Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_205_библиотеки_им_акад_М_И_Перельмана
.pdf
382 The APA Publishing Textbook of Mood Disorders, Second Edition
https://t.me/med1917
the clinical use of ketamine to treat depression to date. Similarly, there has not been
clear evidence of significant uropathy or gastrointestinal disorders associated with
appropriate use of ketamine to treat mood disorders. However, we should be aware
that the onset of these symptoms may require prolonged exposure (Li et al. 2019), and
the absence of a coordinated data collection system for patients receiving ketamine
treatments could make it difficult to reliably identify such cases if they are to develop.
Third, there is a possibility that treatment with ketamine could lead to future drug
abuse and encourage drug diversion. Ketamine is known to have abuse liability and
has been classified as a Schedule III controlled substance by the FDA since 1999. Rec
reational misuse of the drug has been reported since the early 1970s, but its popularity
as a “club drug” grew in the 1980s, spreading to urban centers in several international
locations (Sassano-Higgins et al. 2016). Although there are reports suggesting discon
tinuation symptoms and tolerance associated with chronic, frequent ketamine misuse,
there is no clear evidence of a typical withdrawal syndrome following ketamine dis
continuation. The Monitoring the Future study, assessing the prevalence of substance
misuse in teenagers and young adults, has reported consistent rates of ketamine mis
use since 2002 (Johnston et al. 2016), with an annual U.S. prevalence of ketamine in
2018 of 0.7%, 0.9%, and 0.9%, respectively, among 12th graders, college students, and
young adults. In response to concerns of ketamine misuse internationally, the World
Health Organization Expert Committee on Drug Dependence reviewed the latest evidence on the potential harm to health and dependence-producing properties of ketamine in 2016 (World Health Organization 2016). The committee decided to uphold its
previous recommendations issued in 2006, 2012, and 2014 that ketamine should not be
scheduled or controlled under the international drug control conventions, citing that
illicit use of ketamine has been reported on a relatively small global scale for the past
several decades, with dependence and overdose being rare. Further supporting this
decision is the recognition that ketamine plays an essential role as a general anesthetic
in low-resource countries and that further controlling ketamine may limit the potential
for expanding research into its use in treating depression and other psychiatric disorders. It will be interesting to see how the increased use of ketamine for the treatment
of mood disorders will impact the illicit use of ketamine moving forward.
Lastly, the unknown impact of long-term treatment with ketamine on brain function
in general poses considerable challenges in determining the risks and benefits of
chronic or maintenance ketamine therapy, especially for patients with TRD. As men
tioned, the large majority of studies involving ketamine have focused on the short-term
benefits of the treatment (those lasting days to weeks). There has been relatively little
high-quality work demonstrating the effectiveness and safety of continued ketamine
treatment. This lack of data on long-term treatment is compounded by concerns of
drug dependency, either physiological or psychological, that have led some to wonder
whether it may be difficult for patients to successfully taper and discontinue use of the
drug over time. These concerns can only be addressed with rigorous longitudinal inquiries. Unfortunately, unless a concerted effort is made to collect, analyze, and disseminate this data, guidance on this issue may remain elusive for the foreseeable future.
-
-
-
-
-
Comparing Routes of Delivery
Oral delivery is especially appealing for its ease of use and accessibility; however,
ketamine is subject to extensive first-pass metabolism resulting in relatively low bio-
383 Ketamine and Other Investigational Agents
https://t.me/med1917
availability (Clements et al. 1982), and an oral formulation could increase the risk of
misuse and diversion. Despite these concerns, there have been over a dozen case re
ports and small proof-of-concept studies exploring the possibility of oral dosing for
the treatment of mood disorders (Rosenblat et al. 2019). Although the volume and
quality of the relatively small number of studies to date do not afford us a firm evi
dence base, there is evidence to suggest the potential for clinical benefit and otherwise
acceptable overall tolerability of oral dosing, albeit at a much longer time to onset and
smaller magnitude of antidepressant effect compared with intravenous dosing
(Rosenblat et al. 2019). Attempts have also been made to explore the potential for sublingual (Lara et al. 2013; Nguyen et al. 2015), subcutaneous, intramuscular (Loo et al.
