July 20, 2023 • 14 mins
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Join our journey through a landscape of vortioxetine via neurotransmitters, GABA interneurons, and serotonin receptors, all with the audacious goal of making this complex antidepressant understandable. The hosts' heavy accents might challenge your ears, but their insights will stimulate your brain. This episode is chock-full of wit, laughs, and unexpected revelations about vortioxetine's potential benefits in cognitive dysfunction and its low sexual side effects. Tune in and discover why this isn't your grandma's Prozac!
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Dr. Handratta (00:00):
So vortioxetine it's a very, very complex
(00:03):
medication.
Okay, so this is going to be alittle, this is a, this is a
tricky one actually, even, andfor me to explain on a podcast.
So, so we will try to make it assimple as possible.
Okay?
Thanh (00:14):
Welcome to the Y in Psychiatry,
Dr. Amayo (00:16):
Hi, this is Dr.
Amayo C/L fellow.
Thanh (00:20):
Where we delve into the intricate nuances of psychiatric
topics.
Dr. Handratta (00:23):
My name is Dr.
Handratta attendingpsychiatrist.
I did my residency fromUniversity of Connecticut and
then I did my fellowship fromGeorgetown University in
consultation and liaison.
Thanh (00:33):
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
this journey to unlock themysteries of the human psyche.
(00:56):
Only on The Y in Psychiatry.
Dr. Amayo (01:00):
So welcome to the Y in psychiatry.
I know for our=listeners outthere, I do understand that we
picked the two guys with thethickest accent to host this
podcast.
This is progress.
And I think the biggest questiontoday will be how to pronounce
Vortioxetine.
(01:21):
And believe it or not, I went onYouTube and looking, is it
Vortioxetine v Vortioxetine?
I don't know.
That's.
That's gonna be our challengefor today.
Today we'll be talking aboutvortioxetine why it's unique,
what's special about it.
And as usual my co-host, Dr.
Handratta, is here with us.
Dr.
Handratta vortioxetine is prettynew even for me.
(01:42):
New guy, young guy.
So why is it so unique?
What's so special about thisdrug?
Dr. Handratta (01:48):
So vortioxetine is a newer class of
antidepressant.
Dr. Amayo (01:52):
Is that how you say vortioxetine?
Dr. Handratta (01:54):
Yeah.
I say it as vortioxetine.
So vortioxetine is unique amongthe antidepressants because it's
not like the typical SSRIs orSNRIs.
It will block the serotonintransporter, but it also
modulates the functioning of thepostsynaptic, serotonin
(02:15):
receptors.
It'll definitely affect thepresynaptic serotonin receptors,
but it's also a modulator orother serotonin receptors.
That is what makes it uniqueamong the antidepressant class.
Plus, you can also usevortioxetine in patients who
have major depressive disorderwith cognitive dysfunction,
though it's not FDA approved forthe treatment of cognitive
(02:36):
dysfunction in depression or inelderly patients with dementia.
Dr. Amayo (02:40):
Okay.
So it's like others SSRIs itblocks the serotonin
transporter, so causing aninflux of serotonin, but it also
affects the receptors itself,the modulator of serotonin
receptors.
So it hits it in a whammy kindof deal So why is it marketed?
So it's not they approved, butwhy is the marketing account to
function?
(03:00):
What's their claim to fame?
Dr. Handratta (03:02):
The theory behind right now, nothing is proved
right.
We cannot study actuallyreceptor profile in the brain.
It's very difficult, basically,like you can do it, but it's
not, we haven't yet reached tothat point.
So the hypothesis behindvortioxetine improving cognitive
functioning is because itincreases the level of
acetylcholine as well asdopamine in your prefrontal
(03:24):
cortex.
Dr. Amayo (03:25):
Okay.
Dr. Handratta (03:25):
And that is what helps to improve the cognitive
functioning.
Dr. Amayo (03:30):
How does it do that?
How does it improve,acetylcholine and dopamine in
the brain?
Dr. Handratta (03:34):
So let's talk about the mechanism of action.
Like how does vortioxetineworks?
Dr. Amayo (03:38):
Please.
That's what I was trying to getto from the beginning, holding
out on me, sir!
Dr. Handratta (03:41):
So it's very complicated, right?
The way vortioxetine works isthat it blocks the serotonin
transporters.
