[Narrator] Here we're going to dive into the genetics
of some of the specific psychiatric disorders
that were covered in the textbook chapters
that were assigned for this module.
So certainly not everything, not by a long shot,
but just going to hit on some
of the more common psychiatric disorders
that have some genetic components
that have been identified in them.
And we'll use those as basically models
for understanding how genetics may play a role
in different psychiatric disorders,
and basically the state of the field as of now
and where it may be moving in the future.
So just to get started here,
as I mentioned in the previous lecture,
it is not nature or nurture.
It is always nature and nurture, especially,
especially when we're talking about psychiatric disorders.
These are multifactorial,
meaning both environment and genetics play a role.
They're polygenic,
which means there are many different genes likely involved,
and there are complex disorders
involving an interplay of genetics and environment.
So if we look here in the top right corner
of the slide with this Venn diagram
of nature on one side, nurture on the other,
this intersection here should actually be really, really big
because most diseases and most disorders
that humans experience
fall into the category of being affected by both,
actually almost all of them I would venture to say,
have components of both to varying extents, right?
So when we talked about heritability,
remember that term
that can be a bit confusing to understand.
But when we're talking about heritability here,
we're trying to distinguish the amount that has caused,
the amount of the variability
within that particular trait.
So within having the disorder or not having the disorder,
that can be attributed to,
specifically to genetics versus environments.
And you're really not seeing anything
either being 100% or 0%.
Everything is in between.
It's in between, you know, there's some of both.
So that's where we're coming from here
and that's what we're trying to understand.
It's not to say in any of this material,
is it ever to say
that any of these disorders
are exclusively genetic diseases,
meaning that a person will inherit it.
They have, you know,
there's nothing can be done either for them
or, you know, either to prevent the disease
or cause the disease.
It's either going to happen to a person or it's not.
It's not like cystic fibrosis, say, for example,
or sickle cell anemia,
where you are inheriting a mutation from your parents
and you will develop the disease.
And there really isn't anything can be done
to prevent that from happening
'cause that's really a fully genetic disease.
And it's also not like something
that would be completely just controlled
by the environment, right?
I mean, it's not on one extreme or the other.
These psychiatric disorders, in particular,
fall really squarely in between both nature and nurture
or genetics and environment, if you will.
When we're looking at these disorders,
it comes back a lot to the same pathways involved
in disruption of neurotransmitter signaling
or receptors in neural cells.
And these are regulated by proteins coded for in our genes,
which would be the nature component of things, so to speak.
And this commonly contributes to psychiatric disorders.
And also our neural cells, at the same time, are programmed
specifically to respond to environmental cues like stress
or a good situation or a bad situation
or something potentially harmful
or something potentially beneficial.
We are programmed to be able
to respond to that.
And that response,
that affects the neurotransmitter signaling,
it affects the receptors, it affects the neural cells,
and that's not genetic.
That's in response to the environment.
So you have both at play at the same time.
They're both in, like,
really intimately connected with one another
and affect each other to, you know, varying degrees.
So this is, again, this is where we're coming from.
Inheritance has been linked with psychiatric disorders
since the early 20th century.
However, the actual pathways and genes involved
are only now starting to be understood.
So while it was seen,
it was appreciated even in, like, you know, the early 1900s,
that in families that have a history
where there are individuals who present
with schizophrenia, for example, that there will be,
they're more likely to have individuals in that family
who will also have schizophrenia.
That it was, it seems to be inherited,
at least to some extent.
Now, unfortunately,
what that also fed into at that particular time
in our history, not to get too far off on a tangent,
but just to provide you
a little bit of historical context here,
eugenics was actually used to,
as sort of the rationale
for why many individuals
were basically, against their will,
were put into these sanitariums
or insane asylums, if you will,
that again, involuntary, against their will,
simply because, and they have a family history
of having a mental illness.
Because, say, for example, their mother or their father,
even some extreme examples,
say, their mother or their father was an alcoholic
or had schizophrenia
or, you know, had some issue that they were dealing with,
then they might, say, for example,
that, well, since your parents had it
or one of your parents had it,
you are more likely to have it.
So we're just going to go ahead and take the step
of putting you into an asylum against your will
because we know most likely you'll develop this as well.
And many times they didn't. Many times they didn't.
I mean, except for the stress that was caused
by being put into an asylum against their will,
which, no doubt, can lead to the environmental side
of developing different psychiatric disorders.
