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Annual Review of Clinical Psychology
Ketamine and the Future of
Rapid-Acting Antidepressants
Lace M. Riggs1,2 and Todd D. Gould2,3,4
1Program in Neuroscience and Training Program in Integrative Membrane Biology, University
of Maryland School of Medicine, Baltimore, Maryland 21201, USA;
email: lacemriggs@gmail.com
2Department of Psychiatry, University of Maryland School of Medicine, Baltimore,
Maryland 21201, USA; email: gouldlab@me.com
3Departments of Pharmacology and Anatomy & Neurobiology, University of Maryland School
of Medicine, Baltimore, Maryland 21201, USA
4Baltimore Veterans Affairs Medical Center, Veterans Affairs Maryland Health Care System,
Baltimore, Maryland 21201, USA
Annu. Rev. Clin. Psychol. 2021. 17:207–31
First published as a Review in Advance on
February 9, 2021
The Annual Review of Clinical Psychology is online at
clinpsy.annualreviews.org
https://doi.org/10.1146/annurev-clinpsy-072120-
014126
Copyright © 2021 by Annual Reviews.
All rights reserved
Keywords
ketamine, (2R,6R)-hydroxynorketamine, rapid-acting antidepressant,
treatment-refractory depression, glutamate, brain-derived neurotrophic
factor, BDNF
Abstract
The therapeutic onset of traditional antidepressants is delayed by several
weeks and many depressed patients fail to respond to treatment altogether.
In contrast, subanesthetic ketamine can rapidly alleviate symptoms of de-
pression within hours of a single administration, even in patients who are
considered treatment-resistant. Ketamine is thought to exert these effects by
restoring the integrity of neural circuits that are compromised in depression.
This hypothesis stems in part from preclinical observations that ketamine
can strengthen synaptic connections by increasing glutamate-mediated
neurotransmission and promoting rapid neurotrophic factor release. An
improved understanding of how ketamine, and other novel rapid-acting an-
tidepressants, give rise to these processes will help foster future therapeu-
tic innovation. Here, we review the history of antidepressant treatment ad-
vances that preceded the ketamine discovery,critically examine mechanistic
hypotheses for how ketamine may exert its antidepressant effects, and discuss
the impact this knowledge has had on ongoing drug discovery efforts.
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Contents
INTRODUCTION.............................................................. 208
HISTORICAL PERSPECTIVE ON ANTIDEPRESSANT TREATMENT
ADVANCES................................................................... 209
First-Generation Antidepressants................................................ 209
Second-GenerationAntidepressants............................................. 212
Limitationsof ExistingPharmacotherapies....................................... 213
RAPIDANTIDEPRESSANTMECHANISMS OFACTION ..................... 214
KetamineasaPrototypeRapid-Acting Antidepressant............................ 214
Ketamine Is an N-methyl--aspartateReceptor Antagonist....................... 215
Ketamine Enhances Glutamatergic Transmission and Promotes Synaptogenesis . . . . 216
The Conicting Role of N-methyl--aspartate Receptor Inhibition in the
AntidepressantActionsofKetamine........................................... 218
ADVANCING ANTIDEPRESSANT TREATMENT DEVELOPMENT . . . . . . . . . 220
Theoretical Advances and Treatment Developments Emerging
fromtheKetamine Discovery................................................. 220
Considerations for Translating Basic Scientic Findings
to ImproveClinical Care ..................................................... 221
CONCLUSIONS ................................................................ 223
INTRODUCTION
Major depressive disorder is the leading cause of disability in the world and is characterized by an
amalgam of symptoms that can severely undermine overall quality of life (Vos et al. 2017, WHO
2017). Depressed individuals are not only burdened by near-constant sadness,but also suffer from
a diminished sense of self-worth, extreme fatigue, difculty concentrating, disruptions to sleep,
and a reduced ability to experience pleasure (i.e., anhedonia). Antidepressants, which historically
were thought to exert their effects by modulating monoamines (e.g., serotonin, norepinephrine,
dopamine) in the central nervous system, include monoamine oxidase inhibitors, tricyclic and
tetracyclic compounds, and selective monoamine reuptake inhibitors. While these antidepres-
sants can be effective (Cipriani et al. 2018), several weeks of continuous treatment is typically
required for them to exert a clinically signicant therapeutic effect (Sinyor et al. 2010). Addition-
ally, many patients are prone to symptom relapse (Fornaro et al. 2019, Sim et al. 2016) or may fail
to respond to antidepressant treatment altogether (Gaynes et al. 2020, Trevino et al. 2014). An-
tidepressants also have undesirable side effects ( Jakobsen et al. 2017) that contribute to treatment
discontinuation in those who do respond (Demyttenaere et al. 2001). Unfortunately, a lack of ef-
fective treatment can lead to negative coping strategies, like substance abuse, deliberate self-harm,
and at worst, attempted or completed suicide. For these reasons, novel antidepressant treatment
development is one of the most urgent clinical priorities that we face today.
While it is important to improve treatment options for depression, our understanding of de-
pression pathophysiology is incomplete, and does not provide the strong empirical foundation
upon which tangible treatment advances critically rely.This issue is due in part to an overreliance
on incomplete mechanistic hypotheses of antidepressant action, which represents a major theo-
retical barrier to therapeutic innovation. Indeed, only a handful of new antidepressants have been
approved by the US Food and Drug Administration (FDA) in the last several decades, and all
but one, (S)-ketamine (esketamine; Spravato®), act on the monoaminergic system (Protti et al.
Riggs •Gould
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2020). Some of the recent impetus to investigate novel antidepressant mechanisms of action came
from the discovery that subanesthetic (R,S)-ketamine (hereafter referred to as ketamine) has rapid
antidepressant effects in patients with treatment-resistant major depression (Berman et al. 2000,
Zarate et al. 2006a). Ketamine is thus the rst pharmacotherapy proven to relieve depression
within hours of a single administration, and, no less, in patients who are unresponsive to existing
forms of treatment. The antidepressant efcacy of ketamine not only led to the FDA’s eventual
approval of the (S)-ketamine stereoisomer for treatment-resistant major depression (Zheng et al.
2020) but also prompted extensive investigation into the mechanisms that could account for its
unique antidepressant effects. Early work focused on ketamine’s anesthetic mechanism of action as
an N-methyl--aspartate glutamate receptor (NMDAR) antagonist, whereas more recent studies
have examined its NMDAR-inhibition-independent actions on synaptic transmission and behav-
ior. Collectively, these studies have provided insight into the cellular processes that appear to
be necessary for ketamine to exert its antidepressant effects. However, a better understanding of
rapid antidepressant mechanisms of action is still needed to develop novel treatments with im-
proved tolerability, as ketamine has dissociative properties and abuse potential that limit its use
for psychiatric indications.
While the ketamine discovery provides hope for patients suffering from treatment-resistant
major depression, it is also accompanied by many unknowns that require further investigation.
For instance, why are some, but not all, treatment-resistant patients responsive to ketamine, and
does it have similar efcacy in patients who do respond to traditional antidepressants? Why do
symptoms tend to reemerge within a few weeks of treatment, even in those who respond optimally
to a single administration of ketamine? Are there unique side effects associated with long-term ke-
tamine treatment in patients who require repeated infusions to prevent symptom relapse? Can the
antidepressant effects of ketamine be extended by other antidepressant interventions, or is it possi-
ble that ketamine can enhance the efcacy of existing treatments? And probably the most actively
discussed: What is the mechanism that accounts for the antidepressant actions of ketamine, and
is this functionally separable from those underlying its side effects? To date, there has been a sig-
nicant effort to prove the legitimacy of the NMDAR-inhibition hypothesis in the antidepressant
actions of ketamine, but it is also important to consider whether theoretical advancement is stied
by the lack of rigorous attempts to falsify it. Indeed, an equivalent burden of proof was needed
before it was fully appreciated that depression is not simply due to an imbalance of monoamines;
it was the persistence of this belief, however, that led monoamine-based treatments to dominate
the drug market for several decades. Moving forward, it is incumbent upon us to investigate rapid
antidepressant mechanisms of action in more depth, and with the precision and scrutiny needed
to readily make tangible improvements in depression treatment. We discuss this by providing an
overview of the antidepressant treatment advances that preceded the ketamine discovery,and then
present current mechanistic hypotheses for how ketamine may be exerting its antidepressant ef-
fects. We also discuss the impact this knowledge has had on current drug discovery efforts and
provide recommendations for translating mechanistic insights into clinical application.
