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Ketamine and the Future of Rapid-Acting Antidepressants

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Abstract

http://www.annualreviews.org/eprint/VH4BGBCTZ2HTFA9RMXGX/full/10.1146/annurev-clinpsy-072120-014126 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 depression 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 antidepressants, give rise to these processes will help foster future therapeutic innovation. Here, we review the history of antidepressant treatment advances 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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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 Conicting 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 Scientic 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, difculty 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 signicant 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 efcacy 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 efcacy 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 efcacy 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-
nicant 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 stied
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 signicant antidepressant efcacy 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 efcacy 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, specically 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).
 Riggs Gould
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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 eects
were discovered
Side eects
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
classied as an atypical antidepressant)
Imipramine
Originally studied as a neuroleptic, but was
discovered to exert antidepressant actions
with fewer side eects than MAOIs
Side eects
Dry mouth, constipation, blurred vision,
drowsiness, hypotension, urinary retention,
confusion, fainting, seizures, tachycardia
Atypical antidepressants
Variable eects on monoamine reuptake, or
unknown mechanism of action
Other atypical antidepressants
Trazodone, nefazodone, mirtazapine (also
classied as a TeCA)
Bupropion
Commonly used atypical antidepressant
thought to act as a norepinephrine-
dopamine reuptake inhibitor
Side eects
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 eects
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 aect histaminergic
or muscarinic systems
Side eects
Nausea, vomiting, dry mouth, constipation,
fatigue, dizziness, sexual dysfunction,
hypertension, seizures
(S)-ketamine
The rapid and sustained antidepressant
eects 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 eects
Side eects
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 specic therapeutic
approaches. Upon investigating the specicity 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 prole 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 signicant 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 prole (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 prole. It was therefore necessary to identify novel
compounds that could exert antidepressant effects with improved biological specicity 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 efcacy 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 efcacy 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 specicity 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 specicity 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 decit 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 signicance 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 efcacy 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 benecial 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 decits
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 afnity for monoamine transporters
(Can et al. 2016), these initial hypotheses led Soa & 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 sufcient for antidepressant ac-
tion. Antidepressant efcacy 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 (Soa & 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 inuences 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 efcacy 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 signicant 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 efcacy 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 sufciently 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 (Soa & 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 efcacy (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 signicant 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 efcacy 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 efcacy. 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 inux. 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 efcacy 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 decits 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 decits 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 specicity (Dravid
et al. 2007), and although GluN2B-specic 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 Conicting 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)
 Riggs Gould
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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 efcacy 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 efcacy (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-afnity 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). Specically, 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 efcacy 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 efcacy 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 efcacy 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 identication 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 proles) are identied, clinical trials are then conducted to determine their
safety and efcacy 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 efcacy. 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 efcacy 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 Scientic Findings
to Improve Clinical Care
While the ketamine discovery has led to signicant clinical and theoretical advances, the eld
has not developed a novel rapid-acting antidepressant that has succeeded in late-stage clinical
efcacy trials based on knowledge regarding ketamine’s antidepressant mechanism of action. The
conicting 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 sufcient, 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 identied 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 scientic
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 difcult 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
reect 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 efcacy,
but the presence of a positive result does not fully/unequivocally predict antidepressant potential).
Given that basic scientic 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 scientic 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 benet from a willingness to test
major predictions of mechanistic hypotheses in the pursuit of truth, as opposed to conrming
scientic beliefs with observations that are based on assumptions that have not been inde-
pendently veried (for a detailed and engaging discussion of the scientic hypothesis and its
utility, see Alger 2019). This approach can help thwart the tendency for epiphenomena to be
overinterpreted as having causal inuence on experimental end points and can improve the
theoretical foundation upon which novel treatments are designed. This is of equal benet 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 benet 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 signicant 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 efcacy 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 efcacy and latency of ther-
apeutic action, and whose signicant 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 signicant theoretical, scientic, 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 difcult to treat with existing
pharmacotherapies.
2. The antidepressant efcacy 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 signicant 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 conicts 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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... Depression is a common and often devastating neuropsychiatric disorder that is difficult to treat. Monoaminergic-based antidepressants take several months to exert a clinically significant therapeutic effect, though, many patients are prone to symptom relapse or fail to respond altogether [1]. In patients who are treatment-resistant, a subanesthetic dose of ketamine can rapidly alleviate symptoms of depression within hours of a single administration [1][2][3]. ...
