July 5, 2023 • 10 mins
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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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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Dr. Amayo (00:00):
Are, are you recording?
I wanna record the joke.
So remember you put the joke infront of the music.
So what's the difference betweena psychiatrist and a magician?
Magician pulls rabbits out ofhats, whereas a psychiatrist
pulls habits out of rats.
Thanh (00:17):
Oh, wait aren't those psychologist?
Dr. Amayo (00:19):
It was psychologist!
Thanh (00:22):
Welcome to the Y in Psychiatry!
Dr. Amayo (00:24):
Hi, this is Dr.
Amayo C/L fellow.
Thanh (00:28):
Where we delve into the intricate nuances of psychiatric
topics.
Dr. Handratta (00:31):
My name is Dr.
Handratta attending psychiatristI did my residency from
University of Connecticut and myfellowship from Georgetown
University in consultation andliaison
Thanh (00:42):
Each episode features interview style discussions that
explore the intersection of themind medicine and the human
experience.
Together we'll uncover thehidden why and the
groundbreaking discovery shapingthe psychiatric landscape.
So grab a seat, warm beverage,tune in, and let's embark on
(01:02):
this journey to unlock themysteries of the human psyche.
Only on The Y in Psychiatry.
Today we exploreantidepressants, those complex
concoctions, that promiserelief, but sometimes keep us
waiting, wondering.
(01:23):
In this warm Haven of knowledge,our journey begins with a
question that, echos through thecorridors of the mind.
How do serotonergicantidepressants work in the
brain?
And what parts respond?
What secrets do they unlockwithin our neural networks?
And as we venture further, wefind ourselves developed in a
shroud of anticipation.
Why does it take time for thesemedications to have an effect?
(01:47):
As our host guides us throughthe labyrinth landscape of the
brain.
We seek solace in understanding.
Dr. Amayo (01:57):
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 (02:10):
Hi guys.
Dr. Amayo (02:11):
All right, just to recap what we talked about why
we get depressed and we learnedabout the salience network, the
executive network, and thedefault mode, and all of these
networks are being connected bythe monoamines.
So, spring boarding off there, Iwas wondering when a patient
comes in with depression, ourfirst line medication is an SSRI
(02:32):
or an SNRI, um, that's classic.
So how do those work where Iknow there are serotonin
modulators or serotonin reuptakeinhibitors, but why does that
work?
How does that work?
What does serotonin gotta dowith all this?
Dr. Handratta (02:45):
So that's a, that's a great question.
Right.
So, because those are the commonmedications we use, so the way
most of our conventionalantidepressants like SSRIs or
SNRIs or NDRIs, they basicallyblock the transporters, right?
So when you, you block thetransporters, you prevent the
re-uptake of theneurotransmitters from the
(03:06):
synaptic cleft.
that is one part or one way thatit works.
And then you have the autoreceptors that are present at
the presynaptic andsomatodendritic region of the
neuron So the auto receptorsusually put a break on the
release of neurotransmitter.
So if you look at autoreceptors, what are they?
So if you stimulate an autoreceptor, you either decrease
(03:27):
the release of aneurotransmitter or you decrease
the firing of a neuron.
On the other hand, if you blockan auto receptor, you increase
the release of aneurotransmitter, or you
increase the firing of theneurons, right?
So initially when you block thetransporters, there's a lot of
neurotransmitter that isfloating in the synaptic cleft.
It'll act on the auto receptorson the nerve terminal that will
(03:49):
decrease the release ofneurotransmitter till these auto
receptors are desensitized.
Right?
Dr. Amayo (03:55):
Lemme see if I, if I got it right.
So our SSRI blocks the reuptaketransporters and that leads to a
increase of neurotransmitter inthe synaptic cleft, and auto
receptors are on the neuronterminals and cell body called
somato-dendritic region whenthere is an excess of
neurotransmitters in thesynaptic cleft they decrease
(04:17):
release of neurotransmitter fromthe presynaptic nerve terminals.
Dr. Handratta (04:21):
So, perfect.
So now, What happens is thatthese terminal nerve terminal
auto receptors, after some timethey get desensitized.