2016), and intranasal (Lapidus et al. 2014) dosing in order to avoid the complications
of intravenous dosing. Again, the quality, size, and number of these studies do not al
low any meaningful conclusions to be drawn regarding the comparable efficacy and
safety of the different routes of administration (Andrade 2017). Collectively, these
studies all seem to suggest, similarly to the rodent studies, that the efficacy and sideeffect profiles are closely tied to the peak plasma levels achieved. The relevance of
other pharmacokinetic factors to the ultimate clinical utility of the treatment—such as
time to maximal concentration, area under the curve, and plasma clearance rate—still
needs to be determined.
Esketamine
-
-
-
Adequately addressing efficacy and safety issues with high-quality data is expensive.
Costs have been the major factor impeding the collection of high-quality data with ra
cemic ketamine. However, many of these concerns have been successfully addressed
in pursuing the FDA approval of esketamine nasal spray (Spravato
tion to an oral antidepressant for patients with TRD (Bahr et al. 2019). Ketamine is a
racemic mixture composed of equal amounts of left- and right-handed enantiomers
(mirror images of the molecule that are nonsuperimposable and cannot be made identical by reorientation). Esketamine is the (S)-enantiomer isolate of the racemate, analogous to the left hand as arketamine, the (R)-enantiomer, is to the right hand. While the
enantiomers are identical in atomic composition, the unique structural orientation of
each enantiomer results in different pharmacological properties. Esketamine has a
greater affinity for the NMDA glutamate receptor, thus allowing for a greater amount
of NMDA receptor blockade with lower doses of the drug (White et al. 1980). This difference in NMDA receptor binding affinity is believed to account for varying effects
of the two enantiomers on several physiological and psychological measures (Vollenweider et al. 1997). Practically, the greater potency of esketamine also affords greater
flexibility in the route of delivery, as a clinically therapeutic concentration may be de
livered in a reduced volume of vehicle.
TM
) as augmenta-
Evidence for Antidepressant Action
On the basis of the original hypothesis that the proximal effects of ketamine on the
NMDA receptor generated the cascade of events resulting in antidepressant effects,
the decision was made to explore the antidepressant action of esketamine, given its
greater NMDA receptor affinity (Table 22–2). A small Phase II study was completed
in 2016 showing esketamine’s antidepressant action when the drug was delivered intravenously over 40 minutes, a protocol similar to the one most commonly used for
-
-
384 The APA Publishing Textbook of Mood Disorders, Second Edition
https://t.me/med1917
racemic ketamine (Singh et al. 2016a). The results of the relatively small proof-of-concept study were nearly identical to those reported previously with racemic ketamine,
with marked improvements in depression ratings seen within 1 day. In this case, how
ever, there was evidence to support equal efficacy of a lower (0.2 mg/kg) dose of esketamine over placebo. This suggestion of enhanced potency of esketamine over
racemic ketamine further afforded the advantage of considering an alternative route
of delivery of a more concentrated solution, and the decision was made to explore the
possibility of delivering the medication intranasally, which would be more practical
for outpatient physicians to administer. As noted previously, there was preliminary
evidence to suggest intranasal delivery of racemic ketamine could produce antide
pressant effects, but the magnitude of the response appeared to be reduced (Lapidus
et al. 2014). This relatively reduced efficacy was thought to be related to the inability
to achieve optimal plasma and ultimately brain concentrations using the intranasal
route. These new data suggested that the alternative use of esketamine may suffi
ciently affect NMDA receptor function even when provided intranasally.
Intranasal Esketamine in Clinical Trials
A Phase II study of 67 adults with TRD examining the effects of three fixed doses of
intranasal esketamine suggested the presence of sustained antidepressant effects for
doses ranging from 28 to 84 mg administered twice weekly, with the appearance of
an ascending dose-response relationship (Daly et al. 2018). This study was followed
by a series of large Phase III clinical trials: two randomized, placebo-controlled trials
involving 223 and 346 participants, respectively, using either fixed (Fedgchin et al.
2019) or flexible (Popova et al. 2019) dosing of 56 mg and 84 mg; a relapse-prevention
randomized withdrawal study with 705 participants (Daly et al. 2019); and a longterm safety study of 802 TRD patients receiving up to 1 year of weekly or biweekly
treatments (Wajs et al. 2020). In addition, a flexible-dose study with doses of esketa
mine ranging from 28 mg to 84 mg was conducted in 138 TRD patients age 65 years
or older (Ochs-Ross et al. 2020).
