Pharmacotherapy of depression

drug therapy of depression

1. Pharmacotherapy of depression Dr Manish mohan Junior resident SRGMCFR,Trivandrum

2. Contents Introduction Pathophysiology Classification of antidepressants Pharmacokinetics and pharmacodynamics Adverse effects and drug interactions CYP enzymes and antidepressants

3. MAJOR DEPRESSIVE DISORDER SAD MOOD LOSS OF INTEREST LOW ENERGY GUILT PSYCHOMOTOR RETARDATION SUICIDAL THOUGHTS MELANCHOLIA

4. Pathophysiology of Major Depression Monoamine hypothesis Neurotrophic hypothesis Neuroendocrine Factors

5. Neurotrophic hypothesis Brain-derived neurotrophic factor (BDNF) - neural plasticity - resilience - neurogenesis Tyrosine kinase receptor B in both neurons and glia BDNF - atrophic changes in hippocampus , medial frontal cortex and anterior cingulate

6. Monoamine hypothesis Deficiency - nor-adrenaline (NE) and dopamine (DA) and serotonin(5ht) in the CNS Evidence – Reserpine, which has antihypertensive actions due to its ability to deplete catecholamines (DA and NE) and 5HT from peripheral sympathetic nerve endings, caused depression Drugs that promote catecholamines and serotonin in the synapse relieved depression – MAOI – block metabolism of DA and NE – TCA – block reuptake of NE and 5HT

7. Neuroendocrine Factors MDD- - elevated cortisol levels - no suppression of ACTH release in the dexamethasone suppression test - chronically elevated levels of corticotropin-releasing hormone Abnormal thyroid function

8. ANTIDEPRESSANT CLASSIFICATION Selective Serotonin Reuptake Inhibitors Selective Serotonin And Noradrenaline Reuptake Inhibitors Tricyclic Antidepressants Tetracyclic and Unicyclic Antidepressants 5 –HT Receptor Modulators Monoamine Oxide Inhibitors

9. Selective Serotonin Reuptake Inhibitors Inhibition of the serotonin transporter (SERT) Fluoxetine was introduced in the United States in 1988 Fluoxetine Paroxetine Sertraline Citalopram Escitalopram Dapoxetine

10. Pharmacokinetics

11. Selective Serotonin Reuptake Inhibitors

12. Pharmacodynamics Extracellular serotonin Receptors on the transporter Serotonin, Na and cl- Conformational change SSRIs allosterically inhibit the transporter At therapeutic doses, about 80% of the activity of the transporter is inhibited

13. Antidepressant dose ranges

14. Side Effects of SSRIs Nausea , diarrhea and emesis (5HT3) Insomnia, increased anxiety, irritability, and decreased libido (5HT2) Paroxetine ---weight gain

15. SSRI Discontinuation Syndrome * SSRIs should NOT be stopped Abruptly Dizziness, nausea, fatigue, headache, insomnia, restlessness, unstable gait and shock like sensations (rare) More apparent with short acting SSRIs (paroxetine > fluvoxamine > sertraline > citalopram >> fluoxetine)

16. Drug Interactions Paroxetine and Fluoxetine CYP2D6 inhibitors TCA Fluvoxamine CYP3A4 inhibitor Diltiazem SSRIs + MAOI Serotonin syndrome

17. Advantages of SSRIs Ease of use Better tolerability Produce little /no sedation Do not interfere with psychomotor function No anticholinergic side effects No alpha adrenergic blocking action Do not inhibit cardiac function

18. Serotonin-Norepinephrine Reuptake Inhibitors Selective Serotonin- Norepinephrine reuptake inhibitors (SNRIs) TCAs

19. SELECTIVE SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS

20. venlafaxine (bicyclic compound) Desvenlafaxine Duloxetine (3 ring structure ) Milnacipran ( cyclopropane ring) Other uses - generalized anxiety - stress - urinary incontinence - vasomotor symptoms of menopause.