... Monoaminergic-based antidepressants take several months to exert a clinically significant therapeutic effect, though, many patients are prone to symptom relapse or fail to respond altogether [1]. In patients who are treatment-resistant, a subanesthetic dose of ketamine can rapidly alleviate symptoms of depression within hours of a single administration [1][2][3]. These antidepressant effects are transient, in that symptoms tend to return in the days or weeks immediately following the initial ketamine infusion. ...
... The pro-cognitive effects of single and repeated ketamine (0.5 mg/kg, 40-min infusion) are at least in part related to its antidepressant actions [19] since improvements in cognitive function are correlated with a greater antidepressant response up to a week following infusion [23,[28][29][30]. These procognitive effects appear to be unique to ketamine's antidepressant mechanism of action [1] since the cognitive deficits that are associated with depression tend to persist even when patients respond favorably to traditional antidepressants [24,25,31]. Additional studies are needed to better understand the clinical factors that modulate the cognitive effects of ketamine, said to include age, sex, dose, route of administration, and length and frequency of drug treatment [22,32]. ...
Article
Full-text available
A single subanesthetic infusion of ketamine can rapidly alleviate symptoms of treatment-resistant major depression. Since repeated administration is required to sustain symptom remission, it is important to characterize the potential untoward effects of prolonged ketamine exposure. While studies suggest that ketamine can alter cognitive function, it is unclear to what extent these effects are modulated by the frequency or chronicity of treatment. To test this, male and female adolescent (postnatal day [PD] 35) and adult (PD 60) BALB/c mice were treated for four consecutive weeks, either daily or thrice-weekly, with (R,S)-ketamine (30 mg/kg, intraperitoneal) or its biologically active metabolite, (2R,6R)-hydroxynorketamine (HNK; 30 mg/kg, intraperitoneal). Following drug cessation, memory performance was assessed in three operationally distinct tasks: (1) novel object recognition to assess explicit memory, (2) Y-maze to assess working memory, and (3) passive avoidance to assess implicit memory. While drug exposure did not influence working memory performance, thrice-weekly ketamine and daily (2R,6R)-HNK led to explicit memory impairment in novel object recognition independent of sex or age of exposure. Daily (2R,6R)-HNK impaired implicit memory in the passive-avoidance task whereas thrice-weekly (2R,6R)-HNK tended to improve it. These differential effects on explicit and implicit memory possibly reflect the unique mechanisms by which ketamine and (2R,6R)-HNK alter the functional integrity of neural circuits that subserve these distinct cognitive domains, a topic of clinical and mechanistic relevance to their antidepressant actions. Our findings also provide additional support for the importance of dosing frequency in establishing the cognitive effects of repeated ketamine exposure.
... For instance, Glu2/3 receptor antagonists have been reported to increase glutamate release at excitatory terminals, mimicking the reported action of (2R,6R)-HNK . AMPAR activation by presynaptic glutamate surge may trigger subsequent events, such as augmentation of BDNF/TrkB and mTORC1 signaling pathways, resulting in increased translation and transcription of proteins implicated in synaptic plasticity, and eventually leading to sustained structural alterations in neural circuit (Nishitani et al., 2014;Zanos et al., 2018b;Pham et al., 2018;Hashimoto, 2019;Riggs and Gould, 2021). These series of consequences may be shared by different antidepressants to some extent. ...
... Strict scrutinizes of these mechanisms may deepen our understanding about the etiology and pathophysiology of depression, and help translating mechanistic insights into clinical applications. Readers are encouraged to refer to some excellent reviews (Duman et al., 2016;Muir et al., 2019;Kavalali and Monteggia, 2020;Jelen et al., 2021;Jia et al., 2021;Riggs and Gould, 2021) for a more comprehensive coverage of these topics. Besides glutamatergic system, monoaminergic and opioid systems may also be remodeled by ketamine. ...
