Depression&Antidepressant Drugs

Depressionfeelings of hopelessness, worthlessness, sadness, guilt, and desperation.

Loss of appetite, insomnia, crying, diminished sexual desire, loss of ambition, fatigue and agitation.

Pain, sever digestive disturbances, and difficulty breathing.

Suicide rates (7-15% in depressed individuals) 1-1.5% in total population

untreated episodes usually last 7-14 months

recur and often increase in frequency with age

Affective Disorders: Depression

characterized by extreme and inappropriate exaggeration of mood

most individuals are "normal" in between episodes.

Depressive and anxiety disorders are the leading causes of disability, 25% of all visits to health care centers worldwide.

10-20% lifetime prevalence in U.S.

Classification of Major Affective Disorders

E pisoda lD epress ion

S easona lA ffec tiveD isorder

A typica lD epress ion

M a jor/E ndogenousD epress ion

M ania Bipola rdepress ion

M a jor A ffec tive D isorders

Episodal (reactive) Depression

Adverse life events.Physical illness.Steroidal hormonesDrugs.Other psychiatric disorders.

More than 60% of all depressions.

ocurring in response to real stimuli:

Major Endogenous Depression

A genetically determined biochemical disorder

manifested by inability to experience ordinary pleasure or to cope with ordinary life events

About 25% of all depressions.Recurrent, Cyclic

The monoamine hypothesis

The Neuroendocrine hypothesis

The genetics hypothesis

The Biologic hypothesis

………

The pathogenesis of major depression:

Depression due to deficit of monoamines and mania due to excess

effect of antidepressants– SSRIs– TCAs– MAOIs

Reserpine induced depression (prevents vesicular storage of monoamines

Attenuation of serotonin in depressed patients

Monoamine Hypothesis

Antidepressants

• TCAs

MAOIs

SS

RIs

TCAs

TCAs

TCAs

TC

As

SSRIs

SSRIs

SS

RIs

SSRIs

MAOIs

MAOIsMAOIs

MAOIs

MAOIs

MAOIs

Venflaxine

Ven

flaxine

Ven

flaxine

MAOIs

MAOIs

maprotiline

Amoxepine

doxepin

isocarboxazide

Nortriptyline

Antidepressants

1. Tricyclic anti-depressants (TCAs).Imipramine, desipramine, nortriptyline,protriptyline, amitriptyline, 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,

maprotiline, nomifensine, mianserin.

Mechanism of Action

• Combined NE and SE uptake inhibition– Tricyclic antidepressants (TCAs)– Venlafaxine

• Serotonin uptake inhibition– Serotonin selective reuptake inhibitors (SSRIs)

• 5-HT2 receptor blockers and serotonin uptake – Nefazodone – DA and NE uptake inhibition– Bupropion

• Monoamine oxidase inhibitors (MAOIs)– Nonselective and irreversible– Selective and/or reversible (RIMAs)

Tricyclic Antidepressants (TCAs)

•Amytriptiline•Imipramine•Desipramine•Nortriptyline•Protryptyline•Doxepin.• clomiperamine

N

HCl

HN

HCl

Tricyclic Antidepressants (TCAs)

Mechanism of Action:Inhibition of NT reuptake:

Immediate action = > NE and 5-HT in synapse.

After chronic treatment (2 - 4 weeks):

and 5-HT2 Receptors

Desesitization of 2 and D2 Autoreceptors

cAMP TCAs do not block dopamine transport: Differ from

CNS stimulants

TCAs

Tricyclic Antidepressants (TCAs)

Tricyclic Antidepressants (TCAs)

Characteristic three ring nucleus.

Most are incompletely absorbed,and 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.

Individual variance as high as 10-30 folds to a given dose is due to genetic control of hepatic microsomal oxidative enzymes

High protein binding, high lipid solubility.Takes up to 4 weeks for all TCA antidepressants to have an effect despite their fast inhibitory effect on NT reuptake:

This delay of theraputic effects remain unexplained

Tricyclic Antidepressants (TCAs)

/ CH3 / H

N N

\CH3 \ CH3

tertiary amine secondary amine

3o => 2o

Tricyclic Antidepressants (TCAs)

3°Amines: Imipramine, Amitriptyline

2°Amines: Desipramine, Nortriptyline

Selectivity 3o Amines – 5-HT > NE

2o Amines -- NE > 5-HT

Other effects (con’t):• Metabolism is affected by: Smoking, Barbiturates, SSRIs and

other 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

• Fatal in overdose

Tricyclic Antidepressants (TCAs)

X. MAO INHIBITORS

• Tranylcypromine• Isocarboxacid• Phenelzine

MAO-A NE, 5-HT, Tyramine

MAO-B DA

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.