So when they're desensitized,you release the brake and now
there will be a flow of theneurotransmitter depending upon
how the neurons are stimulated,right?
That is one part.
Then once the neurotransmitterrelease, they act on the
(04:43):
postsynaptic receptors there aredifferent types of serotonin
receptors, right?
So these serotonin receptors arepresent on GABA, inter neuron
and pyramidal neurons in theprefront cortex and hippocampus
right?
So in short, monoamines likeserotonin, norepinephrine and
dopamine, work on these gabainterneurons and pyramidal
(05:04):
neurons and control, thefunctioning or the firing or the
prefrontal cortex andhippocampus Does it make sense?
Dr. Amayo (05:10):
Yes, sir.
Dr. Handratta (05:11):
Yeah.
But the problem with theconventional antidepressant is
that it takes.
At least two to four weeks tosee a 20% improvement in the
symptoms, especially in patientswho respond to it and it takes
eight to 12 weeks to see themaximum benefit or to reach
remission.
That is a 70% improvement.
(05:33):
So it takes a long, long, longtime actually for these
medications to start working.
Dr. Amayo (05:40):
Why is that?
Dr. Handratta (05:41):
in depression, people have a decrease in the
volume of their hippocampus.
Hmm.
Right.
So most of the conventionalantidepressants, like SSRI,
SNRI, NDRI, what they do is thatthey basically stimulate the
stem cells or also called theprogenitor cells in the
hippocampus to generatesomething called new granule
(06:05):
neurons, which in turn becomesneurons.
So it takes a while for thisneurogenesis to take place,
right?
It takes days for the stem cellor the progenitor cells to
develop into a new granuleneurons, and that is why takes a
long time for the conventionalantidepressants to work in
depression.
Dr. Amayo (06:24):
Okay.
And this granule neuron that bestimulated from the hippocampus,
what, what do they do?
What's their role?
Dr. Handratta (06:31):
The New granule, neurons.
help the hippocampus to recoverfrom the previous depressive
episode, and now the hippocampuscan communicate with the
prefrontal cortex and thishippocampal prefrontal cortex
communication.
Is responsible for theantidepressant effect.
Uh, okay.
(06:52):
And this was proven veryrecently, actually.
By A study that was done inNorthwestern University by Dr.
Kessler, who's a neurologist,who basically came up with this
particular hypothesis.
Dr. Amayo (07:05):
So the reconnection between hippocampus and the
frontal lobe can help re resetthe salience, uh, executive, um,
network connection.
Dr. Handratta (07:15):
Exactly.
So it basically tries to, so thebrain tries to rewire itself,
right?
So that like, we go back to thenormal physiology, like the
normal way that a brain issupposed to function like a
non-depressed brain, let me putit that way.
Mm-hmm.
Right?
Dr. Amayo (07:31):
And, and so, the role serotonin receptors play on the
gaba inter neurons and thepyramidal neurons.
How, how does that fit intothis?
Dr. Handratta (07:41):
So if you look at the prefrontal cortex and the
hippocampus, right, thestructures are very, very
similar actually, when you lookat the way the gaba inter
neurons and the pyramidalneurons function.
So you have a pyramidal neuron,you have a lot of pyramidal
neurons in your prefrontalcortex, which release glutamate.
Right?
Mm-hmm.
pyramidal neurons are controlledor fine tuned by GABA inter
(08:04):
neurons.
So if you look at GABA interneurons, there are different
types, but we'll focus on twoGABA inter neurons.
One is called somatostatin,another one is called
parvalbumin.
They are named after theproteins they stain for.
That's why they name that way.
All right, so the somatostatin,gaba, inter neuron and the
parvalbumin, they will haveserotonin receptors.
So the somatostatin interneuronsare more like the tuning button
(08:27):
on your radio where you selectthe channels, right?
So it tunes your pyramidalneuron.
On the other hand, theparvalbumin GABA inter neurons
are like the volume button.
So, they will control the firingof the pyramidal neurons.
Right?
So if these inter neurons arenot functioning well, you'll
have less firing of thepyramidal neurons.
