The Psych Guide to Ketamine and Esketamine

The Psych Guide to Ketamine and Esketamine


Hello and welcome back I’m Dr. Wegdan Rashad
and you are listening to the Psychopharmacology Institute podcast. Our goal is to help you keep up with the latest
in psych and become a better prescriber. Before we get started, why don’t you go
to piupdates.com to sign up on our website, earn CMEs, and receive regular psychopharm
nuggets of joy? PI stands for Psychopharmacology Institute,
by the way. So, go for it. [music break] In the last episode, if you remember I posed
a clinical case. Let us revisit it. You have a 45-year old patient with treatment-resistant
depression who you have been treating for some years now. He has recently read about how intranasal
esketamine was FDA approved earlier this year. He would like to try it. My question was; what would you be most concerned
about with esketamine? Thanks for those wonderful clinicians who
got in touch with a response. Some of you said you’d be concerned about
the cost, psychosis, sedation and other adverse effects. Which are indeed valid points. Throughout this episode, we will be uncovering
some of those concerns as well as talking about the indications and clinical caveats
associated with using esketamine. [music break] So it all starts with ketamine being used
as an anesthetic…to be more specific, a ‘dissociative anesthetic’. Dr. Sam Wilkinson from Yale School of Medicine
elaborates. Dr. Wilkinson:
This name refers to at least two concepts. One is that subjects may be disconnected from
their environment but it also may refer to the fact that sensory inputs are reaching
cortical areas but are not always perceived in association areas. Ketamine and esketamine are like non-identical
twins; in more sophisticated terms, esketamine is the S enantiomer of ketamine. Let’s talk a little about the mechanism
of action. Dr. Goldberg:
So the initial idea was that ketamine is a known NMDA receptor antagonist. And there’s a high density of NMDA receptors
in the prefrontal cortex, in pyramidal cells, in the hippocampus and that if you block the
NMDA receptor, it could translate to increased glutamate outflow in particular brain regions
that are involved in mood, let’s say. So the initial idea was well, if we know that
that’s one of the mechanisms of how ketamine works, then the class effect that people looked
for but were really not finding over the last 10 or so years has been to look at other NMDA
receptor antagonists from riluzole to memantine to rapastinel to some of the other drugs we
were talking about today. Most of which have failed to demonstrate an
antidepressant effect and so that led to more questions about, well, why is that? What’s unique about ketamine? Because ketamine seems to have a fairly large
effect, a very large effect with a very small number needed to treat. And yet you can’t just say, okay, let’s
just pick a different NMDA receptor antagonist and hope to see the same thing. That was Dr. Joseph Goldberg, Clinical Professor
of Psychiatry at the Icahn School of Medicine at Mount Sinai. I interviewed him at the 2019 ASCP Annual
Meeting in Scottsdale, Arizona. So Dr. Goldberg mentioned that ketamine works
as an NMDA receptor antagonist. But other drugs do this too. Why is ketamine special? Cou ld it have some tricks up its sleeve? Dr. Goldberg:
Ketamine has got a good dozen receptor targets that range from known mu-opioid receptor binding
to sigma receptor binding to serotonin reuptake inhibition, norepinephrine, alpha-7 nicotinic
receptors, muscarinic receptors. I refer to it as sort of an old-fashioned
dirty drug. So we know that there are many mechanisms
that the drug does. I think the question has come down to matching
up putative mechanisms with clinical observations. Ketamine does more than treat depression. Ketamine is a preoperative anesthetic. Ketamine is an antinociceptive drug. It’s used in regional pain management. It’s a hallucinogen and so on. So a different dose, a different effect is
seen. And we don’t know if we can fully say, well,
the anesthetic effects come from NMDA receptor blockade but maybe the depression effects
come from elsewhere. So that’s what makes ketamine special; it
acts on an array of other receptors and different doses have different effects. You should note though, that esketamine has
not been shown to act on the sigma receptors, which basically modulate the opioid system. [music break] So we have touched upon the mechanism of action
of ketamine and esketamine. Let’s snap back to reality…I mean clinical
practice. Intranasal esketamine or Spravato is now FDA
approved for treatment-resistant depression in conjunction with an oral antidepressant. Ketamine can be used off-label for TRD in
IV infusion form. When I asked Dr. Wilkinson about the efficacy