May have active metabolites, phenelzine is metabolized by acetylation and may have and may vary in different individuals.

Effects persist even after these drugs are no longer detectable in plasma (1-3 weeks).

Mechanism of action: 1) Irreversible MAO inhibitors

Phenelzine and isocarboxazid => hydrazides.

Tranylcypromine => non-hydrazide Decrease metabolism of most biogenic amines NE, 5HT,

DA, tyramine

2) Reversible MAOA inhibitors

Brofaromine, Moclobemide

Delayed mechanisms

Delay in beginning of treatment

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.

X. MAO INHIBITORS

X. MAO INHIBITORS

  Drug-Drug Interactions:•Tricyclic Antidepressants: Hyperpyrexia, Seizures •Fluoxetine, Sertraline, Paroxetine: Hyperthermia, Diaphoreis, Seizures, Delirium •Sympathomimetic Drugs (e.g. amphetamine, phenylephrine, phenylpropanolamine, guanethidine, reserpine): Hypertensive Crisis, •CNS Depressants: Additive Effects •Opioid Analgesics (particularly meperidine: Hypertensive crisis; circulatory collapse •Buspirone: Hypertension •General Anesthetics: Prolonged hypotensive and CNS depressive effects

Other side effects:

• Hypotension

• Hepatotoxicity

• Sedation.

Selective MAOAI are less likely to potentiate pressor actions of tyramine and other indirect sympathomymetic amines than Non selective MAOIs

X. MAO INHIBITORS

So MAOIs are drug of late choice:

selective benefits: phobias and anxiety

XI. SSRIs

•Fluoxetine

•Sertraline

•Paroxetine

•Fluvoxamine

SSRIs are preferred to TCAs:

• Lower anticholinergic effects

• Lower sedation

• Lower weight gain

• Lower cardiovascular effects

XI. SSRIs

Mechanism of action:Specific serotonin uptake inhibitors increase 5-HT by

inhibiting reuptake. Delayed mechanisms

» Desensitization of 5-HT1A,D,7 Autoreceptors

» Decrease in 5-HT2A receptors Increase NE

» ………….

XI. SSRIs

XI. SSRIs

XII. Heterocyclics2nd Generation heterocyclics

• amoxapine

• maprotiline

• trazodone

• bupropionThird Generation heterocyclics

• mirtazapine

• venlafaxine

• nefazodone

fewer side effects   reduced dangers of drug-drug interactions   are less likely to exacerbate other illnesses   and are less toxic in over dosage

XII. Heterocyclics

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.

XII. Heterocyclics

Mechanism of Action:1) NT reuptake inhibition.

maprotiline.2) 5-HT receptor antagonism (for 5-HT2A or 2C

receptors).

nefazodone, and trazodone3) Alteration of NE & DA output

bupropion, amoxapine

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 & 5-HT & DA reuptake inhibitor.

Maprotiline: A tetracyclic drug, with less sedative and antimuscarinic side effects. Evokes seizures at high doses.

Blocks NT reuptake.

XII. Heterocyclics

Trazodone:Antagonist of 5-HT2A or 2C receptors and 5-HT1A autoreceptors.

Unpredictable efficacy in depression.

Highly sedative (hypnotic), but minimal antimuscarinic action.

priapism is an important side effect.

Bupropion:

Resembles amphetamine.

Blocks DA & NE reuptake.

Causes CNS stimulation.

Inhibits appetite.

Aggravates psychosis.

Minimum sexual disorders

XII. Heterocyclics

XII. Heterocyclics Third Generation

Mirtazapine: A derivative of mianserin. Antagonist of 5-HT2A or 5-HT2C 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-HT2A or 5-HT2C receptors. Moderately sedating. Potent inhibitor of CYP3A4, so cannot be given with cisapride

Noradrenergic Control of Serotonergic Release

NE5-HT

NE

2-AR

1-AR

1 2 3

Mianserin

5-HT1

5-HT2

5-HT3

Receptors

XIV. Alternative Therapies

No way of a priori knowing which therapy will be best for a patient.