Article
Full-text available
Major depressive disorder (MDD) is a devastating psychiatric disorder which exacts enormous personal and social-economic burdens. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has been discovered to exert rapid and sustained antidepressant-like actions on MDD patients and animal models. However, the dissociation and psychotomimetic propensities of ketamine have limited its use for psychiatric indications. Here, we review recently proposed mechanistic hypotheses regarding how ketamine exerts antidepressant-like actions. Ketamine may potentiate α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR)-mediated transmission in pyramidal neurons by disinhibition and/or blockade of spontaneous NMDAR-mediated neurotransmission. Ketamine may also activate neuroplasticity- and synaptogenesis-relevant signaling pathways, which may converge on key components like brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) and mechanistic target of rapamycin (mTOR). These processes may subsequently rebalance the excitatory/inhibitory transmission and restore neural network integrity that is compromised in depression. Understanding the mechanisms underpinning ketamine’s antidepressant-like actions at cellular and neural circuit level will drive the development of safe and effective pharmacological interventions for the treatment of MDD.
... Even when effective, conventional treatments may take weeks to provide significant symptomatic relief [5,6], extending the personal and social burden of depression and increasing risk of negative consequences such as suicide [7]. Several hypotheses have been proposed to explain the low success rates of current antidepressant treatment, including the intrinsic heterogeneity of depression, and the largely monothematic mechanism of action of conventional drugs by modulation of monoamines (serotonin, norepinephrine, and dopamine) [8][9][10]. ...
Article
(R,S)-ketamine (ketamine) and its enantiomer (S)-ketamine (esketamine) can produce rapid and substantial antidepressant effects. However, individual response to ketamine/esketamine is variable, and there are no well-accepted methods to differentiate persons who are more likely to benefit. Numerous potential peripheral biomarkers have been reported, but their current utility is unclear. We conducted a systematic review/meta-analysis examining the association between baseline levels and longitudinal changes in blood-based biomarkers, and response to ketamine/esketamine. Of the 5611 citations identified, 56 manuscripts were included (N = 2801 participants), and 26 were compatible with meta-analytical calculations. Random-effect models were used, and effect sizes were reported as standardized mean differences (SMD). Our assessments revealed that more than 460 individual biomarkers were examined. Frequently studied groups included neurotrophic factors (n = 15), levels of ketamine and ketamine metabolites (n = 13), and inflammatory markers (n = 12). There were no consistent associations between baseline levels of blood-based biomarkers, and response to ketamine. However, in a longitudinal analysis, ketamine responders had statistically significant increases in brain-derived neurotrophic factor (BDNF) when compared to pre-treatment levels (SMD [95% CI] = 0.26 [0.03, 0.48], p = 0.02), whereas non-responders showed no significant changes in BDNF levels (SMD [95% CI] = 0.05 [−0.19, 0.28], p = 0.70). There was no consistent evidence to support any additional longitudinal biomarkers. Findings were inconclusive for esketamine due to the small number of studies (n = 2). Despite a diverse and substantial literature, there is limited evidence that blood-based biomarkers are associated with response to ketamine, and no current evidence of clinical utility. Molecular Psychiatry; https://doi.org/10.1038/s41380-022-01652-1
... Ketamine could provide an alternative treatment for patients with markedly treatment-resistant depression, especially in the short-term. Given ketamine's ability to reduce severe depressive symptoms and suicidality within hours (Hashimoto, 2020;Pham & Gardier, 2019;Sahib et al., 2020;Riggs & Gould, 2021), it appears ideal as an emergency response to suicidality, especially in a medical context (Domany, Shelton, & McCullumsmith, 2020;Domany & McCullumsmith, 2021, pp. 1-16). ...
Article
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Psychedelic substances such as psilocybin and ketamine may represent the future of antidepressant treatment, due to their rapid and prolonged effects on mood and cognition. The current body of psychedelic research has focused on administration and treatment within a psychiatric context. Here, instead, we put to the test the contention that it is necessary to evaluate the current state of this literature from a broader biopsychosocial perspective. Examining these arguably neglected social and psychological aspects of psychedelic treatment can provide a more holistic understanding of the interplay between the interconnected domains. This review of six major clinical trials applies a biopsychosocial model to evaluate the antidepressant effects of psilocybin and ketamine assisted therapy. We conclude that combination psychedelic treatment and psychotherapy facilitate more enduring and profound antidepressant effects than produced by ketamine or psilocybin alone. Emphasising the advantages of therapeutic intervention will encourage those who may attempt to self-medicate with psychedelics to instead seek a framework of psychological support, minimising associated risks of unregulated use.