HISTORICAL PERSPECTIVE ON ANTIDEPRESSANT
TREATMENT ADVANCES
First-Generation Antidepressants
The rst medication generally considered to have signicant antidepressant efcacy was the hy-
drazine compound iproniazid, which is an isopropyl derivative of the antituberculosis agent iso-
niazid. In tuberculosis patients, iproniazid led to a marked improvement in appetite, emotional
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well-being, and quality of sleep (Salzer & Lurie 1953, Smith 1953). Subsequent studies showed
that iproniazid reduced symptoms of depression in nontuberculosis patients, which contributed
to its use as an antidepressant (Ayd 1957, Crane 1957, Loomer et al. 1957). More than 600,000
depressed patients were estimated to have been prescribed iproniazid during its rst year in psy-
chiatric use (Maxwell & Eckhardt 1990), attesting to how pervasive the need for depression phar-
macotherapy was at that time.
The enhanced antidepressant efcacy of iproniazid relative to isoniazid provided some initial
insight into its possible antidepressant mechanism of action. Iproniazid is chemically distinguished
from isoniazid by its isopropyl moiety, which enhances its potency to inhibit monoamine oxidase
(MAO) (Smith et al. 1963, Zeller & Barsky 1952, Zeller et al. 1955). MAO is an enzyme that
catalyzes the oxidative deamination of amine-containing molecules. Among its substrates are the
monoamines serotonin, norepinephrine, and dopamine,which act as prominent neuromodulators
in the central nervous system. Consistent with its actions as an MAO inhibitor (MAOI), iproniazid
administration was found to acutely enhance the concentration of endogenous brain serotonin in
mice, rats, and rabbits, whereas peripheral serotonin levels remained unchanged (Udenfriend et al.
1957). Additionally, iproniazid treatment led to greater enhancements in serotonin than in nore-
pinephrine, specically in brainstem nuclei from which serotonergic and noradrenergic projec-
tions originate (Shore & Brodie 1958). This nding suggested that serotonin might be implicated
in iproniazid’s antidepressant actions. Indeed, the antihypertensive agent reserpine was known to
have prodepressive properties (Freis 1954), and was thought to exert its effects, in part, by reducing
serotonin release (Sheppard & Zimmerman 1960, Shore et al. 1957) by blocking its transport into
synaptic vesicles (Stitzel 1976). While at that time serotonin had only recently been discovered in
the central nervous system (Twarog & Page 1953, Whitaker-Azmitia 1999), these data provided
circumstantial evidence that depression may be caused by an imbalance of serotonin and, possibly,
other brain-localized monoamines (Brodie & Shore 1957, Woolley & Shaw 1954). Although the
use of iproniazid was eventually discontinued because of its hepatotoxicity, these ndings formed
the basis of future drug development efforts (López-Muñoz et al. 2007), which led to the synthesis
of additional, more selective MAOIs that were later used as antidepressants (Figure 1). Impor-
tantly, these discoveries also revealed depression to be a neuropsychiatric disease that is partly
physiological in its origin.
The role of monoamines in the antidepressant actions of MAOIs gained additional traction
when the antidepressant properties of monoamine reuptake inhibitors were discovered. As with
iproniazid, this discovery arose through clinical happenstance: The tricyclic monoamine reuptake
inhibitor imipramine was being investigated as a potential neuroleptic, but instead was found to
improve depressive symptoms (Kuhn 1958, Lehmann et al. 1958). This discovery led to the devel-
opment of other imipramine-like tricyclic antidepressants (TCAs) (Fangmann et al. 2008), which,
together with MAOIs, represent the rst generation of antidepressants (Figure 1). One of the
major distinctions between these two drug classes is that MAOIs enhance the concentration of
monoamines by blocking their degradation, whereas TCAs prevent them from being transported
back into the presynaptic terminal once they have been released. Thus, while MAOIs increase
the availability of monoamines, TCAs prolong the actions of monoamines during ongoing activ-
ity by blocking their reuptake from the synaptic cleft. While some TCAs, such as amitriptyline
and imipramine, impose a greater inhibition of serotonin reuptake (Carlsson et al. 1969, Lidbrink
et al. 1971), others, like nortriptyline and desipramine, exert more potent effects on the reuptake
of norepinephrine (Bunney & Davis 1965, Carlsson 1970). These observations contributed to the
monoamine hypothesis of depression (Bunney & Davis 1965, Schildkraut 1965), which predicts a
causative relationship between decreased monoaminergic signaling and depression susceptibility
(for a detailed discussion, see Hirschfeld 2000).
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1950 1960 1970 1980 1990 2000 2010 2020
Monoamine oxidase inhibitors
Reduce monoamine degradation by
inhibiting monoamine oxidase
Other MAOIs
Selegiline, isocarboxazid, phenelzine,
tranylcypromine
Iproniazid
Initially used as an antituberculosis agent,
during which time its antidepressant eects
were discovered
Side eects
Nausea, restlessness, insomnia, drowsiness,
dizziness, headache, stroke, fainting, heart
palpitations, blood pressure changes
Tricyclic and
tetracyclic antidepressants
Inhibit the reuptake of serotonin and
norepinephrine
Other TCAs
Desipramine, amitriptyline, nortriptyline,
doxepin, trimipramine, protriptyline
TeC A s
Maprotiline, amoxapine, mirtazapine (also
classied as an atypical antidepressant)
Imipramine
Originally studied as a neuroleptic, but was
discovered to exert antidepressant actions
with fewer side eects than MAOIs
Side eects
Dry mouth, constipation, blurred vision,
drowsiness, hypotension, urinary retention,
confusion, fainting, seizures, tachycardia
Atypical antidepressants
Variable eects on monoamine reuptake, or
unknown mechanism of action
Other atypical antidepressants
Trazodone, nefazodone, mirtazapine (also
classied as a TeCA)
Bupropion
Commonly used atypical antidepressant
thought to act as a norepinephrine-
dopamine reuptake inhibitor
Side eects
Dry mouth, dizziness, blurred vision,
vomiting, constipation, hypotension,
fainting, weight gain, liver failure, seizures
Selective serotonin
reuptake inhibitors
Selectively inhibit the reuptake of serotonin
Other SSRIs
Citalopram, escitalopram, paroxetine,
uvoxamine, vilazodone, sertraline
Fluoxetine
First FDA-approved drug that was shown to
selectively inhibit the reuptake of serotonin;
among the most commonly used
antidepressants
Side eects
Nausea, nervousness, sexual dysfunction,
irritability, sleep disturbances, fatigue,
seizures
Serotonin-norepinephrine
reuptake inhibitors
Selectively inhibit the reuptake of serotonin
and norepinephrine
Other SNRIs
Levomilnacipran, duloxetine, desvenlafaxine
Venlafaxine
First SNRI to be used as an antidepressant;
unlike TCAs, does not aect histaminergic
or muscarinic systems
Side eects
Nausea, vomiting, dry mouth, constipation,
fatigue, dizziness, sexual dysfunction,
hypertension, seizures
(S)-ketamine
The rapid and sustained antidepressant
eects of (R,S)-ketamine led the FDA to later
approve the (S)-ketamine stereoisomer for
treatment-resistant major depression. These
drugs are thought to act primarily through a
non-monoaminergic-based mechanism to
exert their eects
Side eects
Dissociation, dizziness, nausea, altered
sensory processing, anxiety
Glutamatergic agents
Various mechanisms of action to promote
glutamatergic transmission; not yet
approved for depression
(Caption appears on following page)
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Figure 1 (Figure appears on preceding page)
Antidepressant treatment advances receiving FDA approval for major depression. Iproniazid, a monoamine oxidase inhibitor, was
initially used in the treatment of tuberculosis. It was soon discovered that iproniazid possesses antidepressant properties, which were
attributed to its actions as an MAOI. Iproniazid is often credited for having brought pharmacotherapeutic strategies to the forefront of
depression treatment. Later, it was discovered that the chlorpromazine derivative, imipramine, also has antidepressant properties.