The genetics, it's not a one-to-one,
it's not like we're looking, again,
it's not like we're looking at Mendelian diseases here
where we can actually predict exactly the risk
of a person developing it,
or can we say that you for sure will develop this disorder.
Not at all.
And unfortunately that was the approach taken at the time.
And it was an extreme measure, of course, that was taken.
And much of it was related to,
had underpinnings of motivations
of racism and classism as well
that motivated individuals to persecute
those of particular nationalities or races
or socioeconomic status,
and use the justification of genetics.
So just to remain, keep that in your mind
that historical context of that.
That happened in the United States
in and around 1920s, '30s, that timeframe.
So this was not that long ago.
And it even happened in Vermont.
There definitely, there's a history of the eugenics movement
specifically in Vermont as well.
So if you're ever interested in learning more about that,
please let me know
because I do actually have some good resources
that you may be interested in reading more about.
So let's go back to the pathway that I mentioned,
the neurotransmitters,
and how this has really been associated
with a number of different psychiatric disorders.
Mutations in genes that encode proteins
involved in making sensing, secreting, reuptaking,
and degrading neurotransmitters
are commonly associated with psychiatric disorders.
So as you can appreciate then,
there are many different genes.
Even though we're looking at one pathway,
we're saying we're looking at neurotransmitters.
Well, it's not just the genes that encode neurotransmitters,
it's also the genes that encode neurotransmitter receptors,
the genes that encode the proteins
that are necessary for secreting neurotransmitters,
those that are necessary for sensing them,
for reuptaking them, for all the different effects.
I mean, we're talking hundreds of genes here.
This isn't a small set of, you know, a couple of genes.
It's many different genes,
and they each may play a small role
in the likelihood of developing
a particular psychiatric disorder.
These are also common targets
for treating conditions like depression.
However, these treatments will only work in people
who have the targeted pathway disrupted,
leading to a future role of genetic testing
and targeted treatment of psychiatric disorders.
So, for example, you're treating someone
who has depression with an SSRI.
If the individual does not actually have any issue
with their serotonin levels,
and in fact this was caused
by something other than serotonin reuptake,
then the drug isn't actually going to really be effective
in that person because you're not,
the pharmacologic agent
isn't targeting the proper pathway.
So while a person may have,
you may have 10 people who all have depression,
they all might have depression that's the result
of something going wrong in different parts of the pathway.
And each pharmacologic agent
may only target one or two parts of the pathway.
And if that person isn't being affected, you know,
doesn't have an alteration in that part of the pathway,
then the drug's really not going to have an effect.
And I think that contributes a lot to why there is
failure to respond to certain therapies in individuals,
and it can take a while to find the right therapy for them.
So the hope is that in the future, certainly,
with the increased information
that we'll have from research and genetics,
and better development of genetic testing,
potentially we can come up
with those targeted treatments for psychiatric disorders
similar to what we're experiencing now in oncology,
where we talked about last week,
where you have those very specific targeted therapies,
say, for example, targeting the EGF receptor
when it's being overexpressed or overactivated.
We know a specific person, you know,
we can take a biopsy of a person's tumor,
we can identify, yes, they have a mutation
or a duplication that's leading to EGF receptor
being overactivated.
So this therapy will work.
The hope is that in the future,
and I think this is a reasonable hope, that in the future,
we'll be able to do something similar for individuals
with psychiatric disorders.
Certainly in that case,
what we would likely be looking at would be
a germline mutation.
So it's something that they've inherited,
and as opposed to cancer
where it's gonna be different in every person's cell.
In this case, you could actually take
just a cheek swab, spit sample, whatever,
and test their DNA,
and look for maybe disruption of certain genes
that are related to specific pathways
so that now we can find targeted therapeutics.
And as I'm sure you can appreciate,
the faster you get someone
on an effective pharmacologic therapy
for something like depression
or any of these psychiatric disorders,
the more effective it's going to be
and the better it's going to be for that patient.
So connections between different psychiatric disorders,
this was an interesting paper
that was published in Nature Genetics,
and they were looking at heritability of schizophrenia,
bipolar disorder, ADHD, autism, and MDD
in a large and diverse population pool.
So not only were they looking at,
again, remember what heritability is?
Heritability is looking at the,
it's sort of like those twin studies that we talked about.
