After years of off-label use, the United States FDA approved the first ketamine-related drug
in 2019.
Though, it's a fairly unique intranasal preparation of S-ketamine, called Spravato.
Before this, nearly everyone received intravenous infusions of racemic ketamine, containing
both S-ketamine and R-ketamine, and the racemate remains a popular option for depression.
Despite how it may seem from the Spravato approval, there's good reason to believe S-ketamine
may not superior to the racemate or to R-ketamine.
When someone uses ketamine, they're exposed to two isomers, specifically the S- and R-enantiomers
of ketamine.
Those are effectively two different drugs with their own properties.
The affinity of S-ketamine for the NMDA receptor is 4 times larger than R-ketamine's affinity,
and when used for anesthesia, its potency is around 4 times greater than that of R-ketamine.
Therefore, the NMDA receptor has long been viewed as the most important target of ketamine,
given its correlation with the anesthetic and analgesic effects.
But if we go by the preclinical research, that may not be the most important mediator
of ketamine's antidepressant properties.
Instead, R-ketamine could be superior.
We should always be careful when interpreting animal research, but if that research carries
over to humans, R-ketamine would likely be longer-lasting, more effective, and potentially
safer.
The enantiomers seem to be similarly effective in the hours after they're used, but R-ketamine
stands apart from S-ketamine when it comes to activity 4-7 days later.
The enantiomers may also offer distinct effects that are valuable in psychiatric conditions.
If so, racemic ketamine could be the best option and using a single enantiomer may only
make sense if R-ketamine is confirmed to be safer.
Although ketamine and S-ketamine are the only options on the market right now, research
on R-ketamine is underway.
Perception Neuroscience is developing R-ketamine with the belief that's more effective and
safer, yet is often overlooked.
This is one of the companies controlled by ATAI Life Sciences, which is a major investor
in Compass Pathways, a company that's developing psilocybin as an antidepressant.
Currently, it's working on a Phase I trial to test R-ketamine's pharmacokinetics and
tolerability, so it will be a while before we have comprehensive efficacy data.
The CEO of Perception Neuroscience, Dr. Terence Kelly, says they hope to show R-ketamine is
at least as effective as S-ketamine and ketamine, and that it has fewer side effects and safety
concerns.
Since most of the focus has historically been on S-ketamine and the NMDA receptor, there's
minimal research on R-ketamine and we still lack head-to-head clinical trials of the enantiomers,
making it impossible to know whether R-ketamine is as promising as it seems.
Since 2000, when the first controlled trial of intravenous ketamine was published, most
studies have used essentially the same protocol, consisting of a 40-minute infusion of 0.5
mg/kg of ketamine.
Few studies have tried alternative routes of administration or looked at the individual
enantiomers.
The lack of clinical research comparing the enantiomers means we cannot say which is superior.
Data from different trials cannot simply be compared given the influence of different
patient populations, study designs, and other factors.
However, the available studies do provide some insight.
Research with S-ketamine shows it can quickly reduce depressive symptoms, including in treatment-resistant
patients, and a portion of the benefits persist for around a week after a single dose.
For example, a trial in 2016 reported a 65% response rate one day after patients with
treatment-resistant depression received intravenous S-ketamine, whereas none of the placebo patients
responded.
In general, the efficacy of S-ketamine is similar to that of ketamine, though there
are some indications that intravenous ketamine may be a bit more effective.
One of the only publications comparing S-ketamine with ketamine was on two treatment-resistant
patients.
The treatments had a similar effect on depression, with one patient not responding to either
drug, while the other had a 46-58% reduction in symptoms for a few days.
In both cases ketamine had more transient perceptual and psychological side effects
than S-ketamine.
But with such a small sample size, this isn't very informative.
Spravato was created by Janssen Pharmaceuticals, which is owned by Johnson & Johnson.
In 2019 it became the only approved ketamine-related treatment for depression in the US, and it's
administered as an intranasal formulation in a clinical setting.
The studies are mixed on intravenous ketamine, and that's even more true with intranasal
S-ketamine.
In 2018, two Phase 3 trials for S-ketamine in treatment-resistant depression were published.
One was in elderly patients, where S-ketamine was combined with a newly initiated oral antidepressant.
While it seemed to have an effect, that study failed on its primary measure of efficacy.
And the second study was in adults, where the primary efficacy endpoint showed S-ketamine
was moderately effective.
The lackluster results persisted going into 2019, when Janssen sought approval from the
FDA.
