The Y in Psychiatry
"The Y in Psychiatry" – a pragmatically endearing podcast talking to the med students, residents, fellows, and attendings of the medicine world about the nuances of psychiatry.
Each episode features focused discussions that explore the intersection of the mental health, medicine, and the human experience.
Together, we'll uncover the hidden "Y" – the compelling reasons, profound insights, and groundbreaking discoveries shaping the psychiatric landscape.
So grab a seat, warm beverage, tune in, and let's embark on this journey to unlock the mysteries of the human psyche, only on "The Y in Psychiatry."
The Y in Psychiatry
E3 - Special K Bar: Granular Granule Neurons and Ketamine
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On this episode, we will continue our antidepressant journey and find out what the buzz around ketamine is all about. Hear Dr. Miracle and Dr. Hendratta discuss the use of ketamine in the treatment of depression. Explore everything from its receptors in the brain, why it works so fast, and why psychiatrists may be turning to this in their everyday practice. Tune in to find out what’s so special about Special K.
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One is called reward seeking behavior. Okay. Where you actually run towards the reward. Another one is called misery fleeing behavior that you run away from misery. That is towards safety.
Dr. Amayo:That's, that's my baseline.
Dr. Handratta:Yes. That's baseline.
Thanh:Welcome to the Y in Psychiatry,
Dr. Amayo:Hi, this is Dr. Amayo C/L fellow.
Thanh:Where we delve into the intricate nuances of psychiatric topics
Dr. Handratta:My name is Dr. handratta attending psychiatrist. I did my residency from University of Connecticut and then I did my fellowship from Georgetown University in consultation and liaison.
Thanh:Each episode features interview style discussions that explore the intersection of the mind medicine and the human experience. Together we'll uncover the hidden why and the groundbreaking discovery shaping the psychiatric landscape. So grab a seat, warm beverage, tune in, and let's embark on this journey to unlock the mysteries of the human psyche. Only on The Y in Psychiatry.
Dr. Amayo:So welcome back to the Y in psychiatry. It is your host, Dr. Amayo. I also go by Miracle. I'm a consultant liaison fellow, and as usual my co-host, Dr. Handratta, is here with us. Today we have a treat. We are going to be talking about special K, and by that I mean ketamine. It's one of the newer antidepressants uh, out here on the market and its been having a lot of press a lot of, fanfare and today we're and, uh, Dr. Handratta, I just want to start, I just want to start simple.
Dr. Handratta:Before we talk about ketamine, the definition I want to clarify is treatment resistant depression because that's where we commonly use ketamine is when patients have treatment-resistant depression. So what does it mean? So there are different definitions but the one that is widely accepted is when a patient has failed two different antidepressants that belong to two different class prescribed at an adequate therapeutic dosage, and for an adequate. Duration of time, right? So if they have failed two of them at a therapeutic dosage and tried for the duration of time, that is about eight to 12 weeks. Then we say that the patient has treatment resistant depression. So when patients actually have treatment resistant depression, that's when we usually think about, Alternative treatment for depression and one of the alternative treatment that has been proved to be pretty beneficial in treatment resistant depression is a use of ketamine.
Dr. Amayo:Sounds like ketamine is the best, why aren't we just giving it out there? Why are we waiting for treatment-resistant depression to use it? What should we be concerned about?
Dr. Handratta:So as we know, ketamine is always given in association with a conventional antidepressants. Yeah. You just do not give ketamine just by itself. The patient is also on another conventional antidepressants, right? The problem with ketamine is its abuse potential. So Ketamine is used as an anesthetic as well as an analgesic agent. Yeah. So there is a huge abuse potential, especially of IV ketamine. And that's why it's actually not used as a first line treatment for depression. And saying is true actually for IV ketamine as well as the intranasal esketamine. Yeah, sure.
Dr. Amayo:Okay, so mainly the abuse potential. So can patients get addicted to ketamine treatment? Yes. Is that correct? Okay.
Dr. Handratta:Yes, they can get addicted to ketamine treatment. Plus you cannot give ketamine at home because a lot of patients do in the first 60 minutes will dissociate. And that is a reason whenever a patient comes to the ketamine clinic, they're always accompanied by a family member. They're not supposed to drive actually, after the treatment, somebody actually has to take them home. Yeah. So there is quite a good amount of risk using ketamine or esketamine as a first line treatment and to be used at home.
