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ANTIDEPRESSANTS

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INDIAN DENTAL ACADEMY
Classification of Major Affective Disorders
Episodal
Depression
Seasonal
Affective
Disorder
Atypical
Depression
Major/
Endogenous
Depression
Mania Bipolar
depression
Major Affective
Disorders
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Episodal (reactive) Depression
Adverse life events.
Physical illness.
Hormonal steroids.
Drugs.
Other psychiatric disorders.

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Reactive (episodal) Depression
More than 60% of all depressions.
Core depressive syndrome: feelings
of misery, apathy, inadequacy,
pessimism, anxiety, tension, guilt.
Bodily complaints
May respond spontaneously or to a
variety of administrations.

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Major Endogenous Depression
Recurrent, Cyclic, Seasonal.
Degree of depression is not adequate
for precipitating event.
Automaton (unresponsive).

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Major Endogenous Depression
Core Symptoms:
Feeling of misery, apathy and pessimism.
Withdrawn.
Low self esteem, feelings of guilt, inadequacy and
ugliness.
Loss of interest in pleasurable activities.
Indecisiveness, loss of motivation.
Retardation of thought and action. Sleep
disturbance and significant weight change (without
dieting or changes in appetite).
Psychomotor agitation or retardation. www.indiandentalacademy.com
Major Endogenous Depression
Core Symptoms (cont):
In severe cases, it is accompanied by
hallucinations and delusions.
Recurrent suicidal ideation, a suicide attempt or a
specific suicide plan.
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Mania
Mania alone is rare (10%) and most frequently
cycles with Major/endogenous depression (Manic-
Depressive Disease, Bipolar Disorder).

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Mania
Core Symptoms:
It is characterized by an elevated high mood.
Talkative, go on-and-on about the things they will
do.
Increased self-esteem.
Auditory hallucinations.
Decrease need to sleep.
Lack judgement, indiscrete.
SuperME

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III. Biological Correlates of
Depression
1. Hypersecretion of cortisol.
2. Escape from dexamethasone suppression.
3. Blunted TSH response to TRH.
4. Blunted GH response to hypoglycemia.
5. Altered 24hr rhythm of prolactin secretion.
6. Decreased 5-HT metabolites in plasma.
7. Decreased REM latency.


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IV. Biological Basis for Depression
1. Has a genetic component.
2. Depression can be drug-induced.
3. Depression can be drug-repressed.
4. Depression can be treated with drugs.
5. Depression can be treated with
Electroconvulsive Therapy (ECT).

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The precise cause of affective disorders
remains elusive.
Evidence implicates alterations in the firing
patterns of a subset of biogenic amines in
the CNS, Norepinephrine (NE) and
Serotonin (5-HT).

Activity of NE and 5 -HT systems?.

V. Biogenic Theory of Depression
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VI. NE System
Almost all NE pathways in the brain originate from the cell
bodies of neuronal cells in the locus coereleus in the
midbrain, which send their axons diffusely to the cortex,
cerebellum and limbic areas (hippocampus, amygdala,
hypothalamus, thalamus).
Mood: -- higher functions performed by the
cortex.
Cognitive function: -- function of cortex.
Drive and motivation: -- function of brainstem
Memory and emotion: -- function of the
hippocampus and amygdala.
Endocrine response: -- function of hypothalamus.

and receptors.
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VII. Serotonin System
As with the NE system, serotonin neurons located
in the pons and midbrain (in groups known as
raphe nuclei) send their projections diffusely to the
cortex, hippocampus, amygdala, hypothalamus,
thalamus, etc. --same areas implicated in
depression. This system is also involve in:
Anxiety.
Sleep.
Sexual behavior.
Rhythms (Suprachiasmatic nucleus).
Temperature regulation.
CSF production.
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Antidepressants
TCAs

TCAs
TCAs
SSRIs
SSRIs
MAOIs
MAOIs
MAOIs
MAOIs
MAOIs
Venflaxine
MAOIs
maprotiline
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Antidepressants
1. Tricyclic anti-depressants (TCAs).
Imipramine, desipramine, nortriptyline,
protryptyline, amytriptiline, doxepin.
2. Monoamine oxidase inhibitors (MAOIs).
Isocarboxacid, phenelzine, tranylcypromine.
3. Selective serotonin reuptake inhibitors (SSRIs)
Fluoxetine, sertraline, paroxetine, trazodone.
4. Atypical anti-depressants (Others)
New TCAs, amoxapine, bupropion,
alprazolam, maprotiline, nomifensine, mianserin.
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Mechanism of Action
1. Inhibition of NE and 5-HT reuptake.
(TCAs, SSRIs, Newer TCAs).
2. Inhibition of MAO enzymes.
(MAOIs).
3. 5-HT
2A
and 5-HT
2C

antagonists.
(Nefazodone, trazodone, mirtazapine)
4. Alteration of NE output .
(Bupropion)
5. Stimulation of 5-HT
1A
receptors.
(
6. 2AR antagonists.
(mirtazapine)
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Tricyclic Antidepressants (TCAs)

amytriptiline
imipramine
desipramine
nortriptyline
protryptyline
doxepin.