Now usually regularantidepressants, they have to
block about 70 to 80% of theserotonin transporter to have
the anti-depressant effect.
Okay.
But at that particular level, alot of antidepressants can also
cause sexual side effects.
Okay.
(04:02):
Vortioxetine usually blocksabout 50% of the serotonin
transporters.
So that is one advantage that wehave.
Apart from blocking theserotonin transporter, it also
works on the serotoninreceptors.
Now, before talking about theserotonin receptor, let's talk
about the neuronal circuitry inthe prefrontal cortex and
hippocampus.
Okay?
And most commonly involved inpatients with depression, And
(04:23):
another point that I want tostress is that the cortex is the
one that controls the release ofmonoamines from the brainstem.
Okay.
Brainstem has three differentmono-minergic system in there.
One is locus ceruleus, whichreleases norepinephrine.
The second one is raphi nucleus,which is responsible for
(04:44):
serotonin and then you have theventral segment area for
dopamine.
So the cortex is not firingwell.
The pyramidal neurons are notfiring efficiently, so there is
not enough monoamines that isreleased.
So if you improve the firing ofthe pyramidal neuron, you can
improve the release of thesemonoamines.
And we know that mono-minergicdeficiency is one of the theory
(05:07):
behind depression right now inthe prefrontal cortex and in the
hippocampus, you have somethingcalled GABA interneurons.
They're different types.
But we are gonna put everythingtogether and we'll just say GABA
interneuron for simplicity.
Now this GABA interneuron puts abrake on the pyramidal neuron.
That means That it fine tunesthe pyramidal neuron, right?
(05:28):
So it makes the firing of thepyramidal neuron appropriate or
very synchronous.
Now, there is a GABA interneuronproblem in patients with
depression.
Now, these GABA interneurons arereached in serotonin receptors,
so are the pyramidal neurons.
But we are just gonna focus onthe GABA interneurons.
So these GABA interneuron arerich in serotonin receptors.
We are gonna talk about three ofthem, 5HT1A, 5HT1B, and 5HT3
(05:54):
receptors.
5HT1A and 1B are auto receptors.
That basically means that if youstimulate them on the cell body,
it decreases the firing of theneurons.
If you stimulate on the nerveterminal, it decreases the
release of theneurotransmitters.
Dr. Amayo (06:10):
Are they found on both the cell body and the
neuroterminal?
Dr. Handratta (06:15):
The 5HT1B and 1B are present on the nerve
terminals on the left terminals1A is a somatic as well as
terminal oral receptor.
Okay.
But when you block these autoreceptors, it's just the
opposite.
If they're present on the cellbody, it increases the firing,
if they're present on nerveterminal, increase the release
of neurotransmitter.
Okay.
Okay.
(06:35):
5HT3 receptor is an ionotropicreceptor.
It's not like a metabotropicreceptors like other serotonin
receptors and 5HT3, when youstimulate them, you increase the
firing of the neurons and therelease of neurotransmitter, and
if you block them, you decreaseit.
Now the way vortioxetine worksis that it's an agonist at
(06:55):
5HT-1A receptor.
So when you stimulate 5HT-1A onthe GABA interneuron, you
decrease the firing of this GABAinterneuron.
So you basically disinhibit thepyramidal neuron, so more firing
of the pyramidal neurons, right?
Then it's a partial agonist at5HT-1B, so partial agonist, when
you stimulate the 5HT1-B, youdecrease the firing of the GABA
interneurons, we increase thefiring of the pyramidal neuron.
(07:16):
And we know that the pyramidalneuron is not firing well in
patients with depression, right?
Yeah.
It's firing lower than normal.
And then it also blocks 5HT3receptors.
So when you block the 5HT3receptors on GABA interneuron,
you decrease the firing.
Okay, so overall you'reincreasing the firing of the
pyramidal neuron, which in turnactually stimulates the
brainstem, increasing themonoamines.
(07:37):
Makes sense?
Dr. Amayo (07:38):
So in depression, there is one of, one of our
theory is there's a lack ofmonoamine neurotransmitters, and
that's coming from thebrainstem.
Now, the pyramidal neurons fromthe prefrontal cortex tells the
brainstem to release monoamines,and it does that through the
pyramidal neurons, and now thereare these GABA inter neurons
that puts a break on thepyramidal neurons.
(07:59):
So it's like a chain reaction.
