in this lecture I'm going to talk about
antidepressant so let's get right into
it we all experienced changes in mood
sometimes we feel happy and energetic
and other times we feel set and
irritable fortunately these moods
usually don't last long and we can go
about our normal daily routine however
life is not always that simple because
there are times when we might experience
unusually long periods of sadness guilt
and decrease inches in activities this
is what we call depression sometimes
depression can occur alone and other
times it is a part of the larger
disorder such as bipolar disorder people
with bipolar disorder experienced
periods of depression alternating with
periods of mania in which person feels
abnormally optimistic elf or ik and
energetic now treatment of depression
and bipolar disorder often involves use
of antidepressant drugs which work by
elevating levels of certain
neurotransmitters in the brain this led
to development of monoamine hypothesis
which states that depression results
from deficiency in one or more of the
three key mono amines namely serotonin
norepinephrine and dopamine another
hypothesis states that this mono amine
depletion could also cause the
postsynaptic receptors to upregulate
thus leading to depression
lastly the mono amine hypothesis of gene
expression suggests that there might be
an abnormal functioning gene that is
responsible for causing depression now
all that being said keep in mind that
these hypotheses are overly simplistic
and they don't accurately explain
everything that we observed in research
studies however they do give us partial
explanation as to why antidepressants
work so now let's switch gears and let's
talk about antidepressant drugs based on
their mechanism of action
antidepressants can be divided into five
different classes number 1 selective
serotonin reuptake inhibitors SSRIs for
short number 2 serotonin norepinephrine
reuptake inhibitors SNRIs for short
number three tricyclic antidepressants
TCAs for short
number four monoamine oxidase inhibitors
Mao ice for short and lastly number five
atypical antidepressants so now before
we start discussing each class let me
draw some neurons that will help us
understand how these antidepressants
differ in the way they work so here we
have presynaptic certain are general or
in other words serotonin producing
neuron and next to it I'm going to draw
a presynaptic nor adrenergic neuron or
in other words norepinephrine producing
Europe now these two neurons interact
with their postsynaptic counterparts so
as you may have already guessed
postsynaptic receptors of noradrenergic
neurons are beta and alpha 1 while
postsynaptic receptors of certain
Erdrich neuron are serotonin often
abbreviated as v dash HD receptors now
keep in mind that there's quite a few
subtypes of serotonin receptors but for
now let's just keep it simple so going
back to our two neurons the serotonin is
synthesized from an amino acid
tryptophan by certain urging neurons and
it is they're stored in vesicles
awaiting regulated release on the other
side norepinephrine is synthesized from
enemy amino acid tyrosine by na
adrenergic neurons and it is also stored
in vesicles awaiting release so now what
exactly happens when these new
transmitters are released well there are
a few key things to remember when
serotonin and norepinephrine get
released they begin to stimulate the
receptors and at the same time they're
transported from the synapse back to
their neurons in a process called
reuptake
now serotonin is reabsorbed by serotonin
transporter abbreviated as Ser tea while
norepinephrine is reabsorbed by
norepinephrine transporter abbreviated
as an et another important thing to
remember is that once the serotonin and
norepinephrine get reabsorbed back to
their neurons they're partially
repackaged into synaptic vesicles and
partially broken down into inactive
metabolites by an enzyme monoamine
oxidase abbreviated Mao now let's move
on to discussing antidepressant drugs
and let's start with selective serotonin
reuptake inhibitors so as you can tell
from their name
SSRIs inhibit reuptake of serotonin and
they accomplish that by blocking
serotonin transporter this results in
increased levels of serotonin available
two by two postsynaptic receptors
examples of SSRIs include citalopram
escitalopram clock setting fluvoxamine
paroxetine and sertraline now besides
being used for depression SSRIs are also
used for other psychiatric disorders
such as generalized anxiety
post-traumatic stress disorder and
obsessive-compulsive disorder okay
so this whole mechanism of action looks
pretty straightforward but then you may
wonder why these antidepressants take
weeks to produce maximum benefit well a
new research gives us a little insight
into why this happens so recently
scientists discovered that in people
with depression
g-proteins tend to cluster in the
patches of brain cell membranes rich in
cholesterol called lipid rafts now when
stuck on these rafts G proteins lack
access to molecule called cyclic AMP II
which is necessary to work and transmit
signals of serotonin however later on it
was discovered that SSRIs also tend to
build up in these lipid rafts which
resulted in the gradual movement of G