Dr. Amayo:And I know that there's also a concern or a contraindication for psychosis. Possible to worsen psychosis? Do we know how that works? Is it because we dissociate?
Dr. Handratta:So some of the research data have actually shown that the functional connectivity between the thalamus as well as the hippocampus and the thalamus and the prefrontal cortex is responsible for the psychotic symptoms we see when ketamine is given, right? Because there's a disconnection between the thalamus and the hippocampus and thalamus and the prefrontal cortex in patients with schizophrenia. Right, we know that through different research data, some people who actually have a predisposition for psychosis, because of this impact functional connectivity between the thalamus and the prefrontal cortex, thalamus, hippocampus are more prone for psychosis than they're introduced to ketamine.
Dr. Amayo:How does Ketamine help?
Dr. Handratta:So in short and simple language, ketamine is an NMDA receptor antagonist, and it has an agonist property at AMPA receptors. So both are receptors that are acted on by glutamate. So these are ionotropic receptors.
Dr. Amayo:And AMPA is also a glutamate receptor, so it's a agonist on AMPA and as well, an antagonist on NMDA, which is another glutamate receptor. Is that correct?
Dr. Handratta:That's right.
Dr. Amayo:Oh wow.
Dr. Handratta:So the way ketamine works is, so let's go back to the pyramidal neurons as well as the GABA interneurons. So our prefrontal cortex is rich in GABA interneurons, and as we mentioned previously, GABA interneurons are responsible for fine tuning of the pyramidal neurons, which are glutaminergic in nature. So the way ketamine works is it basically blocks the NMDA receptors on these GABA inter neurons. So when you block the NMDA receptors on the GABA interneurons, you decrease the release of GABA. Your prefrontal cortex, apart from the pyramidal neurons that it has, it also has glutaminergic input coming into the prefrontal cortex. One of the glutaminergic input that comes into the prefrontal cortex is from the thalamus. Another one is from the hippocampus and so on, right? So all these neurons that enters into the prefrontal cortex, they are rich in GABA a receptors. So when you block the NMDA receptor on the GABA inter neuron, you disinhibit these incoming pyramidal neurons. Okay? So you basically increase the release of glutamate from the presynaptic glutaminergic pyramidal neurons Does it make sense so far?
Dr. Amayo:Yes. Yes. So the prefrontal cortex, has lots of pyramidal neurons, which is a mainly glutaminergic neurons, and then this pyramidal neurons has the GABA interneurons, which act as a break for them, slows down the glutaminergic neurons. Now, ketamine blocks the GABA interneurons, which increases glutamate by the pyramidal neurons.
Dr. Handratta:Exactly. So by inhibiting the GABA interneurons, you basically disinhibit the incoming glutaminergic connection into the prefrontal cortex.
Dr. Amayo:So is it mainly the glutaminergic connection from the thalamus and the hippocampus that we are targeting?
Dr. Handratta:So those are some of the examples of incoming neurons into the prefrontal cortex. Okay. Then you have the post-synaptic pyramidal neurons in the prefrontal cortex. And these pyramidal neurons will have NMDA receptors and AMPA receptors because glutamate has to act on the prefrontal cortex pyramidal neurons. Right Now, as we mentioned, ketamine blocks the NMDA receptors. So what ketamine will do is that it'll block the NMDA receptors on the prefrontal cortex, pyramidal neurons. One of the downstream effect of blocking these NMDA receptor is increasing BDNF: that is brain-derived neurotropic factors. And there is also an increase in something called mTOR, which is mammalian target of rapamycin. So the overall effect of increasing BDNF, an mTOR that is target of rapamycin is to stimulate the process of synaptogenesis that is increasing the number of dendritic spines on these pyramidal neurons so that they can actually be more active. Does it make sense?
Dr. Amayo:And I have more connection? Yes. Makes sense.
Dr. Handratta:Right now, this is one mechanism of action of ketamine. Now, ketamine is also broken down into a metabolite called as hydroxynorketamine. This hydroxynorketamine is an agonist on the AMPA receptors.