GABA, interneurons, which isalso dysfunctional in
depression, but GABAinterneurons puts a break on the
pyramidal neurons and pyramidalneurons then doesn't tell the
brainstem to release monoaminesNow, vortioxetine works on these
GABA interneurons andspecifically on the 5HT1A,
5HT1B, and the 5HT3 receptors,5HT1A and 1B is an auto receptor
(08:23):
and so basically vortioxetine isan agonist, these two auto
receptors.
And so when it agonizes them orhelps them out, leads to less
firing of the GABA interneuronsand less firing of the GABA
interneurons means more firingof the pyramidal neurons.
And then 5HT3 is an antagonistwhich basically does the same
(08:44):
with less firing of the GABAinterneurons, more firing of the
pyramidal neurons, which leadsto more influx of monoamines.
Now the from, if I understandthis straight so not only is
there an increase in serotonin,dopamine and norepinephrine.
There's also an increase inacetylcholine as a result of
this, which, from 1 1 Bacetylcholine up means cognitive
(09:06):
function up as well.
And did I get that right?
Dr. Handratta (09:09):
Yeah, you got that absolutely right.
Dr. Amayo (09:11):
From what I'm getting, so the best time to use
and why to use vortioxetineseems like if cognitive issues
is a part of the depressivesymptoms and then if they're
also having sexual side effects.
Dr. Handratta (09:23):
I want to hit the second part of the mechanism of
action of vortioxetine.
Because how does it increase theacetylcholine in the prefrontal
cortex?
So now you have thesemonoaminergic nerve terminals in
your prefrontal cortex, as wellas the hippocampus.
Now these nerve terminals arefrom the dopaminergic center,
the serotonergic center, and thenoradrenergic center, as well as
(09:46):
the cholinergic center.
The cholinergic center is a baseof the forebrain.
Now these nerve terminals in theprefrontal cortex and
hippocampus are kept under checkby these GABA interneurons.
So by vortioxetine, by acting onthose serotonin receptor GABA
inter neuron, it blocks thoseGABA interneurons.
So now these nerve terminals aredisinhibited.
So now there will be an increasein the level of serotonin,
(10:07):
dopamine, norepinephrine,acetylcholine in your prefrontal
cortex.
That is what improves thecognitive functioning.
Dr. Amayo (10:14):
I just wanna make sure I understand that.
So you're saying theacetylcholine hub is not in the
brain stem.
It's in the basal forebrain soeven though it disinhibits the
pyramidal neurons Going into thebrainstem also to be the pyramid
neurons going to the base of ourbrain.
Dr. Handratta (10:32):
So the thing is that these are all
interconnected.
Okay.
But the basal forebrain is notthe only cholinergic system in
the brain.
There's cholinergic neurons alsopresent in other areas of brain
like parenchymal tegmental area,lateral dorsal tegmental,
they're different areas.
But the basal forebrain area hasnerve terminals that goes into
the prefrontal cortex, which isusually blocked by the GABA,
(10:52):
which puts brake.
So vortioxetine by inhibitingthe GABA interneurons disinbits
these nerve terminals.
Gotcha.
Yeah.
More acetylcholine basically inthe prefrontal cortex.
Because as we said, there's aGABA interneuron dysfunction and
depression, so it definitelyaffects those cholinergic nerve
terminals.
Yeah, makes sense overall.
Dr. Amayo (11:10):
Yeah, it makes sense overall leads to an more influx
of these neurotransmittersincluding acetylcholine.
Now, I think you alluded alittle bit to the sexual side
effects.
Why does it help with sexualside effects?
Dr. Handratta (11:21):
Now, how does it affect the sexual dysfunction?
So vortioxetine Is one of theantidepressants that is used
when patients develop sexualside effects to other
antidepressants.
And this is also a boardquestion for people.
So according To research data onvortioxetine the sexual side
effect is almost equivalent toplacebo.
Right now, most of theantidepressants have to block
(11:43):
about 70 to 80% of the serotonintransporters to have an
antidepressant effect.
That's why Trazodone, when youuse a small dose is a hypnotic,
and it's not an antidepressantbecause between 25 to 150
milligram, it doesn't cause thatmuch blockage of the serotonin
transporters.
So when you actually block theserotonin transporters at that
high level, you basicallydevelop sexual side effects
(12:03):
because you are flooding thesystem with serotonin, right?
On the other hand, vortioxetinedoesn't block the serotonin
transporter that much, right?