proteins out of the rafts toward regions
of membrane where they are able to
function
so here we have a possible reason why
antidepressants take so long to produce
maximum benefit now when it comes to
side effects excessive stimulation of
serotonin receptors in the brain may
lead to insomnia increase anxiety and
irritability next excessive stimulation
of spinal serotonin receptors may lead
to sexual side effects including
erectile dysfunction and stimulation of
serotonin receptors in the
gastrointestinal tract as well as in the
CNS may lead to nausea vomiting and
diarrhea
lastly abrupt withdrawal of an SSRI can
result in temporary deficiency of
synaptic straightenin which in turn may
lead to unpleasant symptoms such as
headache nausea vomiting agitation and
sleep disturbances now let's move on to
serotonin norepinephrine reuptake
inhibitors so SN arise just like SSRIs
work by inhibiting reuptake of serotonin
via inhibition of serotonin transporter
but what makes them different is their
ability to additionally inhibit
norepinephrine transporter this result
in increased levels of both serotonin
and norepinephrine which can then bind
to the postsynaptic receptors examples
of SN arise include venlafaxine death
and the vaccine duloxetine and leave a
meal NASA pet now similarly to
accessorize s inner eyes are also used
for depression anxiety and panic
disorders however unlike accessorize s
inner eyes have been shown to be also
effective in reducing pain associated
fibromyalgia as was other pain caused by
neuropathy this unique pharmacological
action of SSRIs
is thought to be related to enhanced
noradrenergic activity within the
central nervous system now when it comes
to side effects they are very similar to
those of SSRIs however because of
additional noradrenergic activity s
inner eyes may increase blood pressure
and heart rate
now let's move on to try cyclic
antidepressants so this class of
antidepressants was named after their
core chemical structure which contains
three rings connected together unlike
the other classes of antidepressants
DCA's mechanism of action is not as
straight forward so just like Essen
arise TCS were found to primarily
inhibit reuptake of both serotonin and
norepinephrine by blocking both of their
transporters however different
tricyclics
agents do this with different level of
selectivity in other words some TCS such
as the zebra mean are more selective
inhibitors of norepinephrine transporter
then serotonin transporter furthermore
TCS also block many other receptors such
as alpha receptors histamine receptors
and muscarinic receptors
however blockade of these other
receptors is thought to be responsible
for their side effects more than their
antidepressant activity examples of TCS
include amitriptyline moxa pain clammy
Ramin desipramine doxepin yep I mean map
protein nortriptyline and protract lean
now
TCAs are mainly used for depression
however due to their broad mechanism of
action they also proved to be beneficial
in treatment of other medical problems
for example amitriptyline and no
tripling have been used for migraine
prevention as well as treatment of
neuropathic pain on the other hand TCS
such as doxepin have been used for
insomnia now when it comes to side
effects inhibition of other receptors
leads to orthostatic hypotension and
dizziness inhibition of histamine
receptors leads to sedation and
inhibition of mass chronic receptors
leads to anticholinergic effects such as
blurred vision dry mouth constipation
and urinary retention
lastly TCS blocked cardiac sodium
channels and produce
facts similar to anti-arrhythmic agents
such as quantity this ultimately can
lead to cardiac conduction abnormalities
now let's move on to monoamine oxidase
inhibitors so monoamine oxidase is a
mitochondrial enzyme that degrades mono
amines such as serotonin and
norepinephrine Mao exists in two
subtypes a and B which are differently
distributed in tissues such as brain gut
and liver now
Mao subtype a preferentially metabolizes
serotonin but will also metabolize
norepinephrine and dopamine while Mao
subtype be preferentially metabolizes
dopamine this is why the inhibition of
Mao subtype a is thought to be
responsible for antidepressant effects
of majority of Mao ice so the primary
mechanism of action is pretty
straightforward Mao is inhibit the
activity of Mao enzymes preventing
breakdown of monoamine neurotransmitters
ultimately increasing their availability
now examples of Mao is include I so car
boxes it phenelzine and channels cipro
mean which are all River irreversible
inhibitors of both Mao subtype a and Mao
subtype B which in turn makes them
effective for treatment of depression
another example Mao I which is a bit
different from the rest is allegedly
which is a selective inhibitor of Mao
subtype B and therefore has been shown
to be effective in reduced reducing
symptoms of Parkinson's disease which
results from depletion of dopamine so
now on the surface it seems like Mao ice
could be a good choice for the first or
the second line antidepressant however
in practice there are usually a very
last choice and the reason is that Mao
is shown not only high incidence of drug
drug interactions but also drug food
interactions as I mentioned early