... When it comes to pharmacotherapy, sub-anesthetic doses of ketamine, a N-methyl-D-aspartate receptor (NMDAR) antagonist, is currently one of the most promising interventions for rapid reduction of STB, but only 55-60% of individuals respond with a complete remission (Wilkinson et al., 2018). The exact mechanism through which ketamine achieves its anti-suicidal and anti-depressant effects is still not fully understood (Riggs and Gould, 2021). Many hypotheses emphasize the importance of increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) signalling, its involvement in bottom-up information transmission and a consequent increase in synaptic and spine plasticity (Zanos and Gould, 2018;Lengvenyte et al., 2019). ...
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Currently, psychiatric practice lacks reliable predictive tools and a sufficiently detailed mechanistic understanding of suicidal thoughts and behaviors (STB) to provide timely and personalized interventions. Developing computational models of STB that integrate across behavioral, cognitive and neural levels of analysis could help better understand STB vulnerabilities and guide personalized interventions. To that end, we present a computational model based on the active inference framework. With this model, we show that several STB risk markers – hopelessness, Pavlovian bias and active-escape bias – are interrelated via the drive to maximize one’s model evidence. We propose four ways in which these effects can arise: (1) increased learning from aversive outcomes, (2) reduced belief decay in response to unexpected outcomes, (3) increased stress sensitivity and (4) reduced sense of stressor controllability. These proposals stem from considering the neurocircuits implicated in STB: how the locus coeruleus – norepinephrine (LC-NE) system together with the amygdala (Amy), the dorsal prefrontal cortex (dPFC) and the anterior cingulate cortex (ACC) mediate learning in response to acute stress and volatility as well as how the dorsal raphe nucleus – serotonin (DRN-5-HT) system together with the ventromedial prefrontal cortex (vmPFC) mediate stress reactivity based on perceived stressor controllability. We validate the model by simulating performance in an Avoid/Escape Go/No-Go task replicating recent behavioral findings. This serves as a proof of concept and provides a computational hypothesis space that can be tested empirically and be used to distinguish planful versus impulsive STB subtypes. We discuss the relevance of the proposed model for treatment response prediction, including pharmacotherapy and psychotherapy, as well as sex differences as it relates to stress reactivity and suicide risk.
... contributes to the antidepressant effects of ketamine [52,166]. ...
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Treating major depression is a medical need that remains unmet by monoaminergic therapeutic strategies that commonly fail to achieve symptom remission. A breakthrough in the treatment of depression was the discovery that the anesthetic (R,S)-ketamine (ketamine), when administered at sub-anesthetic doses, elicits rapid (sometimes within hours) antidepressant effects in humans that are otherwise resistant to monoaminergic-acting therapies. While this finding was revolutionary and led to the FDA approval of (S)-ketamine (esketamine) for use in adults with treatment-resistant depression and suicidal ideation, the mechanisms underlying how ketamine or esketamine elicit their effects are still under active investigation. An emerging view is that metabolism of ketamine may be a crucial step in its mechanism of action, as several metabolites of ketamine have neuroactive effects of their own and may be leveraged as therapeutics. For example, (2R,6R)-hydroxynorketamine (HNK), is readily observed in humans following ketamine treatment and has shown therapeutic potential in preclinical tests of antidepressant efficacy and synaptic potentiation while being devoid of the negative adverse effects of ketamine, including its dissociative properties and abuse potential. We discuss preclinical and clinical studies pertaining to how ketamine and its metabolites produce antidepressant effects. Specifically, we explore effects on glutamate neurotransmission through N-methyl D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), synaptic structural changes via brain derived neurotrophic factor (BDNF) signaling, interactions with opioid receptors, and the enhancement of serotonin, norepinephrine, and dopamine signaling. Strategic targeting of these mechanisms may result in novel rapid-acting antidepressants with fewer undesirable side effects compared to ketamine.