It doesn't have to, right?
Because it also acts on otherserotonin receptors.
So because of that, it is moreeffective in patients who have
depression with sexual sideeffects or who have developed
depression.
You treated them with SSRI anddeveloped sexual side effects.
(12:24):
Makes sense.
Makes sense.
But again, we do not understandit completely.
This is a hypothesis again.
Dr. Amayo (12:29):
Yeah.
And so it's not as potent of aserotonin transporter blocker.
And I guess very fairly in thesystem, there's not that much
higher influx of serotonin is.
So it was on the receptorsitself?
Dr. Handratta (12:44):
It does actually.
So if you look at it, it'saffinity for serotonin
transporter is pretty high.
It's this KI value is like about1.6.
I don't wanna go into that, butit's a very strong affinity for
the serotonin transporters.
Dr. Amayo (12:57):
But doesn't block it all the way.
Dr. Handratta (12:59):
So you don't have to because you can, because you
have so much effect on otherserotonin receptor.
It's like atypicalantipsychotics Okay.
Like one of the atypicalantipsychotics that we use is
lumateperone, which doesn't haveto block too much of those
dopamine because has effects onthe receptor.
So I'm not gonna go intolumateperone, but the, what I'm
trying to say is that otherantidepressant work by blocking
(13:20):
the serotonin transporter,vortioxetine doesn't have to
just rely on the serotonintransporters.
It can act on the otherserotonergic receptors to have
the antidepressant effect.
Dr. Amayo (13:30):
That, that makes sense.
I guess my, what would you callthat?
So it doesn't, it has a highaffinity for the rece.
For the transporters, but itdoesn't block it as much.
What's that property called?
Dr. Handratta (13:39):
What it means is that it's a serotonin
transporter, but it's also aserotonin receptor modulator.
Okay.
Which is lacking in most of theconventional antidepressant,
other conventionalantidepressant just release the
serotonin.
Which then goes and acts on theserotonin receptors.
But since this is serotonin, itwill have an agonist property on
all the serotonin receptors.
But vortioxetine is veryspecialized: it has agonist at
(14:01):
one receptor antagonist,agonist.
So it's very well engineered.
Dr. Amayo (14:04):
And I think that explains it all.
Thank you.
Dr. Handratta (14:07):
Thank you, Dr.
Katrina (14:14):
Thank you for joining us on today's episode.
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.
Until next time, keep smiling,keep shining, and stay curious.
So vortioxetine it's a very, very complex
(00:03):
medication.
Okay, so this is going to be alittle, this is a, this is a
tricky one actually, even, andfor me to explain on a podcast.
So, so we will try to make it assimple as possible.
Okay?
Thanh (00:14):
Welcome to the Y in Psychiatry,
Dr. Amayo (00:16):
Hi, this is Dr.
Amayo C/L fellow.
Thanh (00:20):
Where we delve into the intricate nuances of psychiatric
topics.
Dr. Handratta (00:23):
My name is Dr.
Handratta attendingpsychiatrist.
I did my residency fromUniversity of Connecticut and
then I did my fellowship fromGeorgetown University in
consultation and liaison.
Thanh (00:33):
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
this journey to unlock themysteries of the human psyche.
(00:56):
Only on The Y in Psychiatry.
Dr. Amayo (01:00):
So welcome to the Y in psychiatry.
I know for our=listeners outthere, I do understand that we
picked the two guys with thethickest accent to host this
podcast.
This is progress.
And I think the biggest questiontoday will be how to pronounce
Vortioxetine.
(01:21):
And believe it or not, I went onYouTube and looking, is it
Vortioxetine v Vortioxetine?
I don't know.
That's.
That's gonna be our challengefor today.
Today we'll be talking aboutvortioxetine why it's unique,
what's special about it.
And as usual my co-host, Dr.
Handratta, is here with us.
Dr.
Handratta vortioxetine is prettynew even for me.
(01:42):
New guy, young guy.
So why is it so unique?
What's so special about thisdrug?
Dr. Handratta (01:48):
So vortioxetine is a newer class of
antidepressant.
Dr. Amayo (01:52):
Is that how you say vortioxetine?
Dr. Handratta (01:54):
Yeah.
I say it as vortioxetine.
So vortioxetine is unique amongthe antidepressants because it's
not like the typical SSRIs orSNRIs.