So what portion of the variants that we see in a population
can be attributed to genetic variation
as opposed to environment.
So what we see here is,
you can see on the right hand side in the graph
that they showed in that paper,
ADHD, bipolar, schizophrenia, MDD, autism spectrum disorder
are all quite heritable on their own.
They have heritability anywhere
from about 15% to about 30%.
And this is heritability attributed
to the specific single nucleotide polymorphisms
that they were exploring.
This is not total heritability. Okay?
So let's make an important distinction here.
So when you look at this and you say,
"Well, wait, this is showing that autism spectrum disorder
has a heritability of only 15%."
Well, no, that's 15% that can be attributed
to these specific single nucleotide polymorphisms
that they were exploring.
So this was not really, the study was not done with twins,
it was actually done looking at specific sequences
that they thought might be involved
in developing these disorders.
Mostly because they are commonly
variants in the population.
And what what I mean by that is that if you look within,
say, 100 people, and you look within the stretch of DNA,
there's a high likelihood that any two people
will have actually different sequences at that location
as opposed to the average region of our genomes
where we compare to one another
and we'll see that they're like exactly the same.
In certain stretches, they're more likely to be different.
And so they're looking at those stretches,
which are called common SNPs
or common single nucleotide polymorphisms.
And so they just looked at some of those.
And that means that
when we look at the heritability estimates here,
this is not total heritability,
this is heritability that can be attributed to these SNPs,
to these specific SNPs.
What does that tell us?
It tells us that these SNPs don't, are not,
the total contribution of the genetic part
of development of these different diseases.
So that means there are other stretches of DNA
that they did not look at
that are contributing in some way
to the developments of these disorders.
Okay, hopefully that's pretty clear.
So again, this is not total heritability
because it's not based on twin studies.
This is heritability based only on the select SNPs
that they decided to look at in the study.
But what they did find, which was kind of interesting,
was that there are some co-heritabilities,
and what does that mean?
Well, that is actually telling us
that certain of these SNPs that they looked at
can not only increase the likelihood
of one of these diseases,
but can actually increase the likelihood
of maybe two or more of these different diseases together.
So a single gene or, you know,
in this case there are several different genes
that this applies to,
but, say, a single gene can actually increase
not just the likelihood of developing schizophrenia,
but can also increase the likelihood
of developing bipolar disorder.
And why do we really care about this?
Well, it tells us a couple of interesting things.
It tells us that for one thing,
potentially someone who is at risk for schizophrenia
is also at a higher risk for developing bipolar disorder
because they seem to share similar pathways,
but also tells us the molecular etiology of these disorders
may have some overlap.
So while clinically we define them as two separate diseases,
they're actually, you know, it's probably some spectrum
that they're part of the same disease family
from a molecular perspective.
But from a phenotype perspective,
when we actually look at two patients,
we define them as two separate diseases,
Schizophrenia, bipolar disorder.
But really it's more shades of gray.
It's not that black and white.
Because they share similar genes, they share the same genes.
In some cases that will contribute
to either of these diseases.
So what would make a person become schizophrenic
versus developing bipolar disorder?
Well, we don't really know, but that probably has,
you can probably attribute a lot of that to environment
and also the combination of the other genes
that are involved in inheriting that disorder.
Remember there are 30, 40, 50, 60,
however many different genes
that may be implicated in each of these diseases.
While they may share some of those genes,
there are other genes
that only will contribute to bipolar disorder
or only will contribute to schizophrenia.
And so it's those combinations
of the different variants in those genes
that will likely push a person
more towards one or the other,
in addition to their environmental influences.
Plus then we have to consider,
again, it's not black and white.
It's not schizophrenia and bipolar disorder,
two completely different diseases.
They're actually, they share some molecular pathways.
So let's go back to, for a moment, to epigenetics.
You all remember that, hopefully very fondly, (chuckles)
from our earlier modules when we talked
about DNA methylation and histone modifications.
So DNA methylation has been really a hot topic
in the psychiatric disorders.
And remember the DNA methylation patterns
are formed in our cells over our lifetime,
especially in the first 12 years of life.
If you look at this graph on the right,
you see that this is the percentage of DNA methylation
that we have, percentage of cytosines
that are methylated in our cells,
depending upon the stage of our life.
And so what we can see is that there's this huge increase
from when time of conception,
when there's virtually no methylation
to basically, you know, one, two years old.