(08:48):
This is what actually causes aproblem because in patients with
depression, there is lessglutamate and there is also a
problem, the functioning of thesomatostatin gaba interneurons
Dr. Amayo (08:58):
Sure.
Yeah.
So only the, so not only isthere less glutamate, it's less,
it's running less smooth andless fluid.
Yes.
To the defect in somatostatinGABA interneurons.
Dr. Handratta (09:11):
Exactly.
Right.
So, and the, you have to alsoremember that the cortex.
Something that controls therelease of neurotransmitter from
the brainstem.
So the monoamine neurons arepresent in your brainstem, and
they're controlled by the firingof this pyramidal neurons.
So in depression, if thisgabapentin inter-neurons are not
functioning well, or they'rehypofunctioning, the pyramidal
(09:32):
neuron is not firing.
So there's not enough glutamate.
And if there's not enoughglutamate or pyramidal neuron
firing, there's not enoughmonoamine released from the
brainstem.
So it's a vicious cycle.
Dr. Amayo (09:42):
So the serotonin, we work on the serotonin receptors
on the GABA inter neurons, andtherefore stopping the cycle
from, I guess from the insideout.
And so by working on the GABAinter neurons, the GABA inter
neurons will work on thepyramindal neurons.
The pyramidal neurons will leadto increasing glutamate firing.
Increased glutamate firing inthe frontal lobe will then lead
(10:04):
to, overall increase monoaminesin the entire, from the
brainstem over everywhere.
Dr. Handratta (10:11):
That's absolutely right.
So it's a top down control ofthe monoamine release.
Dr. Amayo (10:16):
Okay.
I think, I think we have it.
Katrina (10:22):
Thank you for joining us on today's episode.
Feel free to smash thatsubscribe button like your
serotonin hammering a synapticcleft.
Our tireless team is alreadyhard at work, cobbling together
another potpourri of fascinatingdiscussion for next week, so be
sure to tune in, visit ourwebsite and our podcast feed and
let us know your thoughts on theepisode.
Subscribe so you don't miss ourreleases every Wednesday.
(10:46):
Until next time, keep smiling,keep shining, and stay curious.
Are, are you recording?
I wanna record the joke.
So remember you put the joke infront of the music.
So what's the difference betweena psychiatrist and a magician?
Magician pulls rabbits out ofhats, whereas a psychiatrist
pulls habits out of rats.
Thanh (00:17):
Oh, wait aren't those psychologist?
Dr. Amayo (00:19):
It was psychologist!
Thanh (00:22):
Welcome to the Y in Psychiatry!
Dr. Amayo (00:24):
Hi, this is Dr.
Amayo C/L fellow.
Thanh (00:28):
Where we delve into the intricate nuances of psychiatric
topics.
Dr. Handratta (00:31):
My name is Dr.
Handratta attending psychiatristI did my residency from
University of Connecticut and myfellowship from Georgetown
University in consultation andliaison
Thanh (00:42):
Each episode features interview style discussions that
explore the intersection of themind medicine and the human
experience.
Together we'll uncover thehidden why and the
groundbreaking discovery shapingthe psychiatric landscape.
So grab a seat, warm beverage,tune in, and let's embark on
(01:02):
this journey to unlock themysteries of the human psyche.
Only on The Y in Psychiatry.
Today we exploreantidepressants, those complex
concoctions, that promiserelief, but sometimes keep us
waiting, wondering.
(01:23):
In this warm Haven of knowledge,our journey begins with a
question that, echos through thecorridors of the mind.
How do serotonergicantidepressants work in the
brain?
And what parts respond?
What secrets do they unlockwithin our neural networks?
And as we venture further, wefind ourselves developed in a
shroud of anticipation.
Why does it take time for thesemedications to have an effect?
(01:47):
As our host guides us throughthe labyrinth landscape of the
brain.
We seek solace in understanding.
Dr. Amayo (01:57):
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 (02:10):
Hi guys.
Dr. Amayo (02:11):
All right, just to recap what we talked about why
we get depressed and we learnedabout the salience network, the
executive network, and thedefault mode, and all of these
networks are being connected bythe monoamines.
