Pharmacology – ANTIDEPRESSANTS – SSRIs, SNRIs, TCAs, MAOIs, Lithium ( MADE EASY)

in this lecture I’m going to talk about
antidepressants so let’s get right into it we all experience changes in mood
sometimes we feel happy and energetic and other times we feel sad 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 decreased interest in activities this is what we call depression sometimes
depression can occur alone and other times it is a part of a larger
disorder such as bipolar disorder people with bipolar disorder experience
periods of depression alternating with periods of mania in which person feels
abnormally optimistic euphoric 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 monoamines namely serotonin
norepinephrine and dopamine another hypothesis states that this monoamine
depletion could also cause the postsynaptic receptors to upregulate
thus leading to depression lastly the monoamine 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 one selective
serotonin reuptake inhibitors SSRIs for short number two serotonin norepinephrine
reuptake inhibitors SNRIs for short number three tricyclic antidepressants
TCAs for short number four monoamine oxidase inhibitors
MAOIs 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 serotonergic neuron or in other words serotonin producing
neuron and next to it I’m going to draw a presynaptic noradrenergic neuron or
in other words norepinephrine producing neuron now these two neurons interact
with their postsynaptic counterparts so as you may have already guessed
postsynaptic receptors of noradrenergic neuron are beta and alpha-1 while
postsynaptic receptors of serotonergic neuron are serotonin often
abbreviated as 5-HT 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 serotonergic neurons and it is there stored in vesicles
awaiting regulated release on the other side norepinephrine is synthesized from
an amino acid tyrosine by noradrenergic neurons and it is also stored there in vesicles awaiting release so now what exactly happens when these neurotransmitters 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 SERT while norepinephrine is reabsorbed by
norepinephrine transporter abbreviated as NET 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 to bind to postsynaptic receptors
examples of SSRIs include Citalopram Escitalopram Fluoxetine 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 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 better 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 serotonin 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 SNRIs 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 results
in increased levels of both serotonin and norepinephrine which can then bind
to the postsynaptic receptors examples of SNRIs include Venlafaxine Desvenlafaxine Duloxetine and Levomilnacipran now similarly to
SSRIs SNRIs are also used for depression anxiety and panic
disorders however unlike SSRIs SNRIs have been shown to be also
effective in reducing pain associated fibromyalgia as well as other pain caused by neuropathy this unique pharmacological action of SNRIs
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 SNRIs may increase blood pressure and heart rate
now let’s move on to tricyclic 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
TCA’s mechanism of action is not as straight forward so just like SNRIs TCAs were found to primarily inhibit reuptake of both serotonin and
norepinephrine by blocking both of their transporters however different
tricyclic agents do this with different level of
selectivity in other words some TCAs such as Desipramine are more selective
inhibitors of norepinephrine transporter then serotonin transporter furthermore
TCAs 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 TCAs include Amitriptyline Amoxapine Clomipramine Desipramine Doxepin Imipramine Maprotiline Nortriptyline and Protriptyline
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 Nortriptyline have been used for migraine prevention as well as treatment of
neuropathic pain on the other hand TCAs such as Doxepin have been used for
insomnia now when it comes to side effects inhibition of alpha receptors
leads to orthostatic hypotension and dizziness inhibition of histamine
receptors leads to sedation and inhibition of muscarinic receptors
leads to anticholinergic effects such as blurred vision dry mouth constipation
and urinary retention lastly TCAs block cardiac sodium
channels and produce effects similar to antiarrhythmic agents
such as Quinidine 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 monoamines 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 B preferentially metabolizes
dopamine this is why the inhibition of MAO subtype A is thought to be
responsible for antidepressant effects of majority of MAOIs so the primary
mechanism of action is pretty straightforward MAOIs inhibit the
activity of MAO enzymes preventing breakdown of monoamine neurotransmitters
ultimately increasing their availability now examples of MAOIs include Isocarboxazid Phenelzine and Tranylcypromine which are all irreversible
inhibitors of both MAO subtype A and MAO subtype B which in turn makes them
effective for treatment of depression another example of MAOI which is a bit
different from the rest is Selegiline which is a selective inhibitor of MAO
subtype B and therefore has been shown to be effective in reducing
symptoms of Parkinson’s disease which results from depletion of dopamine so
now on the surface it seems like MAOIs 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 MAOIs show not only high incidence of drug-drug interactions but also drug-food interactions as I mentioned earlier
MAO enzymes are present in the gut there they play important role in breakdown of
monoamines ingested in food the problem arises when inhibited MAO
enzymes can’t metabolize tyramine which is contained in foods that have been
aged or fermented now built-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 MAOIs 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 Trazodone
Nefazodone Vilazodone and Vortioxetine 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 serotonergic neurotransmission
additionally Mirtazapine is thought to have some postsynaptic serotonin
receptor blocking activity as well as antihistaminic activity which explains
its sedating effects next we have Trazodone and Nefazodone their
therapeutic effect is thought to be related to their ability to inhibit
reuptake of serotonin as well as block postsynaptic serotonin receptors of
subtype 2a which are the bad serotonin receptors activation of these
serotonin 2a receptors is thought to contribute to depression additionally
both of these agents antagonize histaminic H1 and adrenergic alpha-1 receptors which may account for their sedative effects next we have Vilazodone which has similar sounding name to Trazodone and Nefazodone but again it
has its own unique mechanism of action so Vilazodone is a serotonin partial
agonist reuptake inhibitor meaning it partially stimulates serotonin receptors
and it inhibits reuptake of serotonin finally we have Vortioxetine which has a
mechanism of action that is still a little unclear but it is believed to be
related to its ability to inhibit serotonin 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 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 phosphatidylinositol 4,5-bisphosphate PIP2 for short to the signaling molecules diacylglycerol DAG for short and inositol 1,4,5-trisphosphate IP3 for short next IP3’s action is terminated by
conversion to inositol 4,5-bisphosphate IP2 for short and at this
point the enzyme inositol phosphatase comes around and dephosphorylates IP2
to inositol phosphate IP1 for short and lastly another inositol phosphatase dephosphorylates IP1 to free inositol which is necessary for the
regeneration of PIP2 so now what Lithium does is it inhibits both inositol
phosphatase enzymes and thus decreases cellular responses to neurotransmitters
that are linked to this second messenger system now Lithium also was found to
inhibit glycogen-synthase-kinase-3 GSK3 for short mimicking the Wnt
protein signaling pathway so basically we have this Wnt proteins which are
secreted glycoproteins acting as a signaling molecules when they bind to
receptors of the so called frizzled family they induce certain reactions
which ultimately result in inhibition of GSK3 now GSK3 regulates critical
processes such as axon remodelling synapse formation plasticity and
neurogenesis what the research has found though is that the abnormal activation
of GSK3 seems to be associated with several neurological and psychiatric
disorders such as bipolar disorder so because Lithium inhibits GSK3 directly
and non-directly it’s likely that this particular mechanism contributes to its
therapeutic 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

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