And then there's another increase
between five and 20-ish years old,
17, 20 years old.
And so we're accumulating these over our lifetime.
Remember that DNA methylation patterns can be influenced
by response to our environmental cues.
So again, here's another place,
environment and genetics getting cozy with one another,
affecting one another in many different ways.
So it's never just nature or nurture,
it's both together all the time,
and just affecting each other in ways
we probably don't even fully understand yet.
But in this case,
we do kind of understand a little bit about methylation.
So we do know that stress can,
stress and diets,
and sort of overall health and well-being,
and probably other factors we don't yet understand
can influence methylation patterns.
And as you can see,
those methylation patterns are very dynamic
and being set in childhood.
And let's link that back to a recent research
which showed specific DNA methylation patterns
are present in adults with PTSD
who suffered abuse as children
that are different from those with PTSD
who did not experience child abuse.
So what does this tell us? What does this tell us?
This tells us that child abuse
actually affects our DNA methylation patterns,
which can affect the way in which we respond to situations,
to develop disorders or can recover from disorders,
how, you know, different diseases
will actually present in us.
All of this can be affected by what we experience,
especially in childhood.
And so what the study was looking at
was individuals who have PTSD.
And they divided them into two groups,
those who had experienced child abuse, those who had not.
And then they looked at DNA methylation patterns
and gene expression between those.
And what they found was that, huh,
well, the gene expression levels in certain genes
are very different between these two individuals
or between these two groups of individuals,
even though they both have PTSD.
So what could be causing that?
They looked then at DNA methylation patterns
between those two individual, two groups of individuals.
Well, what they found was that they're very different.
And that individuals who experienced child abuse
actually have relatively similar
DNA methylation patterns to one another,
presumably because of the stress that they experienced
during a time when their DNA methylation patterns
were being established and set.
And that affects gene expression,
which affects what the disease etiology most likely.
So maybe this will help to inform how we treat PTSD,
how we treat individuals
who have different psychiatric disorders
who did experience childhood abuse or had different,
maybe experienced malnutrition as a child
or had different kinds of stress in their life as a child.
It's really fascinating to me,
and I included another reading on this that's related to,
a press release that's related
to this particular publication.
You're more than welcome to,
of course, read the publication.
It just gets very detailed.
And so I didn't include the actual publication,
but, of course, you're more than welcome to look at that.
But the press release really captures
the impact of that study.
And this is definitely the direction
in which psychiatric disorder genetic research is going.
It's not just looking at our genetic code,
but also looking at our epigenetic code.
So let's take a look at some specific disorders.
So bipolar disorder,
there are a number of different genes
that have been associated with bipolar disorder
including COMT, which degrades catecholamines like dopamine.
And allelic variation can affect emotional regulation
through excess of dopamine associated with mania phase.
MAOA is another gene which degrades serotonin.
So an excess of serotonin can impact reward pathways
and lead to aggression and emotional instability.
There was also another paper,
a publication that came out that was looking at MAOA,
and potentially its DNA methylation patterns,
which may be influenced in childhood as well.
So just to summarize briefly what that publication showed,
again, getting back to the influence of childhood stress
and childhood abuse on DNA methylation patterns
which can affect adult presentation of disease,
what they saw was that in individuals
who were abused as children,
that they were more likely to be aggressive as adults.
And also, that those individuals
who were aggressive as adults,
who experienced childhood abuse
had different patterns of methylation on their MAOA gene
compared to individuals who were aggressive,
who did not experience childhood abuse
or compared to individuals, and so basically,
or compared to individuals who are not aggressive.
That it was the abuse itself, the childhood abuse,
which can actually set into action
a chain of events,
which basically means the childhood abuse
leads to changes in DNA methylation patterns
in genes like MAOA.
And then that sets for that individual,
for the rest of their lifetime,
how their MAOA gene is going to be expressed.
And when they reach adulthood,
their MAOA gene is misexpressed
leading to increased aggression.
And you can imagine the cycle of abuse
that potentially could result from that.
So even cycles of childhood abuse in families
can also be contributed to genetic aspects.
But those genetic aspects are determined
or significantly influenced by environment.
So it's a cycle in many ways,
like a vicious cycle that feeds on itself.
So just an interesting perspective,
I think, to keep in mind with that,
and the importance of childhood development
and stress on children,
not just in that phase of their development,
but also as adults.