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(2R,6R)-hydroxynorketamine (HNK) is a metabolite of ketamine that exerts rapid and sustained antidepressant-like effects in preclinical studies. We hypothesize that the rapid antidepressant actions of (2R,6R)-HNK involve an acute increase in glutamate release at Schaffer collateral synapses. Here, we used an optogenetic approach to assess whether (2R,6R)-HNK promotes glutamate release at CA1-projecting Schaffer collateral terminals in response to select optical excitation of CA3 afferents. To do this, the red-shifted channelrhodopsin, ChrimsonR, was expressed in dorsal CA3 neurons of adult male Sprague Dawley rats. Transverse slices were collected four weeks later to determine ChrimsonR expression and to assess the acute synaptic effects of an antidepressant-relevant concentration of (2R,6R)-HNK (10 μM). (2R,6R)-HNK led to a rapid potentiation of CA1 field excitatory postsynaptic potentials evoked by recurrent optical stimulation of ChrimsonR-expressing CA3 afferents. This potentiation is mediated in part by an increase in glutamate release probability, as (2R,6R)-HNK suppressed paired-pulse facilitation at CA3 projections, an effect that correlated with the magnitude of the (2R,6R)-HNK-induced potentiation of CA1 activity. These results demonstrate that (2R,6R)-HNK increases the probability of glutamate release at CA1-projecting Schaffer collateral afferents, which may be involved in the antidepressant-relevant behavioral adaptations conferred by (2R,6R)-HNK in vivo. The current study also establishes proof-of-principle that genetically-encoded light-sensitive proteins can be used to investigate the synaptic plasticity induced by novel antidepressant compounds in neuronal subcircuits. Open Access Link until July 25, 2022: https://authors.elsevier.com/c/1fBmW_fK6V6oK
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While psychedelic-assisted therapies are currently being studied for several indications in clinical trials, there is legal and ethical ambiguity for mental health professionals concerning these compounds. Seventy-six mental health professionals completed an online survey asking them to rank their interest in topics related to psychedelic therapy, research, legal obstacles, barriers to incorporating psychedelics in practice, and terminology related to the field. Results showed that providers want more clearly defined terminology and operating procedures concerning business matters such as malpractice and clinic guidelines, legal and ethical clarity on administering psychedelics in private practice and integration work, and further opportunities for psychedelic therapy training. The survey responses were reflected upon through the legal and ethical lens of the current psychedelic landscape.
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(R,S)-Ketamine is rapidly metabolized to form a range of metabolites in vivo, including 12 unique hydroxynorketamines (HNKs) that are distinguished by a cyclohexyl ring hydroxylation at the 4, 5, or 6 position. While both (2R,6R)- and (2S,6S)-HNK readily penetrate the brain and exert rapid antidepressant-like actions in preclinical tests following peripheral administration, the pharmacokinetic profiles and pharmacodynamic actions of 10 other HNKs have not been examined. We assessed the pharmacokinetic profiles of all 12 HNKs in the plasma and brains of male and female mice and compared the relative potencies of four (2,6)-HNKs to induce antidepressant-relevant behavioral effects in the forced swim test in male mice. While all HNKs were readily brain-penetrable following intraperitoneal injection, there were robust differences in peak plasma and brain concentrations and exposures. Forced swim test immobility rank order of potency, from most to least potent, was (2R,6S)-, (2S,6R)-, (2R,6R)-, and (2S,6S)-HNK. We hypothesized that distinct structure-activity relationships and the resulting potency of each metabolite are linked to unique substitution patterns and resultant conformation of the six-membered cyclohexanone ring system. To explore this, we synthesized (5R)-methyl-(2R,6R)-HNK, which incorporates a methyl substitution on the cyclohexanone ring. (5R)-Methyl-(2R,6R)-HNK exhibited similar antidepressant-like potency to (2R,6S)-HNK. These results suggest that conformation of the cyclohexanone ring system in the (2,6)-HNKs is an important factor underlying potency and that additional engineering of this structural feature may improve the development of a new generation of HNKs. Such HNKs may represent novel drug candidates for the treatment of depression.