Dr. Amayo:So this is how it affects the AMPA receptors through its metabolites.
Dr. Handratta:Exactly. And when you stimulate the AMPA receptor, the downstream effect is the same. It basically increases the BDNF as well as the target of rapomycin.
Dr. Amayo:Yeah, as well as mTOR and our regular antidepressants, our regular SSRIs does have similar effects, similar downstream effect to increase BDNF. What makes ketamine, better during this? Is it because of the dual action with the AMPA receptors?
Dr. Handratta:That's a great question. So why does ketamine work faster than conventional antidepressants? Now the way most of the antidepressants work, whether it be ECT or it be SSRIs, SNRIs, NDRIs, or ketamines is by increasing BDNF and is brain derived neurotropic factors.
Dr. Amayo:Okay.
Dr. Handratta:What conventional antidepressants do is that they basically help in the process of neurogenesis in the hippocampus, right? Because research work has shown that there's a decrease in the volume of hippocampus in patients with depression. Especially an area of the hippocampus called dentate gyrus. So conventional antidepressants will stimulate the neurogenesis in the hippocampus. In the hippocampus there is an area called dentate gyrus where you have progenitor stem cells. All right. What antidepressant does is that it stimulates the stem cells so that the stem cells then develop into immature granule neurons finally become a mature neurons. So this entire process of neurogenesis takes weeks. So this is one of the theory why conventional antidepressant takes weeks to show the benefit.
Dr. Amayo:Sure. Fact, 70%. Yes.
Dr. Handratta:On the other hand, what Ketamine actually does is that it acts directly on these immature granule neurons, which are called as the adult born immature granule neurons. So that is the reason why ketamine works faster as compared to the conventional antidepressant because of its direct effect on these immature granule neurons.
Dr. Amayo:Wow. And do we know what it does directly to these immature granule neurons?
Dr. Handratta:So when you stimulate the immature granule neurons, so these immature granule neurons are rich in NMDA and AMPA receptors. So when you stimulate them, what it does is that it increases the synaptic connection between the hippocampus and the prefrontal cortex. Okay. So it increases the communication between the two, which is which is the hypothesis that is responsible for the antidepressant effect
Dr. Amayo:Yeah, the antidepressant effects. That, that makes sense. And before I ask my last question on ketamine, I just wanna summarize. So Ketamine is used for treatment resistant depression, which is a failure of two antidepressant. Ketamine works by antagonizing NMDA glutamate receptors and is an agonist of AMPA glutamate receptors. Now this, doing this has a downstream effect of one increasing BDNF, which promotes the BDNF and mTOR, which promotes and stimulates synaptogenesis so causing more neuron connections. And then ketamine has an added benefit of itself working directly to the immature granule neurons, which are basically progenitor cells in the dentate gyrus of the hippocampus. And as we're doing this again, increases the synaptogenesis and increases the connection between the hippocampus and the prefrontal cortex, and in a way, this is similar to how other antidepressant works. Ketamine is just very good and better at doing it. Okay. And just one last question on that. So so does ketamine widen that gap between the thalamus and the prefrontal cortex when it's given in these patients?
Dr. Handratta:Yeah. It's basically like the disconnection between the thalamus and the hippocampus and the thalamus and the prefrontal cortex predisposes these patients more to psychotic features. Because ketamine is an NMDA receptor antagonist. And patients with schizophrenia, they have hypofunctioning NMDA receptors. Okay. So when you block an NMDA receptor in susceptible individuals, you increase the risk of psychosis.
Dr. Amayo:Let's save it for our psychotic episode, but that makes sense. And so, ketamine, the things to be concerned for is abuse potential, its possibility to cause dissociation, and for patients that are predisposed to psychosis, it increases the risk of developing psychosis. That's enough for this episode. Thank you for listening.
Dr. Handratta:Thank you, Dr. Amayo.
Katrina:Thank you for joining us on today's episode. Our tireless team is already hard at work, cobbling together another potpourri of fascinating discussion for next week, so be sure to tune in, visit our website and our podcast feed and let us know your thoughts on the episode. Subscribe so you don't miss our releases every Wednesday. Until next time, keep smiling, keep shining, and stay curious.
