Anti depressant Drugs

Rezaei M. MD

Psychiatrist

Tricyclics

Tertiary amines:Imipiramine

Amitriptyline

Clomipramine

Trimipiramine

Doxepin

Secondary aminesDesipiramine

Nortriptyline

protriptyline

Tetracyclics

Amoxapine Maprotiline

Minaserin

Pharmacological actions

Absorbed from oral administration

Peak plasma concentration 2-8 hrs

Half 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 concentration

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

serteraline, paroxetine , phenothiazine, carbamazepine

Genetic 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 effects

Psychiatric effectsA 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 .Amitriptyline

Imipramine

Doxepin

Trimipramine

Dry mouth, constipation, blurred vision , urinary retention,Treatment Beware of narrow angle glaucoma

Severe reactions may induce CNS anticholinergic syndrome with confusion and delirium

Sedation Amitriptyline

Trimipramine Doxepin

The least sedative effects are in desipiramine and protriptyline

Autonomic effectsOrthostatic HOTN ,Partly because of @1-adrenergic blockade Nortriptyline least likely cause the problem

Fludrocortisone may be helpful

Other effects include sweating , palpitation, HTN

Cardiac effectsIn the usual therapeutics doses: tachycardia, flattened T

wave, prolonged QT interval, and depr essed ST segment

Because 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 extremities

Speech block

Paresthesia

Peroneal palsy

Ataxia

Amoxapine is unique in causing Parkinsonian symptoms

Akathisia

Dyskinesia

rarely; neuroleptic malignant syndrome

Maprotiline may cause seizures ifDose increase too quickly

Dose 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 maprotiline

Jaundice is rare

Agranulocytosis, 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 gain

Impotence

Gynecomastia

Amenorrhea

Nausea

Hepatitis

Vomiting

SIADH

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 liver

Paroxetine 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 melancholia

Over 50% of persons who respond poorly to one SSRI will respond favorably to another.

Augmentation strategiesIn depressed persons with partial response:

Bupropion

Lithium

Levothyroxine

Sympathomimetics

Pindolol

Clonazepam

Suicide Markedly reduce the risk of suicide

Depression during pregnancy No documented adverse reaction

SSRI 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 illPrecise 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 OCD

Effective 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 Phobia

Posttraumatic Stress DisorderSSRI`s are more effective than TCAD and MAO`s inhibitor

Marked 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 Gain

Headaches; 18-20% Anxiety Insomnia and Sedation

Vivid dreams and Nightmares

Seizures 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

concentrationDiarrhea

Restlessness

Agitation , hyperreflexia, autonomic instability, rapid fluctuations of vital signs

Myoclonus , seizures, hyperthermia, rigidity,Delirium , coma, cardiovascular collapse and death.

SSRI`s Withdrawal

Dizziness

Weakness

Nausea

Headaches

Rebound depression

Anxiety

Insomnia

Poor concentration

Upper respiratory symptoms

Paresthesia

Migranelike symptoms

BUPROPION

More effective against symptoms of depression than those of anxiety.

Half life 12 hrs.Blockade of dopamine reuptake

Therapeutic indications:Depression Bipolar Disorders

ADHD

Cocaine Detoxification

Smoking cesation

BUPROPION

Adverse reactionHeadache

Insomnia

Upper respiratory symptoms

Nausea

Restlessness

Agitation

Irritability

Weight loss 25%

Dry mouth

constipation

Trazodone

Half life is 6-11 hrs

Specific inhibitor of serotonin reuptake

Depressive Disorder

Insomnia

Venlafaxine

May have faster onset of action than other antidepressant

Most effective drugs for treatment of severe depression with melancholic features & GAD

Half life 3.5 hrs( SR-form 9 hrs )

Inhibitor of serotonin & norepinephrine reuptake and weak inhibitor of dopamine reuptake

Therapeutic indicationsDepression

GAD

OCD

Panic Agarophobia , social phobia, ADHD

Adverse reactions:Nausea

Somnolence

Dry mouth

Dizziness

Constipation

Asthenia Anxiety

Anorexia

Blurred vision

Abnormal ejaculation and orgasm

Errectile disturbance and impotence

Duloxetine

Inhibitor of serotonin and norepinephrine

MAIO DrugsUsed less frequently than others

Increase biogenic amine neurotransmitter level

There are two type of MAO : A & B

MAOA metabolize NEP, SER, EPI

MAOB metabolize DOP, TYR

Therapeutic indications:Depression, Atypical depression

Panic Agarophobia PTSD

Eating Disorder Social phobia

Pain Disorder