Anti depressant Drugs

Rezaei M. MD Psychiatrist

Tricyclics

Tertiary amines:ImipiramineAmitriptylineClomipramineTrimipiramineDoxepin

Secondary aminesDesipiramineNortriptylineprotriptyline

Tetracyclics

Amoxapine MaprotilineMinaserin

Pharmacological actions

Absorbed from oral administrationPeak plasma concentration 2-8 hrsHalf life vary from 10 to 70 hrs ( nortriptyline, maprotiline

and protriptyline may have longer half lives )5-7 days are needed to reach steady state plasma

concentrationMetabolized in liver by cytochrome p-450 enzyme Drug interaction with quinidine, cimetidine , fluxetine,

serteraline, paroxetine , phenothiazine, carbamazepineGenetic variability between persons are responsible for up

to 40-fold differences in plasma concentrations of TCA`s

Mechanism of action:Block the reuptake of NEP and serotonin

Competitive antagonists at the muscarinic acetylcholine, histamine H1, @1 and @2-adrenergic receptors.

( Amoxapine, nortriptyline, desipramine, maprotiline have the least anticholinergic activity .

Doxepine has the most antihistaminergic activity,

clomipramine is the most sertonin-selective of the TCAs)

Adverse effectsPsychiatric effects

A major adverse effect is the possibility of inducing a manic episode in patients +/- history of BMD I disorder

Anticholinergic effectsPatient may develop a tolerance for these effects with continued

treatment .AmitriptylineImipramineDoxepinTrimipramine

Dry mouth, constipation, blurred vision , urinary retention,Treatment Beware of narrow angle glaucomaSevere reactions may induce CNS anticholinergic syndrome with confusion

and delirium

Sedation AmitriptylineTrimipramine DoxepinThe least sedative effects are in desipiramine and

protriptylineAutonomic effects

Orthostatic HOTN ,Partly because of @1-adrenergic blockade Nortriptyline least likely cause the problemFludrocortisone may be helpfulOther effects include sweating , palpitation, HTN

Cardiac effectsIn the usual therapeutics doses: tachycardia, flattened T

wave, prolonged QT interval, and depr essed ST segmentBecause the drug prolong conduction time, their use in

patients with preexisting conduction defects is contraindicated.

The drug should be discontinued several days before elective surgery because of occurrence of

hypertensive episodes during surgery in patients receiving TCAs .

Neurlogical effects Desipramine and protriptyline are associated with

psychomotor stimulation :Myoclonic jerks and tremors of tongue and upper extremitiesSpeech blockParesthesiaPeroneal palsyAtaxia

Amoxapine is unique in causing Parkinsonian symptomsAkathisiaDyskinesiararely; neuroleptic malignant syndrome

Maprotiline may cause seizures ifDose increase too quicklyDose keep at high level for too long

Overall TCAs have relatively low risk for inducing seizures, except in patients who are at risk for seizures.

Allergic and hematological effects

Rash in 4-5 % in maprotilineJaundice is rareAgranulocytosis, leukopenia and leukocytosis are rare.However , a patient with fever or sore throat during

the first few months of TCA treatment, should have a CBC immediately .

Other adverse effects: Weight gainImpotenceGynecomastiaAmenorrheaNauseaHepatitisVomitingSIADH

SSRI

Major differences between them is different pharmacokinetics profiles

Fluoxetine has the longest half life of 2-3 days, others of about 2o hrs.

All well absorbed orally and metabolized in the liverParoxetine and fluoxetine are metabolized by CYP 2D6,

be careful in coadministration of drugs with the same enzyme metabolizer

Fluvoxamine inhibits the CYP 3A4, so interfere with terfenadine and astemizole.

If taken with food, it reduce nausea and diarrhea.

Therapeutic indications of SSRI

Depression ; they are first line in the general population ( mild and moderate Dep. ), the elderly, the medically ill

and those who are pregnant.Serteraline may be more effective for treatment of

severe depression with melancholiaOver 50% of persons who respond poorly to one SSRI will

respond favorably to another.