Imipramine is a TCA that is thought to exert its effects by reducing monoamine reuptake. Thus, while MAOIs reduce monoamine
degradation, TCAs help maintain them in the synapse after having been released. These observations led to the hypothesis that
monoamines have a direct and causal role in the etiology of depression, and formed the basis of future drug design. While additional
MAOIs and TCAs entered the drug market, their use was associated with adverse effects that warranted more specic therapeutic
approaches. Upon investigating the specicity of other chlorpromazine derivatives, it was discovered that uoxetine (then, LY110140)
acts as an SSRI, and thus it became the rst SSRI to be implemented as an antidepressant. The improved side effect prole of SSRIs
made them a favored alternative to the rst generation of antidepressants (blue) and spurred the use and development of other
monoamine-selective agents that comprised the second generation of antidepressants (teal and green) that include SNRIs. However,
while these advances represent a major turning point in the treatment of depression, monoaminergic-based treatments require several
weeks of continuous administration to take effect, whereas many patients fail to respond altogether. The possibility for a rapid-acting
therapeutic option came at the turn of the century when it was discovered that (R,S)-ketamine rapidly alleviates symptoms of depression
within hours of a single subanesthetic dose administration (Berman et al. 2000). It was later shown that the rapid antidepressant effects
of ketamine extend to patients who do not respond to traditional monoaminergic-based pharmacotherapies (Zarate et al. 2006a). This
nding led the FDA to later approve the (S)-ketamine stereoisomer for treatment-resistant major depression in 2019 (orange). Drug
discovery efforts thus shifted from monoaminergic-based mechanisms of action to those that modulate glutamatergic transmission
(gold). While the success of ketamine as an antidepressant spurred active investigation into glutamatergic-based mechanisms of action,
other NMDAR antagonists and glutamatergic-based compounds have not yet shown the rapid and sustained antidepressant properties
of ketamine (Newport et al. 2015). Abbreviations: FDA, US Food and Drug Administration; MAOI, monoamine oxidase inhibitor;
NMDAR, N-methyl--aspartate glutamate receptor; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin
reuptake inhibitor; TCA, tricyclic antidepressant; TeCA, tetracyclic antidepressant.
Second-Generation Antidepressants
The advent of rst-generation antidepressants was a signicant advance for the treatment of de-
pression and helped prompt investigation into its underlying pathophysiology. However, MAOIs
have life-threatening side effects, such as hypertension, nephrotoxicity, hepatic necrosis, and
tyramine-precipitated intracranial hemorrhage. TCAs also have an unfavorable (if less severe)
side effect prole (e.g., tachycardia, dizziness, hypotension, blurred vision, memory impairment,
drowsiness) due to their tendency to also inhibit muscarinic and histaminergic receptors (Otte
et al. 2016). Unfortunately, both classes of drugs have been used as a means of committing sui-
cide, which contributes to their overall risk prole. It was therefore necessary to identify novel
compounds that could exert antidepressant effects with improved biological specicity and safety.
Since imipramine had been previously derived from the diphenhydramine congener chlorpro-
mazine, diphenhydramine analogs were synthesized to identify derivatives that had the therapeu-
tic efcacy of imipramine but that lacked its undesirable side effects (Molloy et al. 1994). Indeed,
it was known that serotonin and norepinephrine were present in distinct and separable neuronal
populations with distinct projections, and thus it was hypothesized that more precise pharmaco-
logical approaches could be used to target a single monoamine system. This led to subsequent
investigation into the selectivity with which diphenhydramine-derived compounds could inhibit
monoamine reuptake (Wong et al. 2005). Initial studies focused on serotonin because of its then
purported role in depression (Schildkraut 1965, Weil-Malherbe & Szara 1971), and because there
was at least some evidence implicating enhanced serotonin in the antidepressant actions of MAOIs
(Coppen et al. 1963, Shore & Brodie 1958) and TCAs (Carlsson 1970, Carlsson et al. 1968). It
was discovered that one of these compounds, LY110140, acted as a selective serotonin reuptake
inhibitor (SSRI) (Wong et al. 1974), which subsequently became the rst SSRI to be approved as
an antidepressant, named uoxetine (Prozac®) (Wong et al. 2005).
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SSRIs are distinguished from TCAs mainly by their higher potency and selectivity to inhibit
serotonin reuptake. The antidepressant efcacy of SSRIs was taken as further support for the
unique contribution of serotonin in the actions of antidepressant compounds. However, while
some rst-generation antidepressants showed modest specicity to enhance serotonin, pharma-
cological observations seemed to collectively suggest that norepinephrine (and to a lesser extent,
dopamine) could still have a prominent role in the pathophysiology or heterogeneity of depres-
sion (Bunney & Davis 1965, Maas 1978, Schildkraut 1965). Given that many patients failed to
respond to SSRIs, it was hypothesized that some patients may belong to a biochemical sub-
group that responds more favorably to compounds that preferentially block the reuptake of nor-
epinephrine (Nolen et al. 1988, Nyström & Hällström 1987). While crossover studies, in which
both drug classes are sequentially administered within each patient, failed to show convincing sup-
port for such specicity in drug response (Nolen et al. 1988, Nyström & Hällström 1987), this
idea contributed in part to the development of compounds that differentially target the serotonin,
norepinephrine, and dopamine reuptake transporters. These include selective norepinephrine-,
serotonin-norepinephrine-, and dopamine-norepinephrine reuptake inhibitors, as well as sero-
tonin partial agonist/reuptake inhibitors, which, together with SSRIs,represent the second gener-
ation of antidepressants (Figure 1). Today,these drugs are the rst line of treatment for depression
and can be prescribed in combination when patients do not fully remit with monotherapy.
Limitations of Existing Pharmacotherapies
While second-generation antidepressants have less off-target effects than do rst-generation an-
tidepressants, they still have adverse properties that affect their tolerability (e.g., nausea, irritability,
insomnia, sexual dysfunction) ( Jakobsen et al. 2017, Papakostas 2008). Furthermore, monoamine
antidepressants as a whole typically require several weeks of continuous treatment to exert their
full therapeutic effect (Sinyor et al. 2010). Even so, many patients either fail to respond (Gaynes
et al. 2020, Trevino et al. 2014) or experience symptom relapse (Fornaro et al. 2019, Sim et al.
2016), which suggests that traditional antidepressants are inadequate en bloc. There is also a lack
of convincing evidence for the monoamine hypothesis, which is based on the assumption that
monoamines have a direct and causal role in the etiology of depression itself. Predictions that
extend from this hypothesis are that (a) a reduction in monoamines will increase depression sus-
ceptibility; (b) the extent of that reduction is associated with the severity of depression; (c) antide-
pressant response is contingent upon, and mirrors the time course of, monoamine restoration; and
(d) symptom relapse is due to the reemergence of a decit in monoamine levels. There has been a
lack of convincing evidence in support of these predictions, and as a result, it is generally accepted
that the monoamine hypothesis cannot fully explain depression symptomatology,nor can it foster
the development of treatments that will be widely effective (Hirschfeld 2000).
While it is clear that monoaminergic synaptic transmission is involved in the affective, be-
havioral, and cognitive domains of depression (Delgado 2000, Jacobsen et al. 2012, Schildkraut
1965), monoamines primarily serve a neuromodulatory role, and thus likely impinge on other
physiological processes that are of more direct etiological signicance to the onset and mainte-
nance of depression (Heninger et al. 1996, Hirschfeld 2000, Lee & Han 2019). Even during an era
focused on monoamines, it seemed probable that—while traditional antidepressants do increase
monoamines—their therapeutic efcacy may be due to other molecular and/or cellular adapta-
tions that emerge over time, and are revealed after chronic treatment (Hyman & Nestler 1996).
Indeed, changes in neural connectivity were becoming increasingly implicated in depression, so it
was feasible to consider that antidepressants were capable of producing structural change over sev-
eral weeks of continuous treatment (Duman 1998, Manji et al. 2001). The mechanisms underlying
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this process could form the basis of rational drug design (Duman et al. 1997), aimed at strength-
ening synapses in a lasting and therapeutically benecial way (Gould et al. 2019, Thompson et al.
2015). Despite these early propositions and the limitations of existing treatments, virtually all an-
tidepressants that were subsequently approved by the FDA act primarily on the monoaminergic
system (Figure 1); the assumption that antidepressants exert their effects by restoring decits
in monoamine signaling led drug discovery and development efforts to focus almost exclusively
on this mechanism of action. Ultimately, this narrow focus contributed to the lack of new treat-
ment modalities since the initial discovery of iproniazid’s antidepressant properties in the 1950s.
It should be recognized, however, that the advent of traditional antidepressants is responsible for
many clinical and theoretical advances that have been essential, such as recognizing depression as a
biological disease, triggering active investigation into its pathophysiology, and providing different
treatment options for individuals suffering from depression.