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Tricyclic Antidepressants (TCAs)
Characteristic three ring nucleus.
Most are incompletely absorbed, all are
metabolized in liver => High first pass effect:
1) Transformation of the tricyclic nucleus
=> hydroxylation => conjugation =>
glucoronides.
2) Alteration of aliphatic side chain =>
demethylation of the nitrogen => active
metabolites.
High protein binding, high lipid solubility.
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Tricyclic Antidepressants (TCAs)

/ CH
3
/ H
N N
\ CH
3
\ CH
3

tertiary amine secondary amine
3
o
=> 2
o

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Tricyclic Antidepressants (TCAs)

3Amines: Imipramine, Amitriptyline


2Amines: Desipramine, Nortriptyline

Selectivity 2
o
Amines -- NE > 5-HT
3
o
Amines -- 5-HT > NE www.indiandentalacademy.com
Tricyclic Antidepressants (TCAs)
Mechanism of Action:
- Inhibition of NT reuptake.
- Immediate action = > NE and 5-HT in synapse.
- After chronic treatment (2 - 4 weeks) = >
NE-R and 5-HT
2
R.
NE release and turnover.
NE-stimulated cAMP in brain.
Sensitization of 5-HT receptors.
* Adaptive Responses *
- Takes up to 4 weeks for all TCA antidepressants to
have an effect.


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Tricyclic Antidepressants (TCAs)
Side Effects:
Atropine-like side effects: dry mouth,
paradoxical excessive perspiration,
constipation, blurred vision, mydriasis,
metallic taste, urine retention => muscarinic
blockade.
Orthostatic hypotension => 1-AR and
possibly 2-AR blockade.
Drowsiness, sedation and weight gain =>
Histamine-Receptor blockade.
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Tricyclic Antidepressants (TCAs)
Side Effects (cont):
Most serious side effect is cardiac toxicity
=> Palpitations, tachycardia, dizziness =>
excessive CNS stimulation => NE in Heart.

Sexual dysfunction, including loss of libido,
impaired erection and ejaculation and
anorgasmia
. COMPLIANCE
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Tricyclic Antidepressants (TCAs)
Other effects (cont):
Metabolism is affected by: Smoking, Barbs,
estrogens, neuroleptics and anticonvulsants.
Can lower seizure threshold.
All TCAs can cause: vagal block, postural
hypotension, arrythmias, sinus tachycardia.
All potentiate CNS depressants (BZDs, Barbs,
ETOH) => coma and death.
TCA administration in bipolar disorder may
precipitate acute mania or rapid cycling.
Fatal in overdose (a 2 wk supply can kill anyone).

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X. MAO INHIBITORS


Isocarboxacid
Phenelzine
Tranylcypromine.
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X. MAO INHIBITORS
Developed for the treatment of tuberculosis
(iproniazid derivatives) - 1951.
These drugs are not widely used today, although
a small number of patients appear to do better in
MAOIs than TCAs or the newer drugs.
Are readily absorbed from GI tract and widely
distributed throughout the body.
May have active metabolites, inactivated by
acetylation.
Effects persist even after these drugs are no
longer detectable in plasma (1-3 weeks).

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X. MAO INHIBITORS
Mechanism of action:
Inhibit MAO enzymes (non-selective):
1) Irreversible MAO inhibitors
Phenelzine and isocarboxazid => hydrazides.
2) Reversible MAO Inhibitors.
Tranylcypromine => non-hydrazide,
prolonged blockade, but reversible within 4hr.

Decrease metabolism of most biogenic amines
(NE, 5HT, DA, tyramine, octopamine).
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X. MAO INHIBITORS
Mechanism of action (cont):
Acute administration causes:
NE and 5-HT in synaptic terminals in brain but
NE in PNS. NE synthesis.
Acute euphoria
Suppressed REM sleep.
Chronic administration causes:
NE-stimulated cAMP in brain.
Down regulation of receptors.
Down regulation of 5-HT
2
receptors.

