both in patients and in animal models, confirming alterations in prefrontal/limbic connectivity.^56,83,84 Interestingly, a detailed study of ketamine’s pharmacokinetics and antidepressant effects showed its behavioral actions far outlast its half-life,⁸⁵ which is about 186 min in humans and 13 min in mice.^86,87 This prolonged drug effect has recently been attributed to the propensity of ketamine to become trappedvia a hydrophobic pathway in NMDA receptors, particularly in the lateral habenula region of the brain.^74,85 Ketamine’s antidepressant effect might also depend on a variety of neuroactive metabolites including norketamine and (2R,6R)-hydroxynorketamine, which might also contribute to the prolongation of its effect.⁸⁸ Finally, it must be highlighted that ketamine acts on multiple central nervous targets other than NMDA receptors, including opioid receptors⁸⁹ (for a review, see Zanos and Gould³⁴).

Nitrous Oxide

To date, at least six clinical trials have explored the efficacy and safety of the inhaled anesthetic gas nitrous oxide (laughing gas) as an antidepressant. The results, albeit early, are impressive for patients with major depressive disorder or treatment-resistant depression. For example, two trials of patients with treatment-resistant depression have shown that a single, 1-h treatment with nitrous oxide (50% mixture in oxygen) confers a significant reduction in depression scores relative to placebo (50% air or nitrogen in oxygen), which lasts at least 24 h.^90,91 Nitrous oxide also reduces suicidal ideation⁹² and appears to improve executive function.⁹³ A meta-analysis of two trials of nitrous oxide reported pooled standard mean differences in depression scores of –2.36 (95% CI, –3.37 to –1.34) at 24 h and –0.60 (95% CI, –1.13 to –0.07) at 1 week after treatment.¹³ Results on the Hamilton Depression Rating Scale included a decrease of 8.6 points at 24 h and 5.5 points at 1 week (from 23.5 at baseline) on the 17-item scale,⁹¹ and a reduction of 6.6 (from 21.3 at baseline) observed at both timepoints on the 17-item scale.⁹⁰ A similar intervention with 50% nitrous oxide administered twice weekly for 4 weeks led to significant improvement among patients taking conventional antidepressants for major depressive disorder. The authors reported an effect size of 0.58 for nitrous oxide compared with 0.39 for placebo, with remission (defined as minimal residual symptoms) in 75% of patients in the nitrous oxide group (vs. 11% of those receiving placebo).⁹⁴

We recently reported on the first double-blind randomized controlled trial of low-dose nitrous oxide (10% in 90% oxygen for 10 min, followed by 25% for 20 min)versus midazolam (2 mg administered intravenously) for bipolar depression. In this study, a comparator drug (midazolam) that had psychomimetic but not antidepressant properties was used in the control arm. The purpose of using midazolam was to reduce patients’ expectation bias, and to mitigate against functional unblinding (i.e., unblinding based on differential subjective experience of the interventions). The use of psychoactive comparators is an ongoing research priority in studies designed to determine optimal concentrations and regimens for treatment of depressive disorders.^95,96 In this trial, a cohort of adults with bipolar disorder type I or II and contemporaneous treatment-refractory depression were treated with nitrous oxide or midazolam (0.5 mg and 1.5 mg intravenously).⁹⁷ In addition, these patients underwent concurrent magnetic resonance imaging studies during drug administration to examine cerebral perfusion as a predictor and indicator of a treatment response. The results showed a significant reduction in depression scores in both treatment groups (despite the short duration and low dose of nitrous oxide relative to what was used in other clinical trials). There was a greater same-day reduction in depression severity among patients treated with nitrous oxide, but no between-group differences in the primary outcome measured at 24 h.⁹⁷ In addition, lower baseline regional cerebral blood flow predicted response to nitrous oxide but not midazolam, and the two treatments had differential effects on real-time changes in cerebral blood flow during and after treatment.⁹⁷

