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General Anesthetics to Treat Major Depressive

Disorder: Clinical Relevance and Underlying
Laszlo Vutskits, MD, PhD

Major depressive disorder is a frequent and devastating psychological condition with tremen-
dous public health impact. The underlying pathophysiological mechanisms involve abnormal
neurotransmission and a relatedly impaired synaptic plasticity. Since general anesthetics are
potent modulators of neuronal activity and, thereby, can exert long-term context-dependent
impact on neural networks, an intriguing hypothesis is that these drugs could enhance impaired
neural plasticity associated with certain psychiatric diseases. Clinical observations over the
past few decades appear to confirm this possibility. Indeed, equipotency of general anesthesia
alone in comparison with electroconvulsive therapy under general anesthesia has been demon-
strated in several clinical trials. Importantly, in the past 15 years, intravenous administration of
subanesthetic doses of ketamine have also been demonstrated to have rapid antidepressant
effects. The molecular, cellular, and network mechanisms underlying these therapeutic effects
have been partially identified. Although several important questions remain to be addressed,
the ensemble of these experimental and clinical observations opens new therapeutic possibili-
ties in the treatment of depressive disorders. Importantly, they also suggest a new therapeutic
role for anesthetics that goes beyond their principal use in the perioperative period to facilitate
surgery.  (Anesth Analg 2017;XXX:00–00)

ental disorders are seriously debilitating condi- Moreover, investigations over the past few decades, sug-
tions characterized by a combination of abnormal gesting both neuroprotective and neurotoxic effects of GAs,8
thoughts, perceptions, emotions, behavior, and converge toward the assumption that these drugs may serve
relationships with others. These pathologies are among as context-dependent modulators of neuronal plasticity.9
the leading causes of disability-adjusted life years world- This, in turn, raises the intriguing hypothesis that GAs may
wide, resulting in enormous personal suffering and eco- have a therapeutic impact on abnormal neuronal plasticity
nomic loss.1,2 Since the burden of mental illness continues patterns in patients with mental disorders. The purpose of
to grow,3 understanding the pathological mechanisms the present review is to provide insights into this possibility
underlying these diseases and developing efficient thera- by presenting the accumulating experimental and clinical
peutic approaches are therefore of high priority public evidence supporting the therapeutic value of GAs in major
health importance. While our knowledge and achievements depressive disorders (MDDs).
to reach these goals remain rudimentary, an emerging gen-
eral concept is that mental disorders are characterized by MAJOR DEPRESSIVE DISORDER: PREVALENCE
abnormal neuronal activity patterns in several brain regions AND TREATMENT OPTIONS
leading, thereby, to abnormal plasticity of neuronal net- MDD is a seriously debilitating condition with a lifetime prev-
works.4–6 In this context, both fundamental and translational alence of approximately 17%.10 It is also the leading cause of
researches aimed to decipher mechanisms of actions of gen- expenses linked to the burden of mental diseases.2 Diagnostic
eral anesthetics (GAs) are of potential interest. These drugs criteria for MDD are defined by a series of well-defined
comprise a family of largely heterogeneous chemical sub- symptoms, many of which overlap with other clinical entities,
stances, which, via powerful modulation of neuronal activ- such as anxiety disorders. The heterogeneity of symptoms
ity, can rapidly induce transient loss of consciousness and characterizing MDD most probably reflects a diverse array
amnesia upon administration. Despite the seemingly on/off of mechanisms involved in this pathology and makes the
effects of GAs on consciousness, it is now well established design of a unified approach to treat this disorder particularly
that even single exposure to these drugs can induce long- challenging.4,5 This difficulty is also reflected with the seri-
term effects on central nervous system (CNS) physiology.7 ous limitations of currently available pharmacological treat-
ments. Indeed, monoamine reuptake inhibitors, monoamine
From the Department of Anesthesiology, Pharmacology and Intensive Care,
University Hospitals of Geneva, Geneva, Switzerland. oxidase inhibitors, or other atypical agents such as bupropion
Accepted for publication September 19, 2017. or mirtazapine may require several weeks of administration
Funding: None. before providing therapeutic effects, and suicidal behavioral
The author declares no conflicts of interest. patterns can even increase during this period.11 Importantly,
Reprints will not be available from the author. these drugs operate with a relatively low rate of efficacy, and
Address correspondence to Laszlo Vutskits, MD, PhD, Department of An- this is often accompanied by a high incidence of relapse.12,13
esthesiology, Pharmacology and Intensive Care, University Hospitals of Development of new drugs with faster action and more effica-
Geneva, 4, rue Gabrielle-Perret-Gentil, 1211 Geneva 4, Switzerland. Address
e-mail to cies is therefore strongly warranted.
Copyright © 2017 International Anesthesia Research Society Before the advent of the psychopharmacological revolu-
DOI: 10.1213/ANE.0000000000002594 tion in the 1950s, electroconvulsive therapy (ECT) was the