It will block the serotonintransporter, but it also
modulates the functioning of thepostsynaptic, serotonin
(02:15):
receptors.
It'll definitely affect thepresynaptic serotonin receptors,
but it's also a modulator orother serotonin receptors.
That is what makes it uniqueamong the antidepressant class.
Plus, you can also usevortioxetine in patients who
have major depressive disorderwith cognitive dysfunction,
though it's not FDA approved forthe treatment of cognitive
(02:36):
dysfunction in depression or inelderly patients with dementia.
Dr. Amayo (02:40):
Okay.
So it's like others SSRIs itblocks the serotonin
transporter, so causing aninflux of serotonin, but it also
affects the receptors itself,the modulator of serotonin
receptors.
So it hits it in a whammy kindof deal So why is it marketed?
So it's not they approved, butwhy is the marketing account to
function?
(03:00):
What's their claim to fame?
Dr. Handratta (03:02):
The theory behind right now, nothing is proved
right.
We cannot study actuallyreceptor profile in the brain.
It's very difficult, basically,like you can do it, but it's
not, we haven't yet reached tothat point.
So the hypothesis behindvortioxetine improving cognitive
functioning is because itincreases the level of
acetylcholine as well asdopamine in your prefrontal
(03:24):
cortex.
Dr. Amayo (03:25):
Okay.
Dr. Handratta (03:25):
And that is what helps to improve the cognitive
functioning.
Dr. Amayo (03:30):
How does it do that?
How does it improve,acetylcholine and dopamine in
the brain?
Dr. Handratta (03:34):
So let's talk about the mechanism of action.
Like how does vortioxetineworks?
Dr. Amayo (03:38):
Please.
That's what I was trying to getto from the beginning, holding
out on me, sir!
Dr. Handratta (03:41):
So it's very complicated, right?
The way vortioxetine works isthat it blocks the serotonin
transporters.
Now usually regularantidepressants, they have to
block about 70 to 80% of theserotonin transporter to have
the anti-depressant effect.
Okay.
But at that particular level, alot of antidepressants can also
cause sexual side effects.
Okay.
(04:02):
Vortioxetine usually blocksabout 50% of the serotonin
transporters.
So that is one advantage that wehave.
Apart from blocking theserotonin transporter, it also
works on the serotoninreceptors.
Now, before talking about theserotonin receptor, let's talk
about the neuronal circuitry inthe prefrontal cortex and
hippocampus.
Okay?
And most commonly involved inpatients with depression, And
(04:23):
another point that I want tostress is that the cortex is the
one that controls the release ofmonoamines from the brainstem.
Okay.
Brainstem has three differentmono-minergic system in there.
One is locus ceruleus, whichreleases norepinephrine.
The second one is raphi nucleus,which is responsible for
(04:44):
serotonin and then you have theventral segment area for
dopamine.
So the cortex is not firingwell.
The pyramidal neurons are notfiring efficiently, so there is
not enough monoamines that isreleased.
So if you improve the firing ofthe pyramidal neuron, you can
improve the release of thesemonoamines.
And we know that mono-minergicdeficiency is one of the theory
(05:07):
behind depression right now inthe prefrontal cortex and in the
hippocampus, you have somethingcalled GABA interneurons.
They're different types.
But we are gonna put everythingtogether and we'll just say GABA
interneuron for simplicity.
Now this GABA interneuron puts abrake on the pyramidal neuron.
That means That it fine tunesthe pyramidal neuron, right?
(05:28):
So it makes the firing of thepyramidal neuron appropriate or
very synchronous.
Now, there is a GABA interneuronproblem in patients with
depression.
Now, these GABA interneurons arereached in serotonin receptors,
so are the pyramidal neurons.
But we are just gonna focus onthe GABA interneurons.
So these GABA interneuron arerich in serotonin receptors.
We are gonna talk about three ofthem, 5HT1A, 5HT1B, and 5HT3
(05:54):
receptors.
5HT1A and 1B are auto receptors.
That basically means that if youstimulate them on the cell body,
it decreases the firing of theneurons.
If you stimulate on the nerveterminal, it decreases the
release of theneurotransmitters.
Dr. Amayo (06:10):
Are they found on both the cell body and the
neuroterminal?
Dr. Handratta (06:15):
The 5HT1B and 1B are present on the nerve
terminals on the left terminals1A is a somatic as well as
terminal oral receptor.