Psychological Treatment ECT (Electroconvulsive therapy) St. John’s Wort (Hypericum)

• peripheral neuropathy: TCAs• Chronic neuralgia / chronic pain syndrome• Obsessive-compulsive disorder: SSRIs and clomipramine• Attention-deficit hyperactive disorder(ADHD): TCAs• Panic and phobia disorders• Nocturnal enuresis: Imiperamine(Ephedrine, DDAVP)• Eating disorders: specially Fluoxetine• Generalized anxiety: TCAs

Other Medical uses of antidepressants

Class/Generic NamesAmitriptylineImipramineDoxepinDesipramineNortriptylineTrimipramineProtriptylineClomipramineMaprotilineMirtazapineFluoxetineSertralineParoxetineFluvoxamineCitalopram

Reboxetine*

Amoxapine

TrazodoneNefazodone

Bupropion

Venlafaxine

Alprazolam

IsocarboxazidPhenelzineTranylcypromine

Oral Dosage Range (mg/day)75-30075-30075-30075-30075-30075-20020-60100-25075-22515-455-8025-20010-50100-30020-40

2-4

200-600

150-600100-600

300-450

75-375

1-4.5

10-3015-9030-60

TRICYCLICS

TETRACYCLICS

SEROTONIN REUPTAKE INHIBITORS

NOREPINEPHRINE REUPTAKE INHIBITORS

AMINOKETONES

TRIAZOLOPYRIDINES

DIBENZOXAZEPINE

PHEYLETHYLAMINES

TRIAZOLOBENZODIAZEPINES

MONOAMINE OXIDASE INHIBITORS

Trade NameElavilTofranilSinequanNorpraminPamelorSurmontilVivactilAnafranilLudiomilRemeronProzacZoloftPaxilLuvoxCelexa

Vestra

Ascendin

DesyrelSerzone

Wellbutrin

Effexor

Xanax

MarplanNardilParnate

* Not Available in US

TABLE 1: ANTIDEPRESSANTS

CardiacOrthostasis,

hypertension,heart block,tachycardia

UrogenitalErectile dysfunction,ejaculation disorder,

anorgasmia, priapism

Central Nervous SystemDizziness, cognitive impairment,

sedation, light-headedness,somnolence, nervousness,

insomnia, headache, tremor,changes in satiety and appetite

GastrointestinalNausea, constipation,vomiting, dyspepsia,

diarrhea

Autonomic Nervous SystemDry mouth, urinary retention,

blurred vision, sweating

Potential Side Effects of Antidepressant Therapy

Tricyclic Antidepressants (TCAs)

Side Effects:

• Atropine-like side effects: • dry mouth, paradoxical excessive perspiration, constipation,

blurred vision, mydriasis, metallic taste, urine retention, cofusion, delirium => muscarinic blockade.

• Orthostatic hypotension => 1and possibly 2 blockade.

• Drowsiness, sedation and weight gain => Histamine-Receptor blockade.

• Vomiting and sexual effects:

5-HT beside 5-HT3

As many other drugs antidepressants are metabolized more rapidly by children and more slowly by patients over 60 years old Dose adjustment require

Pro-Arrhythmic Effects (Class I Antiarrytmic type) Pro-Arrhythmic Effects (Class I Antiarrytmic type) 1.Sinus Tachycardia 2.Supraventricular Tachycardia 3.Ventricular Tachycardia 4.Ventricular Fibrillation 5.5.Prolongation of PR, QRS or Prolongation of PR, QRS or QT Interval 6.6.ST Segment and ST Segment and T Wave changes changes 7.7.Bundle branch block or complete heart block Bundle branch block or complete heart block

Tricyclic Antidepressants (TCAs)

DRUGS SEDATION ANTICHOLINERGIC ORTHOSTATTICHYPOTENSION

CARDIACEFFECTS

Dibenzoxapines AmoxapinePhenylpiperazine Trazadone NefazodoneAminoketones BupropionSerotonin andNorepinephrineReuptake Inhibitors VenlafaxineSerotonin andNorepinephrineReuptake Activity MirtazapineMonoamineOxidase Inhibitors Isocarboxazid Phenelzine Tranylcypromine

Low

HighLow

High

Low

Moderate

LowLowHigh

Low

LowLow

Very Low

Very Low

Low

NoneNoneVery Low

None

ModerateLow

Moderate

Very Low

Low

HighHighVery Low

None

LowLow

Low

Low

Low

NoneNoneNone

Adverse Effects of Antidepressants

pharmacology of antidepressants and mood stabilizers

DRUGS SEDATION ANTICHOLINERGIC ORTHOSTATICHYPOTENSION

CARDIACEFFECTS

Heterocyclics Amitriptyline Clomipramine Desipramine Doxepin Imipramine Maprotiline Nortriptyline Protriptyline TrimipramineSelective SerotoninReuptake Inhibitors Fluoxetine Paroxetine Sertraline

HighHighLowHighModerateModerateModerateLowHigh

LowLowLow

HighHighLowModerateModerateModerateModerateModerateHigh

NoneNoneNone

ModerateLowLowModerateHighLowLowLowModerate

NoneNoneNone

HighModerateModerateModerateHighModerateModerateModerateHigh

NoneNoneNone

pharmacology of antidepressants and mood stabilizers

Adverse Effects of Antidepressants

Side Effects (con’t):• Most serious side effect is cardiac toxicity(specially

with Imipramine) => Palpitations, tachycardia and arrhythmia

Accumulation of hydroxilated metabolites in the heart Blockade of Na channels

This side effects are less with secondary TCAs:

Nortryptyline, Desipramine

Tricyclic Antidepressants (TCAs)

• Pharmacodynamic – AD + sedatives - additive, esp.. alcohol

– AD + Sympathomimetics - hypertensive crisis

– MAOI + SSRIs - serotonin syndrome (may be lethal) SSRI + MAOI a “NO! NO!” Serotonin Syndrome

(akathisia, muscle twitches, shivering, seizure and coma)

• Pharmacokinetic– SSRIs or Some Tricyclics + Inhibitors of P450-2D6 and

P450-3A4 - arrhythmias (may be fatal)

– Increase in metabolism by carbamazepine and smoking

– Decrease in protein binding by phenytoin, ASA

DRUG INTERACTIONSDRUG INTERACTIONS

• Antidepressants and mood stabilizers may be inhibitors, inducers, or substrates of one or more cytochrome P450 isoenzymes

• Knowledge of their P450 profile is useful in predicting drug-drug interactions

• When some isoenzymes are absent or inhibited, others may offer a secondary metabolic pathway

• P450 1A2, 2C (subfamily), 2D6, and 3A4 are especially important to antidepressant metabolism and drug-drug interactions

Antidepressants and the Cytochrome P450 System

Venlafaxine, citaloprame and sertraline have minimal interaction with cytochrome P450 isoenzymes

Antidepressants and the Cytochrome P450 System

Some of important interactions:

Fluvoxamine:

increase in BZDs, clozapine, Theophyline, Warfarine concentration

Fluoxetine and Trazodone:

increase in Astemizole and Terfenadine and TCAs concentration

Nefazodone:

can potentiate the effects of BZDs

Factors Influencing Choice

Features of illness, e.g. agitation, hypersomia

Suicide riskOther therapyOther illness.Side effectsCostSpecial problems e.g.

Age, driving, pregnancy

Mania

Mania alone is rare (10%) and most frequently cycles with Major/endogenous depression (Manic-Depressive Disease, Bipolar Disorder).

exact opposite symptoms of depression

elation (full of energy and fun)

decreased need for sleep

Talkative, go on-and-on about the things they will do.

Flight of ideas

Excessive involvement in pleasurable activities

spending excessive amounts of money

  hypersexual Mechanism of disease:

Increase In catecholamines and ……..???

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 (Haloperidole)

2) Anticonvulsive: Valproic acid & Carbamazepine

Li+

Mechanism of action• Inhibits breakdown of IP2 to IP1 (during PIP hydrolysis) =>

depletion of DAG and IP3 and [Ca2+] in response to receptor activation (i.e. from 5-HT2R, 1-AR, muscarinic receptors and others).

• Alterations in adenylate cyclase and phospholipase C.

• Alters the coupling of the receptors with their second messengers by reducing coupling of G-proteins.

• Can reduce release of NTs (DA & NE except 5-HT).

• Change in the distribution of Na+

XVI. Anti-Manic Drugs

PIP

PIP2

G IP3

IP2

IP1

InositolPI

XLi+

PLC

XVI. Anti-Manic Drugs

X

Receptor

DAG

Li+

Li+ is effective in the treatment of acute mania and maintenance

Other uses include:

• Improve the notrophile count in chemotherapy

• Prophylaxy of cluster headache(a periodical headache in men)

• Bulimia

• Syndrom of inappropriate secretion of ADH

• Hyperthyroidism

XVI. Anti-Manic Drugs

Li+

• This drug has a low theraputic index and patient should be monitored

• Inhibits ADH => diuresis.

• May decrease thyroid function.

• Tremor, ataxia, aphasia

• Polydipsia, polyuria(ADH)

• Decrease in Na: increase in Li uptake in tubules

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

• Useful in refractory depression when added to SSRIs or TCAs, but not a good antidepressant alone.

XVI. Anti-Manic Drugs

• Na+

• use of diuretics

• change in renal function

• pregnancy

Li+ overdosage

XVI. Anti-Manic Drugs

Hemodyalisis is the prefer way to decrease Li+ concentration

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: ???

XVI. Anti-Manic Drugs

CarbamazepineEffective as an antimania medication

Mechanism of action:

May be due to decrease overexcitability of neurons (anticonvulsive effect).

Olanzepine and ClonazepamAre use as adjuvant in the acute or refractory mania

XVI. Anti-Manic Drugs

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