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Rapid-acting antidepressants disprove the dogma that antidepressants need several weeks to become clinically effective. Ketamine, the prototype of a rapid-acting antidepressant, is an N‑methyl-D-aspartate (NMDA) receptor blocking agent. A single i.v. application of ketamine induces rapid changes in glutamatergic neurotransmitter systems, leading to preferential activation of glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. This evokes the activation of brain-derived neurotrophic factor (BDNF), causing plastic changes in the central nervous system within 24 h. In the prefrontal cortex ketamine leads to a regeneration of synaptic contacts, which have been damaged by chronic stress. This regeneration correlates with improvement of depression-like behavioral changes in rodent models. Classical monoaminergic antidepressants can cause similar changes but with considerably longer latency periods. For clinical application a nasal spray of esketamine has been developed, since this enantiomer has the highest affinity for NMDA receptors; however, since R‑ketamine and certain ketamine metabolites also have antidepressant effects in preclinical models, these are currently being tested in clinical studies. Moreover, there are many other glutamatergic substances under clinical investigation for antidepressant effects without ketamine-like adverse effects. In addition, there are also several promising rapid-acting antidepressants that do not primarily act via the glutamate system, such as the gamma-aminobutyric acid (GABA) receptor modulator brexanolone or the serotonin receptor agonist psilocybin.
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Effective pharmacotherapy for major depressive disorder remains a major challenge, as more than 30% of patients are resistant to the first line of treatment (selective serotonin reuptake inhibitors)1. Sub-anaesthetic doses of ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist2,3, provide rapid and long-lasting antidepressant effects in these patients4,5,6, but the molecular mechanism of these effects remains unclear7,8. Ketamine has been proposed to exert its antidepressant effects through its metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK)9. The antidepressant effects of ketamine and (2R,6R)-HNK in rodents require activation of the mTORC1 kinase10,11. mTORC1 controls various neuronal functions12, particularly through cap-dependent initiation of mRNA translation via the phosphorylation and inactivation of eukaryotic initiation factor 4E-binding proteins (4E-BPs)13. Here we show that 4E-BP1 and 4E-BP2 are key effectors of the antidepressant activity of ketamine and (2R,6R)-HNK, and that ketamine-induced hippocampal synaptic plasticity depends on 4E-BP2 and, to a lesser extent, 4E-BP1. It has been hypothesized that ketamine activates mTORC1–4E-BP signalling in pyramidal excitatory cells of the cortex8,14. To test this hypothesis, we studied the behavioural response to ketamine and (2R,6R)-HNK in mice lacking 4E-BPs in either excitatory or inhibitory neurons. The antidepressant activity of the drugs is mediated by 4E-BP2 in excitatory neurons, and 4E-BP1 and 4E-BP2 in inhibitory neurons. Notably, genetic deletion of 4E-BP2 in inhibitory neurons induced a reduction in baseline immobility in the forced swim test, mimicking an antidepressant effect. Deletion of 4E-BP2 specifically in inhibitory neurons also prevented the ketamine-induced increase in hippocampal excitatory neurotransmission, and this effect concurred with the inability of ketamine to induce a long-lasting decrease in inhibitory neurotransmission. Overall, our data show that 4E-BPs are central to the antidepressant activity of ketamine.
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Twenty-four hours after administration, ketamine exerts rapid and robust antidepressant effects that are thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine. Twenty patients suffering a major depressive episode were randomized to pretreatment with oral rapamycin (6 mg) or placebo 2 h prior to the intravenous administration of ketamine 0.5 mg/kg in a double-blind cross-over design with treatment days separated by at least 2 weeks. Depression severity was assessed using Montgomery-Åsberg Depression Rating Scale (MADRS). Rapamycin pretreatment did not alter the antidepressant of ketamine at the 24-h timepoint. Over the subsequent 2-weeks, we found a significant treatment by time interaction (F(8,245) = 2.02, p = 0.04), suggesting a prolongation of the antidepressant effects ketamine by rapamycin. Two weeks following ketamine administration, we found higher response (41%) and remission rates (29%) following rapamycin + ketamine compared to placebo + ketamine (13%, p = 0.04, and 7%, p = 0.003, respectively). In summary, single dose rapamycin pretreatment failed to block the antidepressant effects of ketamine, but it prolonged ketamine's antidepressant effects. This observation raises questions about the role of systemic vs. local blockade of mTORC1 in the antidepressant effects of ketamine, provides preliminary evidence that rapamycin may extend the benefits of ketamine, and thereby potentially sheds light on mechanisms that contribute to depression relapse after ketamine administration.
