1. ANTIDEPREESANT DRUGS Dr Soe Aung Myint 30-1-2013

2. Depression is serious disorder that affects approximately 14 million adults in the US each year Lifetime prevalence rate of depression in the US ---16% of adults(21% 0f woman,13% men), >32 million people

3. Biological theories of mental illness Schizophrenia -dopaminergic overactivity Depression - deficiency of monoamines (NA and/or serotonin) activity Mania - overactivity of catecholamine transmission in CNS

4. Major Depression Major Depression Diagnostic criteria At least 5 of the following symptoms for 2 weeks (criteria 1 or 2 essential): 1. Depressed mood (Feelings of sadness) 2. Loss of interest or pleasure (Anhedonia) 3. Significant appetite or weight loss or gain 4. Insomnia or hypersomnia 5. Psychomotor agitation or retardation 6. Fatigue or loss of energy 7. Feelings of worthlessness or excessive guilt 8. Impaired thinking or concentration; indecisiveness 9. Suicidal thoughts/thoughts of death

5. MANIA MANIA Speech – more talkative than usual, loud, exaggerated, clang associations. Flight of ideas or subjective experiences that thoughts are racing. Psychomotor overactivity. Highly elevated self-esteem or grandiosity. Erratic & disinhibited behaviour Excessive spending money, gambling, Hypersexuality, promiscuity. Increased libido, excessive energy, insomnia (expressed as no need to sleep). Distractibility (attention too easily drawn to unimportant or irrelevant external stimuli. About 75% of all manic patients are assaultive About 75% of all manic patients are assaultive Manic patients do attempt & homicide.

6. Antidepressants A) Inhibitors of monoamine reuptake (MARI) i) Non selective (Noradrenaline & serotonin reuptake inhibitors) tricyclic antidepressants Tricyclics - (Tertiary amine tricyclic antidepressants) imipramine, amitryptyline, doxepin, amoxapine, clomipramine, trimipramine ii)Selective (noradrenaline reuptake inhibitors) Tricyclics - (Secondary amine tricyclic antidepressants) Maprotiline, reboxetine desipramine, protriptyline, nortriptyline SSRI iii)Selective (serotonin *5HT, reuptake inhibitors )(SSRI) fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram, venlafaxine,Duloxetine(SNRI)

7. Antidepressants MAOI (B) Inhibitors of Monoamine Oxidase enzymes (MAOI) i. Irreversible - phenelzine, isocarboxazid, tranylcypromine ii. Reversible - moclobemide (C) Atypical antidepressants bupropion, trazodone, mirtazapine, nefazodone, mianserin

8. ANTI-DEPRESSANTS For endogenous depression Tricyclic antidepressants - similar to phenothiazines in structure (have three ring nucleus) - may be classified into those with marked sedation less sedation CNS stimulation Amitriptyline ImipramineProtryptyline Doxepin Desipramine Mechanism of action Increase brain catecholamines (NA & 5HT) by preventing reuptake into cellular stores. (MARI)

9. TRICYCLIC ANTIDEPRESSANTS

11. TCA Ph A 1. CNS Elevation of mood in depressed patients. Antidepressant effect seen in 2-4 weeks. In non depressed persons sleepiness, anxiety and toxic anticholinergic effects can be seen. Mania, excitement and& insomnia can be induced in susceptible persons. 2. ANS -  adrenergic blockage initially - anticholinergic effects such as dry mouth, blurred vision, constipation & urinary retention occur at therapeutic dose especially with Amitriptyline - sweating is common although its mechanism is unknown

13. Onset of therapeutic effects of the major antidepressant drugs

14. TCA Ph A 3. CVS - orthostatic hypotension & sinus tachycardia - arrhythmias & conduction defect with overdose 4. Respiratory system - depression with overdose 5. Anti-histaminergic action

16. Pharmacokinetics Incompletely absorbed. Significant ‘first pass’ metabolism present. Highly protein bound. Highly lipid soluble with large volume of distribution.

17. TCA Uses 1.mainly psychotic depression & also severe reactive depression 2.enuresis in children (Imipramine) 3.phobic anxiety syndrome 4.obsessive compulsive syndrome 5.neuralgias 6.bulimia 7.irritable bowel syndrome 8.hyperkinesia in children

18. TCA Untoward effects 1. CNS - drowsiness, sedation, fine tremor, ataxia, transition of depressed patient to manic state 2. Anticholinergic effects 3. CVS - orthostatic hypotension & reflex tachycardia 4. Obstructive jaundice (rare) 5. Leucopoenia (rare) 6. Acute poisoning is common and life threatening and can produce seizure and coma.