Nitrous oxide is an attractive candidate for treating depression because of its relatively low cost, widespread availability, and—when used under appropriate medical supervision—excellent safety record. A prospective study of more than 35,000 administrations indicated that the rate of serious adverse events possibly related to nitrous oxide was 0.03%.⁹⁸ Adverse events are already minimal in trials of 50% nitrous oxide for depression, but a phase II study of nitrous oxide for treatment-resistant depression showed comparable antidepressant efficacy with a lower (25%) concentration, with only rare side effects (e.g., headaches and nausea in 10% and 5% of participants, respectively) and no serious adverse events.⁹⁹ As with ketamine, future studies of nitrous oxide are needed to address topics such as optimum dosing, patient selection, appropriate monitoring, and duration of drug effect. A future randomized controlled trial will examine the administration of 40% nitrous oxide for treatment-resistant depression, and is designed to enhance blinding by using midazolam as a psychoactive comparator.¹⁰⁰ Also, a review of the major clinical trial registry, clinicaltrials.gov, indicated multiple other ongoing clinical trials of nitrous oxide for the treatment of major depressive disorder,^101,102 late-life depression,¹⁰³ and perinatal depression.¹⁰⁴

Like ketamine, nitrous oxide acts as a noncompetitive inhibitor of the NMDA receptor,¹⁰⁵ although actions on other ion channels have been proposed. Electrophysiologic recordings of NMDA-mediated currents in rat hippocampal neurons first showed that nitrous oxide inhibited neuronal NMDA-gated currents in a dose-dependent fashion, shifting the EC₅₀ for NMDA-induced current nearly threefold to the right.¹⁰⁶ Through its activity at NMDA (as well as AMPA) receptors, brief exposures of nitrous oxide (30% formulation) have also been shown to cause persistent enhancement of synaptic responses in CA1 hippocampal cells from a rat model.¹⁰⁷ Similar to ketamine, antidepressant concentrations of nitrous oxide may block only a subset of NMDA receptors. However, antagonism of NMDA receptors may not be the only—or even the most important—mechanism of action relevant to its proposed antidepressant effect. Additional potential mechanisms include interactions with AMPA, kainite, serotonin, GABA type A (GABA_A), or glycine receptors,¹⁰⁸ with a positive effect on functional connectivity in the brain and electrical event–related potentials.¹⁰⁹ Unlike ketamine, nitrous oxide is rapidly eliminated without any active metabolites.¹⁰⁷ In a mouse model, 50% nitrous oxide upregulates the expression of neuronal nitric oxide synthase, thereby enhancing BDNF levels in the medial prefrontal cortex, which in turn acts downstream to promote synaptic plasticity.¹¹⁰ Because nitric oxide is intrinsically vasodilating, this mechanistic model is consistent with our own observation that nitrous oxide alterations in cerebral blood flow contribute to the antidepressant response.⁹⁷ Nitrous oxide has also been shown to inhibit T-type calcium channels (contributing to its analgesic effect),¹¹¹ and preliminary results of a recent preclinical study indicate that nitrous oxide’s inhibition of calcium-sensitive potassium (SK2) channels in layer 5 neurons of the prefrontal cortex is a primary mechanism for its antidepressant effect (Cichon J, Joseph T, Wasilczuk A, et al. Nitrous oxide activates layer 5 prefrontal cortical neurons via SK2 channel inhibition for antidepressant effect. Preprint. Posted online January 25, 2024. Research Square rs-3706278. doi:10.21203/rs.3.rs-3706278/v1). However, to date, no studies have addressed the role that the opioid signaling system might play in the antidepressant effect of nitrous oxide (as has been done for ketamine).⁸⁹ Thus, the current state of evidence relating to the antidepressant mechanism of nitrous oxide remains limited.