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Hydroxynorketamines (HNKs) are formed in vivo after (R,S)-ketamine (ketamine) administration. The 12 HNK stereoisomers are distinguished by the position of cyclohexyl ring hydroxylation (at the 4, 5, or 6 position) and their unique stereochemistry at two stereocenters. Although HNKs were initially classified as inactive metabolites because of their lack of anesthetic effects, more recent studies have begun to reveal their biologic activities. In particular, (2R,6R)-and (2S6)-HNK exert antidepressant-relevant behavioral and physiologic effects in preclinical models, which ledtoarapid increase in studies seeking to clarify the mechanisms by which HNKs exert their pharmacological effects. To date, the majority of HNK research has focused on the actions of (2R,6R)-HNK because of its robust behavioral actions in tests of antidepressant effectiveness and its limited adverse effects. This review describes HNK pharmacokinetics and pharmacodynamics, as well as the putative cellular, molecular, and synaptic mechanisms thought to underlie their behavioral effects, both following their metabolism from ketamine and after direct administration in preclinical studies. Converging preclinical evidence indicates that HNKs modulate glutamatergic neurotransmission and downstream signaling pathways in several brain regions, including the hippocampus and prefrontal cortex. Effects on other neurotransmitter systems, as well as possible effects on neurotrophic and inflammatory processes, and energy metabolism, are also discussed. Additionally, the behavioral effects of HNKs and possible therapeutic applications are described, including the treatment of unipolar and bipolar depression, post-traumatic stress disorder, chronic pain, neuroinflammation, and other anti-inflammatory and analgesic uses. © 2021, American Society for Pharmacology and Experimental Therapy. All rights reserved.
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The monoamine hypothesis of depression, namely that the reduction in synaptic serotonin and dopamine levels causes depression, has prevailed in past decades. However, clinical and preclinical studies have identified various cortical and subcortical regions whose altered neural activities also regulate depressive-like behaviors, independently from the monoamine system. Our systematic review indicates that neural activities of specific brain regions and associated neural circuitries are adaptively altered after chronic stress in a specific direction, such that the neural activity in the infralimbic cortex, lateral habenula and amygdala is upregulated, whereas the neural activity in the prelimbic cortex, hippocampus and monoamine systems is downregulated. The altered neural activity dynamics between monoamine systems and cortico-limbic systems are reciprocally interwoven at multiple levels. Furthermore, depressive-like behaviors can be experimentally reversed by counteracting the altered neural activity of a specific neural circuitry at multiple brain regions, suggesting the importance of the reciprocally interwoven neural networks in regulating depressive-like behaviors. These results promise for reshaping altered neural activity dynamics as a therapeutic strategy for treating depression.
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Ketamine exerts rapid antidepressant action in depressed and treatment-resistant depressed patients within hours. At the same time, ketamine elicits a unique form of functional synaptic plasticity that shares several attributes and molecular mechanisms with well-characterized forms of homeostatic synaptic scaling. Lithium is a widely used mood stabilizer also proposed to act via synaptic scaling for its antimanic effects. Several studies to date have identified specific forms of homeostatic synaptic plasticity that are elicited by these drugs used to treat neuropsychiatric disorders. In the last two decades, extensive work on homeostatic synaptic plasticity mechanisms have shown that they diverge from classical synaptic plasticity mechanisms that process and store information and thus present a novel avenue for synaptic regulation with limited direct interference with cognitive processes. In this review, we discuss the intersection of the findings from neuropsychiatric treatments and homeostatic plasticity studies to highlight a potentially wider paradigm for treatment advance.
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The drug ketamine has been extensively studied due to its use in anaesthesia, as a model of psychosis and, most recently, its antidepressant properties. Understanding the physiology of ketamine is complex due to its rich pharmacology with multiple potential sites at clinically relevant doses. In this review of the neurophysiology of ketamine, we focus on the acute effects of ketamine in the resting brain. We ascend through spatial scales starting with a complete review of the pharmacology of ketamine and then cover its effects on in vitro and in vivo electrophysiology. We then summarise and critically evaluate studies using EEG/MEG and neuroimaging measures (MRI and PET), integrating across scales where possible. While a complicated and, at times, confusing picture of ketamine's effects are revealed, we stress that much of this might be caused by use of different species, doses, and analytical methodologies and suggest strategies that future work could use to answer these problems.