In February, an FDA panel voted 14-to-2 in favor of recommending that Spravato be approved.
They reviewed the results from five Phase 3 trials and other relevant studies, encompassing
1,700 people.
They recommended approval despite only two of the five Phase 3 trials showing a significant
positive result, and in general, S-ketamine only had modest effects.
Those who voted for approval said they believed Spravato could help at least a portion of
patients and based on a survey conducted by Janssen, patients were comfortable with the
side effects (like hallucinations and dissociation) if the drug could potentially help them.
Concerns about weak efficacy and side effects, such as dissociation and hypothetical abuse
potential, were cited by the two panelists who voted against approval.
By March 2019, the FDA had officially approved intranasal S-ketamine for use in conjunction
with an oral antidepressant in treatment-resistant depression patients.
Its availability is restricted, with patients having to receive the drug in the presence
of a healthcare provider, instead of taking it home.
Because it was studied in treatment-resistant patients, modest efficacy is more encouraging
than it would be for a normal population of depressed patients.
Since they've already shown some resistance to available treatments, it doesn't take a
large effect for intranasal S-ketamine to be helpful.
That said, the unimpressive Spravato studies suggest people may still respond better to
off-label intravenous ketamine.
Most of the studies comparing the enantiomers have been performed in animals, where R-ketamine
is usually superior, lasts longer, and may be safer.
In mice exposed to social defeat stress, which produces depressive-like behavior, both S-ketamine
and R-ketamine alleviated the negative effects, but R-ketamine was more potent.
In a similar model using learned helplessness in rats, only R-ketamine was effective when
behavior was tested five days after drug administration.
And in rats with corticosterone-induced depressive behavior, ketamine and R-ketamine worked,
but S-ketamine was largely ineffective.
Both enantiomers had positive effects shortly after dosing, but the effect of R-ketamine
was larger and more persistent.
The same was shown in mice using two tests commonly used as preliminary indicators of
antidepressant activity, the Tail Suspension Test and Forced Swim Test, in which animals
who are experiencing a depression-like state become more immobile and give up faster.
In both tests, S-ketamine was more potent at 30 min, then the enantiomers were equipotent
at 24 hours, but by 48 hours, only ketamine and R-ketamine were effective.
As you can probably tell from the methods, which involve things like social defeat stress,
corticosterone exposure, and immobility tests, these studies do not directly map on to human
experience.
But these tools have been found to detect drugs that may be effective in humans and
the neurological changes caused by things like social defeat stress mirror aspects of
depression physiology in people.
Using these imperfect but helpful animal tests, researchers have identified mechanisms that
may be important for ketamine's effect, as well as differences in the pharmacology of
the enantiomers.
A simple explanation for differences between S- and R-ketamine would be that one enantiomer
has different pharmacokinetics or is better at entering the brain.
If this were true, one enantiomer could be superior simply because people are exposed
to a larger dose of it, not because its mechanism in the brain is superior.
But this explanation has mostly been ruled out.
In rodents, levels of S- and R-ketamine are similar in the brain and blood, and both are
cleared from plasma in 4-8 hours.
Differences have been reported in humans, but they're small.
In healthy males who received small 7 mg infusions, the kinetics were similar, though the clearance
of R-ketamine was 20% smaller, contributing to a somewhat larger exposure to R-ketamine.
And in patients with complex regional pain syndrome who received a 5-day continuous infusion
of ketamine, plasma levels of R-ketamine and its metabolites were 30-40% higher than levels
of S-ketamine and its metabolites.
Those differences could be somewhat impactful, but they're unlikely to produce meaningful
differences in antidepressant efficacy.
Some mechanisms appear to be important for both enantiomers.
Blocking glutamatergic AMPA receptors or interfering with the neurotrophin BDNF can reduce or block
the efficacy of S-ketamine and R-ketamine.
In contrast, the antidepressant effect of S-ketamine in mice may involve activation
of the mTORC1 pathway, whereas R-ketamine is biased towards activity along the ERK pathway.
When the ERK pathway was inhibited, only R-ketamine lost its behavioral effects.
And when mTORC1 was inhibited by rapamycin, only S-ketamine activity was blocked.
Through those pathways, cells respond to external signals by adjusting the activity of systems
involved in neuroplasticity, metabolism, and cell survival.
Some of the proteins regulated by those pathways facilitate synapse formation, changing the
strength of synaptic connections, and affecting cell survival and activity.