The HTR2A gene, improper DNA methylation of this gene
is associated with schizophrenia and bipolar disorder.
So there's another one
that's has DNA methylation implicated.
the S100B, improper gene expression
associated with bipolar disorder.
The mechanism for this is unclear.
And so this gene was identified
through some of those linkage studies
and through some of the genome-wide association studies.
So it was not a candidate gene approach.
So we don't really know why
this particular gene would be involved
or what it's actually doing in bipolar disorder,
but it has been shown to be associated.
The CLOCK gene, you write about this
or you will read about this in the textbook,
this is related to circadian rhythm,
it's a transcription factor.
We all remember those, right?
Transcription factor regulates expression of genes
associated with circadian regulation.
It may be associated with bipolar disorder
and sleep disturbances,
as well as cognitive tasks and moral judgments.
So you can see how this would significantly influence
the development and expression
of something like bipolar disorder.
You, if there's a mutation
or misexpression of a transcription factor,
remember what those do?
They regulate the expression of many different genes.
So it's like a master regulator is what we would call this.
So if you screw up,
or something gets screwed up in this master regulator,
it's not just screwing up that one protein
that this gene codes for,
it's screwing up the expression for all the different genes
this particular transcription factor regulates.
And that can be a lot.
So this is one of the biggies,
most likely big genes that is,
well, I should, let me rephrase.
The size of the gene doesn't matter.
It's the influence this gene has
most likely is quite significant
because it is a transcription factor.
Major depressive disorder.
Heritability estimated at around 38%.
Greater heritability in those who develop MDD early,
before the age of 30,
and have significant number of recurrences
or also who have severe symptoms associated with it,
those seem to have a greater genetic influence
than major depressive disorder that occurs later in life
or individuals who do not have
a significant number of recurrences.
So more mild symptoms
that may not have as much of a genetic component
as the more severe form of MDD.
It's thought to be influenced by over 30 different genes,
each contributing a small amount
to the overall susceptibility of the person to MDD,
in addition to environmental influences.
And several different loci.
And remember loci is plural for locus.
And a locus is a location on a chromosome.
So that's all loci is,
it's just a specific spot on a chromosome,
as opposed to, you know,
there may be a gene there, it may be some,
it may be a region that regulates the expression of a gene,
but that's all loci is, just plural for locus.
Several different loci have been linked with MDD
through linkage studies, remember those?
But none have yet conclusively identified haplotypes
or SNPs, which can be used for risk assessment.
Additional research will likely identify these soon though.
So remember that linkage studies,
they help to narrow us in.
We zoom in on the regions that may be associated,
that have some stretch of DNA in them
that are associated with development of the disease.
So this is moving forward with major depressive disorder,
but it hasn't yet come all the way to fruition
so that we can say, for example, if you have this haplotype,
which remember what haplotype is,
that's a set of alleles of genes
that are either maybe
or are close to in proximity
to a gene that affects the inheritance
of a particular disorder.
So we haven't yet reached the point
where we know which haplotypes
are going to be associated with greater risk of MDD.
Candidate genes like the SLC6A4
and 5-HTTLPR, which affect serotonin transport
have been implicated in MDD,
but no conclusive connections have been made
between specific alleles and risk.
So while we think these genes are involved,
they most likely are involved.
We don't really know which genetic variance,
so which changes in the sequence
we can point to and say, "Yep, if you have this,
you are more likely to develop MDD.
Or your risk,
it goes up from the risk of the general population
to this higher risk level.
We don't know that just yet.
So, but progress is absolutely rapidly occurring
and moving in that direction.
So feel good in knowing that hopefully
I'm doing a decent enough job
of giving you some background
so that when this does come out,
and I am telling you it will,
and you know, again, that five to 10 year timeframe
for sure, we will see significant changes
in how diseases are or these disorders are,
you know, the risk assessment is conducted,
how they're diagnosed, and even how they're treated,
and you will have a solid, a foundation and understanding
of what has gone into that research,
and what it actually means for the patient
and for your practice.
So that's good to know.
Okay, moving on.
Substance issues and addiction.
So (chuckles) this gets a little bit tricky
because, depends upon the substance,
depends upon the level of addiction
and abuse that's occurring.
Yeah. So it gets very complicated.
Not that these others are not complicated, (chuckles)
obviously they all are,
but this adds whole new levels of complications to the mix.