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X. MAO INHIBITORS

MAO-A NE, 5-HT, Tyramine
MAO-B DA

Selective MAOIs:
Inhibitors MAO-A
Moclobemide, Clorgyline
Inhibitors of MAO-B.
Deprenyl, Selegiline
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X. MAO INHIBITORS
Wine-and-Cheese Reaction
- Fatal interaction with tyramine-
containing foods (fermented foods in
particular, such as wine and cheese).
- MAO-A => Tyramine in the body
=>NE in circulation => induces
hypertensive crisis => can lead to
intracranial bleeding and other organ
damage.


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X. MAO INHIBITORS
Negative drug interactions with:
Any drug metabolized by MAOs* including
SSRIs, TCAs and meperidine, alcohol, CNS
depressants, sympathomimetics,
phenylephrine (O/C nasal decongestants),
ampetamines, and other indirect-acting
adrenergic drugs.
* Interaction with drugs metabolized by MAOs (e.g.
Meperidine (opioid analgesics) => hyperpyrexia or
hyperexcitation syndrome involving high fever,
delirium and hypertension).

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X. MAO INHIBITORS
Other side effects:
Hypotension
Hepatotoxicity.
Sedation.
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XI. SSRIs

Fluoxetine
Sertraline
Paroxetine
Fluvoxamine
(Labeled for obsessive-compulsive disorder)
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XI. SSRIs
Most widely prescribed drugs for
depression.
They have few side effects and seem to be
rather safe. More rational prescribing and
better patient compliance.
Adverse effects include: nausea, decreased
libido, decrease sexual function.
Low threat for overdose. Suicide may be
considered in severe depression.

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XI. SSRIs
Mechanism of action:
Specific serotonin uptake inhibitors increase
5-HT by inhibiting reuptake.


Current theory holds that:
Enhanced stimulation or responsiveness of
postsynaptic 5-HT
1A
receptors is particularly
important in the action of antidepressants.
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XI. SSRIs
Fluoxetine is the prototype.
Approximately 70% of depressed patients will
respond to an SSRI therapy at the end of 6 weeks
(4 to 6 weeks before effects are evident to patient).
T
1/2
of 16 24 hrs. except for fluoxetines
metabolite norfluoxetine (T
1/2
= 8 days).
Fluoxetine and paroxetine inhibit liver enzymes,
particularly P450-2D6.
Paroxetine and Sertraline have PK parameters
similar to TCAs.

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XI. SSRIs
Drug-drug interactions:
dangerous with other antidepressant drugs,
MAOIs in particular.

Serotonin Syndrome:
hyperthermia, muscle rigidity, myoclonus, rapid
changes in mental status and vital signs.
Thus it is important to wait up to 6 weeks after
medication is stopped, before starting with another
drug.
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XII. Heterocyclics
2nd Generation heterocyclics
amoxapine
maprotiline
trazodone
bupropion
Third Generation heterocyclics
mirtazapine
venlafaxine
nefazodone
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XII. Heterocyclics
The second and third generation antidepressants
are by no means a homogeneous group.
As with the TCA's , they all have variable
bioavailability.
High protein binding.
Some have active metabolites.
Trazodone and Venlafaxine have the shortest
plasma half-lives, which mandates divided doses
during the day.
Nefazodone and fluvoxamine cause inhibition of
CYP3A4.
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XII. Heterocyclics
Mechanism of Action:
1) NT reuptake inhibition.
maprotiline.
2) 5-HT receptor antagonism (for 5-HT
2A

or
2C
receptors).
nefazodone, mirtazapine, and
trazodone
3) Alteration of NE Output.
bupropion, amoxapine, and trazodone.
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XII. Heterocyclics
Amoxapine. Metabolite of Loxapine (an anti-
psychotic) -- retains some antipsychotic
activity and DA receptor antagonism =>
parkinson's-like symptoms. May be useful
if psychosis is present. NE output.

Maprotiline. A tetracyclic drug, resembles
desipramine with less sedative and
antimuscarinic side effects. Evokes
seizures at high doses. Blocks NT
reuptake.
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XII. Heterocyclics

Trazodone. Antagonist of 5-HT
2A
or
2C

receptors. Unpredictable efficacy. Highly
sedative (hypnotic), but minimal
antimuscarinic action.