20. TCA Drug interactions - synergistic with sympathomimetics (inhibition of NA reuptake) severe toxicity with MAOIs - severe toxicity with MAOIs (resembling atropine poisoning) (resembling atropine poisoning) - displaced by phenylbutazone, aspirin (protein binding) - increase metabolism by enzyme inducers like barbiturates and phenytoin - potentiate the effect by enzyme inhibitors like cimetidine

21. SELECTIVE SEROTONIN REUPTAKE INHIBITORS

22. Mechanism of action Selective inhibition of serotonin reuptake Pharmacological actions - Effective antidepressant and the effect is seen in 2- 4 wks - less sedative, antimuscarinic, cardiotoxic than Tricyclics - has wide therapeutic index and fatal overdosage is rare

23. SSRI Pharmacokinetics Well absorbed. Fluoxetine is metabolized in the liver to norfluoxetine which is an active metabolites with long t 1/2. Uses Depressive illness Obsessive compulsive neurosis Obesity

24. SSRI Untoward effects - diarrhoea, nausea & vomiting (dose related) - headache, restlessness, anxiety Status - no problem with weight gain - no food and drug interaction - high cost Drug interaction With MAOI can produce serotonin syndrome (hyperthermia, muscle rigidity, myoclonus)

26. MONOAMINE OXIDASE INHIBITORS

27. Mechanism of action Irreversible inactivation of monoamine oxidase (non selective) [MAO-A has effect on NA, 5HT, tyramine and MAO-B has more selective effect on dopamine] Reversible MAOI is Moclobemide

29. MAOI Pharmacological actions both normal and depressed mood elevation in both normal and depressed patients slow onset of antidepressant action (take weeks) and therapeutic effect persists for 2-3 weeks after stopping the drug (other antidepressants should not start 1-2 weeks after stopping MAOI) but reversible MAOI (MOCLOBEMIDE) is a short acting one and has less interactions.

30. MAOI Pharmacokinetics Readily absorbed from GIT & acetylated in liver Uses 1. severe depression refractory to other treatment 2. phobias 3. panic attack 4. Parkinsons disease (SELEGILINE:MAO-B inhibitor)

31. MAOI Untoward effects - hypotension - excessive central stimulation - tremor, excitement, agitation, insomnia, convulsion (Tranylcypromine) - weight gain - atropine like symptoms - hepatotoxicity (Isocarboxazid) - more serious effects - hepatic coma, hyperpyrexia, convulsions and cardiac arrest (have to discontinue the therapy)

32. MAOI Drug interaction - prolong & intensify actions of CNS depressants & anticholinergics atropine poisoning - with tricyclic antidepressants may cause severe toxicity resembling atropine poisoning - antagonize the actions of anticonvulsants hypertensive crisis food tyramine - hypertensive crisis with sympathomimetics & with monoamines in food such as fermented food and beverages containing tyramine (eg. beer, wine, yeast, chicken liver, meat extract, chocolate, large amount of coffee, citrus fruits)

33. Atypical antidepressants - are not more clinically effective than older ones - have quicker onset - less side effects such as sedation & autonomic effects - less toxicity with overdose DOXEPIN - tricyclic antidepressant - highly selective 5HT uptake inhibitor - quicker onset of action - less CVS & anticholinergic activity & preferred in elderly

34. Atypical antidepressants… AMOXAPINE - tetracyclic antidepressant - inhibit NA uptake - block dopamine D2 receptor - produce quicker antidepressant response than tricyclics - lowers seizure threshold and can precipitate seizure (not to be used in children) - less cardiotoxic and less anticholinergic MIANSERIN - presynaptic  2 blocker (increase NA release) - less CVS and anticholinergic activity - can produce blood dyscrasias, jaundice and fits

36. MOOD STABILIZERS Maintenance therapy for affective disorders LITHIUM LITHIUM (carbonate or citrate) -monovalent cation -lightest of alkali metals similar to Na +, K +, Ca ++ & Mg ++ & has tendency to replace Na + & K + from the body fluid. Mechanism of action Uncertain but may effect electrolyte & ion transport across membranes.

37. Pharmacological actions Prevents mood swings in both manic and depressive directions. Useful for prophylaxis of both mania and depression in affective disorders but require normal sodium intake and normal cardiac and renal function

38. Pharmacokinetics Completely absorbed by GIT. Oral bioavailability is 100%. Not bind to plasma protein. Distributed non-uniformly and concentration is high in saliva, brain, bones and thyroid. Not metabolized & is entirely excreted by kidney. Competes with sodium at the renal tubular reabsorption while excreted by kidney (increases drug level with low salt diet). t ½ = 20 hrs

39. Untoward effects 1. nausea, vomiting, diarrhoea 2. fine or coarse tremors nephrogenic diabetes insipidus 3. polyuria, sodium retention, oedema, nephrogenic diabetes insipidus due to inhibition of ADH on renal adenylate cyclase (hypothyroid) 4. thyroid enlargement (hypothyroid) 5. weight gain 6. serious effects - confusion, stupor, coma and convulsions - hypotension, arrhythmias, cardiac failure

40. Contraindications - fluid & electrolyte imbalance - abnormal renal, cardiac & neurological functions - pregnancy (anomaly of heart, neonatal goitre) Drug interactions Lithium retention with diuretics & NSAIDs

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