GABAergic Neurotransmission

In addition to alterations in excitatory neurotransmission, dysregulation of GABAergic inhibition has been strongly implicated in mood disorders in both clinical and preclinical studies.^112,113 GABA, the major inhibitory neurotransmitter in the mammalian brain, acts primarily on GABA_A receptors. These pentameric chloride ion channel complexes are formed from various subunits (α1 to 6, β1 to 3, γ1 to 3, ρ1 to 3, δ, ε, π, and θ) derived from 19 different genes.¹¹⁴ The GABA_A receptors generate two distinct forms of synaptic and tonic inhibition in the central nervous system.¹¹⁵ Synaptic GABA_A receptors are activated by high concentrations of GABA released from presynaptic terminals and generate rapid, transient postsynaptic currents.¹¹⁶ Extrasynaptic GABA_A receptors are activated by low, ambient levels of GABA spilling over from synapses or released from glia or neurons; these high-affinity receptors generate a persistent low-amplitude tonic inhibitory conductance.¹¹⁷

The hypothesis that dysregulation of the GABA signaling system contributes to depression is supported by multiple lines of clinical and preclinical evidence. For example, low levels of GABA are present in both the cerebral spinal fluid¹¹⁸ and brain tissue of patients with depression,¹¹⁹ and the expression of GABA-synthesizing enzymes is similarly reduced.¹²⁰ Also, GABAergic interneurons¹²¹ and the expression of GABA_A receptors are reduced in the context of major depressive disorder.¹²² Evidence supporting the GABAergic hypothesis of depression includes positive results in recent clinical trials.^123,124 The U.S. Food and Drug Administration recently approved neurosteroids, including brexanolone and zuranolone, that preferentially increase the function of extrasynaptic δ subunit-containing GABA_A receptors for the treatment of postpartum depression (although these neurosteroids act on multiple subtypes of synaptic and extrasynaptic GABA_A receptors). Such neurosteroids may be largely unfamiliar to anesthesiologists; however, it is interesting to note that there have been several attempts to develop them as novel anesthetics. For example, the neurosteroid alfaxalone was used in clinical practice for several years, but ultimately withdrawn in 1984 due to hypersensitivity reactions attributed to its excipient (Cremophor EL, BASF SE, Germany).¹²⁵ Recent work has characterized new, aqueous formulations of alfaxalone, reporting fast-onset and -offset anesthetic efficacy comparable in some respects to propofol.¹²⁶

Alfaxalone’s effect on mood disorders has not been thoroughly investigated, but the success of brexanolone and zuranolone has focused attention on modifying GABAergic inhibition to treat mood disorders. However, the contribution of GABA inhibitory neurotransmission to depression and other mood disorders is complex and may depend on multiple factors including age, sex, genetics, and environmental factors, as has been previously reviewed by various authors.^36,113,127 As an example, paradoxically, both positive allosteric modulators and negative allosteric modulators that selectively modulate α5 subunit–containing GABA_A (α5GABA_A) receptors exert antidepressant properties.¹¹² Moreover, classic benzodiazepines (specifically nonselective positive allosteric modulators, including diazepam) do not exert antidepressant properties.^112,128 Nevertheless, the GABAergic signaling system has emerged as a putative target in anesthetic neuropsychiatry, and a variety of drugs that target GABA_A receptors are being studied in the treatment of depression.¹⁷

Propofol

Propofol, the most widely used intravenous anesthetic drug, is a positive allosteric modulator of GABA_A receptors.¹²⁹ This drug has recently received attention as a potential antidepressant. In 1991, a report on 80 patients described advantages of propofol over methohexitone as the anesthetic of choice for electroconvulsive therapy, reporting a more positive mood for 4 h after treatment among those who received propofol.¹³⁰ In 2018, an open-label pilot trial of 10 patients treated for treatment-resistant depression with 10 consecutive infusions of propofol administered three times weekly and dosed to suppress electroencephalographic activity for 15 min found that depression scores improved with an effect size of 1.32 (95% CI, 0.21 to 2.42).¹⁴ These antidepressant effects lasted at least 3 months for five of the six patients who met the criteria for a positive response.¹⁴ An additional trial was recently undertaken, and a preliminary report describes 24 patients with treatment-resistant depression randomized to receive six sequential treatments with low-dose (average 1.98 mg/kg per treatment session) or high-dose (average 9.30 mg/kg) propofol, reporting a dose-dependent antidepressant effect (Tadler SC, Jones KG, Lybbert C, et al. Propofol for treatment resistant depression: A randomized controlled trial. Preprint. Posted online September 15, 2023. medRxiv 23294678. doi:10.1101/2023.09.12.23294678). Patients in the high-dose propofol group experienced a mean reduction of 33% or –9.3 points (95% CI, –12.9 to –5.6) on the 24-item Hamilton Depression Rating Scale (Tadler SC, Jones KG, Lybbert C, et al. Propofol for treatment resistant depression: A randomized controlled trial. Preprint. Posted online September 15, 2023. medRxiv 23294678. doi:10.1101/2023.09.12.23294678). According to the clinical trial registry clinicaltrials.gov, at least one further investigation of the antidepressant properties of propofol is currently underway.¹³¹

