1. Anti depressant Drugs Rezaei M. MD Psychiatrist

2. Tricyclics  Tertiary amines:  Imipiramine  Amitriptyline  Clomipramine  Trimipiramine  Doxepin  Secondary amines  Desipiramine  Nortriptyline  protriptyline

3. Tetracyclics  Amoxapine  Maprotiline  Minaserin

4. 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

5.  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)

6. Adverse effects  Psychiatric effects  A major adverse effect is the possibility of inducing a manic episode in patients +/- history of BMD I disorder  Anticholinergic effects  Patient 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

7.  Sedation  Amitriptyline  Trimipramine  Doxepin  The least sedative effects are in desipiramine and protriptyline  Autonomic effects  Orthostatic HOTN,Partly because of @1-adrenergic blockade  Nortriptyline least likely cause the problem  Fludrocortisone may be helpful  Other effects include sweating, palpitation, HTN

8.  Cardiac effects  In 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.

9.  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

10.  Maprotiline may cause seizures if  Dose 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.

11. 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.

12.  Other adverse effects :  Weight gain  Impotence  Gynecomastia  Amenorrhea  Nausea  Hepatitis  Vomiting  SIADH

13. 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.

14. 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.

15.  Augmentation strategies  In depressed persons with partial response :  Bupropion  Lithium  Levothyroxine  Sympathomimetics  Pindolol  Clonazepam

16.  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.

17.  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 depression  They have to continue taking SSRI`s for at least 1 year.

18.  Depression in children  Children 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.  OCD  Fluvoxamine and Serteraline are approved for treatment of pediatric OCD  Effective dose for OCD is higher than those required for depression.

19.  Panic Disorders  SSRI`s are far superior to benzodiazepines for treatment of panic disorder with depression.  Are effective for childhood panic symptoms  Social Phobia  Posttraumatic Stress Disorder  SSRI`s are more effective than TCAD and MAO`s inhibitor  Marked improvement of both intrusive and avoidant symptoms.  Specific phobias, GAD, separation anxiety

20.  Bulimia Nervosa and other Eating Disorder  Fluoxetine  Obesity ; fluoxetine in combination with behavioral program  Premenstural Dysphoric Disorder  Fluoxetine and Serteraline

21.  Adverse Reactions of SSRI`s  Sexual 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

22. Serotonin Syndrome  Concurrent administration of an SSRI with MAOI, l- tryptophan, or lithium can rise plasma serotonin concentration  Diarrhea  Restlessness  Agitation, hyperreflexia, autonomic instability, rapid fluctuations of vital signs  Myoclonus, seizures, hyperthermia, rigidity,  Delirium, coma, cardiovascular collapse and death.

23. SSRI`s Withdrawal  Dizziness  Weakness  Nausea  Headaches  Rebound depression  Anxiety  Insomnia  Poor concentration  Upper respiratory symptoms  Paresthesia  Migranelike symptoms

24. 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

25. BUPROPION  Adverse reaction  Headache  Insomnia  Upper respiratory symptoms  Nausea  Restlessness  Agitation  Irritability  Weight loss 25%  Dry mouth  constipation

26. Trazodone  Half life is 6-11 hrs  Specific inhibitor of serotonin reuptake  Depressive Disorder  Insomnia

27. 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 indications  Depression  GAD  OCD  Panic  Agarophobia, social phobia, ADHD

28.  Adverse reactions:  Nausea  Somnolence  Dry mouth  Dizziness  Constipation  Asthenia  Anxiety  Anorexia  Blurred vision  Abnormal ejaculation and orgasm  Errectile disturbance and impotence

29. Duloxetine  Inhibitor of serotonin and norepinephrine

30. MAIO Drugs  Used 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