Depressive states are associated with reduced neuroplasticity and reductions in the size
of depression-relevant brain regions like the prefrontal cortex and hippocampus.
By activating the mTORC1 or ERK pathways, the physiology of depression may be counteracted.
And what makes ketamine distinct from conventional antidepressants is that reversing stress-
and depression-induced neurological changes happens in hours, not weeks.
Another difference between the enantiomers is at the level of the gut microbiome, which
potentially contributes to depression.
In mice, chronic stress altered the gut microbiome and those changes were partially reversed
by ketamine, with R-ketamine being more potent than S-ketamine.
R-ketamine was also more potent for alleviating depressive behavior, and the enantiomers had
different effects on specific classes, families, and genera of bacteria.
A separate study comparing R-ketamine with the NMDA receptor antagonist lanicemine reported
different behavioral effects and changes in the gut microbiome.
R-ketamine was more effective in behavioral tests, and in the gut, it was much more effective
at reversing some of the microbial changes caused by stress.
Like most hypothetical connections between the gut microbiome and psychology, the apparent
effect of ketamine on the gut microbiome may turn out to be irrelevant.
Just because R-ketamine is a superior antidepressant-like substance in animals and also has more gut
microbiome effects doesn't mean those things have anything to do with each other.
Lastly, S-ketamine has stronger activity on the opioid system than R-ketamine.
Given the apparent superiority of R-ketamine, this would suggest the opioid system is not
that important for ketamine's pharmacology even though that mechanism could make sense.
A paper in 2018 received a bit of attention because it suggested a role for the opioid
system in the antidepressant effect of intravenous ketamine.
When patients were pretreated with the opioid receptor antagonist naltrexone, ketamine's
antidepressant effect was significantly reduced.
However, even if this finding is replicated, it may just mean a functioning endogenous
opioid system is required for the complete expression of ketamine's benefit, not that
ketamine itself is working like an opioid, and therefore it doesn't reveal any differences
between the enantiomers.
If R-ketamine is better than S-ketamine, an attractive explanation is metabolism.
Several ketamine metabolites are active and some may be present at sufficient levels to
contribute to the antidepressant effect.
If so, the existing research primarily supports a role for R-ketamine metabolites, especially
(2R,6R)-hydroxynorketamine.
This metabolite became a major topic of discussion in 2016, after study published in Nature suggested
it was vital for ketamine's effect.
Inhibiting ketamine's metabolism, particularly to (2R,6R)-HNK, blocked its antidepressant-like
effect in rodents.
Because that metabolite comes from R-ketamine, this would suggest the R-enantiomer is more
important.
That metabolite was also shown to function independently of the NMDA receptor, but it
did affect AMPA receptors.
Claims about the metabolite have softened as more research has been conducted.
The same research team published a paper in 2019 that supported their earlier findings,
but their framing of the results shifted towards the metabolite being a contributing factor,
not vital.
R-ketamine and deuterated R-ketamine produced the same NMDA receptor antagonism in mice,
but deuteration inhibited metabolism to (2R,6R)-HNK.
R-ketamine was more potent for alleviating depressive behavior, though the deuterated
drug still had an effect at a higher dose.
Other studies have questioned any meaningful role for the metabolite.
In the learned helplessness model, R-ketamine was effective in rats, but (2R,6R)-HNK was
ineffective even when administered at twice the dose of R-ketamine.
When the drugs were delivered to the brain through the intracerebroventricular route,
there was a rapid, durable effect from R-ketamine for at least one week.
But directly using (2R,6R)-HNK was ineffective even though its brain concentration was larger
than when the metabolite was generated from R-ketamine metabolism.
Deuteration of R-ketamine also didn't remove its rapid and persistent efficacy in mice
despite metabolism being reduced.
In conflict with the early research on (2R,6R)-HNK, a 2018 study found that reducing R-ketamine
metabolism with CYP450 inhibitors actually enhanced the effect, enabling a subtherapeutic
dose of R-ketamine to become active.
The inhibitors greatly reduced metabolism to (2R,6R)-HNK, but they also produced a 10-fold
larger exposure to R-ketamine, which complicates the interpretation of the study because the
large increase in R-ketamine could conceivably overcome a reduction in efficacy caused by
blocking metabolism.
This metabolite doesn't seem to be the key component of ketamine's pharmacology.
This remains an active area of research and (2R,6R)-HNK might be therapeutic, especially
with persistent rather than acute antidepressant effects.