The flexible-dosing study comparing the change in depression severity from baseline to day 28 between two groups of TRD patients treated with either esketamine
plus a new oral antidepressant or placebo plus this antidepressant showed a greater
improvement in the group receiving esketamine, with most of the separation between
the groups occurring over the first 24 hours and being sustained for the duration of
the study (Popova et al. 2019). At the end of the 4-week study, two-thirds of patients
randomly assigned to receive esketamine were taking 84 mg, and a greater propor
tion of patients treated with esketamine plus the oral antidepressant demonstrated a
response (69.3% vs. 52.0%) or had experienced a remission of symptoms (52.5% vs.
31.0%). The results of the fixed-dose study were less clear (Fedgchin et al. 2019), highlighting that not all Phase III esketamine studies met their designated primary outcome. Although both doses (56 mg and 84 mg) produced numerically greater changes
in the Montgomery-Åsberg Depression Rating Scale measure of depression severity,
as well as higher rates of response (54.1% and 53.1%) and remission (36.0% and
38.8%) compared with saline placebo (38.9% and 30.6%, respectively), the primary
outcome measure comparing the new oral antidepressant plus esketamine versus the
new oral antidepressant plus placebo did not meet the prespecified statistical significance criterion. In total, the two studies consistently demonstrated an increased ben-
-
-
-
-
-
TABLE 22–2. Representative selection of randomized controlled trials of esketamine in subjects with treatment-resistant major
https://t.me/med1917
depressive disorder
Ketamine and Other Investigational Agents
Sample
(age range)
Singh et al. 2016a 30
(18–64 y)
Daly et al. 2018
(Phase II)
Fedgchin et al. 2019
(Phase III)
Popova et al.
2019 (Phase III)
67
(20–64 y)
223
(18–64 y)
346
(18–64 y)
Design
Double-blind IV
Double-blind,
delayed start,
placebo controlled
with open-label
extension
Double-blind,
parallel-group,
placebo controlled
Double-blind,
parallel-group,
placebo controlled
Route,a schedule, dose Outcome
Single 40-minute infusion;
IN
Fixed-dose phase
Open-label, flexible-dose phase
IN
Fixed dose (56 mg or 84 mg),
IN
Flexible dose; twice weekly × 4 weeks;
saline vs. esketamine 0.2 mg/kg
vs. 0.5 mg/kg
(28 mg, 56 mg, or 84 mg):
twice weekly × 2 weeks;
saline (placebo) vs. esketamine
28 mg vs. 56 mg vs. 84 mg
(starting at 56 mg on day 15):
twice weekly × 2 weeks,
then weekly × 3 weeks,
then biweekly through 9 weeks
twice weekly × 4 weeks; saline
(placebo) vs. esketamine 56 mg
vs. 84 mg
saline (placebo) vs. esketamine 56 mg
or 84 mg
b,c
Significant improvement at each dose
tested at 2 hours through 7 days
Significant improvement compared with
placebo after week 1, with an ascending
dose-response curve; improvement
sustained with reduced dosing
frequency and repeated administration
Response rate, day 28: placebo = 39%;
56 mg = 54% (P=0.027 vs. placebo);
84 mg = 53% (P=0.088 vs. placebo)
Response rate, day 28: placebo = 52%;
esketamine 56 mg or 84 mg = 69%
(P=0.020 vs. placebo)
385
TABLE 22–2. Representative selection of randomized controlled trials of esketamine in subjects with treatment-resistant major
https://t.me/med1917
depressive disorder (continued)
386
Sample
Route,a schedule, dose Outcome
IN
Flexible dose; twice weekly × 4 weeks,
then weekly or biweekly to 12 weeks,
then random assignment to placebo
vs. esketamine continuation
IN
Flexible dose (28 mg, 56 mg, or 84 mg)
Daly et al. 2019
(Phase III)
Wajs et al. 2020
(Phase III)
(age range)
705
(18–64 y)
802
(≥18 y)
Design
Double-blind,
randomized
withdrawal following
stable response or
remission at week 16
Open-label, long-term
safety
Induction phase: twice weekly × 4 weeks
48-week optimization/maintenance
phase: weekly or biweekly for patients
who were responders
Ochs-Ross et al.