Okay.
But when you block these autoreceptors, it's just the
opposite.
If they're present on the cellbody, it increases the firing,
if they're present on nerveterminal, increase the release
of neurotransmitter.
Okay.
Okay.
(06:35):
5HT3 receptor is an ionotropicreceptor.
It's not like a metabotropicreceptors like other serotonin
receptors and 5HT3, when youstimulate them, you increase the
firing of the neurons and therelease of neurotransmitter, and
if you block them, you decreaseit.
Now the way vortioxetine worksis that it's an agonist at
(06:55):
5HT-1A receptor.
So when you stimulate 5HT-1A onthe GABA interneuron, you
decrease the firing of this GABAinterneuron.
So you basically disinhibit thepyramidal neuron, so more firing
of the pyramidal neurons, right?
Then it's a partial agonist at5HT-1B, so partial agonist, when
you stimulate the 5HT1-B, youdecrease the firing of the GABA
interneurons, we increase thefiring of the pyramidal neuron.
(07:16):
And we know that the pyramidalneuron is not firing well in
patients with depression, right?
Yeah.
It's firing lower than normal.
And then it also blocks 5HT3receptors.
So when you block the 5HT3receptors on GABA interneuron,
you decrease the firing.
Okay, so overall you'reincreasing the firing of the
pyramidal neuron, which in turnactually stimulates the
brainstem, increasing themonoamines.
(07:37):
Makes sense?
Dr. Amayo (07:38):
So in depression, there is one of, one of our
theory is there's a lack ofmonoamine neurotransmitters, and
that's coming from thebrainstem.
Now, the pyramidal neurons fromthe prefrontal cortex tells the
brainstem to release monoamines,and it does that through the
pyramidal neurons, and now thereare these GABA inter neurons
that puts a break on thepyramidal neurons.
(07:59):
So it's like a chain reaction.
GABA, interneurons, which isalso dysfunctional in
depression, but GABAinterneurons puts a break on the
pyramidal neurons and pyramidalneurons then doesn't tell the
brainstem to release monoaminesNow, vortioxetine works on these
GABA interneurons andspecifically on the 5HT1A,
5HT1B, and the 5HT3 receptors,5HT1A and 1B is an auto receptor
(08:23):
and so basically vortioxetine isan agonist, these two auto
receptors.
And so when it agonizes them orhelps them out, leads to less
firing of the GABA interneuronsand less firing of the GABA
interneurons means more firingof the pyramidal neurons.
And then 5HT3 is an antagonistwhich basically does the same
(08:44):
with less firing of the GABAinterneurons, more firing of the
pyramidal neurons, which leadsto more influx of monoamines.
Now the from, if I understandthis straight so not only is
there an increase in serotonin,dopamine and norepinephrine.
There's also an increase inacetylcholine as a result of
this, which, from 1 1 Bacetylcholine up means cognitive
(09:06):
function up as well.
And did I get that right?
Dr. Handratta (09:09):
Yeah, you got that absolutely right.
Dr. Amayo (09:11):
From what I'm getting, so the best time to use
and why to use vortioxetineseems like if cognitive issues
is a part of the depressivesymptoms and then if they're
also having sexual side effects.
Dr. Handratta (09:23):
I want to hit the second part of the mechanism of
action of vortioxetine.
Because how does it increase theacetylcholine in the prefrontal
cortex?
So now you have thesemonoaminergic nerve terminals in
your prefrontal cortex, as wellas the hippocampus.
Now these nerve terminals arefrom the dopaminergic center,
the serotonergic center, and thenoradrenergic center, as well as
(09:46):
the cholinergic center.
The cholinergic center is a baseof the forebrain.
Now these nerve terminals in theprefrontal cortex and
hippocampus are kept under checkby these GABA interneurons.
So by vortioxetine, by acting onthose serotonin receptor GABA
inter neuron, it blocks thoseGABA interneurons.
So now these nerve terminals aredisinhibited.
So now there will be an increasein the level of serotonin,
(10:07):
dopamine, norepinephrine,acetylcholine in your prefrontal
cortex.
That is what improves thecognitive functioning.
Dr. Amayo (10:14):
I just wanna make sure I understand that.
So you're saying theacetylcholine hub is not in the
brain stem.
It's in the basal forebrain soeven though it disinhibits the
pyramidal neurons Going into thebrainstem also to be the pyramid
neurons going to the base of ourbrain.