XXX 2017 • Volume XXX • Number XXX

Copyright © 2017 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.

mainstream therapeutic option to treat psychiatric disor- anesthesia alone.23 In contrast to these observations, a slight
ders.14 In the 16th century, orally taken camphor was applied superiority of ECT compared to simulated ECT under thio-
by the Swiss physician Paracelsus to produce seizures in an pentone was suggested by another study where 12 patients
attempt to treat psychiatric conditions. A similar method received ECT under anesthesia and only 4 subjects com-
was reintroduced in the early 1930s by Von Meduna, who prised the simulated group.24
used intramuscular injection of camphor, later replaced by Following these initial observational studies, random-
intravenous infusion of pentylenetetrazol, to treat catatonic ized trials were set to compare anesthesia alone with ECT
stupor in schizophrenic patients by convulsions.15 The use under anesthesia in terms of therapeutic efficacy. In a cohort
of electricity for seizure induction was first reported by of 32 patients suffering depressive psychosis, 6 brief unilat-
the Italian psychiatrist and neurophysiologist Cerletti and eral ECT sessions under methohexitone anesthesia over a
Bini16 who reported successful treatment of a young mute period of 2 weeks showed comparable improvement on the
catatonic patient in 1938. This method has rapidly gained Hamilton Rating Scale for Depression25 with a simulated
widespread use in the psychiatric community and, since procedure where study subjects received only anesthesia.26
these early days, has undergone continuous refinements to In line with these observations, in a 6-month-long follow-
improve therapeutic potential.14 There is now convincing up of 70 patients with severe depression, the Northwick
clinical evidence suggesting that ECT is indeed a valid ther- Park Electroconvulsive Therapy trial demonstrated equiva-
apeutic tool for treatment of depression, including severe lent therapeutic value of 8 successive ECT sessions over a
and resistant forms.17 period of 4 weeks under thiopentone anesthesia when com-
Despite decades of clinical use and the identification of pared with a similar simulated ECT protocol where only
a large palette of effects of ECT on the CNS, it still remains thiopentone was administered.27 Thus, these trials brought
unclear what are the mechanism(s) of action(s) through convincing arguments in favor of the beneficial impact
which this treatment paradigm exerts its therapeutic poten- of general anesthesia in depressive states and raised the
tial.18 An emerging view is that ECT increases brain plas- intriguing possibility that anesthetics-induced decrease in
ticity.19 Indeed, ECT is a potent facilitator of serotonin-, neural activity might be an important component account-
norepinephrine- and dopamine-mediated neurotransmis- ing for these effects. To further test this hypothesis, in 2
sion, and it also increases the expression of several neu- subsequent trials, Langer et al28,29 demonstrated that 6 ses-
rotrophic factors, including brain-derived neurotrophic sions of isoflurane anesthesia-induced brief burst suppres-
factor (BDNF).20,21 Importantly, ECT triggers structural sion over 2 weeks had comparable effects with the delivery
changes in the brain, including angiogenesis, gliogenesis, of 6 bitemporal ECT sessions under general anesthesia in