2020 (Phase III)
138
(≥65 y)
Double-blind,
parallel group,
placebo controlled
IN
Flexible dose; twice weekly × 4 weeks;
saline (placebo) vs. esketamine 28 mg,
56 mg, or 84 mg
a
Route: IN=intranasal; IV=intravenous.
b
Rating scale used in all studies: Montgomery-Åsberg Depression Rating Scale.
c
Outcome: P=P value (difference from placebo); [HR]=hazard ratio; CI=confidence interval.
b,c
Significant decrease in risk of relapse
with esketamine continuation
in stable responders (51% risk reduction,
HR=0.49; 95% CI=0.29–0.84)
and remitters (70% risk reduction,
HR=0.30; 95% CI=0.16–0.55)
Common treatment-emergent adverse
events: dizziness (32.9%), dissociation
(27.6%), nausea (25.1%), headache
(24.9%)
Response rate, week 4:
placebo = 13%;
esketamine 56 mg or 84 mg = 27%
(P=0.058 vs. placebo)
The APA Publishing Textbook of Mood Disorders, Second Edition
387 Ketamine and Other Investigational Agents
https://t.me/med1917
efit from the addition of esketamine to the initiation of a new oral antidepressant in
TRD patients, with the separation between the two treatment conditions occurring
within the first day and persisting, but not growing, over the remaining 4 weeks of
the study. The short-term Phase III flexible esketamine dosing trial in patients age 65
years or older also did not meet its primary outcome, although esketamine also
demonstrated a trend toward improvement over placebo when added to a new oral
antidepressant (Ochs-Ross et al. 2020). While rates of treatment-emergent adverse
events and tolerability in this older patient population were comparable to rates in
studies with younger patients, the patients in this study remained at lower induction
doses in earlier phases of the study, which may have resulted in a delay in separation
of response from control. Sub-analyses from this study also suggested that treatment
response in patients older than 75 years may be similar to that in patients from other
esketamine trials encompassing a younger age groups and that patients older than 65
years may require longer overall periods of induction or acute-phase treatment to
achieve benefits similar to those in younger cohorts. These issues remain open ques
tions for further study with respect to esketamine.
The next important question addressed in this series of trials related to the safety
of repeated dosing over an extended period and durability of the benefit with and
without continued treatment. The long-term safety study was able to demonstrate
persistent antidepressant effects lasting for up to a year with either ongoing weekly
or every-other-week dosing in a large percentage of the patients responding to the initial 4-week index course (Wajs et al. 2020). However, the randomized withdrawal
study provided evidence suggesting that in many cases patients may require ongoing
treatments with esketamine in order to maintain the antidepressant response (Daly et
al. 2019). The increase in relapse rate following discontinuation was notably higher in
the patients who experienced a response (>50% improvement in symptom severity)
but not remission, with 57.6% having a return of their depression after discontinuation of the esketamine over the course of the study. If esketamine treatment was maintained along with the oral antidepressant, slightly over one-fourth of the patients
relapsed, whether they had achieved remission or not.
The long-term safety study (Wajs et al. 2020) also helped to address the major concern of adverse effects. Here, participants could receive esketamine dosed at flexible
intervals between dosing sessions, either weekly or biweekly interchangeably, depend
ing on 4-week interval symptom scores over the course of 1 year. As expected, there
were several common transient treatment-emergent adverse events, including dizziness, dissociation, nausea, and headache, all occurring in one-fourth to one-third of patients treated over that time period. Only about one-tenth of the patients discontinued
esketamine because of these side effects. Seven percent of the participants experienced
serious adverse events over the study duration, and two deaths were reported, but neither of the deaths was considered to be related to esketamine. It is important to note
that no evidence of respiratory depression was found during the treatments.
To address concerns regarding long-term CNS and urinary system exposure to repeated dosing of the drug, cognitive performance and urinary symptoms were
closely monitored. Cognitive performance generally either improved or remained
stable relative to baseline assessments, and there were no reported cases of interstitial
cystitis over the duration of the study. In general, treatment-emergent dissociative
symptoms were transient, resolving within 90 minutes after the start dosing. How-
-
-
388 The APA Publishing Textbook of Mood Disorders, Second Edition
https://t.me/med1917
ever, the intensity of the transient adverse events, especially sedation and dissociation, in some individuals, and the remaining concerns for substance misuse and drug
diversion, led the FDA to restrict distribution and use of the treatment under a Risk
Evaluation and Mitigation Strategy that requires patients to administer the drug in
the presence of a health care provider in an approved health care setting, with monitoring lasting at least 2 hours after initiating dosing (U.S. Food and Drug Administration 2020).