21. Pharmacokinetics CYP2D6 Venlafaxine O -desmethylvenlafaxine

22. Pharmacodynamics NET - 12-transmembrane domain complex that allosterically binds NE Venlafaxine is a weak inhibitor of NET Desvenlafaxine Duloxetine NET + SERT Milnacipran SNRIs lack – antihistamine, alpha adrenergic blocking and anticholinergic effects of TCA

23. DOSE RANGING mg/day

24. ADVERSE EFFECTS Nausea, constipation, insomnia, headaches, and sexual dysfunction. Immediate-release formulation of venlafaxine sustained diastolic hypertension(10-15%) Duloxetine ----hepatotoxic Discontinuation syndrome

25. Drug Interactions Duloxetine (moderate inhibitor of CYP2D6 ) Elevate TCA Milnacipran----------CYP3A4 --------- KETOCONAZOLE SNRIs are contraindicated in combination with MAOIs

26. Tricyclic antidepressants

27. Other uses for TCAs Treatment of pain conditions Enuresis Insomnia

28. MOA Antagonism of SERT and NET NET (desipramine, nortriptyline, protriptyline, amoxapine) SERT and NET (imipramine, amitriptyline, clomipramine ,doxepin) (H1 histamine, 5HT2, α1 adrenergic, and muscarinic cholinergic receptors)

29. Pharmacokinetics well absorbed long half-lives Metabolism - demethylation - aromatic hydroxylation - glucuronide conjugation Metabolism –CYP2D6

30. Antidepressant dose ranges mg/day

31. Adverse effects Anticholinergic effects (dry mouth, constipation, urinary retention, blurred vision, and confusion) α- blocking property orthostatic hypotension H 1 antagonism by the TCAs is associated with weight gain and sedation The TCAs are class 1A antiarrhythmic agents and arrhythmogenic at higher doses

32. Drug Interactions CYP2D6 inhibitors elevate TCA MAOIS + TCA Serious toxicity TCAs potentiates CNS depressants (alcohol) Carbamazepine TCA metabolism

33. 5-HT receptor modulators Trazodone m- chlorphenylpiperazine (m- cpp ) Nefazodone hydroxynefazodone and m- cpp

34. CONT……. Vortioxetine ------(newer agent ) 5-HT3, 5-HT7,5-HT 1D receptor blocker + SERT BLOCKER

35. MOA: blockade of the 5-HT receptor 5-HT 2A receptor is G protein coupled receptor Neocortex

36. Pharmacokinetics Nefazodone is a potent inhibitor of the CYP3A4 Vortioxetine (oxidation)--------CYP2D6

37. Pharmacodynamics Nefazodone is a weak inhibitor of SERT and NET Potent antagonist of the postsynaptic 5-HT 2A receptor Trazodone - selective inhibitor of SERT + - presynaptic α- adrenergic–blocking property + - modest antagonist of the H 1 receptor

38. Dose range mg/day

39. Adverse Effects sedation and gastrointestinal disturbances Trazodone- can induce priapism orthostatic hypotension Hepatotoxicity (Nefazodone )

40. Drug Interactions Triazolam levels are increased by concurrent administration of nefazodone Nefazodone with simvastatin 20-fold increase in plasma levels of simvastatin ritonavir or ketoconazole ------ increases in trazodone

41. Tetracyclic and Unicyclic Antidepressants Bupropion (unicyclic aminoketone structure) Mirtazapine Amoxapine tetracyclic chemical structure Maprotiline Vilazodone – multi ring structure .

42. Pharmacokinetics Bupropion - rapidly absorbed - protein binding of 85% - undergoes extensive hepatic metabolism - Bupropion has a biphasic elimination Amoxapine 7-hydroxyamoxapine(D2 blocker)

43. vilazodone 72 25 ND ND ND

44. Pharmacodynamics Bupropion – moderate inhibitors of NE and 5-HT reuptake - pre synaptic release of catecholamines Mirtazapine – antagonist of presynaptic alpha 2 auto receptor. Amoxapine and Maprotiline Potent NET inhibitors Vilazodone is a potent serotonin reuptake inhibitor + partial agonist of 5 HT 1A receptor.