and neurogenesis, along with increased dendritic arboriza- terms of both objective and subjective mood scales for up
tion and synaptogenesis.19 As depression is associated with to 5 weeks. Importantly, the capacity for sustained concen-
decreased neuroplasticity,4 it is thus tempting to speculate tration was significantly better in patients having received
that the ensemble of these aforementioned highly complex isoflurane compared to the ECT group.29 These antidepres-
effects, aimed to promote neuroplasticity, might be required sant and neurocognitive effects of isoflurane anesthesia
for the therapeutic action of ECT. were subsequently reconfirmed in a group of 20 patients
with medication-refractory depression.30 In this study, ECT
A THERAPEUTIC ROLE FOR ANESTHESIA IN had modestly better effect at follow-up in severity-matched
PATIENTS WITH DEPRESSIVE DISORDERS patients, while the isoflurane group showed better neuro-
To avoid significant discomfort and related complications, cognitive score improvement.30 More recently, a prospective
application of ECT is intimately linked to the delivery of pilot study demonstrated antidepressant properties of 50%
general anesthesia in most cases. Since general anesthesia, nitrous oxide inhalation in patients with treatment-resistant
in itself, is a robust modulator of brain states, determining MDD.31
whether the therapeutic value of ECT is indeed linked to the
passage of electrode-delivered electricity or to the impact of RAPID ANTIDEPRESSANT EFFECTS OF KETAMINE
GAs on neural networks is an important question. To elu- Over the past 15 years, a growing number of randomized
cidate this issue, clinical trials should compare active ECT clinical trials demonstrate rapid and potent antidepressant
with a stimulated procedure in which shocks are not deliv- actions of the competitive N-methyl-d-aspartate (NMDA)
ered under general anesthesia. Early studies addressing this receptor antagonist ketamine in patients with mood dis-
issue resulted in conflicting conclusions and were open to orders.32 In contrast with the aforementioned clinical
important methodological criticism due to very low sample observations, where GAs were administered to patients
size and the lack of adequate comparison groups. Initial with depressive symptoms to investigate the putative link
observations suggest comparable improvement in social between the anesthesia component of ECT and the thera-
performance of 30 patients presenting chronic catatonic peutic effect, the rational for using ketamine stems from the
schizophrenia after treatment with either ECT, nonconvul- so-called initiation and adaption postulate. This hypothesis
sive stimulation under thiopental anesthesia, or thiopental states that the delayed effects of currently used classic phar-
anesthesia alone.22 Accordingly, no statistically significant macological antidepressants are primarily due to the delayed
difference was found in depression outcome in a group of adaptive effects of these drugs on glutamatergic neurotrans-
patients with mixed diagnoses of depressive states after mission systems, which stand in the center of the therapeu-
straight ECT without anesthesia, ECT plus succinylcholine, tic response.33 In line with this postulate, preclinical studies
ECT plus thiopentone, thiopentone alone, and nitrous oxide demonstrate the prompt efficacy of NMDA antagonists in

Copyright © 2017 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
Anesthesia and Depression