of ketamine he replied with the following. Dr. Wilkinson:
Ketamine has emerged as a prototypical rapid-acting antidepressant. Early efficacy studies showed a high rate
of response in the range of 64% to 71% to a single dose of ketamine among individuals
with treatment-resistant depression. Later clinical reports of the effectiveness
of ketamine in clinical samples have demonstrated generally a lower response rate in the range
of 50%. Now, this discrepancy between efficacy and
effectiveness is not entirely unexpected and can frequently be seen as new treatments are
taken from clinical trials to real world settings. Fair enough. It is exciting but there’s still more room
to identify just how effective it is. [music break] So what should we, as clinicians be concerned
about? Well, let’s talk about esketamine here. Patients need to have their blood pressure
monitored, since it can cause hypertension. Also, due to possible nausea and vomiting
after administration, it is advised to not eat for at least 2 hours and not to drink
half an hour before taking Spravato. Furthermore, since it’s technically a dissociative
anesthetic; there’s a clear risk of…well…dissociation and sedation. Dr. Wilkinson:
Another important question is whether repeated use of ketamine can induce long-lasting cognitive
or perceptual changes or psychotic symptoms. A number of studies conducted by Celia Morgan
and colleagues have found changes in cognitive abilities and schizophrenia-like symptoms
among frequent ketamine recreational users. Compared to other groups such as ex-ketamine
users and non-ketamine polydrug users, frequent ketamine users have shown impairments in spatial
working memory as well as pattern recognition task. Notably, frequent ketamine users also scored
higher on measures of dissociative and delusional symptoms compared to other groups including
ex-ketamine users and non-ketamine polydrug users. The unanswered question then seems to be:
How much ketamine is too much? There are legitimate concerns of the long-term
effects of ketamine on cognition and abuse. However, there have been no systematic reports
of iatrogenic addiction or persistent psychosis thus far from the studies that examined the
therapeutic effect of ketamine in mood disorders. So in summary there are still unaddressed
concerns about the long-term use of ketamine in terms of abuse potential, long-lasting
cognitive and perceptual symptoms. [music break] So here’s the thing. Ketamine and esketamine have opened many new
doors. They bring us closer to having a rapidly acting
antidepressant/anti suicidal agents but they also raise concerns for their long term safety. Dr. Wilkinson:
The possibility of rebound suicidal ideation remains that could occur within a few weeks
or months of a patient receiving ketamine for suicidal ideation. How much followup should be put in place for
these patients who abort or have a shortened hospitalization as a result of their exposure
to ketamine? In addition, no study so far has demonstrated
that ketamine can reduce the risk of suicidal behavior, only of suicidal ideation. And it’s important to point out that suicidal
ideation is not a very specific indicator or predictor of suicidal behavior. That’s an interesting little nugget of information! And there’s still a lot to talk about in
terms of ketamine and esketamine. I just hoped to cover the basics of it today
and further down the road we will venture further into some specifics on how to prescribe
them. And that’s about it for today. Now here come the key points. Ketamine and esketamine are known as dissociative
anesthetics that act as NMDA antagonists as well as on many other receptor sites. Ketamine has emerged as a prototypic rapid-antidepressant
and it is also found to be useful for treatment-resistant depression. There are long term concerns associated with
ketamine use including abuse potential, increased risk of psychosis and also cognitive deterioration. Did you know that a lot of today’s content
was extracted from our CME presentation entitled “Ketamine in Clinical Practice”? Check it out on our website. Visit PIupdates.com and become a premium member
already! We have a bunch of CMEs for you to collect! If you are a psychiatrist in the US, we also
offer SA credits. You can also go on our website and join our
newsletter to receive weekly updates delivered straight to your inbox. The following people participated in this
episode: Dr. Flavio Guzman as the general editor, Andy Rhode as the audio engineer,
Pamela Gonzalez as the project manager and myself, Dr. Wegdan Rashad as the host. We’d also like to thank Dr. Sam Wilkinson
and Dr. Joseph Goldberg for being with us. Thank you for joining us in today’s podcast
until the next episode, goodbye!

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