So, spring boarding off there, Iwas wondering when a patient
comes in with depression, ourfirst line medication is an SSRI
(02:32):
or an SNRI, um, that's classic.
So how do those work where Iknow there are serotonin
modulators or serotonin reuptakeinhibitors, but why does that
work?
How does that work?
What does serotonin gotta dowith all this?
Dr. Handratta (02:45):
So that's a, that's a great question.
Right.
So, because those are the commonmedications we use, so the way
most of our conventionalantidepressants like SSRIs or
SNRIs or NDRIs, they basicallyblock the transporters, right?
So when you, you block thetransporters, you prevent the
re-uptake of theneurotransmitters from the
(03:06):
synaptic cleft.
that is one part or one way thatit works.
And then you have the autoreceptors that are present at
the presynaptic andsomatodendritic region of the
neuron So the auto receptorsusually put a break on the
release of neurotransmitter.
So if you look at autoreceptors, what are they?
So if you stimulate an autoreceptor, you either decrease
(03:27):
the release of aneurotransmitter or you decrease
the firing of a neuron.
On the other hand, if you blockan auto receptor, you increase
the release of aneurotransmitter, or you
increase the firing of theneurons, right?
So initially when you block thetransporters, there's a lot of
neurotransmitter that isfloating in the synaptic cleft.
It'll act on the auto receptorson the nerve terminal that will
(03:49):
decrease the release ofneurotransmitter till these auto
receptors are desensitized.
Right?
Dr. Amayo (03:55):
Lemme see if I, if I got it right.
So our SSRI blocks the reuptaketransporters and that leads to a
increase of neurotransmitter inthe synaptic cleft, and auto
receptors are on the neuronterminals and cell body called
somato-dendritic region whenthere is an excess of
neurotransmitters in thesynaptic cleft they decrease
(04:17):
release of neurotransmitter fromthe presynaptic nerve terminals.
Dr. Handratta (04:21):
So, perfect.
So now, What happens is thatthese terminal nerve terminal
auto receptors, after some timethey get desensitized.
So when they're desensitized,you release the brake and now
there will be a flow of theneurotransmitter depending upon
how the neurons are stimulated,right?
That is one part.
Then once the neurotransmitterrelease, they act on the
(04:43):
postsynaptic receptors there aredifferent types of serotonin
receptors, right?
So these serotonin receptors arepresent on GABA, inter neuron
and pyramidal neurons in theprefront cortex and hippocampus
right?
So in short, monoamines likeserotonin, norepinephrine and
dopamine, work on these gabainterneurons and pyramidal
(05:04):
neurons and control, thefunctioning or the firing or the
prefrontal cortex andhippocampus Does it make sense?
Dr. Amayo (05:10):
Yes, sir.
Dr. Handratta (05:11):
Yeah.
But the problem with theconventional antidepressant is
that it takes.
At least two to four weeks tosee a 20% improvement in the
symptoms, especially in patientswho respond to it and it takes
eight to 12 weeks to see themaximum benefit or to reach
remission.
That is a 70% improvement.
(05:33):
So it takes a long, long, longtime actually for these
medications to start working.
Dr. Amayo (05:40):
Why is that?
Dr. Handratta (05:41):
in depression, people have a decrease in the
volume of their hippocampus.
Hmm.
Right.
So most of the conventionalantidepressants, like SSRI,
SNRI, NDRI, what they do is thatthey basically stimulate the
stem cells or also called theprogenitor cells in the
hippocampus to generatesomething called new granule
(06:05):
neurons, which in turn becomesneurons.
So it takes a while for thisneurogenesis to take place,
right?
It takes days for the stem cellor the progenitor cells to
develop into a new granuleneurons, and that is why takes a
long time for the conventionalantidepressants to work in
depression.
Dr. Amayo (06:24):
Okay.
And this granule neuron that bestimulated from the hippocampus,
what, what do they do?
What's their role?
Dr. Handratta (06:31):
The New granule, neurons.
help the hippocampus to recoverfrom the previous depressive
episode, and now the hippocampuscan communicate with the
prefrontal cortex and thishippocampal prefrontal cortex
communication.
