Antidepressants

Theories of Antidepressant Drug

Action (s)
All effective antidepressants have identifiable
immediate interactions with 1/more
monoamine monotransmitter receptor or
enzyme
Antidepressant block:
- monoamine reuptake
- alpha2 receptors
- enzyme monoamine oxidase (MAO)
 The Neurotransmitter Receptor
Hypothesis of Antidepressant Action

One theory to explain the ultimate of

delayed therapeutic action of antidepressants
is neurotransmitter receptor hypothesis of
antidepressant action.
 Whether or not neurotransmitter
receptors are abnormal in depression,
the neurotransmitter receptor
hypothesis of antidepressant action
proposes that antidepressants, no
matter what the their initial actions on
receptor and enzyme, eventually
causes desensitization or down
regulation cause delayed onset of
antidepressants action of drugs.
 Fig 6-4
The monoamine Hypothesis of
antidepressant on Gene Expression

This hypothesis of gene expression

proposes that depression itself is linked to
abnormal functioning of neurotransmitter
inducible gene expression,
 Particularly neurotrophic factors such as brain
derived neurotrophic factors(BDNF) leading
to atrophy and apoptosis of critical
hippocampal neurons.
Whether or not the transduction of a
monoaminergic neural impulse into gene
expression is actually abnormal in depression
.so the momoamine hypothesis of
atidepressant action on gene expression
proposes that antidepressant, no matter what
the initial actions on receptors and enzyme,
eventualy cause critical genes to be activated
or inactivated.
Pharmacokinetics of antidepressants
Is study about drugs how the body acts on
drugs. These pharmacokinetics action are
mediated through the hepatic and gut drug
metabolizing system known as the
cytochorome P450(CYP450)
This enzyme in the gut wall and liver
converts the drug substrate into
biotransformed product in the bloodstream
and passing through the gut wall and liver,
the drugs exist partly as unchanged drugs
and partly biotransformed products.
 Five of the most important enzymes foe
antidepressants drug metabolism are:
CYP450 1A2
Antitricyclic is substrate for this enzyme,
especially the secondary amines such as
clomipramine and impramine.