RAPID ANTIDEPRESSANT MECHANISMS OF ACTION
Ketamine as a Prototype Rapid-Acting Antidepressant
Ketamine is a phencyclidine-derived dissociative anesthetic that was synthesized in an effort to
minimize the length of anesthetic action and to reduce the severity of postanesthetic emergence
delirium (Domino 2010, Domino et al. 1965). Ketamine also augments sympathetic processes that
alter cardiovascular function (although to a lesser extent than phencyclidine), which can lead to
tachycardia and hypertension (Zanos et al. 2018a). It was initially thought that ketamine exerts
these sympathomimetic effects by inhibiting norepinephrine reuptake (Liebe et al. 2017, Miletich
et al. 1973). While it was later shown that ketamine lacks afnity for monoamine transporters
(Can et al. 2016), these initial hypotheses led Soa & Harakal (1975) to test whether these sec-
ondary sympathomimetic effects confer ketamine with preclinical antidepressant-like actions. At
the time, preclinical antidepressant screening procedures were based on existing mechanistic hy-
potheses that an increase in monoamine release is necessary and sufcient for antidepressant ac-
tion. Antidepressant efcacy was thus established to the extent that a compound could reverse the
physiological effects of monoamine depletion (i.e., ptosis, hypothermia) or exacerbate the phys-
iological effects of an increase in monoamines (i.e., tremor, toxicity). While orally administered
ketamine appeared to exert these antidepressant-like actions in mice and rats, such effects were
relatively modest when compared to the TCA imipramine (Soa & Harakal 1975). Despite prelim-
inary evidence that subanesthetic ketamine could facilitate psychotherapy and relieve symptoms
of psychiatric disease (Khorramzadeh & Lotfy 1973), its clinical antidepressant potential was not
further investigated at that time.
While the antidepressant effects of ketamine awaited discovery, its dose-dependent psy-
chotomimetic properties gained it attention as a pharmacological strategy to understand the
pathophysiology of psychosis (Krystal et al. 1994). Subanesthetic ketamine also has euphoric prop-
erties and inuences sensory perception—features that promote its recreational use and abuse
liability (Zanos et al. 2018a). These properties appear to have initially overshadowed anecdo-
tal hints that subanesthetic ketamine could attenuate symptoms of depression, and possibly with
greater efcacy than existing antidepressants (Domino 2010). The clinical antidepressant effects
of ketamine were rst reported in a double-blind, placebo-controlled, randomized clinical trial
by Berman et al. (2000), which revealed that ketamine could rapidly alleviate symptoms of de-
pression. When a subanesthetic dose of ketamine (0.5 mg/kg) was infused intravenously over a
period of 40 min, depression rating scores were reduced within 4 h, and this effect lasted for
up to 3 days postadministration (Berman et al. 2000). Consistent with previous reports (Krystal
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et al. 1994), the authors demonstrated that the psychotomimetic properties of subanesthetic ke-
tamine, which primarily occur during the time of the infusion (Berman et al. 2000, Krystal et al.
2019), are absent by 4 h posttreatment, and are thus temporally separable from the drug’s an-
tidepressant effects. Zarate et al. (2006a) later examined the antidepressant actions of ketamine in
treatment-resistant depressed patients, who, on average, had previously failed six antidepressant
trials. Despite the length and severity of their depression, ketamine led to a rapid reduction of
symptoms in the majority of patients, which lasted for up to 1 week postadministration (Zarate
et al. 2006a). Importantly, the antidepressant effect of ketamine in treatment-resistant depressed
patients maintains a signicant separation from placebo when an active anesthetic control is used
under blinded conditions (Murrough et al. 2013). The rapid and sustained antidepressant effects
of ketamine have now been reported in a number of clinical studies (Kryst et al. 2020), which have
prompted specialized treatment clinics to open in private and academic sectors (Wilkinson et al.
2017).
Ketamine Is an N-methyl-D-aspartate Receptor Antagonist
Two decades after it was initially synthesized, it was discovered that ketamine acts as a noncompet-
itive NMDAR antagonist (Anis et al. 1983, Lodge et al. 1983). NMDARs belong to the ionotropic
class of glutamate receptors (i.e., those that allow ions to ow across the cellular membrane upon
glutamate binding) that specialize in fast synaptic transmission, which also includes α-amino-
3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and kainate receptors.
NMDARs are unique in that their calcium permeability is ten-fold higher than that of other
cations, and four-fold higher than that of calcium-permeable AMPARs (Traynelis et al. 2010).
NMDARs are more sensitive than AMPARs to glutamate binding (EC50 =0.5–3 versus 3–560 μM,
respectively) and are also slower to desensitize (τ=59–2,000 versus 1–10 ms, respectively)
(Traynelis et al. 2010). These biophysical properties make NMDARs an essential transducer of
intracellular calcium, which acts as a second messenger to modulate the efcacy of synaptic trans-
mission and many other cellular processes. While prolonged elevations of intracellular calcium
can be excitotoxic, extracellular magnesium helps to oppose calcium-dependent excitotoxicity by
occluding the channel pore at negative membrane potentials (i.e., NMDARs are not permeable
to magnesium as they are to sodium, potassium, and calcium).The presence of magnesium within
the channel confers NMDARs with a voltage-dependence of activation, such that a depolariza-
tion threshold needs to be reached before NMDARs will become activated by glutamate binding.
That is, the interior of the cell must be sufciently positive from other ongoing ionic uxes for
NMDARs to themselves pass ionic current when glutamate is bound; this is due to electrostatic
repulsion of magnesium from within the channel. Ketamine is a use-dependent open channel
blocker that competes with magnesium binding deep within the channel pore, where it remains
bound when the receptor transitions to a closed conformation (Glasgow et al. 2018, MacDonald
et al. 1987). Its rapid off-rate upon channel reopening is thought to confer it with a shorter du-
ration of anesthetic action than its structural analog, phencyclidine (Domino 2010, Domino et al.
1965).
While ketamine is believed to exert its anesthetic effects by blocking NMDAR-mediated
synaptic transmission (Zanos et al. 2018a), some early preclinical data suggested that NMDAR
antagonism could have antidepressant potential (Trullas & Skolnick 1990). In contrast to the
early monoamine-based screening procedures described above (Soa & Harakal 1975), increases
in escape-directed behavior in forced swim test (Porsolt et al. 1977) and tail suspension test
(Steru et al. 1985) were later considered a more accurate predictor of antidepressant action.
With this approach, NMDAR antagonists were found to dose-dependently reduce behavioral
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despair, and to a degree that was comparable to that of traditional antidepressants with known
clinical efcacy (Trullas & Skolnick 1990). Similar results were later observed following ketamine
administration (e.g., Chaturvedi et al. 1999, Maeng et al. 2008, Mantovani et al. 2003), which
provided circumstantial support for the role of NMDAR inhibition in its clinical antidepressant
actions (Berman et al. 2000, Zarate et al. 2006a).
Ketamine Enhances Glutamatergic Transmission and Promotes Synaptogenesis
There has been a signicant effort to understand how blocking NMDAR transmission could ac-
count for the unique antidepressant properties of ketamine. Some initial insight came from a
preclinical study by Moghaddam et al. (1997), which revealed that a single administration of ke-
tamine evokes a transient dose-dependent increase in the concentration of extrasynaptic glutamate
in the medial prefrontal cortex in vivo. This study showed that subanesthetic ketamine leads to
a net increase in cortical excitation—a nding in contrast to what may have been predicted of
a compound that blocks NMDAR-mediated excitatory synaptic current. The authors proposed
that lower doses of ketamine may promote glutamatergic transmission by preferentially atten-
uating the inhibitory tone that typically impinges on the excitatory (pyramidal) neurons in this
region. This occurs because inhibitory interneurons are normally (tonically) active, which places
excitatory pyramidal neurons in a state of functional quiescence. Since ketamine is a blocker of
open/active NMDARs, it is predicted that ketamine would more readily inhibit tonically active in-
hibitory interneurons. Consistent with this prediction, Homayoun & Moghaddam (2007) showed
that the NMDAR antagonist dizocilpine (MK-801) reduces the ring rate of putative fast-spiking
inhibitory interneurons, which disinhibits cortical pyramidal neuron activity. A similar disinhi-
bition phenomenon has been observed with ketamine in ex vivo hippocampal slice preparations
(Widman & McMahon 2018), suggesting that these effects may extend to other brain regions
that are involved in mood regulation. Overall, this work contributed to the hypothesis that an
acute disinhibition of glutamate release could restore the integrity of synaptic connections that
are compromised in depression (Duman 2014, Li et al. 2010). That is, ketamine may exert its
antidepressant actions by strengthening the efcacy of synaptic transmission, which resembles a
plasticity-related process that is made possible by the brain’s intrinsic ability to constantly un-
dergo change at the level of individual synapses. Alternatively, it is possible that ketamine exerts
its effects by decreasing excitation in regions whose activity promotes depressive-like phenotypes,
as opposed to increasing the activity of euthymic-related regions. Indeed, ketamine has been re-
ported to block NMDAR-mediated burst ring in the lateral habenula, where excess activity has
been associated with behavioral despair and anhedonia (Yang et al. 2018). In contrast to the gluta-
matergic disinhibition hypothesis, these studies support a model in which monoaminergic circuits
are rapidly disinhibited by ketamine’s inhibition of lateral habenula activity (Yang et al. 2018).