Other Investigational Glutamatergic Agents
in the Pipeline
The unwanted side effects experienced with ketamine and esketamine, along with the
restrictions on the accessibility of treatments requiring in-office administration, have
prompted the search for other pharmacotherapies with similar mechanisms of action
and abilities to produce rapid-onset antidepressant effects, but with improved safety
profiles. Many of the novel drugs under investigation are pharmacologically quite
similar to ketamine, either having direct effects on the NMDA receptor or targeting
other components of glutamatergic or GABAergic neurotransmission. Other drugs
target shared intracellular mechanisms with ketamine or produce physiological and/
or psychological effects similar to those of ketamine.
Arketamine is the sister enantiomer of esketamine contained within the racemic
mixture. Given that arketamine has a lower affinity for the NMDA receptor, reduced
anesthetic properties, and fewer acute effects on cognition and perception (Vollenweider et al. 1997), it has not been the target of nearly as much research. However,
many of these same properties make it an extremely interesting prospect clinically, if
it retains some of the same antidepressant properties as the racemic mixture. Al
though there are several reports of the R-enantiomer having antidepressant-like
properties in rodent studies (Yang et al. 2015), only one very small open-label clinical
trial has been published to date suggesting it may possess rapid-onset antidepressant
properties at doses producing minimal transient effects on arousal, cognition, and
perception (Leal et al. 2021). Much attention was drawn to a report demonstrating that
a metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), exerts behavioral,
electroencephalographic, electrophysiological, and cellular antidepressant-related actions, and is essential for ketamine to produce antidepressant effects in mice (Zanos et
al. 2016). The finding that this metabolite appeared to have a very low affinity for the
NMDA receptor raised questions about the true role of the NMDA receptor in ketamine’s mechanism of action. However, conflicting studies in the rodent models (Shirayama and Hashimoto 2018) and two recent studies documenting a relationship
between higher (2S,6S;2R,6R)-HNK concentrations and weaker antidepressant re
sponse in humans have made it challenging to interpret the contribution of these metabolites to the overall mechanism of antidepressant action (Farmer et al. 2020;
Grunebaum et al. 2019).
Several pharmacological relatives of ketamine have also been investigated for potential antidepressant properties. Similar to ketamine, lanicemine (AR-R 15896AR,
AZD-6765, BHV-5000) is a nonselective NMDA receptor antagonist with moderately
-
-
389 Ketamine and Other Investigational Agents
https://t.me/med1917
high affinity for the receptor. With data suggesting rapid-onset antidepressant effects
following a single infusion (Sanacora et al. 2014), the drug was advanced to Phase II
randomized, placebo-controlled trials. The first of these studies, comparing fixed
doses of 100 mg and 150 mg lanicemine with saline placebo in 152 participants,
showed both doses of the drug to have superior antidepressant effects compared with
placebo on a variety of measures (Sanacora et al. 2014). However, a second study of
300 participants randomly assigned to receive fixed doses of 50 mg or 100 mg, or pla
cebo, did not show either of the doses to have antidepressant effects superior to those
of placebo (Sanacora et al. 2017), leaving questions of whether the initial study re
sulted in a type I error or whether the high placebo response rate in the second study
obscured any potential antidepressant efficacy.
Memantine, another nonselective NMDA receptor antagonist that has notable differences in receptor affinity, was also studied for antidepressant properties in a few
small-scale clinical trials in mood disorders under various study designs. In general,
these studies did not produce evidence to suggest a meaningful antidepressant response (Kishi et al. 2017).