But some genetic variants affect reward pathways
requiring more stimulation to achieve the same effect
achieved in others who do not require as much stimulation.
So this could cause people to,
basically need to take more of a drug, need to do more,
need more risk taking behaviors
in order to get the same reward effect
that others get from less of that behavior.
The presence of other psychiatric disorders,
which themselves have genetic influences
may lead an individual to substance abuse
making the etiology of addiction and substance abuse
a very complex picture.
Given that many of you practice in psychiatric,
have a psychiatric practice,
I, you know, hope this information
will be useful to you as well.
But I also appreciate that, really,
regardless of where you practice, given that
Vermont has one of the highest rates of substance abuse
of really almost any kind of substance in the United States,
clearly this is an issue that I would imagine,
maybe if not just most,
maybe even all of you have experience
in one way or another with your patients
or your patients' families
when you're talking about addiction or substance abuse.
So hopefully you'll find this information
useful to some extent
or at least can give you a different kind of perspective
even if you don't,
even if your practice isn't in strictly in psychiatry.
But yeah, it gets very complex
because as you can appreciate,
having some of these other psychiatric disorders
can actually lead a person to be more likely
to start to abuse certain substances
and as a method of coping.
And then you get this whole mixture
of the genetic influence that's contributing
to those psychiatric, other psychiatric disorders
that also may be influencing the likelihood of addiction,
simply by the fact that it increases their likelihood
of developing these other psychiatric disorders.
So it's complex.
Craving and withdrawal are affected
by gene expression changes due to an adaptation of the cells
to the presence of the substance.
So here, this is where, you know,
the cells can become acclimated,
and they're not as responsive
to the same levels of the substance
that the individual was introducing previously.
So the individual starts taking more, doing more,
increasing it, increasing the frequency,
increasing the amounts.
And that can lead to substance abuse
because they're not getting the same reward
they were once experiencing in their neural pathways
with the same amount of substance
that that they're taking now.
Other substance abuse conditions
may be related to metabolism of the substance.
This is an interesting one.
The ALDH and the ADH, the alcohol dehydrogenase
and aldehyde dehydrogenase genes function,
any dysfunction in those genes reduces the risk
of alcoholism by worsening negative effects of alcohol
and symptoms of hangover.
So in individuals that you might see
who, say, for example, don't feel well
after drinking maybe one or two drinks of alcohol
or who start to experience, you know, start to get flushed
or feel exceptionally tired
or have a bad hangover reaction,
those people are less likely to actually become alcoholics
because they feel really bad when they drink alcohol,
(chuckles) which kind of makes sense.
And that's part of what has contributed
to the differences in alcoholism
in different races and ethnicities.
So if you look in Asian populations,
there's a lower risk of,
there's a lower incidence of alcoholism.
And that's thought to be affected, at least in part,
by their alcohol dehydrogenase
and aldehyde dehydrogenase genes,
which they don't work as well as, they're less efficient,
that's the word I'm looking for, sorry.
They're less efficient than the aldehyde dehydrogenase
and alcohol dehydrogenase proteins
that are found in, say, Caucasians,
for example, on average.
It's on average, certainly.
So as a result, there, you have,
you may have seen this in individuals or experienced this,
where someone who is of Asian heritage
that they, it's described as the,
I think it's called the Asian flush,
something like that, where, you know, they'll,
where in, say, in a typical situation,
this is certainly not the case, you know, universally,
but in typical situation, someone of Asian heritage
drinks one or two servings of alcohol,
they will start to have a reddening of the face,
they will flush, they'll start to not feel well.
And that reduces
the reward effect of alcohol.
And so there's just, you know,
they're a lot less likely to become alcoholic.
You compare that with individuals
who have high functioning alcohol
or aldehyde dehydrogenase proteins.
And basically that means
that they're able to metabolize it well.
So they don't get the negative effects of alcohol,
but they do get a lot of the positive effects of alcohol,
and that's going to contribute to alcoholism.
So these genes, they don't really,
they don't code for proteins
that affect anything in neurons.
It has nothing to do with the neurons there.
That has more to do with, you know, in the liver,
the liver function being able to process
and metabolize alcohol that,
so basically what you can see is that, you know,
there's many different pathways
that can contribute to addiction
through different ways.
And also pharmacogenomics could prove valuable
in treatment as successful naltrexone response
in alcoholism has been linked with a specific SNP
in the OPRM1 gene or the mu opioid receptor gene.