various animal models of depression,34,35 and, conversely, therapeutic effects will provide us with valuable informa-
antidepressant administration has been shown to affect tion to design better-targeted clinical studies in the future.
NMDA receptor function and receptor-binding profiles.36,37 Second, identification of anesthetics-triggered molecular
Further indications on the role of glutamatergic systems cascades involved in the antidepressant effects could give
in the pathophysiology of depressive disorders came from rise to designing new drugs specifically targeting these
human studies where proton magnetic resonance imag- pathways. Third, research in this field will contribute to
ing (MRI) revealed increased glutamate levels in the cere- widen our comprehension of the mechanisms through
bral cortex of medication-free subjects with unipolar major which anesthetics modulate neural plasticity. This, in turn,
depression when compared with a matched population of might provide us with useful information for future studies
healthy controls.38 Last but not least, the glutamate-release aimed to focus on the protective effects of these drugs after
inhibitors lamotrigine and riluzole were found to exert anti- brain injury. Last but not least, these studies will continue
depressant properties in clinical trials.39,40 Altogether, these to improve our understanding of the highly complex neu-
laboratory and clinical observations strongly suggest that robiology of mood disorders. The neurobiology of MDD,
drugs acting directly to decrease the efficacy of glutama- although far from being completely elucidated, appears
tergic signaling are expected to demonstrate rapid onset of to comprise a highly complex series of subtle cellular and
action to relieve symptoms in depressed patients. molecular alterations that will ultimately lead to dysfunc-
The first clinical study addressing the rapid antide- tion of complex neural networks (reviewed in Refs. 4 and 5).
pressant actions of ketamine used a randomized, placebo- Hence, one straightforward approach to study the mecha-
controlled crossover design in a small group of 7 patients nisms through which anesthetics might improve depressive
with major depression.41 In this study, intravenous admin- symptoms is to ask how exposure to these drugs impacts on
istration of 0.5 mg/kg ketamine over a period of 40 min- already identified pathways involved in the neurobiology
utes resulted in a significant improvement in depressive of depression. This can be achieved by focusing on the net-
symptoms as early as 4 hours after drug injections, and work, the individual cell, or molecular cascades.
these therapeutic effects were further accentuated over the In terms of neuronal network functions, an emerging
next 72 hours. Very similar observations were subsequently pathophysiological concept is that MDD is characterized
obtained in a cohort of 18 patients with major depression, by brain-region-specific alterations in synaptogenesis and
where, compared to the placebo group, patients receiving neural plasticity, which, in turn, give rise to functional dis-
ketamine showed significant improvement in depression as connections of major cortical and limbic neuronal circuitries
early as 2 hours after drug administration, and, most impor- involved in mood and motivation.50 This altered connectiv-
tantly, this effect remained significant for at least 1 week.42 ity does not obligatorily mean a reduction in the number
These pioneering studies were followed by a large number of synaptic contacts or circuitry hypofunction but can also
of clinical trials, and several meta-analyses are now avail- translate into increased activity in certain brain areas. For
able supporting unanimously the therapeutic potential of example, functional MRI and positron emission tomogra-
ketamine in MDD in both drug-free patients and in those phy in human subjects revealed increased neuronal network
who were under classic antidepressant medications.43–46 activity to negative stimuli in the anterior cingulate cortex,
Among the various symptom clusters characterizing MDD, amygdala, and paralimbic regions, while reduced responses
ketamine appears to rapidly and robustly relieve anhedonia were detected to positive stimuli and reward-related infor-
(ie, the reduced capacity to experience pleasure), suggest- mation in the prefrontal cortex (PFC) and the striatum.51,52
ing its action on the reward system in the brain.46 Relatedly, These findings indicate that dysfunction of neuronal sys-
ketamine administration has been shown to rapidly reduce tems involved in the processing of the rewarding potential
suicidal ideation, a feature that makes this drug uniquely of emotive stimuli might be central to symptoms of MDD
suited to treat suicidal ideation in hospitalized patients.47,48 such as anhedonia or anxiety.53 Importantly, they also raise
Importantly, the safety and tolerability profile of ketamine the intriguing possibility that pharmacological treatment
administration to patients suffering MDD appears to be strategies that lead to improvement of clinical symptoms
satisfactory. Indeed, none of these aforementioned clinical are expected to normalize pathological network activity.
trials reported major or potentially life-threatening com- Administration of ketamine to healthy volunteers
plications. Transient hypertension and tachycardia were induces focal increases in metabolic activity of the prefron-
reported, but rarely required pharmacological intervention. tal and anterior cingulate cortices along with a decrease
The most common adverse events, occurring mostly during in cerebellar metabolism.54,55 In line with these findings,
and in the first 4 hours after drug injection, were drowsi- further preclinical and clinical data show that ketamine
ness, dizziness, poor coordination, blurred vision, and feel- injection rapidly leads to glutamate release in these brain
ing strange or unreal.49 These events led to discontinuation regions.56,57 Proton MRI in humans also demonstrates an
of ketamine injection in <2% of patients.49 association between ketamine administration and acute
increases in cortical glutamate levels.58,59 These metabolic
MECHANISMS OF ACTIONS UNDERLYING changes are accompanied by the onset of an acute and
THERAPEUTIC EFFECTS OF ANESTHETICS transient psychotic state reminiscent of clinical symptoms
Understanding the mechanisms through which anesthetics observed in patients with schizophrenia. Interestingly,
can exert therapeutic effects in MDD is a major challenge ketamine administration to patients suffering schizophre-
for several reasons. First, elucidating pharmacokinetic and nia results in greater psychological changes compared to
pharmacodynamic drug properties that are required for healthy volunteers, and this is correlated with a higher