One potential mechanism underlying the antidepressant actions of propofol and other anesthetic drugs that target GABA_A receptors is a persistent or sustained increase in cell-surface expression of α5GABA_A receptors, which occurs after drug treatment.^132,133 The α5GABA_A receptors are of particular interest because they are highly expressed in the hippocampus and prefrontal cortex (and the olfactory bulb),¹³⁴ brain regions that likely contribute to emotion, cognition, mood disorders, and the antidepressant effects of ketamine.¹³⁵ Consistent with this hypothesis, positive allosteric modulators selective for α5GABA_A receptors have anxiolytic properties and procognitive effects on spatial working memory deficits associated with models of chronic stress and aging,^136,137 effects that are not observed with nonselective positive allosteric modulators such as diazepam. Also, surface levels of α5GABA_A receptors are reduced in the prefrontal cortex of mice subjected to chronic stress.¹³⁸

The anesthetic-induced increase in cell-surface expression of α5GABA_A receptors may compensate for reduced levels of both GABA and neuronal surface levels of GABA_A receptors. This sustained increase in α5GABA_A receptor function involves an anesthetic triggered astrocyte-to-neuron crosstalk, which leads to the release of paracrine factors that increase expression of α5GABA_A receptors in neurons (fig. 3).¹³⁹ The importance of astrocytes and other glia in terms of astrocyte-to-neuron crosstalk, and the role of GABAergic neurotransmission in depression, is being increasing recognized. Importantly, α5GABA_A receptor activity is also involved in learning and memory processes,^140,141 and an unintended consequence of this anesthetic-induced increase in cell-surface expression (which benefits mood) may be impaired memory acquisition and short-term recall.

Other preclinical studies have suggested that any antidepressant effect of propofol may result not from actions on the GABA_A receptors themselves, but rather indirectly from the binding of propofol to and inhibition of dopamine transporters, resulting in the accumulation of dopamine in the nucleus accumbens.¹⁴² Enhanced levels of dopamine in this reward center reversed anhedonia in a mouse model.¹⁴² In addition, a case series has suggested that the enhancement of slow-wave sleep may contribute to the antidepressant effects of propofol.¹⁴³ Interestingly, propofol also reduced cerebral blood flow in the bilateral parietal association cortex and left lateral prefrontal region of patients with severe depression.¹⁴⁴ One study proposed alterations in emotional episodic memory reconsolidation as an alternative antidepressant mechanism of propofol.¹⁴⁵ The reactivation of memory followed by deep sedation with propofol impaired reconsolidation of those elements of the memory with negative emotional valence.¹⁴⁵ Importantly, propofol’s actions on glycine receptors¹⁴⁶ may also contribute, although this mechanism has not been thoroughly explored. It must also be noted that direct comparisons of studies describing propofol’s antidepressant effect are challenging as existing trials differ considerably in terms of their dosing regimens and treatment endpoints, as some titrated propofol to slow-wave electroencephalogram (EEG) signatures¹⁴³ whereas others administered a higher dose to induce EEG burst suppression.¹⁴