This is an interesting one
because it may lead in the future to a person
who, say, is suffering from alcoholism
and wants to try a naltrexone treatment.
They can be tested for the specific SNP
in the OPRM1 gene, and identify whether or not
they're more or less likely to respond well to naltrexone.
Heritability varies but is significant in addiction
to different agents.
So if we're looking at the heritability,
remember what heritability is, of addiction to,
and this was based on the addictive agent,
and looking at many different pairs of twins,
what you can see is that they all have,
all seem to have some genetic component certainly.
Some were, potentially, some more than others,
like cocaine and opiates addiction,
may have a stronger genetic component than the others.
Though it's tough to say,
we'd have to understand the populations
that were used in these studies
to better know how to interpret the data.
But what we can say is that it definitely appears as though
each of these substance abuse conditions
certainly has a genetic component to it.
So pharmacogenomics,
this is defined as the study
of how drug efficacy or tolerability
can be affected by genetic variability in patients.
So it's basically a way to look at someone's,
do a genetic test on someone.
And the test results can tell you, hopefully,
whether or not this person would,
for example, be a fast or slow metabolizer of drug,
and whether or not there's, you know,
higher or lower likelihoods
that they will have certain drug,
negative drug interactions that might be harmful to them.
So how do they do this?
Well, they're looking at genes
in the cytochrome P450 family, cytochrome P450 enzymes.
So enzymes are just proteins that have a specific function.
So cytochrome P450 enzymes are responsible
for phase one metabolism of many different drugs,
including antidepressants.
And they, I mean, just the list is massively long.
You can look it up online for which drugs
are affected by the cytochrome P450 enzymes.
But I'll tell you it's most of them actually.
So this is just basic drug metabolism
in the body.
It's not anything targeted or anything like that,
it's just breaking down the drug.
So allelic variants in the different,
so it's the shorthand for it is CYP450.
So in the different CYP450 category
or family of genes
can affect a person's individual metabolism
of many different drugs.
Some are rapid or ultra rapid
or even slow metabolizers or anywhere in between.
And this information, as you can imagine is really,
can be really useful when deciding dosage
to start a person on.
Some tricyclic antidepressants and anti-convulsants
have been shown to induce or inhibit
the activity of the CYP450 proteins.
And in combination with a rapid or slow metabolizer
could lead to drug interactions.
So you can imagine that this could be a real problem
if taking a tricyclic antidepressant
either amped up or reduced
this class of proteins, these CYP450s,
induced or inhibited their ability to metabolize
all sorts of drugs, not just the tricyclics,
but any other drug that a person might be taking,
that could lead to a drug interaction
because the tricyclic that you're taking,
slowing down or speeding up metabolism
of all the other drugs they're taking,
which could lead to, if, for example,
its slowed down metabolism
could lead to a higher accumulation
of the effective amount of the drug
that's in a person's system,
and could lead to basically overdose for that person.
Or if it's slow, if it sped up there, the CYP450,
it could just metabolize the drug too fast
and then the level of the drug they have in their system
is going to be too low to be effective.
Individual drug metabolism.
So as I'm sure you're all aware,
over 100,000 deaths and 2.2 million serious events
occur each year in the US due to adverse drug reactions.
This correlates individual genetic variation
with individual drug metabolism
to personalized dosing and therapy selection.
And it's focused on individual drug metabolism
and interactions to minimize those adverse events
and maximize efficacy.
Over 100 drugs approved by the FDA require genetic testing
to determine dosing or therapy selection.
And the common genes tested include
the cytochrome P450 genes for drug metabolism
and also the G6PD set of genes,
which can affect drug interaction.
Let's look at an example here of one of the CYP450 genes.
And so CYP450 is a class of genes,
and there are many genes that fall into that category.
This is one of them, which is CYP2D6.
Genetic variants are common
and effect metabolism of about 25% of all drugs.
So like anything you would ever prescribe for a patient,
25% of them are going to be metabolized
in part by this one gene,
by the protein encoded by this one gene.
That's pretty, it makes it pretty important gene,
and probably important for a patient to know
what his or her
genetic variant is so that they can better understand
whether they are going to be
a slow, intermediate, normal or rapid metabolizer.
And this is a diagram basically showing what can happen
for, say, for example, a slow metabolizer,
and this represents about 10% of the population.
So these are all actually very common variants.