XXX 2017 • Volume XXX • Number XXX

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amount of glutamate release and an increased hypermeta- perception was associated with improvement in depres-
bolic response in the frontal and cingulate cortices in these sion severity after ketamine administration. Comparison of
individuals.56 These observations suggest that the gluta- global brain connectivity, using resting-state functional con-
matergic system may be more sensitive to NMDA receptor nectivity MRI, between healthy volunteers and medication-
antagonisms in schizophrenic patients and, therefore, bring free patients with MDD shows reduced connectivity within
arguments in favor of the “glutamate hypothesis” of this the PFC of the latter group, and this is largely normalized 24
mental illness.60,61 hours after ketamine administration.67 In this study, patients
Recent investigations shed light on how ketamine with clinical improvements after drug injection evidenced
may affect specific brain regions in MDD (Figure  1). more robust increases in functional connectivity of the pre-
(18F)-fluorodeoxyglucose positron emission tomography frontal and insular cortices as well as in the caudate nucleus
revealed no significant change in whole brain metabolism when compared with nonresponders to ketamine, indicat-
2 hours after ketamine injection in a cohort of 20 unmedi- ing that the enhancement of connectivity in these brain
cated treatment-resistant patients with MDD.62 However, circuitries are involved in the antidepressant mechanisms
a priori region of interest analysis of candidate structures of action of ketamine. While these aforementioned stud-
showed decreased metabolism in the right habenula and ies provide us with highly valuable information on neural
the extended medial and orbital prefrontal networks, systems involved in the antidepressant effects of ketamine,
while increased activity was detected in sensory associa- several important questions remain open. Among them, a
tion cortices when compared to baseline activity levels in particularly relevant issue is whether and to what extent
these same subjects.62 Subsequent works from the same the ketamine-induced changes in network activities persist
investigators demonstrated that ketamine but not placebo over time. Indeed, while the beneficial effect of ketamine on
administration increased metabolism in the right striatum depressive symptoms is detectable for an extended period,
and the subgenual anterior cingulate cortex and revealed there are currently no studies available addressing the long-
a positive correlation between the extent of increase in term effect of a single-dose ketamine injection on brain cir-
metabolism in these regions of interest and the improve- cuitry in MDD. In light of the potentially important role of
ment in the Montgomery–Asberg Depression Rating Scale.63 the brain reward system in the pathophysiology of MDD,
Specifically, the ketamine infusion-induced reduction in another important series of as yet unexplored questions
anhedonia levels positively correlated with increased glu- concerns the impact of ketamine on reward and emotional
cose metabolism in the dorsal anterior cingulate cortex and processing in these patients.
putamen as well as with decreased metabolism in the orbito- The molecular and cellular mechanisms underlying the
frontal cortex.64,65 Using a combination of emotional activa- neural substrate-specific changes of brain circuitry in MDD
tion tasks and functional MRI, a recent study demonstrated after ketamine administration is an intense field of research
reduced neural responses to positive faces in the right cau- (Figure 2). It is becoming increasingly clear that depression
date nucleus of treatment-resistant MDD patients, and these is associated with loss of neurotrophic support, which, in
responses were selectively increased when evaluated 1 day turn, may lead to reduced synaptic connectivity in neuronal
after ketamine administration.66 Moreover, connectivity networks.4,68 In postmortem tissue from patients with MDD,
analysis in this same study revealed that greater connec- microarray gene profiling and electron microscopic stereol-
tivity of the right caudate nucleus during positive emotion ogy revealed lower expression of synaptic function-related