The disinhibition hypothesis predicts that the activational balance in these regions is
acutely shifted toward excitatory, and in particular AMPAR, transmission, which could underlie
its antidepressant efcacy. In support of this hypothesis, the preclinical antidepressant-like
actions of ketamine require AMPAR activity as they are blocked by pretreatment with an AMPAR
antagonist (Maeng et al. 2008). Thus, ketamine’s effects may rely on cellular processes that are at,
or downstream of, the AMPAR itself. There are a number of possibilities for what these processes
could be, as the AMPAR is a highly abundant unit of fast synaptic transmission that serves many
diverse physiological roles throughout the brain. Unlike NMDARs, however, AMPARs faithfully
pass excitatory current upon glutamate binding as they do not have a voltage-dependence of
activation. As a result, AMPARs are capable of gating the voltage-dependent processes that
dictate the extent of calcium inux. This is relevant to the AMPAR-dependent antidepressant
actions of ketamine because calcium acts as a second messenger to regulate synaptic transmission,
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membrane excitability, gene expression, and synaptogenesis (Kawamoto et al. 2012, Redmond
& Ghosh 2005). Indeed, the AMPAR-mediated activity-dependent rise in intracellular calcium
triggers the release of brain-derived neurotrophic factor (BDNF) ( Jourdi et al. 2009, Zhang
& Lipton 1999), which is required for ketamine to exert its antidepressant-like effects (Lepack
et al. 2015, 2016; Li et al. 2010; Liu et al. 2012). BDNF is a soluble protein that promotes
neuronal survival and can contribute to the formation of new synaptic connections (i.e., synap-
togenesis). BDNF accomplishes this by binding to its receptor, tropomyosin receptor kinase B
(TrkB), which recruits the intracellular signaling molecules that are needed to execute structural
changes within the cell. For instance, BDNF-TrkB activity can orchestrate the formation of
mechanistic target of rapamycin complex 1 (mTORC1), which is a specialized protein complex
that regulates protein synthesis and cell proliferation ( Jourdi et al. 2009, Zhang & Lipton 1999).
Interestingly, ketamine exerts its antidepressant-like effects by initiating synaptogenesis in an
AMPAR/BDNF/mTORC1-dependent manner (Lepack et al. 2015, 2016; Li et al. 2010; Liu et al.
2012), which involves recruitment of the mTORC1 effector, eukaryotic translation initiation
factor 4E–binding protein 2 (4E-BP2) (Aguilar-Valles et al. 2020), and is thought to evoke a
lasting increase in the efcacy of synaptic transmission (Deyama & Duman 2020, Duman et al.
2021). The sustained actions of ketamine also appear to require AMPAR activity,as its preclinical
antidepressant-like effects are blocked by AMPAR inhibition immediately before testing, 24 h
after treatment (Koike & Chaki 2014, Zanos et al. 2016). Thus, the long-lasting antidepressant
effects of ketamine may be due to sustained adaptations in the number or function of AMPARs—a
common mechanism by which synaptic plasticity has been shown to manifest (Huganir & Nicoll
2013). Indeed, ketamine increases the expression of AMPARs containing the GluA1 subunit 24 h
after systemic administration (Adaikkan et al. 2018, Li et al. 2010, Yamada & Jinno 2019, Zanos
et al. 2016) but not 1 h after treatment (Li et al. 2010, Zanos et al. 2016). These ndings suggest
that the acute AMPAR-activity-dependent actions of ketamine on BDNF signaling initiate synap-
togenic processes that involve sustained increases in AMPAR expression (Figure 2). This process
may underlie the ability of ketamine to restore synaptic decits following chronic stress exposure
(Li et al. 2011)—for instance, by promoting dendritic outgrowth in regions like the medial
prefrontal cortex (Li et al. 2010). Consistent with this hypothesis, longitudinal observations of
cortical spine formation in vivo have revealed that the emergence of depressive-like phenotypes
in mice is associated with reduced synaptic integrity, and that ketamine reverses these decits in
part through targeted dendritic spine remodeling at those synapses (Moda-Sava et al. 2019).
While glutamatergic disinhibition could explain the acute antidepressant actions of ketamine,
an alternative explanation is that ketamine exerts its effects through a BDNF-dependent process
that is independent of disinhibition (Figure 2). One such hypothesis has been proposed by Autry
et al. (2011), who suggested that ketamine promotes BDNF synthesis by blocking NMDAR ac-
tivation by spontaneously released glutamate—that is, glutamate released stochastically from the
presynaptic terminal and not synchronously evoked by an increase in presynaptic activity.Sponta-
neously released glutamate prevents the eukaryotic elongation factor 2 (eEF2) kinase–dependent
inhibition of eEF2 activity, which normally suppresses BDNF synthesis under resting conditions
(Kavalali & Monteggia 2020). This marks an important distinction from the disinhibition hypoth-
esis in predicting that ketamine exerts its effects by blocking synaptic NMDARs on pyramidal
neurons and not by triggering activity-dependent BDNF release or mTORC1 signaling (Autry
et al. 2011). An additional alternative hypothesis has been proposed by Miller et al. (2014), who
suggested that ketamine selectively inhibits GluN2B-containing NMDARs that are preferentially
activated by ambient glutamate at extrasynaptic sites (i.e., outside of the synapse). However, there
is evidence that ketamine does not functionally inhibit NMDARs with subunit specicity (Dravid
et al. 2007), and although GluN2B-specic antagonists exert preclinical antidepressant-like
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actions (Li et al. 2010, Maeng et al. 2008), they have failed to show antidepressant effects in clinical
studies (Gould et al. 2019).
The Conicting Role of N-methyl-D-aspartate Receptor Inhibition
in the Antidepressant Actions of Ketamine
A major assumption of the hypotheses described above is that NMDAR blockade is essential to
the antidepressant actions of ketamine. However, in the same year in which it was discovered that
Ketamine
(2R,6R)-HNK
NAMs
Ketamine
?
Ketamine
Glutamatergic
(excitatory) neuron
GABAergic
(inhibitory)
neuron
Spontaneously
activated
AKT
PAM s
TrkB
mGluR2
VGCC
NMDAR
NMDAR
Extrasynaptic
NMDAR
NMDAR
BDNF protein
AMPAR
GABAR
Ca2+ Ca2+
mTORC1
p7056k
p-eEF2
BDNF
+
GluA1-
containing
AMPAR
PSD95
eEF2K
Mg2+
Antagonists/
NAMs
NAMs
PAM s
(Caption appears on following page)
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Figure 2 (Figure appears on preceding page)
Putative rapid antidepressant mechanisms of action. Ketamine is an NMDAR antagonist that acts as an
anesthetic at higher doses than those effective for depression (Zanos et al. 2018a). At subanesthetic doses,
ketamine possesses acute dissociative and psychotomimetic effects, which are followed by its rapid
antidepressant properties (occurring within hours) that are sustained for several days to weeks. A few
hypotheses have been set forth to explain how ketamine exerts its antidepressant actions. Subanesthetic doses
of ketamine lead to an acute increase in extracellular glutamate, which is proposed to shift the activational
balance toward increased glutamatergic versus inhibitory mediated synaptic transmission. It is proposed that
this increase in glutamate release is due to ketamine’s preferential blockade of NMDARs localized to
inhibitory interneurons that typically decrease activity of excitatory transmission (Duman 2014). Such
disinhibition would result in an increase in AMPAR-mediated synaptic transmission, leading to the
activity-dependent release of BDNF. BDNF-TrkB-dependent recruitment of mTORC1 subsequently
increases the synthesis of synaptic proteins that can enhance the efcacy of synaptic transmission. For
instance, this process may underlie the synaptogenic properties of ketamine, which involve an upregulation
of GluA1-containing AMPARs in the PSD. Alternatively, ketamine has been proposed to block synaptic
NMDARs that respond preferentially to spontaneously released glutamate at rest (Kavalali & Monteggia
2020), though magnesium typically occludes the NMDAR channel pore at negative membrane potentials.