Augmentation strategiesIn depressed persons with partial response:

BupropionLithiumLevothyroxineSympathomimeticsPindololClonazepam

Suicide Markedly reduce the risk of suicide

Depression during pregnancy No documented adverse reactionSSRI may produce a self limited neonatal withdrawal

syndrome that consist of jitterness and mild tachypnea, it begins several hrs after birth and may persist for days to a

few weeks. It is rare and does not interfere with feeding.

Postpartum depression(+/- psychotic feature)Depression in the Elderly and Medically ill

Precise diagnostic evaluation to rule out dementia and delirium.

They are less well tolerated by persons with preexisting GI symptoms.

Chronic depressionThey have to continue taking SSRI`s for at least 1 year.

Depression in childrenChildren of depressed adults are at increased risk of

depression.Adverse effects in children includes GI symptoms, insomnia,

motor restlessness, social disinhibition, and hypomania or mania; so SSRI use with small doses.

OCDFluvoxamine and Serteraline are approved for treatment of

pediatric OCDEffective dose for OCD is higher than those required for

depression.

Panic DisordersSSRI`s are far superior to benzodiazepines for treatment of

panic disorder with depression.Are effective for childhood panic symptoms

Social PhobiaPosttraumatic Stress Disorder

SSRI`s are more effective than TCAD and MAO`s inhibitorMarked improvement of both intrusive and avoidant

symptoms.Specific phobias, GAD, separation anxiety

Bulimia Nervosa and other Eating DisorderFluoxetine

Obesity ; fluoxetine in combination with behavioral program

Premenstural Dysphoric DisorderFluoxetine and Serteraline

Adverse Reactions of SSRI`sSexual dysfunction: inhibited orgasm and decreased libido.Gastrointestinal : nausea, diarrhea, vomiting, dyspepsia, anorexia.Weight GainHeadaches; 18-20% Anxiety Insomnia and SedationVivid dreams and NightmaresSeizures Extrapyramidal Symptoms Galactorrhea Hypoglycemia , rarely hyponatremia and SIADH

Serotonin Syndrome

Concurrent administration of an SSRI with MAOI, l-tryptophan, or lithium can rise plasma serotonin

concentrationDiarrheaRestlessnessAgitation , hyperreflexia, autonomic instability, rapid

fluctuations of vital signsMyoclonus , seizures, hyperthermia, rigidity,Delirium , coma, cardiovascular collapse and death.

SSRI`s WithdrawalDizzinessWeaknessNauseaHeadachesRebound depressionAnxietyInsomniaPoor concentrationUpper respiratory symptomsParesthesiaMigranelike symptoms

BUPROPION

More effective against symptoms of depression than those of anxiety.

Half life 12 hrs.Blockade of dopamine reuptakeTherapeutic indications:

Depression Bipolar DisordersADHDCocaine DetoxificationSmoking cesation

BUPROPIONAdverse reaction

HeadacheInsomniaUpper respiratory symptomsNauseaRestlessnessAgitationIrritabilityWeight loss 25%Dry mouth

constipation

Trazodone

Half life is 6-11 hrsSpecific inhibitor of serotonin reuptakeDepressive DisorderInsomnia

Venlafaxine May have faster onset of action than other antidepressantMost effective drugs for treatment of severe depression with

melancholic features & GADHalf life 3.5 hrs( SR-form 9 hrs )Inhibitor of serotonin & norepinephrine reuptake and weak

inhibitor of dopamine reuptakeTherapeutic indications

DepressionGADOCDPanic Agarophobia , social phobia, ADHD

Adverse reactions:NauseaSomnolenceDry mouthDizzinessConstipationAsthenia AnxietyAnorexiaBlurred visionAbnormal ejaculation and orgasmErrectile disturbance and impotence

Duloxetine

Inhibitor of serotonin and norepinephrine

MAIO DrugsUsed less frequently than othersIncrease biogenic amine neurotransmitter levelThere are two type of MAO : A & BMAOA metabolize NEP, SER, EPIMAOB metabolize DOP, TYRTherapeutic indications:

Depression, Atypical depressionPanic Agarophobia PTSDEating Disorder Social phobiaPain Disorder