Figure 1. Schematic drawing of brain

regions with reported changes in meta-
bolic activity after ketamine adminis-
tration. Positron emission tomography
to measure regional cerebral glucose
metabolism in patients with major
depressive disorder revealed no
change in whole brain metabolism after
ketamine administration.62 However,
ketamine induces brain region-specific
changes in the metabolic activity of sev-
eral components of the “depression cir-
cuitry.”62–66 Importantly, this drug also
restores abnormal neuronal connectiv-
ity patterns observed in the brains of
depressed patients.66 DS indicates dor-
sal striatum; OFC, orbitofrontal cortex;
sgACC, subgenual anterior cingulate
cortex; vmPFC, ventromedial prefrontal
cortex; VS, ventral striatum.

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Anesthesia and Depression

Figure 2. Proposed molecular mechanisms underlying antidepressant effects of ketamine. Via blockade of NMDA receptors on inhibitory
GABAergic neurons, ketamine may enhance glutamate release from the presynaptic terminals of principal neurons. This will result in an
increased activation of AMPA receptors on postsynaptic neurons which in turn will lead to increased activity and activation of protein tran-
scription cascades in these cells. Ketamine may also directly inhibit NMDA receptors on postsynaptic neurons that leads to the activation
of eEF2 and to the synthesis of proteins involved in synaptic plasticity. Ketamine also impacts on postsynaptic AMPA receptors via its active
metabolite HNK that acts as a positive allosteric modulator of this receptor. The ensemble of these molecular pathways will lead to the acti-
vation of the mTOR complex and subsequently to an increased synthesis of BDNF and other proteins aimed to promote synaptic plasticity.
Akt indicates protein kinase B; AMPA, α-amino-3-hydroxy-5 methyl-4-isoxazoleproprionic acid; BDNF, brain-derived neurotrophic factor; eEF2,
eukaryotic elongation factor 2; eEF2K, eukaryotic elongation factor 2 kinase; ERK, extracellular signal regulated kinase; GABA, γ-aminobutyric
acid; GSK, glycogen synthase kinase; HNK, 2S, 6S hydroxynorketamine; mTOR, mammalian target of rapamycin; NMDA, N-methyl-d-aspartate;
p-eEF2, phosphorylated eukaryotic elongation factor 2; TrkB, tyrosine kinase B.

genes along with lower number of synapses when compared signaling pathways involved in MDD. Administration of
with matched controls.69 In line with these human observa- ketamine but not other conventional antidepressant medi-
tions, several stress models of depression in rodents have cations to juvenile rats rapidly and transiently activates
been shown to induce brain-region-specific changes in neu- mTORC1 in the PFC.72 This activation, principally observed
ronal arbor architecture and synapses (for review, see Ref. in synapses, is dose dependent: it only occurs with low,
70). In general, chronic stress induces reduction in the num- subanesthetic doses but not at higher anesthetic regimens.
ber of dendritic spines, small protrusions of the dendritic Importantly, the transient activation of mTORC1 is func-
surface representing the postsynaptic sites of excitatory tionally linked with long-term activation of local protein
synaptic contacts onto neurons.70 There is now extensive synthesis in synapses, thereby leading to the production
genetic evidence suggesting that BDNF plays a key role in of proteins required for the formation, maturation, and
these processes, and the downstream signaling pathways function of new synaptic contacts. Indeed, a single low
that mediate the actions of this neurotrophin have been dose of ketamine leads to a rapid increase in the number
identified.70 Among them, the mechanistic target of rapamy- of dendritic spine synapses in the medial prefrontal cortex
cin complex 1 (mTORC1) is of central importance since it (mPFC), and this is accompanied by increased synaptic
regulates activity-dependent protein synthesis implicated activity.72 Moreover, in animal models of chronic stress, both
in synaptic plasticity.71 Chronic stress-related reduction in the behavioral and synaptic deficits were rapidly reversed
mTORC1 signaling is associated with decreased expression by a single dose of ketamine via activation of mTORC1.73
of synaptic proteins along with a decreased number and A central role for BDNF in the synaptic and behavioral
function of dendritic spine synapses.72 effects of ketamine has also been identified. Indeed, ket-
Increasing amounts of experimental data demonstrate amine-induced blockade of the NMDA receptor leads to
that ketamine can interfere with the majority of cellular decreased eukaryotic elongation factor 2 activity, which, in

