Antidepressant drugs: - Types of depression: 1) Reactivator secondary depression o 60% o Due loss of relatives, or frinds o Disease (e.g.

, hypothyroidism) o Drugs & senility 2) Major (endogenous) depression o 25% o Genetically determined; not related to environmental factors o Family history usually present 3) Bipolar affective depression manic depressive disorder o 15% o Fluctuation between depression & mania Etiology of depression: o Monoamine theory: Depression caused by functional deficit of monoamine (MA) transmitters at certain sites of brain Monoamine affected: norepinephrine (NE) & 5-HT (5-hydroxytryptamine) Schizophrenia, high dopamine level; block receptor Evidence: 1) Tricyclic antidepressant (TCA), monoamine oxidase inhibitors (MAOI), & electroconvulsive therapy (ECT); might elevate the mood of patient. TCA prevent or inhibit reuptake of monoamines; leaving them in high concentration in synapse MOAIs inhibit enzyme which is responsible for degradation of these monoamines; lead to elevation of mood 2) Reserpine, -methyl tyrosine & methyldopa might decrease mood of patient a. Reserpine is a monoamine depletion agent b. -methyl tyrosine & methyldopa antagonize the effect of dopamine; decreasing patient mood o direct biochemical effect (elevation of concentration of monoamine) of antidepressant appears very rapidly where as the antidepressant effect (therapeutic effect) takes weeks to develop secondary adaptive changes rather than primary is responsible for clinical improvements

Inhibitors of monoamine uptake: Selective Serotonin Reuptake inhibitors (SSRIs):- drug of choice - E.g., Fluoxetine & paroxetine - Acute effect inhibition of active reuptake; increasing level of monoamine concentration; increasing activity of monoamine - Chronic effect down regulation of presynaptic inhibitory; leading to further increase of neurotransmitters release - Properties: o 300-3000 fold great selectivity to inhibit reuptake of 5-HT as compared to NE & very minor dopamine is inhibited 1

o Low muscarinic, -adrenergic & histaminic blocking activity o Fewer side effect & relative safety at high doses; drug of choice in treatment of depression o Adverse effect as therapeutic effects need weeks to develop o No effect in normal people; only in people have low monoamine level Therapeutic effect: o Mainly, treatment of depression o Other psychiatric disorder: Obsessive disorder Panic disorder Anxiety disorder (but benzodiazepine) Pharmacokinetics: o Administration orally; chronic disease o Absorption & distribution well absorbed & well distributed o Excretion Renal o metabolism By MES (Microsomal Enzyme System) might need other conjunction process metabolized into inactive metabolites fluxoetine; produce active metabolites o Fluxoetine has long half life 50 hours o Fluxoetine & paroxetine are inhibitors to MES; although they metabolized by it (so can potentiate other drugs) Side effects: o Nausea o Anxiety (although used in treatment) o Drowsiness o Insomnia o Sexual dysfunction o Increase suicide rate in children & teenagers o Drug interaction Due to inhibitory effect of MES (potentiate effect of warfarin; hemorrhage) Overdose (toxic) effects: o Arrhythmia; less than TCA o Seizures (epileptic) effect due to low seizure threshold serotonin syndrome Serotonin syndrome: (especially when given with monoamine oxidase inhibitors) o Hyperthermia o Mental & vital signs changes Should not add the member of other group drugs (e.g., MAOIs); we should withdraw first one & introduce gradually 2nd one Wash out period; leads nearly or complete elimination of initial drug from body o 4 to 5 half-lives of initial dose Withdrawal symptoms: o Less with fluxoetine Long half-life (50 hours) Metabolized into active metabolite

Tricyclic antidepressant (TCAs): - Nonselective inhibitors of NE & 5-HT - E.g.,: Imipramine & Amitirptyline 2

Good alternative for SSRIs Properties: o Have fair incidence of: side effect Antimuscarinic effect dry mouth, blurry vision Anti-5HT effect failure of therapy; no 100% Antihistaminic effect Anti -adrenergic effect postural hypotension o TCAs rarely might lead to physical & psychological dependence o May cause sudden withdrawal discontinuation syndrome o might lead to choilinergic rebound sudden increase in cholinergic activity therapeutic use: o mainly in treatment of depression o nocturnal enuresis in children; specifically; imipramine; muscarinic blocking effect o migraine & headache; specifically amitriptyline o Sometimes for chronic pain Pharmacokinetics: o Administration orally o Absorption & distribution well absorbed Therapeutic drug monitoring (TDM) is useful in therapy o Variable bioavailability; due to variable 1st pass effect o Metabolism & excretion by MES to inactive & excreted by renal Side effects: o Anticholinergic effect: dry mouth, urinary retention, blurred vision, constipation & might aggravate glaucoma o Tachycardia; due to anticholinergic effect o Arrhythmia & hypertension; more with imipramine o Sedation, nausea, drowsiness & sexual dysfunction Sexual dysfunction is less compared to Drug interaction: o Low therapeutic index; increase dose toxic side effects Depressed supplied by limit number of tablets of TCAs to prevent suicidal attempts o TCAs + MAOIs hyperpyrexia & hypertension crisis, convulsion & coma contraindicated combinations o TCA + biogenicamines (epinephrine, norepinephrine & dopamine) potentiate each other o TCAs + ethanol & CNS depressant toxic sedation

Monoamine Oxidase inhibitors (MAOIs): - 2 subgroups: reversible & irreversible - Mechanism of action: inhibit degradation of monoamine by inhibiting enzyme responsible for degradation process MAOI - Limited use; due to complication drug & food interaction last line of treatment o Tranylcypromine; has amphetamine stimulant effect which might lead to insomnia & agitation - Complicated drug & food interaction: o Food (cheese, red-wine, beer or banana) will be metabolized by MAO outside CNS

o Given MAOIs, enzyme will be inhibited; so sudden raise in form of epinephrine & norepinephrine; leading to high sudden rise in blood pressure called hypertensive crises or cheese reaction; treated with prazosin Other monoamine uptake inhibitors: Reboxetine, maprotyline selective norepinephrine reuptake inhibitors (SNERIs) Non-selective Venlafaxine & duloxetine o Similar in action to TCAs but lacking major receptor blocking action o Few side effects & fewer incidence of cardiac effects; safer in overdose & have less toxic activity than TCAs