Isoflurane

The practice of targeting burst suppression on the EEG in studies of anesthetics’ antidepressant effect was inspired by the observation that postictal cortical burst suppression often occurs after electroconvulsive therapy–induced seizures and frequently correlates with superior therapeutic outcomes.^147,148 This notion of therapeutic burst suppression was originally manifest in studies of isoflurane “narcotherapy” (where isoflurane was administered at doses that induced burst suppression in electroencephalographic recordings).¹⁵ In 1995, isoflurane narcotherapy was compared with electroconvulsive therapy in small cohorts of patients (10 patients in each treatment arm) with severe treatment-resistant depression.¹⁵ The results indicated that isoflurane rapidly (measured immediately after a first treatment session) produced antidepressant effects that were comparable to electroconvulsive therapy.¹⁵ In addition, patients receiving electroconvulsive therapy were more likely to experience relapse, and those treated with isoflurane were more likely to have further improvement at final follow-up.¹⁵ Unfortunately, these findings were not replicated in subsequent studies of isoflurane¹⁴⁹ or other volatile anesthetic gases such as sevoflurane when assessed in a double-blind trial wherein patients also received propofol.¹⁵⁰ In 2013, an open-label, two-arm trial compared isoflurane anesthesia to electroconvulsive therapy for treatment of depression: the reduction in depression scores was comparable for the two treatments, with fewer adverse neurocognitive effects attributed to isoflurane.¹⁵¹

A limited number of preclinical studies have probed the mechanisms underlying the purported antidepressant properties of isoflurane. The potential role of cortical burst suppression as a mediator of isoflurane’s antidepressant effect has been supported in EEG studies in rodent models.¹⁵² Another study that used a mouse model of chronic unpredictable mild stress associated the antidepressant effect of isoflurane (measured through behavioral tests) with normalization of BDNF protein expression, activation of tropomyosin receptor kinase B (TrkB), and the formation of new dendritic spines in various brain regions, suggesting that these cellular regulators are at least necessary components of the antidepressant effect of isoflurane.¹⁵³ There is less evidence surrounding the use of other volatile anesthetics as antidepressants but, interestingly, recent preclinical work identifies an antidepressant effect of sevoflurane that is attributed to increased expression levels of TrkB in the hippocampus and prefrontal cortex.¹⁵⁴ However, the presumptive antidepressant mechanisms of volatile anesthetics remain poorly understood.

Depression in Surgical Patients

An important emerging direction for anesthesiologists and psychiatrists to pursue together is understanding the role of depression in perioperative outcomes. Nearly one in five preoperative patients meets the criteria for major depressive disorder,¹⁵⁵ and depression is a major risk factor for postoperative pain and delirium.¹⁵⁶ Mood disorders are closely related to cognition¹⁵⁷ and are therefore highly relevant in the prevention of perioperative neurocognitive disorders.

Anesthesia and surgery likely have underrecognized effects on mental health in the postoperative period. In fact, the administration of ketamine in the perioperative period (a common practice in many centers) may reduce postoperative depression scores.¹⁵⁸ Whether surgical patients with comorbid depression will benefit from ketamine that is administered during surgery has recently been called into question: Liiet al. observed that depression scores did not change when the administration of ketamine was masked by cotreatment with general anesthetic drugs.¹⁵⁹ This result suggested that the psychologic experience or “trip” caused by ketamine, and/or the expectancy bias of participants, may be important factors in ketamine’s antidepressant effect.¹⁶⁰ Also, some anesthetic drugs may have opposing effects on ketamine’s antidepressant properties when administered in combination. For example, the effects of ketamine on cortical firing, which are thought to promote neuroplasticity, are blocked when midazolam is coadministered in mice.¹⁶¹ Other clinical studies suggest that the antidepressant effect of ketamine is attenuated by concomitant treatment with benzodiazepines¹⁶² or opioid receptor antagonism.⁸⁹ Given the potential confounders of studying the effects of intraoperative administration of ketamine, some investigators have begun investigating postoperative ketamine infusions instead.¹⁶³ It will be important to understand the effects of routine anesthetic care on patients with psychiatric illnesses and, similarly, the interactions of the anesthetic drugs with other substances that may have novel psychotropic effects.