CYP450 1A2 demethylates such TCA, but not

thereby inactivate them. In these case
desmethyl metabolite of TCA is still in active
drugs.
CYP450 2D6
Another important enzyme for antidepressant,
TCA is substrate for this enzyme which
hydroxylates and thereby inactivates them
CYP450 3A4
A 3rd important CYP450 enzyme for
antidepressants and moo stabilizers is
3A4.Some benzodiazepines are substrate for
3A4 and some antidepressants are 3A4
inhibitor such SSRI.
 Monoamine oxidase (s)
First clinically effective antidepressant to be
discovered
Discovery led to synthesis of more drugs that
inhibited MAO but lacked unwanted additional
properties
Original MAO inhibitors are all irreversible
enzyme inhibitors bind to MAO irreversibly
destroy its function forever
Enzyme activity return after new enzyme
synthesized
 Called suicide inhibitors because once
enzyme binds inhibitor enzyme commits
suicide never function again until new
enzyme protein synthesized by neurons DNA
in cell nucleus
MAO exists in 2 subtypes: A + B (both
inhibited by original MAO inhibitors, thus
nonselective)
 A form: metabolizes neurotransmitter
monoamines most closely linked to
depression (serotonin + norepinephrine) and
amine most closely linked to control of blood
pressure (norepinephrine)
B form: convert some amine substrates
(protoxins) into toxins that may cause
damage to neurons
 MAO A inhibition linked to antidepressant
action + hypertensive side effects
MAO B inhibition linked to prevention of
neurodegenerative processes (Parkinsons
etc)
2 developments of MAO inhibitors:
- selective inhibitors of MAO A / MAO B
- selective MAO A inhibitors that are reversible
 Nonselective, irreversible MAO
inhibitors (s)
After inhibition of MAO A amines taken from
diet dangerous elevations in blood pressure
intracerebral hemorrhage + death (after
consumption of tyramine food / beverage)
Risk controlled by restricting food + certain
medications
MAO B: no significant MAO A inhibited, little risk
HT, do not require diet
Reversible inhibitors of MAO A
(RIMAs) (s)
Newer class of MAO inhibitors
Potential of making MAO inhibition for
treatment of depression much safer
Eat cheese tyramine still release
sympathomimetic amines amines chase
reversible inhibitor off MAO enzyme
dangerous amines destroyed
Moclobemide, Brofaramine, Befloxatone, RS-
8359, Cimoxatone, Toloxatone
 Selective Serotonin Reuptake
Inhibitors
SSRI comprise a class of drugs with 5 prominent
members:
- Fluoxetine
- Sertraline
- Paroxetine
- Fluvoxamine
- Citalopram
All have single major pharmacologic feature +
no ability to block Na channels
Serotonin selective reuptake inhibitors
(SSRIs)
Fluoxetine (Prozac)
Sertraline (Zoloft)
Paroxetine (Paxil)
Fluvoxamine (Luvox, Feverin, Dumirox,
Floxyfral)
Citalopram (Celexa, Cipramil, Serostat,
Cipram)
SSRIs in comparison to TCA
More powerful and selective serotonin
reuptake inhibiting properties
Do not possess the undesirable side effects
of TCA (danger in overdose)
 Pharmacologic + Molecular MOA of
SSRIs
Action of SSRIs at presynaptic axon terminal
Events occurring at somatodendritic end of
serotonin neuron (near cell body)
Monoamine hypothesis of depression:
- Serotonin may be deficient
- Neuronal firing rates may be diminished
 Neurotransmitter receptor hypothesis:
- Pre + postsynaptic receptors may be up-
regulated
Monoamine hypothesis of delayed gene
action:
- Receptors may not be able to transduce
receptor occupancy by serotonin into
necessary regulation of postsynaptic genes
Pathways, Receptors that mediate
therapeutic actions + Side Effects
Increasing serotonin at synapses reuptake
is blocked serotonin release is disinhibited
therapeutic actions + side effects of SSRIs
However, increase serotonin (every pathway
and every receptor) cause some undesirable
serotonin reactions side effects
 Therapeutic, antidepressant:
- Projection of serotonin neurons (substrate) from
midbrain raphe to frontal cortex
Therapeutic, bulimia / binge eating / eating
disorders:
- Mediated by serotonins pathway from raphe to
hypothalamic feeding + appetite centers
Contrasting antidepressant + antibulimic actions
indicated by differing doses, onset of action, long
term action documentation
Antidepressant profile of SSRIs
Starting dose usually the same as
maintenance dose
Onset of response usually 3 8 weeks
Response is frequently complete remission of
symptoms
Target symptoms do not worsen when
treatment initiated
 Antibulimic profile of SSRIs
Usual starting dose is higher than for other
indications
Onset of response may be faster than for other
indications
May not be as effective as for other indications
in maintaining acute effects chronically
Fluoxetine has best efficacy data to date and
also serotonin 2C properties
Target symptoms do not worsen on initiation of
treatment
 Acute stimulation of at least 4 serotonin receptor
subtypes responsible side effects of SSRIs:
- 5HT2A
- 5HT2C
- 5HT3
- 5HT4
SSRI side effects generally acute starting from
1st dose / acute increase in synaptic serotonin
sufficient to mediate side effects (attenuated
over time)
The undesirable side effects of SSRIs involve:
- Specific serotonin subtypes
- Action of serotonin at receptors in specific areas
of body (brain, spinal cord, gut)
Acute stimulation of 2A + 2C receptors (raphe to
limbic cortex):
- Acute mental agitation
- Anxiety
- Induction of panic attacks (early dosing of SSRI)
 Acute stimulation of 2A receptors (basal
ganglia) serotonins inhibition of dopamine
neurotransmission changes in motor
movements:
- Akathisia (restlessness)
- Psychomotor retardation
- Mild parkinsonism
- Dystonic movements
 Stimulation of serotonin 2A receptors in
mesocortical pleasure centres reduce
dopamine activity:
- Apathy
- Decreased libido
Stimulation of serotonin 3 receptors in
hypothalamus / brainstem:
- Nausea / vomiting
 Stimulation of serotonin 3 + 4 receptors in
gastrointestinal tract:
- Bowel motility
- Gastrointestinal cramps
- Diarrhea
It is not possible for a systematically administered
SSRI to act only at the desirable receptors in the
desirable receptors in the desirable places
It must act only at desirable receptors in the
desirable places (everywhere it is distributed)
 Although SSRIs share same mechanism of
action, therapeutic profiles and overall side
effects profiles, individual patients often react
very differently to one SSRI versus another
There are real differences among the 5 SSRIs
for many individual patients and sometimes only
empirical trial of different SSRIs will lead to best
match of drug to individual patient
Tricyclic antidepressants
The Tricyclic antidepressants were so named
because their organic chemical structure
contains 3 rings. The tricyclic antidepressants
were synthesized about the same time as
other 3 rings molecules that were shows to
be effective tranquilizers for schizophrenia.
Tricyclic antidepressants
The tricyclic antidepressants were
disappoiment when tested as antipsychotics.
Clinician found antidepressants properties .
Long after their antidepressants properties
were observed, the tricyclics were discovered
to block the reuptake pumps for both
serotonin and norepinephrine.
Tricyclic antidepressants
Inhibition of neurotransmitter uptake
-TCA inhibit the neuronal reuptake of
norepinephrine and serotonin into presynaptic
nerve terminal.
By blocking the major route oh
neurotransmitter removal, the TCA increase
concentration of monoamines in the synaptic
cleft resulting antidepressants affect.
Tricyclic antidepressants
In addition, essentially all the tricyclic
antidepressants have at least 3 other actions
1.Blockade of muscarinic cholinergic
receptors
2.Blockade of H1 histamine receptors
3.Blockade of alpha 1 adrenergic receptors
Tricyclic antidepressants
Some of the tricyclic antidepressants also
have the ability to block serotonin 2A
receptors which may contribute to the
therapeutic actions of those agents with this
properties.
Tricyclic antidepressants also block the
sodium channels in the hearts and brain,
which can cause cardiac arrhythmias and
cardiac arrest in overdose.
Tricyclic antidepressants
In term of side effect of the tricyclic
antidepressatns, blockade of alpha 1
adrenergic receptors causes orthostatics
hypotension and dizzyness.
Anticholinergic actions at muscarinic
cholnergic receptors cause blurred vision,
urinary retention, constipation and memory
disturbance.
Tricyclic antidepressants
Blockade of H1
histamine receptors
cause sedation and
weight gain.
Lithium salts
Lithium salts are used prophylatically in
treating manic-depressive patients and in the
treatment of manic dissorders.
They are also effective in treating 60 % - 80%
of patients exhibiting mania and hypomania.
Mode of action still unknown,
 Litium is given orally, and the ion is excreted
by the kidney.
Litium salts are very toxic.Their safety factors
for therapeutic index are extremely
low.
Adverse effects:
1.ataxia
2.tremor
3. confusion and
4. convulsion