Early in the search for ketamine-related compounds with possible antidepressant
action, Traxoprodil (CP-101,606), an NR2B subunit–selective NMDA receptor antag
onist, was studied in a novel proof-of-concept small clinical trial. Although the results
suggested that the drug has antidepressant properties (Preskorn et al. 2008), the drug
was not pursued, likely because of concerns about QTc prolongation (Machado-Vieira
et al. 2017). Rislenemdaz (CERC-301, MK-0657), a second NR2B subunit–selective
NMDA receptor antagonist that was delivered orally, was studied in Phase II studies
that failed to show efficacy on the primary endpoint according to publications and
press releases from the company (Ibrahim et al. 2012).
Dextromethorphan, the commonly used cough suppressant, is also known to have
antagonist effects on the NMDA receptor in addition to activity at sigma
and mu opi-
1
oid receptors, the serotonin transporter (5HTT), and calcium channels, and has been
studied for antidepressant properties in a variety of forms. Retrospective case series
suggested that dextromethorphan combined with the cytochrome P450 (CYP) 2D6 inhibitor quinidine to slow the rate of metabolism could benefit patients with refractory
mood disorders (Kelly and Lieberman 2014; Nofziger et al. 2019). Several recent clin
ical trials examining the antidepressant efficacy of AXS-05, a combination of dextromethorphan and bupropion (an oral antidepressant that also acts as a CYP2D6
inhibitor), have been completed to date, with clinical trial results likely to be available
in the coming years (Wilkinson and Sanacora 2019).
Other drugs attempting to target NMDA receptor function via interactions with
the glycine binding regions of the receptor have also been examined. Rapastinel
(GLYX-13), the most thoroughly studied at this time, has a unique course of drug development (Moskal et al. 2017). It was originally derived from studies aiming to create a monoclonal antibody that could be used to study synaptic plasticity by using
material from newborn rat hippocampi as an immunogen. Further work led to the
identification of a tetrapeptide component of the antibody, GLYX-13, that had activity
on an NMDA receptor– and hippocampus-dependent test of associative learning and
memory. Evidence showing GLYX-13 to override the effects of a competitive glycine
site antagonist, 7-chlorokynurenic acid, suggested it was acting by modulating
NMDA receptor function through interaction with the glycine binding site of the re-
-
-
-
-
390 The APA Publishing Textbook of Mood Disorders, Second Edition
https://t.me/med1917
ceptor. Initial preclinical work was very encouraging, with the drug demonstrating
antidepressant-like effects and cellular changes consistent with those of ketamine in
a variety of rodent models (R.J. Liu et al. 2017). Preliminary Phase II clinical trials fur
ther suggested clinical benefit in treating depression (Preskorn et al. 2015); however,
three large Phase III clinical trials did not find the drug to have benefits superior to
placebo in the treatment of depression (Tumolo 2019).
D-Serine, an endogenous amino acid neurotransmitter, is capable of modulating
NMDA receptor activity by interacting with the glycine binding site on the receptor
and producing an agonist-like action. As mentioned earlier, George Crane (1959) noted
a rapid improvement in depressive symptoms when patients were treated with
cycloserine, a closely related compound to
D-serine, for tuberculosis in the late 1950s.
More recently, there have been a series of preclinical studies showing that
and
D-cycloserine produce antidepressant effects in rodent models (MacKay et al.
D-
D-serine
2019). In parallel, there have been several small proof-of-concept studies suggesting
that
D-cycloserine may have beneficial effects in treating a number of psychiatric dis-
orders, including MDD, especially when used in combination with other therapies.
However, there are conflicting reports (Heresco-Levy et al. 2006, 2013; Schade and
Paulus 2016). The interpretation of these studies is complicated by the fact that
D-
cycloserine can act as a partial agonist at the glycine site, making the dosage of the
medication an extremely important variable in relation to drug effects.
is now in clinical trials in the form of NRX-101 (
D-cycloserine combined with lurasi-
D-Cycloserine
done) for the maintenance of response in patients with bipolar depression with suicidal ideation who have responded to intravenous ketamine.
A third drug targeting the glycine site of the NMDA receptor was also recently
evaluated for antidepressant activity. AV-101 (
L-4-chlorokynurenine), the prodrug
that is converted to 7-chlorokynurenic acid, which binds and modulates the glycine
site of the NMDA receptor, had shown promising results in preclinical studies
demonstrating antidepressant-like effects and cellular changes similar to those of
ketamine in rodent models (Zanos et al. 2015). A small proof-of-concept study re
cently completed at the National Institute of Mental Health did not show evidence to
support the drug’s antidepressant effect in patients with depression, but it suggested
that there may not have been sufficient conversion of the prodrug to 7-chlorokynurenic acid to effectively modulate activity of the receptor (Park et al. 2020).