Dr. Handratta (10:32):
So the thing is that these are all
interconnected.
Okay.
But the basal forebrain is notthe only cholinergic system in
the brain.
There's cholinergic neurons alsopresent in other areas of brain
like parenchymal tegmental area,lateral dorsal tegmental,
they're different areas.
But the basal forebrain area hasnerve terminals that goes into
the prefrontal cortex, which isusually blocked by the GABA,
(10:52):
which puts brake.
So vortioxetine by inhibitingthe GABA interneurons disinbits
these nerve terminals.
Gotcha.
Yeah.
More acetylcholine basically inthe prefrontal cortex.
Because as we said, there's aGABA interneuron dysfunction and
depression, so it definitelyaffects those cholinergic nerve
terminals.
Yeah, makes sense overall.
Dr. Amayo (11:10):
Yeah, it makes sense overall leads to an more influx
of these neurotransmittersincluding acetylcholine.
Now, I think you alluded alittle bit to the sexual side
effects.
Why does it help with sexualside effects?
Dr. Handratta (11:21):
Now, how does it affect the sexual dysfunction?
So vortioxetine Is one of theantidepressants that is used
when patients develop sexualside effects to other
antidepressants.
And this is also a boardquestion for people.
So according To research data onvortioxetine the sexual side
effect is almost equivalent toplacebo.
Right now, most of theantidepressants have to block
(11:43):
about 70 to 80% of the serotonintransporters to have an
antidepressant effect.
That's why Trazodone, when youuse a small dose is a hypnotic,
and it's not an antidepressantbecause between 25 to 150
milligram, it doesn't cause thatmuch blockage of the serotonin
transporters.
So when you actually block theserotonin transporters at that
high level, you basicallydevelop sexual side effects
(12:03):
because you are flooding thesystem with serotonin, right?
On the other hand, vortioxetinedoesn't block the serotonin
transporter that much, right?
It doesn't have to, right?
Because it also acts on otherserotonin receptors.
So because of that, it is moreeffective in patients who have
depression with sexual sideeffects or who have developed
depression.
You treated them with SSRI anddeveloped sexual side effects.
(12:24):
Makes sense.
Makes sense.
But again, we do not understandit completely.
This is a hypothesis again.
Dr. Amayo (12:29):
Yeah.
And so it's not as potent of aserotonin transporter blocker.
And I guess very fairly in thesystem, there's not that much
higher influx of serotonin is.
So it was on the receptorsitself?
Dr. Handratta (12:44):
It does actually.
So if you look at it, it'saffinity for serotonin
transporter is pretty high.
It's this KI value is like about1.6.
I don't wanna go into that, butit's a very strong affinity for
the serotonin transporters.
Dr. Amayo (12:57):
But doesn't block it all the way.
Dr. Handratta (12:59):
So you don't have to because you can, because you
have so much effect on otherserotonin receptor.
It's like atypicalantipsychotics Okay.
Like one of the atypicalantipsychotics that we use is
lumateperone, which doesn't haveto block too much of those
dopamine because has effects onthe receptor.
So I'm not gonna go intolumateperone, but the, what I'm
trying to say is that otherantidepressant work by blocking
(13:20):
the serotonin transporter,vortioxetine doesn't have to
just rely on the serotonintransporters.
It can act on the otherserotonergic receptors to have
the antidepressant effect.
Dr. Amayo (13:30):
That, that makes sense.
I guess my, what would you callthat?
So it doesn't, it has a highaffinity for the rece.
For the transporters, but itdoesn't block it as much.
What's that property called?
Dr. Handratta (13:39):
What it means is that it's a serotonin
transporter, but it's also aserotonin receptor modulator.
Okay.
Which is lacking in most of theconventional antidepressant,
other conventionalantidepressant just release the
serotonin.
Which then goes and acts on theserotonin receptors.
But since this is serotonin, itwill have an agonist property on
all the serotonin receptors.
But vortioxetine is veryspecialized: it has agonist at
(14:01):
one receptor antagonist,agonist.
So it's very well engineered.
Dr. Amayo (14:04):
And I think that explains it all.
Thank you.
Dr. Handratta (14:07):
Thank you, Dr.
Katrina (14:14):
Thank you for joining us on today's episode.
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.
Until next time, keep smiling,keep shining, and stay curious.
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