Is responsible for theantidepressant effect.
Uh, okay.
(06:52):
And this was proven veryrecently, actually.
By A study that was done inNorthwestern University by Dr.
Kessler, who's a neurologist,who basically came up with this
particular hypothesis.
Dr. Amayo (07:05):
So the reconnection between hippocampus and the
frontal lobe can help re resetthe salience, uh, executive, um,
network connection.
Dr. Handratta (07:15):
Exactly.
So it basically tries to, so thebrain tries to rewire itself,
right?
So that like, we go back to thenormal physiology, like the
normal way that a brain issupposed to function like a
non-depressed brain, let me putit that way.
Mm-hmm.
Right?
Dr. Amayo (07:31):
And, and so, the role serotonin receptors play on the
gaba inter neurons and thepyramidal neurons.
How, how does that fit intothis?
Dr. Handratta (07:41):
So if you look at the prefrontal cortex and the
hippocampus, right, thestructures are very, very
similar actually, when you lookat the way the gaba inter
neurons and the pyramidalneurons function.
So you have a pyramidal neuron,you have a lot of pyramidal
neurons in your prefrontalcortex, which release glutamate.
Right?
Mm-hmm.
pyramidal neurons are controlledor fine tuned by GABA inter
(08:04):
neurons.
So if you look at GABA interneurons, there are different
types, but we'll focus on twoGABA inter neurons.
One is called somatostatin,another one is called
parvalbumin.
They are named after theproteins they stain for.
That's why they name that way.
All right, so the somatostatin,gaba, inter neuron and the
parvalbumin, they will haveserotonin receptors.
So the somatostatin interneuronsare more like the tuning button
(08:27):
on your radio where you selectthe channels, right?
So it tunes your pyramidalneuron.
On the other hand, theparvalbumin GABA inter neurons
are like the volume button.
So, they will control the firingof the pyramidal neurons.
Right?
So if these inter neurons arenot functioning well, you'll
have less firing of thepyramidal neurons.
(08:48):
This is what actually causes aproblem because in patients with
depression, there is lessglutamate and there is also a
problem, the functioning of thesomatostatin gaba interneurons
Dr. Amayo (08:58):
Sure.
Yeah.
So only the, so not only isthere less glutamate, it's less,
it's running less smooth andless fluid.
Yes.
To the defect in somatostatinGABA interneurons.
Dr. Handratta (09:11):
Exactly.
Right.
So, and the, you have to alsoremember that the cortex.
Something that controls therelease of neurotransmitter from
the brainstem.
So the monoamine neurons arepresent in your brainstem, and
they're controlled by the firingof this pyramidal neurons.
So in depression, if thisgabapentin inter-neurons are not
functioning well, or they'rehypofunctioning, the pyramidal
(09:32):
neuron is not firing.
So there's not enough glutamate.
And if there's not enoughglutamate or pyramidal neuron
firing, there's not enoughmonoamine released from the
brainstem.
So it's a vicious cycle.
Dr. Amayo (09:42):
So the serotonin, we work on the serotonin receptors
on the GABA inter neurons, andtherefore stopping the cycle
from, I guess from the insideout.
And so by working on the GABAinter neurons, the GABA inter
neurons will work on thepyramindal neurons.
The pyramidal neurons will leadto increasing glutamate firing.
Increased glutamate firing inthe frontal lobe will then lead
(10:04):
to, overall increase monoaminesin the entire, from the
brainstem over everywhere.
Dr. Handratta (10:11):
That's absolutely right.
So it's a top down control ofthe monoamine release.
Dr. Amayo (10:16):
Okay.
I think, I think we have it.
Katrina (10:22):
Thank you for joining us on today's episode.
Feel free to smash thatsubscribe button like your
serotonin hammering a synapticcleft.
Our tireless team is alreadyhard at work, cobbling together
another potpourri of fascinatingdiscussion for next week, so be
sure to tune in, visit ourwebsite and our podcast feed and
let us know your thoughts on theepisode.
Subscribe so you don't miss ourreleases every Wednesday.
(10:46):
Until next time, keep smiling,keep shining, and stay curious.
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