So it's not as though it's a rarity.
One out of 10,000 people will be a slow metabolizer.
No, it's 10%.
10% of people have a variant in their CYP2D6 gene,
which slows down their metabolism of the drugs
that are metabolized through this CYP2D6 pathway.
What happens is that you can, basically over time,
can accumulate a toxic dose of the drug or drugs
that are present in the person.
Then in the intermediate, normal levels, you have,
this is where about
80% of folks fall into this category.
And for those people,
you know, it's generally okay.
It may be sort of on the high side of the
level of drug that is in the body for the intermediates,
but in any case, it still would be helpful
to have that information for folks
when you're prescribing drugs.
Rapid metabolizers or even ultra rapid metabolizers
are about 7% of the population.
And these folks will basically
just metabolize the drug really quickly.
So they're not, they don't keep enough of it around.
So the drug may be less effective.
The concern with those who are slow metabolizers
would be safety concern,
that potentially they're going to have
present in their body a toxic dosage of the drug.
For the rapid metabolizers,
the concern is more about efficacy,
that they're not gonna have enough of it
for the drug to do what it's supposed to do.
So what can you do with this information,
not just about pharmacogenomics,
but about all, everything we've been talking about so far?
Well, okay, so here's the bottom line right now.
No genetic tests are yet available
for susceptibility to or etiology
of bipolar disorder or MDD.
However, this may change in the next five years.
So again, I really do believe this is on the horizon.
But as of right now, there's no real guideline
and no consistent genetic test that's available
that that's reliable, that's been shown to be useful
for basically diagnosing or understanding the risk
for some of these psychiatric disorders.
Genetic tests are available
to determine the alleles a patient has
for various CYP450 genes known to influence drug metabolism.
And this may be useful in many different clinical settings
when considering dosage and therapy selection.
So even if you're not in the psychiatric practice,
I mean, this has to be, I would imagine,
something that will come up in really any practice,
because those CYP450 genes are involved
in metabolism of drugs across the spectrum.
And like, I mean, it's just,
almost all drugs are metabolized
through one of these pathways.
And so this information can be helpful,
especially when getting the,
when there's that narrow window
between effective dose and toxic dose for a drug,
it's going to really be useful
to, I would think, understand a person's,
you know, genetic predisposition
towards being a fast or slow metabolizer
through genetic testing for their CYP450 genes.
And there are certain drugs
that actually really do require
that kind of genetic testing.
For example, warfarin does require genetic testing,
not for CYP450,
but for another gene
that's directly involved in its metabolism.
And there are other drugs
where on the label it is certainly recommended
that a genetic test be completed
in order to better understand the dosing
that would be appropriate for a patient.
So what else can you do with this information?
Educating patients on mood disorders
being complex diseases affected by many factors,
including genetics and environment,
may be important for those who deem them
as character flaws.
But it is, of course, important to include
psychiatric disorders, and family history, and pedigrees,
and is critical to identify possible increased risk
for the patient just so that they can have greater awareness
and can stay on top of it.
But on the other side of that,
genetic risk simply alerts a patient to, and his clinician,
or his or her clinician to maintain greater awareness
of signs and symptoms of the disorder.
And while nothing can be done
to change a person's genetic risk,
environmental influences have a strong impact
on all psychiatric disorders,
and they may be modified.
Focusing on environmental aspects may be most productive
because it gives you something to do,
something that they can affect.
Knowing about a genetic risk for psychiatric disorder
may elicit anxiety, depression,
embarrassment, and hopelessness,
which can worsen the patient's mental state.
Certainly others may feel relief, take solace
or make better informed decisions
when they know more about their risks.
So this is, of course, a judgment call,
and one that is specific to, you know,
to each patient.
So let's summarize
some of what we talked about in this lecture.
Differences in sequences or expression of genes
that are involved in neural processes
like emotion regulation, reward pathways,
circadian rhythm, and risk-taking can all contribute
to the development of a psychiatric disorder.
However, environment is well known
to have a significant influence,
and may present opportunities for treatment,
intervention, or prevention of these disorders.
While few genetic tests are commonly used
in psychiatric medicine today,
there will likely be an increase in genetic testing
to better estimate risk,
to understand which therapies will be most effective,
and to estimate optimal dosing.
And that doesn't just go for psychiatric disorders.
The optimal dosing certainly can go across the spectrum
of, you know, the clinical spectrum.