XXX 2017 • Volume XXX • Number XXX

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turn, results in increased BDNF translation and, thereby, in of MDD, we should definitely not forget the possibility that
enhanced neural plasticity.74 Accordingly, the antidepres- other GAs could also exert similar effects. Indeed, early
sant behavioral properties of ketamine were blocked in studies repeatedly revealed therapeutic effects of general
conditional BDNF deletion mutant mice as well as after anesthesia, and this line of research should be actively pur-
the infusion of a function-blocking anti-BDNF antibody sued.27–30 In line with these clinical data, laboratory obser-
into the mPFC.74,75 Last but not least, both the ketamine- vations also suggest that GAs are powerful modulators of
induced induction of spine synapses and the antidepressant synaptic plasticity via the modulation of neurotransmitter
effects are absent in the BDNF Met allele knock in mice.76 release and growth factor signaling.9 Importantly, similar to
The ensemble of these observations provides a mechanistic ketamine, these drugs can rapidly induce the formation of
explanation of how decreased levels of BDNF and down- new synapses.9,78,79 Therefore, it will be important to deter-
stream mTORC signaling, associated with depressive states, mine whether , and in what dosing and administration regi-
can be reversed via rapid-acting antidepressants such as mens, currently used GAs can have equivalent therapeutic
ketamine.70 According to this hypothesis, ketamine rapidly efficacy in depressive states when compared to ketamine.
reverses spine synapse deficits in the mPFC via a burst of Research in this direction will not only lead to an increased
glutamate via disinhibition of GABAergic interneurons that understanding of the effects of GAs on the CNS but also
control glutamate transmission. The consequent increase might open new avenues for anesthesiology as a discipline
in α-amino-3-hydroxy-5 methyl-4-isoxazoleproprionic acid to administer general anesthesia with a therapeutic goal to
receptor signaling triggers activity-dependent release of improve pathology in mood disorders and, potentially, in
BDNF and its signaling via the tyrosine kinase B receptor. other psychopathologies. A related interesting question is
This, in turn, will stimulate mTORC1 signaling leading, whether depressive states are improved in patients with
thereby, to increased synthesis of synaptic proteins required MDD when they receive anesthesia for surgery. In addi-
for new excitatory synapse formation. Interestingly, in tion, as approximately 20% of patients without previous
both humans and rodents, the antidepressant response to diagnosis of MDD experience depressed mood during the
ketamine is maintained for approximately 7 days, and ket- perioperative period with a direct influence on recovery
amine-induced increases in spine densities persist for the and prognosis,80 elucidating whether any specific anes-
same duration.70 Recent rodent data suggest that the antide- thetic regiment could alleviate these symptoms is of utmost
pressant actions of ketamine are primarily mediated via its importance. This issue is highly complex, since the surgical
active metabolite 2S, 6S hydroxynorketamine (HNK).77 The procedures themselves can significantly improve or worsen
half-life of HNK is significantly longer than that of ketamine, mental states. Nevertheless, some initial reports suggest
and this metabolite induces a rapid and sustained activa- that implementing small dose ketamine during anesthesia
tion of α-amino-3-hydroxy-5 methyl-4-isoxazoleproprionic improves postoperative mood in patients either with or
acid but not of NMDA receptors. Similar to ketamine, HNK without the diagnosis of MDD.81,82 Further studies are defi-
also activates mechanistic target of rapamycin and induces nitely needed to elucidate this exciting question.
eukaryotic elongation factor 2 dephosphorylation leading Another important issue is to elucidate whether the
to increased BDNF expression. Most importantly, at least rapid antidepressant responses induced by GAs, and espe-