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After the development of “classical” tricyclic antidepressants and monoamine oxidase inhibitors, numerous other classes of antidepressant drugs have been introduced onto the market. The selective serotonin reuptake inhibitor class is the best‐known one, but many others exist, usually identified by their mechanism of activity. In this second part of the review, focused on new‐generation antidepressants not included among selective serotonin reuptake inhibitors, the following classes are considered: noradrenergic and selective serotonergic antidepressants; norepinephrine reuptake inhibitors; serotonin, norepinephrine and dopamine reuptake inhibitors; melatonergic agonists and selective serotonergic antagonists; norepinephrine and dopamine reuptake inhibitors; and so forth. These different mechanisms underlie tolerability and safety profiles that can be very different among the classes, with each one providing significant advantages and disadvantages in comparison with others. The main characteristics of the following antidepressants are described: mianserin, mirtazapine, setiptiline, reboxetine, viloxazine, teniloxazine, atomoxetine, nefazodone, agomelatine, bupropion, esketamine, and tianeptine. The paper is focused on their metabolism and interactions, but also includes brief notes on analytical methods useful for their therapeutic drug monitoring.
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Over the last two decades, the discovery of ketamine's antidepressant properties has galvanized research into the neurobiology of treatment-resistant depression. Nevertheless, the mechanism of action underlying antidepressant response to ketamine remains unclear. This study reviews electrophysiological studies of ketamine's effects in individuals with depression as well as healthy controls, with a focus on two putative markers of synaptic potentiation: gamma oscillations and long-term potentiation. The review focuses on: 1) measures of gamma oscillations and power and their relationship to both acute, psychotomimetic drug effects as well as delayed antidepressant response in mood disorders; 2) changes in long-term potentiation as a promising measure of synaptic potentiation following ketamine administration; and 3) recent efforts to model antidepressant response to ketamine using novel computational modeling techniques, in particular the application of dynamic causal modeling to electrophysiological data. The latter promises to better characterize the mechanisms underlying ketamine's antidepressant effects.
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Objectives: This is a meta-analysis of randomized double-blind controlled-placebo trials (RCTs) examining the effectiveness, tolerability, and safety of intranasal esketamine in treating major depressive disorder (MDD). Methods: Standardized mean difference (SMD), risk ratio (RR) and their 95% confidence intervals (CIs) were calculated using RevMan version 5.3. Results: Four RCTs with 7 active arms covering 708 patients with MDD on intranasal esketamine (n = 419) and placebo (n = 289) were included. Compared with placebo, adjunctive intranasal esketamine was associated with significantly greater study-defined response (RR=1.39, 95%CI: 1.18 to 1.64, P<0.0001) and remission (RR=1.42, 95%CI: 1.17 to 1.72, P = 0.0004) at endpoint assessment. Intranasal esketamine had greater study-defined response starting at 2 h (RR= 2.77, 95%CI: 1.62 to 4.76, P = 0.0002), peaking at 24 h (RR=5.42, 95%CI: 1.38 to 21.20, P = 0.02), and at least lasting for 28 days (RR=1.36, 95%CI: 1.16 to 1.58, P = 0.0001). Similarly, intranasal esketamine had significantly greater study-defined remission starting at 2 h (RR=7.71, 95%CI: 2.16 to 27.55, P = 0.002), peaking at 24 h (RR=6.87, 95%CI: 1.55 to 30.35, P = 0.01), and lasting for 28 days (RR=1.38, 95%CI: 1.11 to 1.72, P = 0.004). Intranasal esketamine had a significantly higher rate of discontinuation due to intolerability (RR=3.50, 95%CI: 1.38 to 8.86, P = 0.008). Discontinuation due to any reasons and inefficacy were similar between the two groups. Conclusion: Intranasal esketamine appears to have an ultra-rapid antidepressant effect for MDD, at least lasting for 28 days. The long-term therapeutic effect and safety of intranasal esketamine need to be further examined in large-scale RCTs.