Meo enzymes are present in the gut there
they play important role in breakdown of
mono amines ingested and food the
problem arises when inhibited Meo
enzymes can't metabolize thyromine which
is contained in foods that have been
aged or fermented now build-up tyramine
is taken up into the synaptic nerve
terminals where it acts as a
catecholamine releasing agent the
release of large amount of
catecholamines caused by tyramine leads
to hypertensive crisis and potentially a
stroke this is why patients that are
prescribed nao is due to lack of other
options must be educated about avoiding
tyramine rich foods okay so now finally
we can move on to atypical
antidepressants this class includes
agents that have actions at several
different sites and thus don't exactly
fit into the other classes
examples of atypical antidepressants
include bupropion mirtazapine trazadone
nazarone Villas Odin and Vorta oxygene
now each of these drugs has a little
different mechanism of action so
bupropion is a weak norepinephrine and
dopamine reuptake inhibitor besides
being used for depression bupropion was
found to be effective in reducing
nicotine cravings and withdrawal
symptoms
next mirtazapine is an alpha 2 receptor
antagonist so by blocking presynaptic
alpha 2 receptors mirtazapine increases
noradrenergic and certain urging
neurotransmission
additionally mirtazapine is thought to
have some cost synoptic serotonin
receptor blocking activity as well as
anti histamine activity which explains
its sedating effects next we have
trazodone and NEFAs alone the
therapeutic effect is thought to be
related to their ability to inhibit
reuptake of serotonin as well as blog
post synaptic serotonin receptors of
subtype 2a which are the better
tonal receptors activation of this
serotonin 2a receptor is thought to
contribute to depression additionally
both of these agents antagonize
histamine ik age 1 and adrenergic alpha
1 receptors which may account for their
sedative effects next we have the laser
on which a similar sounding name to
travel on and net phaser on but again it
has its own unique mechanism of action
so the laser tone is a serotonin partial
agonist reuptake inhibitor meaning it
partially stimulates certain receptors
and it inhibits reuptake of serotonin
finally we have Volta oxygen which has a
mechanism of action that is still a
little unclear but it is believed to be
related to its ability to inhibit
certain reuptake as well as activate and
block different subtypes of serotonin
receptors involved in mood regulation
and now before we end I just wanted to
briefly discuss lithium which is a mood
stabilizing drug in its own class
lithium has been used in medicine for a
very long time initially for depression
but currently for bipolar disorders
unfortunately lithium has a fairly
narrow therapeutic index which means
that minor changes in dose or its blood
levels can lead to toxicity now despite
years of research the exact mechanism of
action of lithium as a mood stabilizer
is still not entirely known however a
few mechanisms of action have been
proposed one in particular that has been
extensively studied states that the
lithium inhibits the recycling of
neuronal membrane inositol lipids okay
so this may get a little complicated but
bear with me so in the inositol lipid
pathway g-protein coupled receptors such
as serotonin receptors activate
phospholipase c plc for short which
cleaves phosphatidyl inositol for five
bisphosphate pip2 for short - the
signaling molecules they acyl glycerol
the
G for short and in or throw one for five
tres phosphate ip3 for short next IP
threes action is terminated by
conversion to industrial for five
bisphosphate ip2 for short and at this
point the enzyme in Austral phosphatase
comes around and dephosphorylation I P
to two inositol phosphate I p1 for short
and lastly another industrial
phosphatase D phosphorylates IP one to
three in Oslo which is necessary for the
regeneration of pip2 so now what lithium
does is it inhibits both in Oslo
phosphatase enzymes and thus decreases
cellular responses to neurotransmitters
that are linked to the second messenger
system now lidium also was found to
inhibit glycogen synthase kinase three
GSK three for short mimicking the went
protein signaling pathway so basically
we have this wind proteins which are
secreted lipoproteins acting as a
signaling molecules when they bind to
receptors of the so called threshold
family they induce certain reactions
which ultimately result in inhibition of
GSK 3 now GSK 3 regulates critical
processes such as axon remodelling
synapse formation plasticity and
neurogenesis what the research has found
though is that the abnormal activation
of GSK 3 seems to be associated with
several neurological and psychiatric
disorders such as bipolar disorder so
because lithium inhibits GSK 3 directly
and not directly it's likely that this
particular mechanism contribute to its
drop your egg effect unfortunately this
doesn't end here lithium brings about
changes in all of the major
neurotransmitter systems in the brain
and I think at this point you had enough
so we're not gonna dig further and with
that I wanted to thank you for watching
I hope you enjoyed this video and as
always stay tuned for more