This blockade is proposed to remove the eukaryotic elongation factor 2–mediated inhibition of BDNF
synthesis, a process that is independent of mTORC1 activity. Ketamine may also exert its effects by
selectively inhibiting extrasynaptic NMDARs whose activity is associated with excitotoxicity through
mTORC1 inhibition of protein synthesis (Miller et al. 2014). Lastly, ketamine is rapidly metabolized to a
number of molecules, including hydroxynorketamines, which have been implicated in ketamine’s rapid
antidepressant mechanism of action (Highland et al. 2021). Ketamine metabolites, such as (2R,6R)-HNK,
promote glutamate release independent of NMDAR blockade or glutamatergic network disinhibition (Riggs
et al. 2020), possibly through a mechanism downstream of mGluR2activity (Zanos et al. 2019b). Other
compounds that manifest ketamine-like preclinical antidepressant-relevant actions are proposed to exert
similar synaptic effects, but through mechanisms that are distinct from NMDAR inhibition.NMDAR-PAMs
promote NMDAR activity upon glutamate binding, which induces the activity-dependent release of BDNF.
GABAR-NAMs decrease tonic inhibition of glutamatergic neurons, while mGluR2antagonists attenuate
mGluR2-dependent inhibition of glutamate vesicle release. Abbreviations: AKT, protein kinase B; AMPAR,
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; BDNF, brain-derived neurotrophic
factor; eEF2K, eukaryotic elongation factor 2 kinase; GABAR, γ-aminobutyric acid receptor; HNK,
hydroxynorketamine; mGluR2, metabotropic glutamate receptor 2; mTORC1, mechanistic target of
rapamycin complex 1; NAM, negative allosteric modulator; NMDAR, N-methyl--aspartate glutamate
receptor; PAM, positive allosteric modulator; p-eEF2, phosphorylated eukaryotic elongation factor 2; PSD,
postsynaptic density; TrkB, tropomyosin receptor kinase B; VGCC, voltage-gated calcium channel.
ketamine relieves treatment-resistant major depression (Zarate et al. 2006a), it also was shown
that the NMDAR inhibitor memantine lacks clinical antidepressant effects, even after 7 weeks of
continuous treatment (Zarate et al. 2006b). Furthermore, a meta-analysis of six double-blind, ran-
domized, placebo-controlled trials revealed that memantine is not superior to placebo in antide-
pressant efcacy (Kishi et al. 2017). While memantine functionally inhibits the NMDAR com-
parably to ketamine, it is possible that modest differences in its trapping behavior [71% versus
86%, respectively (Mealing et al. 1999)] or pharmacokinetic properties could account for its lack
of antidepressant effects. However, even high-afnity NMDAR channel blockers do not show the
same preclinical antidepressant-like actions of ketamine (e.g., Autry et al. 2011, Maeng et al. 2008,
Zanos et al. 2016), nor has any NMDAR antagonist that has been tested clinically (Gould et al.
2019). It is thought that other NMDAR antagonists lack antidepressant effects because they in-
hibit the NMDAR in a manner that is adequately distinct from that of ketamine (Duman et al.
2019), though this remains untested.
An alternative explanation is that NMDAR inhibition accounts for the anesthetic properties of
ketamine but not its antidepressant effects (Zanos et al. 2018a). This possibility was raised by pre-
clinical observations with the use of ketamine metabolites, including (2R,6R)-hydroxynorketamine
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(HNK). Specically, preventing the metabolism of ketamine to (2R,6R)-HNK blocks its
antidepressant-like effects, whereas direct administration of (2R,6R)-HNK exerts antidepressant-
like actions that are similar to those of ketamine. This is despite the fact that (2R,6R)-HNK has
no measurable binding to, or functional effects on, the NMDAR at antidepressant-relevant con-
centrations (Fukumoto et al. 2019; Lumsden et al. 2019; Zanos et al. 2016, 2019a). Interestingly,
(2R,6R)-HNK promotes glutamatergic synaptic transmission (Pham et al. 2018, Riggs et al. 2020,
Zanos et al. 2016) and triggers an acute increase in BDNF release, which, as with ketamine, is
required for it to exert its antidepressant-like effects (Fukumoto et al. 2019). A controversial view
that has stemmed from these observations is that the antidepressant actions of ketamine depend,
in part, on its metabolism to (2R,6R)-HNK. While it is possible that ketamine and its metabolites
work synergistically, these ndings suggest that NMDAR inhibition is not essential to the rapid
antidepressant actions of ketamine.
ADVANCING ANTIDEPRESSANT TREATMENT DEVELOPMENT
Theoretical Advances and Treatment Developments Emerging from the
Ketamine Discovery
While there remains debate regarding the role of NMDAR inhibition in the antidepressant actions
of ketamine, there is compelling evidence that an AMPAR-dependent increase in BDNF-TrkB
signaling is necessary for its antidepressant effects, independent of whether they are initiated by
NMDAR blockade. Providing further support for this hypothesis, ketamine promotes dendritic
arborization (i.e., structural growth at neuronal sites that receive synaptic input) of patient-derived
induced pluripotent stem cell neurons, which is blocked by AMPAR-, BDNF-, and mTORC1
inhibition (Cavalleri et al. 2018, Collo et al. 2018). Interestingly, BDNF signaling has also been
implicated in the antidepressant efcacy of monoaminergic-based treatments (Duman et al. 1997),
which suggests that BDNF-dependent signaling could be a general antidepressant mechanism
regardless of the initial pharmacological site of action. Consistent with the role of BDNF signaling,
the delay in therapeutic onset of traditional antidepressants mirrors the slow time course along
which adaptations in BDNF expression occur upon chronic administration (Deyama & Duman
2020, Duman et al. 2021). In a detailed review, Alt et al. (2006) proposed that by modulating
AMPAR activity, one could potentially overcome the limitations of traditional antidepressants by
rapidly triggering BDNF signaling—a process that could give rise to the “holy grail” of treatment,
as they aptly described. It would now appear that ketamine is one such treatment, and indeed,
ketamine has been shown to initiate synaptogenic processes through a rapid AMPAR-dependent
increase in BDNF release (Figure 2). While the rapid increase in BDNF release is proposed
to be related to the rapid antidepressant actions of ketamine, additional studies are needed to
understand whether this process also accounts for the increased response rate among treatment-
resistant depressed patients who respond favorably only to ketamine.
Additional mechanistic validity for the role of BDNF-TrkB signaling in general antidepres-
sant actions comes from preclinical discoveries with compounds that do not inhibit the NMDAR
to exert their antidepressant-like effects. These include NMDAR glycine site agonists and an-
tagonists, NMDAR positive allosteric modulators (PAMs), γ-aminobutyric acid receptor negative
allosteric modulators, metabotropic glutamate receptor 2 antagonists, muscarinic acetylcholine
receptor antagonists, and ketamine metabolites, including (2R,6R)-HNK (Figure 2). Similar to
ketamine, these compounds are proposed to exert their effects by promoting AMPAR-dependent
BDNF-TrkB activity (Duman et al. 2019, Zanos et al. 2018b). For example, the NMDAR-PAM
GLYX-13 (rapastinel) has shown rapid antidepressant-like preclinical effects in the absence of
psychotomimetic properties (Donello et al. 2019, Moskal et al. 2014). Additionally, GLYX-13
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administration leads to a BDNF-mediated increase in mTORC1 signaling (Kato et al. 2018, Liu
et al. 2017) and promotes the efcacy of synaptic transmission (Zhang et al. 2008), similar to that
induced by ketamine (Burgdorf et al. 2013). Consistent with these ndings,a phase II clinical trial
showed that GLYX-13 has rapid dose-dependent antidepressant effects in treatment-resistant de-
pressed patients (Preskorn et al. 2015). Importantly, given that GLYX-13 acts as a PAM to directly
potentiate NMDAR-mediated currents, it lacks the psychotomimetic and dissociative properties
of ketamine that are associated with NMDAR inhibition (Preskorn et al. 2015). Overall, the liter-
ature suggests that antidepressants exert their effects through an increase in the efcacy of excita-
tory synaptic transmission, and that the onset of those effects depends in part on the time course
along which adaptations in BDNF occur.
An important extension of this work is to translate preclinical discoveries and insights to ad-
vance clinical trials in humans. The drug discovery process involves preclinical identication and
testing of new molecules that either target a cellular process that is implicated in the disease or
that mimics the proposed mechanism of action of existing treatments. When such molecules (with
favorable toxicology proles) are identied, clinical trials are then conducted to determine their
safety and efcacy in humans. As discussed above, it is also possible for an existing drug to be used
off-label for a novel indication for which it has shown therapeutic efcacy. This was initially the
case for iproniazid and imipramine: The off-label use of these drugs for the treatment of depres-
sion led to the development of novel MAOIs and TCAs that went on to dominate the drug market
for several years. The proposed mechanism of these antidepressants contributed to rational drug
design, which led to the development of SSRIs and other second-generation antidepressants that
now represent the rst line of treatment for depression. The discovery of ketamine’s antidepressant
effects has led to its off-label use for depression in specialized treatment clinics (Wilkinson et al.