45. Dose range mg/day

46. Adverse effects AMOXAPIN ---PARKINSONIAN SYNDROME ( D2 blocking action ) Mirtazapine -----sedative effect Maprotiline -----seizures Bupropion -------agitation, insomnia and anorexia Vilazodone -----GI upset, diarrhea ,nausea

47. Drug interactions Bupropion -------------CYP2B6------------cyclophosphamide (-) Hydroxy bupropion --------------- ------ desipramine level ( -CYP2D6) Mirtazapine ( 2D6, 3A4, and 1A2)

48. Monoamine oxidase inhibitors Mitochondrial enzyme involved in the oxidative deamination of biogenic amines MAOA metabolizes 5HT ,NE and DA MAOB ------- 5HT and DA Rarely used ( toxicity and drug interactions )

49. Cont …… MAO-A -Peripheral adrenergic nerve endings -intestinal mucosa -Human placenta MAO-B -Brain -Platelets

50. Monoamine oxidase inhibitors Phenelzine Isocarboxazid Tranylcypromine Selegiline Moclobemide Hydrazine derivatives Non-hydrazine

51. MAO-A ---------CLORGYLINE, MOCLOBEMIDE MAO-B-----SELIGILINE

52. Moclobemide Reversible inhibitor of MAO-A Lacks anticholinergic ,sedative, cognitive, psychomotor and cardiovascular adverse effects Useful in social phobia s/e : nausea ,dizziness ,headache, insomnia

53. Pharmacokinetics The MAOIs are metabolized by acetylation

54. Dose range mg/day

55. Adverse effects Orthostatic hypotension Weight gain Confusion Sedative effect (Phenelzine) Discontinuation syndrome ( delirium like ) Impotence

56. Cheese reaction Certain varieties of cheese,beer,wines,pickled meat, and fish Large quantity of tyramine and dopa MAOI ------indirect sympathomimetic stimulation Hypertensive crisis, cerebrovascular accidents

57. Drug interaction MAOI vs SSRIs/SNRIs/TCA Serotonin syndrome MAOI vs Tyramine Malignant hypertension Stroke/ myocardial infarction

58. ATYPICAL ANTIDEPRESSANTS 1. MIANSERIN -Block presynaptic alpha 2 receptor -Antagonism of 5-HT 2 , 5-HT 1c Adverse effect- blood dyscrasias , liver dysfunction

59. 2. TIANEPTIN enhance 5-HT uptake 3.AMINEPTINE

60. Clinical Pharmacology Of Antidepressants

61. 1. Major depression SSRI/SNRIs Trial therapy – 8-12 weeks at therapeutic dose Goal- remission of all the symptoms Inadequate response ----(SSRI +SNRI) + atypical antidepressants Long term maintenance needed -----2 or more serious MDD in the previous 5 years or 3 or more serious episodes in the life time .

62. 2. Anxiety disorders PTSD OCD ( clomipramine, fluvoxamine ) Social anxiety disorder SSRI/SNRI + BZD GAD Panic disorder

63. 3. Pain disorders Diabetic neuropathy -------Duloxetine Fibromyalgia Post herpetic neuralgia------amitriptyline

64. 4. Premenstrual dysphoric disorder Sertraline Fluoxetine

65. 5. Attention deficit hyperactivity disorder TCA -------Imipramine Nortriptyline 1 st line drugs Amoxapine

66. 6. Smoking cessation Bupropion Mechanism –unknown Nortriptyline

67. 6. Enuresis Imipramine 25 mg at bed time 7. Migraine Amitriptyline

68. Some antidepressant–CYP450 drug interactions

69. Summary Pathophysiology Classification of antidepressants Pharmacokinetics and pharmacodynamics Adverse effects and drug interactions CYP enzymes and antidepressants

70. Thank you