The Y in Psychiatry

E2 - The Enigmatic Enigma: Decoding the Mechanisms of Antidepressants

NguyenInDoubt Season 1 Episode 2

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This episode embarks on an intriguing journey into the mysterious world of antidepressants. In this episode, we unravel the mysteries surrounding these medications, delving into how they work in the brain and why they can take time to have an effect. Discover the hidden mechanisms and uncover the secrets behind these transformative treatments. Get ready to embark on a quest for knowledge that will illuminate the path to a better understanding of antidepressants.

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Dr. Amayo:

Are, are you recording? I wanna record the joke. So remember you put the joke in front of the music. So what's the difference between a psychiatrist and a magician? Magician pulls rabbits out of hats, whereas a psychiatrist pulls habits out of rats.

Thanh:

Oh, wait aren't those psychologist?

Dr. Amayo:

It was psychologist!

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 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. Today we explore antidepressants, those complex concoctions, that promise relief, but sometimes keep us waiting, wondering. In this warm Haven of knowledge, our journey begins with a question that, echos through the corridors of the mind. How do serotonergic antidepressants work in the brain? And what parts respond? What secrets do they unlock within our neural networks? And as we venture further, we find ourselves developed in a shroud of anticipation. Why does it take time for these medications to have an effect? As our host guides us through the labyrinth landscape of the brain. We seek solace in understanding.

Dr. Amayo:

Welcome to the Y Psychiatry. This is your host, Dr. Amayo. I go by Miracle. And as usual, uh, my co-host, Dr. Handratta, is here with us.

Dr. Handratta:

Hi guys.

Dr. Amayo:

All right, just to recap what we talked about why we get depressed and we learned about the salience network, the executive network, and the default mode, and all of these networks are being connected by the monoamines. So, spring boarding off there, I was wondering when a patient comes in with depression, our first line medication is an SSRI or an SNRI, um, that's classic. So how do those work where I know there are serotonin modulators or serotonin reuptake inhibitors, but why does that work? How does that work? What does serotonin gotta do with all this?

Dr. Handratta:

So that's a, that's a great question. Right. So, because those are the common medications we use, so the way most of our conventional antidepressants like SSRIs or SNRIs or NDRIs, they basically block the transporters, right? So when you, you block the transporters, you prevent the re-uptake of the neurotransmitters from the synaptic cleft. that is one part or one way that it works. And then you have the auto receptors that are present at the presynaptic and somatodendritic region of the neuron So the auto receptors usually put a break on the release of neurotransmitter. So if you look at auto receptors, what are they? So if you stimulate an auto receptor, you either decrease the release of a neurotransmitter or you decrease the firing of a neuron. On the other hand, if you block an auto receptor, you increase the release of a neurotransmitter, or you increase the firing of the neurons, right? So initially when you block the transporters, there's a lot of neurotransmitter that is floating in the synaptic cleft. It'll act on the auto receptors on the nerve terminal that will decrease the release of neurotransmitter till these auto receptors are desensitized. Right?

Dr. Amayo:

Lemme see if I, if I got it right. So our SSRI blocks the reuptake transporters and that leads to a increase of neurotransmitter in the synaptic cleft, and auto receptors are on the neuron terminals and cell body called somato-dendritic region when there is an excess of neurotransmitters in the synaptic cleft they decrease release of neurotransmitter from the presynaptic nerve terminals.

Dr. Handratta:

So, perfect. So now, What happens is that these terminal nerve terminal auto receptors, after some time they get desensitized. So when they're desensitized, you release the brake and now there will be a flow of the neurotransmitter depending upon how the neurons are stimulated, right? That is one part. Then once the neurotransmitter release, they act on the postsynaptic receptors there are different types of serotonin receptors, right? So these serotonin receptors are present on GABA, inter neuron and pyramidal neurons in the prefront cortex and hippocampus right? So in short, monoamines like serotonin, norepinephrine and dopamine, work on these gaba interneurons and pyramidal neurons and control, the functioning or the firing or the prefrontal cortex and hippocampus Does it make sense?

Dr. Amayo:

Yes, sir.

Dr. Handratta:

Yeah. But the problem with the conventional antidepressant is that it takes. At least two to four weeks to see a 20% improvement in the symptoms, especially in patients who respond to it and it takes eight to 12 weeks to see the maximum benefit or to reach remission. That is a 70% improvement. So it takes a long, long, long time actually for these medications to start working.