2017) and has increased an interest in the use and development of NMDAR antagonists and other
selective glutamatergic modulators for the treatment of depression. Investigational drugs that
have reached clinical trials include nonsubunit-selective NMDAR antagonists, NR2B-selective
NMDAR antagonists, NMDAR glycine site agonists, metabotropic glutamate receptor modula-
tors, the NMDAR-PAM GLYX-13 (discussed above), and the ketamine enantiomers, (S)-ketamine
and (R)-ketamine. To date, intranasal (S)-ketamine is the only one of these compounds to re-
ceive FDA approval for treatment-resistant major depression with concomitant administration
of at least one traditional antidepressant (Zheng et al. 2020). Thus far, other NMDAR antago-
nists appear to lack the antidepressant efcacy of ketamine (Gould et al. 2019, Lener et al. 2017,
Newport et al. 2015)—an observation that provides additional evidence that racemic ketamine and
(S)-ketamine may not exert their antidepressant effects solely through NMDAR inhibition.
Considerations for Translating Basic Scientic Findings
to Improve Clinical Care
While the ketamine discovery has led to signicant clinical and theoretical advances, the eld
has not developed a novel rapid-acting antidepressant that has succeeded in late-stage clinical
efcacy trials based on knowledge regarding ketamine’s antidepressant mechanism of action. The
conicting evidence for the role of NMDAR inhibition in the antidepressant actions of ketamine
only further complicates the situation; the preclinical data discussed herein suggest that NMDAR
inhibition is not necessary for ketamine to exert its antidepressant effects, nor is it sufcient, as
other NMDAR antagonists lack ketamine’s clinical antidepressant properties. But it has become
increasingly recognized that the AMPAR-dependent activation of BDNF-TrkB signaling may be
the functional point of relevance (Figure 2) with regard to restoring the integrity of neural circuits
in the depressed brain. With this in mind, it is critical to better understand how to safely initiate
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these synaptic processes as a means of treatment, but without also inducing ketamine’s euphoric,
dissociative, or psychotomimetic effects.
To this end, mechanisms identied preclinically should be subjected to rigorous tests of their
underlying assumptions, whereas proof-of-principle human studies should be used to readily verify
the clinical relevance of those emergent hypotheses in depressed patients. But the success of clini-
cal trials intrinsically relies on the actualization and precision of preclinical studies, and there is at
least some evidence to suggest that improvements can be made in this area. As one example, many
consider mTORC1 an essential component in the synaptogenic pathway that confers ketamine
with its unique antidepressant properties (Duman et al. 2019, Zanos et al. 2018b). This conclu-
sion is drawn in part from preclinical observations that rapamycin, an mTOR inhibitor, blocks the
antidepressant-like effects of ketamine when infused directly into the rat medial prefrontal cortex
(Li et al. 2010). As rapamycin is already in clinical use as an immunosuppressant, it serves as an
available tool to address the role of mTORC1 in the clinical antidepressant actions of ketamine.
However, Abdallah et al. (2020) recently reported that peripheral administration of rapamycin
modestly extends the antidepressant effects of ketamine in depressed patients, contrary to what
preclinical studies predicted. The method and route of administration may account for this dis-
crepancy,as systemic administration of rapamycin fails to block the preclinical antidepressant-like
effects of ketamine (Autry et al. 2011). While it is interesting to consider whether these results
are due to a unique interaction between ketamine and immune function in depressed patients,
discrepancies such as these serve to highlight the inherent challenge of translating basic scientic
discoveries into the clinic.
These challenges are due in part to the complexity of the human physiological processes that we
use preclinical approaches to make inferences about. Put simply, it is difcult to develop treatments
based on a limited understanding of depression pathophysiology (and rapid antidepressant mech-
anisms of action, for that matter). Often, genetic, pharmacological, environmental, and circuit-
level manipulations are used to induce behavioral states in model organisms that are thought to
reect depressive-like phenotypes. Our predictions about whether a compound or intervention
will have antidepressant potential depend almost entirely on the robustness of these behavioral
outputs. Additionally, behavioral tests that are sensitive to the actions of existing antidepressants
are commonly used as an indicator of a clinically relevant antidepressant-like response. But while
traditional antidepressants enhance rodents’ escape-directed behavior (e.g., forced swimming),
these assays are also sensitive to compounds that do not exert clinical antidepressant actions (thus,
a negative result may be useful in ruling out compounds that do not have antidepressant efcacy,
but the presence of a positive result does not fully/unequivocally predict antidepressant potential).
Given that basic scientic insights have largely failed to produce novel compounds that are suc-
cessful in late-stage clinical trials, it is worth considering whether preclinical depression-related
assays lack the translational power to test the veracity of mechanistic hypotheses. While this is
a multifaceted issue, it may be due in part to a tendency of the eld to model new drug candi-
dates after the therapeutic actions of existing monoaminergic-based antidepressants that are not
widely effective themselves. However, recent efforts to develop compounds based on t he proposed
mechanism of action of ketamine (Figure 2) have surprisingly encountered similar issues when
tested in the clinic. For instance, while GLYX-13 showed antidepressant potential in preclinical
studies and early clinical trials, it failed to improve depressive symptoms compared to placebo in
recent phase III studies (Kato & Duman 2020). Instances like these can shed doubt on the ther-
apeutic potential of compounds under preclinical investigation and can minimize the perceived
relevance of preclinical procedures in developing robust treatments for complex psychiatric con-
ditions. This is a valid concern because preclinical approaches are inherently limited by the cur-
rent understanding of how depression is thought to arise and manifest. Since the etiology and
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pathophysiology of depression are not well understood, behavioral assays may be useful when ad-
dressing scientic questions that are relevant to underlying neural processes, but not necessarily
for their perceived congruence with depression symptomatology in humans. Even so, using behav-
ioral assays to investigate aberrant neural processes in depression will require better description
of the underlying neurobiological substrates.
Ultimately, the antidepressant drug discovery process will benet from a willingness to test
major predictions of mechanistic hypotheses in the pursuit of truth, as opposed to conrming
scientic beliefs with observations that are based on assumptions that have not been inde-
pendently veried (for a detailed and engaging discussion of the scientic hypothesis and its
utility, see Alger 2019). This approach can help thwart the tendency for epiphenomena to be
overinterpreted as having causal inuence on experimental end points and can improve the
theoretical foundation upon which novel treatments are designed. This is of equal benet to
reverse- and forward-translational approaches, in which novel compounds are developed from
existing antidepressant mechanisms of action versus a pathophysiological target, respectively.
The eld also stands to benet from increasing interactions among basic scientists and clinicians.
These can lead to improved preclinical disease models that are a more valid predictor of clinically
relevant end points and can encourage the use of patient-derived, high-throughput preparations
in preclinical studies. Additionally, clinicians can use translational methodologies to investigate
potential biomarkers of antidepressant action. For instance, putative rapid-acting antidepressants
have been shown to increase synchronization of neural activity in preclinical studies, which can
be detected with cortical electrophysiological recording approaches as an increase in network
oscillations in the gamma frequency range (Gould et al. 2019). The measurement of cortical
electrophysiological recordings may serve as an effective biomarker for the preclinical actions of
putative rapid-acting antidepressants (Fitzgerald & Watson 2019), as increases in gamma power
have been consistently reported in patients receiving subanesthetic ketamine administration
(Gilbert & Zarate 2020). While using electrophysiological approaches as an indicator of antide-
pressant action is not without limitation (McMillan & Muthukumaraswamy 2020), these studies
suggest that these measures have signicant translational relevance, and may provide an avenue
for preclinical mechanistic discoveries to be tested clinically in depressed patients.
CONCLUSIONS
Depression therapeutics were essentially nonexistent when the antidepressant efcacy of iproni-
azid was discovered in the 1950s. Unfortunately, the individual and societal impact of depression
has since been managed with medications that are suboptimal in their efcacy and latency of ther-
apeutic action, and whose signicant side effects lead to high rates of treatment discontinuation.
This situation is in part a direct result of depression being poorly understood in terms of its etiol-
ogy,pathophysiology, and clinical manifestation. While great strides have undoubtedly been made,
an improved understanding of depression pathophysiology will help to support the development
of more precise, mechanistically accurate treatments in the decades ahead.
