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PATHOGENESIS AND TREATMENT OF DEPRESSION

In every winters heart there is a

quivering spring, andbehind the veil of each night

there is a smiling dawn.

Khalil Gibran Definition and Classification of Depression

Monoamine and Hypercortisolemic Hypotheses

Pharmacodynamics and Toxicodynamics of

Antidepressants

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ENDOGENOUS DEPRESSION

Unipolar - Melancholy

Bipolar Overactivity / Deep Depression

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MONOAMINE HYPOTHESIS

Hypoadrenergic Disorder - MHPG

Hyposerotonergic Disorders 5HIAA

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EVIDENCE FAVORING MONOAMINE HYPOTHESIS

Monoamine Depletors - Depression

Monoamine Enhancer Ameliorate Depression

CSF Monoamine - Depression

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HYPERCORTISOLEMIC HYPOTHESIS

Overactivity of H-P-A Axis

Plasma Cortisol

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PHARMACOTHERAPY - DEPRESSION

Tricyclic Antidepressants (TCA)

Second Generation Antidepressants

MAO Inhibitors

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TRICYCLIC ANTIDEPRESSANTS

Imipramine (Tofranil)

Desipramine (Norpramin)

Amitriptyline (Elavil)

Protriptyline (Vivactil)

Doxepin (Singequan)

Nortriptyline (Aventyl)

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imipramine

CH2 NCH

3

CH3CH2CH

amitriptyline

N

(CH2)3 NCH3

Hdesipramine

N

(CH2)3 NCH3

CH3

clomipramine

N

(CH2)3 NCH3

CH3

Cl

CH2 NCH3

HCH2CH

nortriptyline

(CH2)3 NCH3

Hprotriptyline

CH2 NCH3

HCH2CH

doxepin

O

O

NCl

N N H

amoxapine

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NorepinephrineSerotoninDopamine

Response

A. Normal monoaminetransmission

NorepinephrineSerotoninDopamine

IncreasedResponse

B. Effect of tricyclicantidepressants

Tricyclicantidepressantdrugs block re-uptake

of neurotransmitter

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Inhibition of nerve terminal NE neuronal uptake system

Increase in synaptic concentrations of NE

Desensitization of nerve terminal 2-adrenoceptors

Increase of neuronal NE release during normal rates of

neuronal firing

Further increase in synaptic concentrations of NE

Desensitization of postsynaptic -adrenoceptors with

no change in postsynaptic 1-adrenoceptor sensitivity

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N

O

R1

R2 C

R1

C

R1R1: -(CH2)3N(CH3)2R2:H

Imipramine

R1: =CH(CH2)2N(CH3)2Amitriptyline

R1: =CH(CH2)2N(CH3)2Doxepin

R1: -(CH2)3NHCH3R2:H

Desipramine

R1: -(CH2)3N(CH3)2R

2

:-Cl

clomipramine

R1: -CH2CH(CH3)CH2N(CH3)2R2:H

Trimipramine

R1: =CH(CH2)2NHCH3Nortriptyline

R1: =(CH2)3NHCH3Protriptyline

R1

H

Structural relationships between various tricyclic antidepressants (TCAs)

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TCA ACUTE TOXICITY

Cardiac Arrhythmias - Propranolol

Convulsion - Diazepam

Anticholinergic symptoms - Physostigmine

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TCA DRUG INTERACTION

Alcohol CNS Depression

Guanethidine - Antihypertensive Action

MAO Hyperpyrexia, Convulsion

Sympathomimetics Hypertensive crisis

Antiepileptics - Efficacy

Oral Hypoglycemics - Efficacy

Phenylbutazone - Efficacy

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SECOND GENERATION ANTIDEPRESSANTS

Maprotiline (Ludiomil), Reboxetine

Amoxapine (Aserdin)

Fluoxetine (Prozac), Citalopram (Celexa)

Trazodone (Desyrel), Nefazodone (Serzone)

Bupropion (Wellbutrin)

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THIRD GENERATION ANTIDEPRESSANTS

Mitrazapine (Remeron)

Nefazodone (Serzone)

Fluvoxamine (Luvox)

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MAO

A. Normal monoamine

transmission

Synapticvesicle

Inactivemetabolites

NorepinephrineSerotoninDopamine

MAO inactivatesmono-amines(norepinephrine,serotonin, anddopamine)that leak from vesicle

Response

MAO

B. Effect of MAO

inhibitors

Synapticvesicle

Inactivemetabolites

NorepinephrineSerotoninDopamine

IncreasedResponse

MAO inhibitorsprevent inactivation of

monoamines withinneuron causing excessneurotransmitter todiffuse into synapticspace

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MAO INHIBITORS

Tranylcypromine (Parnate)

Isocarboxazid (Marplan)

Phenelzine (Nardil)

Moclobemide

Deprenyl (Selegiline)

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LithiumLithium

Valproic acidValproic acid

CarbamazepineCarbamazepine

BIPOLAR AFFECTIVE DISORDERBIPOLAR AFFECTIVE DISORDER TREATMENTTREATMENT

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Lithium

IP1IP1

Inositol

PI

PIP PIP2

PLC

IP2

IP3

Lithium

EFFECTS

DAGG

R

Outside

Receptor

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TremorsTremors propranolol, atenololpropranolol, atenolol

Choreoathetosis, motor hyperactivity, ataxiaChoreoathetosis, motor hyperactivity, ataxia

T

hyroid functionT

hyroid function Nephrogenic diabetes insipidusNephrogenic diabetes insipidus amelorideameloride

Chronic interstitial nephritisChronic interstitial nephritis

EdemaEdema

Sick sinusSick sinus -- contraindicationcontraindication

LITHIUMLITHIUM TOXIC EFFECTSTOXIC EFFECTS