Dr. Amayo:

Why is that?

Dr. Handratta:

in depression, people have a decrease in the volume of their hippocampus. Hmm. Right. So most of the conventional antidepressants, like SSRI, SNRI, NDRI, what they do is that they basically stimulate the stem cells or also called the progenitor cells in the hippocampus to generate something called new granule neurons, which in turn becomes neurons. So it takes a while for this neurogenesis to take place, right? It takes days for the stem cell or the progenitor cells to develop into a new granule neurons, and that is why takes a long time for the conventional antidepressants to work in depression.

Dr. Amayo:

Okay. And this granule neuron that be stimulated from the hippocampus, what, what do they do? What's their role?

Dr. Handratta:

The New granule, neurons. help the hippocampus to recover from the previous depressive episode, and now the hippocampus can communicate with the prefrontal cortex and this hippocampal prefrontal cortex communication. Is responsible for the antidepressant effect. Uh, okay. And this was proven very recently, actually. By A study that was done in Northwestern University by Dr. Kessler, who's a neurologist, who basically came up with this particular hypothesis.

Dr. Amayo:

So the reconnection between hippocampus and the frontal lobe can help re reset the salience, uh, executive, um, network connection.

Dr. Handratta:

Exactly. So it basically tries to, so the brain tries to rewire itself, right? So that like, we go back to the normal physiology, like the normal way that a brain is supposed to function like a non-depressed brain, let me put it that way. Mm-hmm. Right?

Dr. Amayo:

And, and so, the role serotonin receptors play on the gaba inter neurons and the pyramidal neurons. How, how does that fit into this?

Dr. Handratta:

So if you look at the prefrontal cortex and the hippocampus, right, the structures are very, very similar actually, when you look at the way the gaba inter neurons and the pyramidal neurons function. So you have a pyramidal neuron, you have a lot of pyramidal neurons in your prefrontal cortex, which release glutamate. Right? Mm-hmm. pyramidal neurons are controlled or fine tuned by GABA inter neurons. So if you look at GABA inter neurons, there are different types, but we'll focus on two GABA inter neurons. One is called somatostatin, another one is called parvalbumin. They are named after the proteins they stain for. That's why they name that way. All right, so the somatostatin, gaba, inter neuron and the parvalbumin, they will have serotonin receptors. So the somatostatin interneurons are more like the tuning button on your radio where you select the channels, right? So it tunes your pyramidal neuron. On the other hand, the parvalbumin GABA inter neurons are like the volume button. So, they will control the firing of the pyramidal neurons. Right? So if these inter neurons are not functioning well, you'll have less firing of the pyramidal neurons. This is what actually causes a problem because in patients with depression, there is less glutamate and there is also a problem, the functioning of the somatostatin gaba interneurons

Dr. Amayo:

Sure. Yeah. So only the, so not only is there less glutamate, it's less, it's running less smooth and less fluid. Yes. To the defect in somatostatin GABA interneurons.

Dr. Handratta:

Exactly. Right. So, and the, you have to also remember that the cortex. Something that controls the release of neurotransmitter from the brainstem. So the monoamine neurons are present in your brainstem, and they're controlled by the firing of this pyramidal neurons. So in depression, if this gabapentin inter-neurons are not functioning well, or they're hypofunctioning, the pyramidal neuron is not firing. So there's not enough glutamate. And if there's not enough glutamate or pyramidal neuron firing, there's not enough monoamine released from the brainstem. So it's a vicious cycle.

Dr. Amayo:

So the serotonin, we work on the serotonin receptors on the GABA inter neurons, and therefore stopping the cycle from, I guess from the inside out. And so by working on the GABA inter neurons, the GABA inter neurons will work on the pyramindal neurons. The pyramidal neurons will lead to increasing glutamate firing. Increased glutamate firing in the frontal lobe will then lead to, overall increase monoamines in the entire, from the brainstem over everywhere.

Dr. Handratta:

That's absolutely right. So it's a top down control of the monoamine release.

Dr. Amayo:

Okay. I think, I think we have it.

Katrina:

Thank you for joining us on today's episode. Feel free to smash that subscribe button like your serotonin hammering a synaptic cleft. 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.

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