in this rodent experimental setting, HNK lacks ketamine- cially with ketamine, can maintain sustained remission in
related side effects such as motor incoordination. These patients with MDD. Initial safety studies, aimed to eluci-
stunning new observations set the stage for upcoming clini- date this question, reveal that repeated administration of
cal trials by opening new avenues for the development of a ketamine, up to 6 times over a period of 2 weeks, is safe
new generation of rapid-acting antidepressants. and maintains improved mood levels during treatment,
but relapse of symptoms occurs in most patients upon the
CONCLUSIONS AND PERSPECTIVES end of treatment.83–85 Future trials are needed to determine
Impaired neural plasticity is central to the pathogenesis of the safety profile and efficacy of ketamine when repeatedly
psychiatric diseases. The fact that GAs are powerful context- administered over a period of months.
dependent modulators of synaptic activity patterns in neu- Pharmacokinetic dose-response studies to determine the
ronal networks raises a potential therapeutic role for these concentration- and administration-speed-dependent effects
agents in altered mental states. In line with this hypothesis, of ketamine in MDD are also needed. In this regard, recent
an increasing number of clinical reports, accumulating over data suggest that the effects of ketamine on mood are dose
the past decades, demonstrated therapeutic potencies of sev- dependent.86 In this study, the authors compared the effects
eral GAs in depressive states by rapidly alleviating symptoms of 0.1–0.4 mg/kg ketamine in patients with MDD and
with an efficacy comparable to ECT. During the past 10 years, found that the greatest improvements occurred at the high-
particular attention has been focused on the NMDA receptor est dose received. It remains, however, unknown if higher,
antagonist ketamine. This drug has repeatedly shown rapid anesthetic doses of ketamine may also exert comparable
efficacy in depressive states, and some of the mechanisms antidepressant effects. Identifying which particular modali-
underlying this effect have been elucidated. The ensemble of ties characterizing MDD are prone to positively respond to
these observations and related translational research gave rise ketamine needs to be addressed in the future. In fact, new
to new possibilities related to the treatment of MDD. They data suggest the efficacy of ketamine in rapidly reducing
also ignite potential new activities for anesthesia providers. suicidality and in alleviating posttraumatic stress disorder
Several important questions, however, remain open. First, symptoms.87,88 Whether other psychiatric pathologies, such
while ketamine is clearly in the spotlight to treat symptoms as obsessive-compulsive disorders or cocaine dependence,

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Anesthesia and Depression

can also be treated with ketamine is an intense field of cur- receiving electroconvulsive therapy. Eur Neuropsychopharmacol.
rent research.89–91 Last but not least, safety issues related to 2009;19:349–355.
22. Miller DH, Clancy J, Cumming E. A comparison between uni-
toxicity associated with repeated ketamine administration directional current nonconvulsive electrical stimulation given
should be definitely elucidated especially in light of abuse with Reiter’s machine, standard alternating current electro-
liability to this drug.92 E shock (Cerletti method), and pentothal in chronic schizophre-
nia. Am J Psychiatry. 1953;109:617–620.
23. Brill NQ, Crumpton E, Eiduson S, Grayson HM, Hellman LI,
DISCLOSURE Richards RA. Relative effectiveness of various components of
Name: Laszlo Vutskits, MD, PhD. electroconvulsive therapy; an experimental study. AMA Arch
Contribution: This author wrote the manuscript. Neurol Psychiatry. 1959;81:627–635.
This manuscript was handled by: Gregory J. Crosby, MD. 24. McDonald IM, Perkins M, Marjerrison G, Podilsky M. A

controlled comparison of amitriptyline and electroconvul-
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