Without question, the robust rapid and sustained antidepressant effects of ketamine have ini-
tiated signicant theoretical, scientic, and clinical advancements with regard to depression treat-
ment, which have been long overdue. Likely central to ketamine’s antidepressant mechanism of
action is the preclinical nding that it fundamentally exerts its antidepressant effects by enhancing
excitatory (glutamatergic) transmission at select synapses, which initiates a synaptogenic process
that restores the integrity of neural circuits that are affected in depression. However, the utility of
ketamine for psychiatric indications is limited by its dissociative properties and abuse potential.
A better understanding of demographic, clinical, and neurobiological predictors of dissociation
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and abuse will allow a safer, more targeted use of ketamine and future rapid-acting antidepres-
sants. Additionally, it is unclear why NMDAR antagonists lack antidepressant properties relative
to ketamine, and thus the role of NMDAR inhibition has been called into question (Gould et al.
2019, Lener et al. 2017, Newport et al. 2015). Future studies should aim to better understand the
cellular and synaptic processes that are critical to the rapid antidepressant actions of ketamine and
that are both translationally robust and empirically sound. Rigorous attempts need to be made
to either verify or falsify key mechanistic hypotheses, as opposed to providing circumstantial or
epiphenomenal evidence in support of them; a higher burden of proof will be needed if the next
major advance is going to be a true improvement on ketamine.
SUMMARY POINTS
1. Depression is a highly debilitating condition that is difcult to treat with existing
pharmacotherapies.
2. The antidepressant efcacy of traditional antidepressants was discovered by chance, and
their monoamine-based mechanism of action formed the basis of drug development for
more than half a century.
3. Antidepressant mechanisms of action, as well as the requisite delayed time course of their
onset, were reconsidered following the discovery that subanesthetic ketamine has rapid,
robust, and sustained antidepressant effects.
4. It has been hypothesized that ketamine exerts its rapid antidepressant effects by inhibit-
ing the N-methyl--aspartate glutamate receptor (NMDAR), but there is evidence that
ketamine and its metabolites act through NMDAR-independent mechanisms to yield
their antidepressant-relevant effects.
5. There is convincing evidence that ketamine engages plasticity-related mechanisms
to restore neuronal integrity in areas of the brain that are thought to be com-
promised in depression. This process involves an α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid receptor (AMPAR)-dependent increase in brain-derived neu-
rotrophic factor (BDNF) release.
6. While the discovery of ketamine’s antidepressant effects has led to signicant clinical
and theoretical advances, its acute antidepressant mechanism of action is still debated,
and the development of novel ketamine-like antidepressant drug treatments has been
slow to progress.
7. An improved understanding of depression pathophysiology and rapid antidepressant
mechanisms of action is needed in order to develop more effective treatments in the
future.
DISCLOSURE STATEMENT
L.M.R. reports no conicts of interest. T.D.G. is a coauthor on patents and patent applications re-
lated to the pharmacology and use of (2R,6R)-hydroxynorketamine in the treatment of depression,
anxiety, anhedonia, suicidal ideation, and posttraumatic stress disorder. He has assigned patent
rights to the University of Maryland, Baltimore, but will share a percentage of any royalties that
may be received. T.D.G. has received research funding from Allergan and Roche Pharmaceuticals
and has served as a consultant for FSV7, LLC, during the preceding 3 years.
Riggs •Gould
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AUTHOR CONTRIBUTIONS
L.M.R. conceptualized and wrote the manuscript; T.D.G. edited the manuscript for critical intel-
lectual content.
ACKNOWLEDGMENTS
We would like to thank Dr. Gustavo C. Medeiros for a critical review of the manuscript.
This work was supported by National Institutes of Health (NIH) grants F31-MH123066, T32-
GM008181, T32-NS063391, and R25-GM055036 to L.M.R.and by NIH grants MH107615 and
RAI145211A and VA Merit Awards 1I01BX004062 and 101BX003631-01A1 to T.D.G.The con-
tents of this review do not represent the views of the US Department of Veterans Affairs or the
United States Government.
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Annual Review of
Clinical Psychology
Volume 17, 2021
Contents
Smoking Treatment: A Report Card on Progress and Challenges
Timothy B. Baker and Danielle E. McCarthy pppppppppppppppppppppppppppppppppppppppppppppppp1
Network Analysis of Psychopathology: Controversies and Challenges
Richard J. McNally pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp31
Developing and Validating Clinical Questionnaires
Anthony J. Rosellini and Timothy A. Brown ppppppppppppppppppppppppppppppppppppppppppppppppp55
The Hierarchical Taxonomy of Psychopathology (HiTOP):
A Quantitative Nosology Based on Consensus of Evidence
Roman Kotov, Robert F. Krueger, David Watson, David C. Cicero,
Christopher C. Conway, Colin G. DeYoung, Nicholas R. Eaton,
Miriam K. Forbes, Michael N. Hallquist, Robert D. Latzman,
Stephanie N. Mullins-Sweatt, Camilo J. Ruggero, Leonard J. Simms,
Irwin D. Waldman, Monika A. Waszczuk, and Aidan G.C. Wright ppppppppppppppppppp83
History and Status of Prolonged Grief Disorder as a Psychiatric
Diagnosis
Holly G. Prigerson, Sophia Kakarala, James Gang, and Paul K. Maciejewski ppppppppppp109
Violence, Place, and Strengthened Space: A Review of Immigration
Stress, Violence Exposure, and Intervention for Immigrant Latinx
Youth and Families
Sarah A. Jolie, Ogechi Cynthia Onyeka, Stephanie Torres, Cara DiClemente,
Maryse Richards, and Catherine DeCarlo Santiago pppppppppppppppppppppppppppppppppppp127
Social Behavior as a Transdiagnostic Marker of Resilience
Ruth Feldman pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp153
Mental Health and Wealth: Depression, Gender, Poverty,
and Parenting
Megan V. Smith and Carolyn M. Mazure ppppppppppppppppppppppppppppppppppppppppppppppppp181
Ketamine and the Future of Rapid-Acting Antidepressants
Lace M. Riggs and Todd D. Gould pppppppppppppppppppppppppppppppppppppppppppppppppppppppppp207
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Intimate Relationships and Depression: Searching for Causation
in the Sea of Association
Mark A. Whisman, David A. Sbarra, and Steven R.H. Beach ppppppppppppppppppppppppppp233
Saving Lives: Recognizing and Intervening with Youth at Risk
for Suicide
Alejandra Arango, Polly Y. Gipson, Jennifer G. Votta, and Cheryl A. King pppppppppppppp259
Early Environmental Upheaval and the Risk for Schizophrenia
Vincent Paquin, Mylène Lapierre, Franz Veru, and Suzanne King pppppppppppppppppppppp285
DSM-5 Level of Personality Functioning: Refocusing Personality
Disorder on What It Means to Be Human
Carla Sharp and Kiana Wall ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp313
Developmental Perspectives on the Study of Persons
with Intellectual Disability
Jacob A. Burack, David W. Evans, Natalie Russo, Jenilee-Sarah Napoleon,
Karen J. Goldman, and Grace Iarocci ppppppppppppppppppppppppppppppppppppppppppppppppppp339
Clinical and Translational Implications of an Emerging Developmental
Substructure for Autism
John N. Constantino, Tony Charman, and Emily J.H. Jones ppppppppppppppppppppppppppppp365
Conduct Disorders and Empathy Development
Paul J. Frick and Emily C. Kemp ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp391
Cognitive Behavioral Therapy for the Eating Disorders
W. Stewart Agras and Cara Bohon ppppppppppppppppppppppppppppppppppppppppppppppppppppppppp417
Child Sexual Abuse as a Unique Risk Factor for the Development of
Psychopathology: The Compounded Convergence of Mechanisms
Jennie G. Noll ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp439
Clinical Neuroscience of Addiction: What Clinical Psychologists Need
to Know and Why
Lara A. Ray and Erica N. Grodin pppppppppppppppppppppppppppppppppppppppppppppppppppppppppp465
Virtual Reality Therapy in Mental Health
Paul M.G. Emmelkamp and Katharina Meyerbröker ppppppppppppppppppppppppppppppppppppp495
Resilience in Development and Psychopathology:
Multisystem Perspectives
Ann S. Masten, Cara M. Lucke, Kayla M. Nelson, and Isabella C. Stallworthy ppppppppp521
Designing Evidence-Based Preventive Interventions That Reach More
People, Faster, and with More Impact in Global Contexts
Mary Jane Rotheram-Borus pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp551
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Pathology in Relationships
Susan C. South pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp577
Errata
An online log of corrections to Annual Review of Clinical Psychology articles may be
found at http://www.annualreviews.org/errata/clinpsy
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