Attempting to target the proposed downstream mechanisms involved in ketamine’s antidepressant action, NV-5138, a small molecule that activates mTORC1
(mechanistic [mammalian] target of rapamycin complex 1) by binding to sestrin2, has
been studied in rodent models and in early-phase clinical trials (Hasegawa et al. 2019;
Kato et al. 2019). A single dose of NV-5138 produced rapid antidepressant actions in
behavioral models of depression and increased the number and function of synapses
as well as levels of synaptic proteins in the prefrontal cortex of rats. The Phase I studies were designed primarily to examine the safety, tolerability, and pharmacokinetics
of the drug, but they also included a subset of patients with MDD. The results of these
studies should be published in the near future and will provide information to sug
gest whether future clinical trials are warranted.
Moving even further downstream from what is believed to be ketamine’s proximal
mechanism of action, drugs targeting presynaptic glutamate release and postsynaptic
activation of non-NMDA glutamate receptors are being evaluated for antidepressant
-
-
-
391 Ketamine and Other Investigational Agents
https://t.me/med1917
properties. The extent of exploration for many of these drugs has been limited to preclinical investigations; however, several have been studied in early-phase clinical
trials (Kadriu et al. 2019; Murrough et al. 2017; Wilkinson and Sanacora 2019).
Many of the drugs that failed to demonstrate clear efficacy in the clinical trials
showed great promise in rodent models, and some even showed activation of pur
ported mechanistic targets in human studies. It will be important for the future of
translational antidepressant drug development to understand why these models pre
sented incongruous results with the clinical trial data. For some, it may simply be the
case that the drug under investigation did not adequately engage the appropriate tar
get, as was suggested by the rodent models. For example, as noted above, AV-101 (
chlorokynurenine) was developed as a prodrug to 7-chlorokynurenic acid, a wellcharacterized selective NMDA receptor glycine site antagonist that appeared highly
effective in rodent models. However, the conversion to the active metabolite appears
to be limited in humans, not allowing measurable concentrations of 7-chlorokynurenic
acid to reach the central nervous system (Park et al. 2020). Similarly, rapastinel, another purported glycine site modulator, has an indirect effect on NMDA receptor ion
channels as a functional modulator of the glycine site of the NMDA receptor in rodent
models. Thus, the indirect effects may require several additional moderating factors
and therefore reflect a greater chance of cross-species physiological variation.
Given these limitations, it is difficult to interpret how the negative clinical trials
with those compounds inform us about the actual antidepressant potential of NMDA
receptor modulation. The interpretation of the clinical trial data in relation to the underlying hypothesis of antidepressant mechanism of action is also complicated by the
nuances and complexity of clinical trial designs. The early proof-of-concept studies
with ketamine showed very large effect sizes that were obvious within hours of initial
dosing. As the studies became more rigorous, with broader geographic distribution
of patient samples and greater expectancy of drug effects, the magnitude of the effect
size and speed of onset relative to the controlled arm of the studies may have been
somewhat reduced. This reduction was readily observed within the ketamine and es
ketamine studies over time and was highlighted by the contrasting results of the two
lanicemine studies (Sanacora et al. 2017). Altogether, this makes it very difficult to
evaluate the potential of the entire class of drugs or the future likelihood of success
for novel drugs with related mechanisms of action without understanding the finer
details of each drug and study design.
L-4-
-
-
-
-
Conclusion
The emergence of ketamine as a treatment for depression has changed the landscape
of antidepressant drug development and expanded our understanding of the patho
physiology of mood disorders (Figure 22–1). It has proven that, contrary to long-held
beliefs, antidepressant effects can be seen within hours of treatment onset and that it
is possible to develop truly novel antidepressant drugs that do not have proximal effects on the monoaminergic system. It has also helped us reconceptualize our thinking about the mechanisms of antidepressant action. The fact that the antidepressant
effect of ketamine is seen well beyond the presence of the active drug in the body suggests that treatment must initiate a cascade of physiological processes that ultimately
-
Соседние файлы в папке Библиотека им академика М.И. Перельмана