Bupropion. Resembles amphetamine. Blocks
DA reuptake (not important in depression).
Causes CNS stimulation. Inhibits appetite.
Aggravates psychosis. NE output.
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XII. Heterocyclics
Third Generation
Mirtazapine. A derivative of mianserin. Antagonist of
5-HT
2A
or 5-HT
2C
receptors. Also antagonizes
2
-
adrenergic receptors, thus increasing NE and 5-HT
release. Very sedating.

Venlafaxine. Short plasma half-live, thus needs to
be given in divided doses. Potent inhibitor of 5-HT
uptake and weaker at NE reuptake (at low
concentrations it acts like an SSRI).

Nefazodone. Antagonist of 5-HT
2A
or 5-HT
2C

receptors. Moderately sedating. Potent inhibitor of
CYP3A4, so cannot be given with cisapride www.indiandentalacademy.com
XII. Atypical/Heterocyclic
2nd Generation heterocyclics
Amoxapine
Maprotiline
Trazodone
Bupropion
Third Generation heterocyclics
Mirtazapine
Venlafaxine
Nefazodone
Similar to TCAs
5-HT antagonists
2-AR antagonist
SSRI-like
NE output
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Noradrenergic Control of Serotonergic Release
NE
5-HT
NE

2
-AR

1
-AR
1 2 3
Mianserin
5-HT1
5-HT2
5-HT3
Receptors
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XIV. Alternative Therapies
No way of a priori knowing which therapy
will be best for a patient.

Light Therapy
Psychological Treatment
ECT
St. Johns Wort

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XVI. Anti-Manic Drugs
Lithium (Li
+
) remains the drug of choice for the
treatment and prophylaxis of mania.
Acute manic episodes are managed with lithium
salts (carbonate or citrate) alone, or in combination
with:
1) Antipsychotics (carbamazepine, similar in
structure to TCAs but not effective in
depression).
2) Valproic acid
3) Calcium-channel blockers (nifendipine,
diltiazem, verapamil).
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XVI. Anti-Manic Drugs
Li
+

Small monovalent cation (between H
+
and
Na
+
).
Distributed in total body water, similar to
sodium.
May partially inhibit Na
+
-K
+
ATPase.
Inhibits ADH => diuresis.
May decrease thyroid function.
Teratogenic (tricuspid valve malformation).
Excreted by kidney.



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XVI. Anti-Manic Drugs
Li
+

Not to be taken with thiazide diuretics (e.g.
chlorthiazide).
Lithium clearance is reduced by 25%.

All neuroleptics (with the exception of
clozapine), produce more severe
extrapyramidal syndromes when combined
with lithium.

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XVI. Anti-Manic Drugs
Li
+

Helps alleviate the depressive phase of
bipolar illness.

Useful in refractory depression when
added to SSRIs or TCAs, but not a good
antidepressant alone.
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XVI. Anti-Manic Drugs
Li
+

Mechanism of action:
Does not alter receptor numbers but alters the
coupling of the receptors with their second
messengers by reducing coupling of G-proteins.
Regulation of -AR and DAR.
Can reduce release of NTs (5-HT) and affinity of
binding to receptor.
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XVI. Anti-Manic Drugs
Li
+

Mechanism of action (Cont):
Inhibits breakdown of IP
2
to IP
1
(during PIP
hydrolysis) => depletion of DAG and IP
3
and
[Ca
2
+
] in response to receptor activation (i.e.
from 5-HT
2
R,
1
-AR, muscarinic receptors and
others).
Alterations in adenylate cyclase and
phospholipase C.

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XVI. Anti-Manic Drugs
PIP
PIP
2

G
IP
3

IP
2

IP
1

Inositol
PI
X
Li
+

PLC
DAG
Ca
2+
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XVI. Anti-Manic Drugs
Valproic Acid
A well known antiepileptic has been found to
have antimanic effects. Shows efficacy
equivalent as that of lithium during the early
weeks of treatment and is being evaluated for
maintenance treatment. Titrated well, the
sedation can be controlled. Nausea being the
only limiting factor in some patients.
May be used as first line treatment for mania,
although it may not be as effective in
maintenance treatment as lithium for some
patients.
Mechanism of action: ???
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XVI. Anti-Manic Drugs
Carbamazepine
Effective as an antimania medication

Mechanism of action (Cont):
May be due to decrease overexcitability of
neurons (anticonvulsive effect).
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XVI. Anti-Manic Drugs
Ca
2+
Channel blockers
Nifedeipine
Verapamil

Mechanism of action (Cont):
NT Release?
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