But this metabolite doesn't seem to be the key component of ketamine's pharmacology,
so if R-ketamine is better than S-ketamine, metabolism might not be the reason.
Some researchers have suggested S-ketamine has fewer side effects, but that isn't supported.
Both enantiomers cause transient increases in heart rate and blood pressure, and in terms
of psychological and perceptual effects, a study in healthy people found S-ketamine produced
psychotic-like effects, while R-ketamine did not.
Those effects included hallucinations and ego disintegration, which correlated with
increased glucose utilization in the frontal cortex and thalamus specifically with S-ketamine
use.
In females experiencing pain, S-ketamine and ketamine were more potent analgesics than
R-ketamine, but they also produced more side effects like illusions, dream states, hallucinations,
and proprioceptive disturbances.
Therefore, it appears the enantiomers are generally similar, but the acute psychological
and perceptual side effects are more pronounced with S-ketamine.
Consistent with the other acute side effects, a couple studies found cognitive impairment
from intranasal S-ketamine only lasts a couple hours.
In 26 healthy people who received 84 mg intranasally, S-ketamine did not impair driving performance
8 hours later.
And in a separate study, the same dose caused cognitive impairment at 40 minutes, but it
resolved within 2 hours.
NMDA receptor antagonists have repeatedly been associated with neurotoxicity, including
a deficit in neurons that contain a protein called parvalbumin.
That deficit has also been identified in naturally occurring psychotic disorders, suggesting
it may be relevant to the psychological and perceptual issues associated with heavy ketamine
use.
S-ketamine reduced parvalbumin immunoreactivity in the prefrontal cortex and hippocampus of
mice, but R-ketamine did not.
When the enantiomers were repeatedly administered once per week for eight weeks, S-ketamine
again reduced parvalbumin immunoreactivity, unlike R-ketamine, potentially indicating
a negative effect on those neurons.
And a marker of neuronal damage, HSP70, was increased by ketamine and S-ketamine, while
R-ketamine was inactive at antidepressant doses.
These studies suggest the potential neurotoxic effect of ketamine could be associated with
S-ketamine more than R-ketamine.
Some other differences have been reported in animals.
Rewarding and reinforcing effects were assessed with the conditioned place preference test,
which is commonly used to detect drugs that may have a greater risk of psychological dependence
and excessive use.
Ketamine and S-ketamine appeared to be reinforcing, but R-ketamine was not.
And the risk of psychotic and perceptual issues was evaluated using prepulse inhibition, which
tests whether an organism's reaction to a stimulus, such as a burst of noise, can be
reduced by a preceding smaller stimulus.
Schizophrenia is associated with a deficit in PPI, which could reflect the brain being
less able to filter out stimuli.
Proper filtering of sensory information is important for helping us focus only on important
stimuli.
Only S-ketamine reduced PPI in rodents.
This could be relevant to its greater propensity to acutely alter perception and produce hallucinations,
which are undesirable side effects when ketamine is used for depression.
Until R-ketamine is properly studied, we're not going to know the effectiveness and safety
of the enantiomers.
As it stands, racemic ketamine and S-ketamine are clearly active against depression.
Exactly how those compare is unknown because ketamine and S-ketamine are usually studied
against placebo, not each other.
While there is some reason to believe intranasal S-ketamine is inferior to intravenous ketamine,
more research is needed.
Animal studies have repeatedly demonstrated that R-ketamine is more effective and may
have fewer side effects and a better safety profile.
But rats and mice are not humans, and animal models for complex conditions like depression
are very imperfect.
Observing that one enantiomer is better at reducing immobility in a swim test or increases
an animal's preference for sucrose doesn't mean that enantiomer will be better for people.
What this research does show is that R-ketamine should not be overlooked and it deserves to
be studied as a unique therapeutic agent.
Historically it's been viewed as the less important enantiomer, but that's based on
research centered around pain and anesthesia, which likely involve different mechanisms
than those for depression.
Hopefully R-ketamine will receive the attention it deserves given the impressive effects of
ketamine, which have led many researchers and companies to investigate not only ketamine,
but other substances that could improve upon ketamine's rapid antidepressant effect.
That research should include R-ketamine and its metabolites, and the approval of intranasal
S-ketamine should not be taken to mean that it's actually the best option.
This is my second video in a series about ketamine in psychiatry.
The first is linked in the description and more are on the way.
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