Advancing Discovery through Interprofessional Collaboration

To date, anesthesiologists have generally served in supportive roles in the development of anesthetic drugs as antidepressants—mainly by facilitating clinical trials, although there are some notable thought leaders and exceptions.^91,99,131 However, the study and use of anesthetic drugs as antidepressants will be enhanced by creating more intentional partnerships. Several strategies are proposed to develop a subspecialty focused on anesthetic neuropsychiatry and a cadre of “bilingual” clinicians and scientists who are equipped to work at the interface between these two specialties. These strategies include joint research training with an emphasis on postgraduate degree programs, shared design of clinical trials, collaborative grant writing, interdisciplinary departmental rounds, cross-disciplinary opportunities to present at local and international conferences, and allied collaborative funding opportunities. Our experience at the University of Toronto has been that interdisciplinary partnerships and joint interdepartmental funding opportunities, including early-career collaborative grants,¹⁶⁴ have fostered strong research consortiums between anesthesiologists and psychiatrists. Other educational institutes, which are among the early adopters of these close interdisciplinary partnerships between psychiatry and anesthesiology, include the University of Michigan (Ann Arbor, Michigan), Washington University in St. Louis (St. Louis, Missouri), and the University of Utah (Salt Lake City, Utah).

Technological advances are expected to further advance collaborations in this field. Psychiatrists have developed considerable expertise in interventions and imaging such as repetitive transcranial magnetic stimulation, transcutaneous electrical nerve stimulation, focused ultrasonography, deep brain stimulation, and functional magnetic resonance imaging.^165,166 In parallel, anesthesiologists are developing skills in real-time electroencephalography to measure anesthetic depth and appreciate mechanisms of drug action on the brain.^167–170 Combining efforts to understand, modify, and restore neural networks will allow our respective fields to build stronger links and further advance our endeavors. Additional drugs of potential interest include the gabapentinoids gabapentin and pregabalin, which have been evaluated as off-label treatments for anxiety disorders.¹⁷¹ As gabapentin is known to increase the cell surface expression of the δ subunit–containing GABA_A receptors,¹⁷² it may be effective in treating postpartum depression.¹⁷³ As noted above in “Depression in Surgical Patients,” additional potential areas for future collaborative study, beyond the repurposing of general anesthetic drugs as psychotropics, include the use of psychoactive agents in the treatment of pain and prevention of delirium in the postoperative period.

In conclusion, the discovery of the rapid antidepressant properties of ketamine and other general anesthetic drugs underscores the need for collaboration to advance the pace of neuroscientific discovery. Furthermore, through this multidisciplinary work, we can preserve cognitive function and optimize mental health for patients undergoing anesthesia and surgery.

Acknowledgments

The initial impetus for this Special Article was an invitation from Daniel J. Cole, M.D., F.A.S.A. (Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, California), to publish a short report in theASA Monitor (appearing in the January 2024 issue).²⁶ The authors thank Dian-Shi Wang, M.D., Ph.D. (Department of Physiology, University of Toronto, Toronto, Canada), and Lilia Kaustov, Ph.D (Perioperative Brain Health Centre, Sunnybrook Sciences Centre, Toronto, Canada), for their comments and suggestions on an initial draft of the manuscript.

Research Support

Dr. Brenna receives salary support from the Ontario Ministry of Health and Long-Term Care (Toronto, Canada) Clinician Investigator Program Salary Support Grant. No other authors receive financial support relevant to the current article.

Competing Interests

Dr. Orser serves on the Board of Trustees of the International Anesthesia Research Society (San Francisco, California) and is codirector of the Perioperative Brain Health Center (Toronto, Canada;https://www.perioperativebrainhealth.com). She is a named inventor on a Canadian patent (2,852,978) and two U.S. patents (9,517,265 and 10,981,954). The patents, which are held by the University of Toronto (Toronto, Canada), are for new methods to prevent and treat delirium and persistent neurocognitive deficits after anesthesia and surgery, as well as to treat mood disorders. Dr. Orser collaborates on clinical studies that are supported by in-kind software donations from Cogstate Ltd. (New Haven, Connecticut). Dr. Zarate is listed as a coinventor on a patent for the use of ketamine in major depression and suicidal ideation; as a coinventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a coinventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and posttraumatic stress disorder. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. The other authors declare no competing interests.

References