Antidepressants PRITE Review

1. AntidepressantsPRITE Review Samir Sabbag PGY-3 Psychiatry August 24, 2009

2. Overview • Goal in Depresion • Achieve complete remission • With Treatment • Good News – if remission: lower relapse rate • Bad News – remitters have frequent relapses • Suicide rates higher at ages 18-24 • All effective Antidepressants boost • DA, 5HT and NE

3. Monoamine(MA) Hypothesis of Depression

4. MA Boost  Therapeutic Action • 5HT • NE • DA • 5HT • 5HT • NE • DA • 5HT • NE • DA • 5HT • NE • DA • NE • DA • NE • DA • 5HT

5. Selective Serotonin Reuptake Inhibitors (SSRIs)

6. Available SSRIs • Fluoxetine (Prozac) • Paroxetine (Paxil) • Sertraline (Zoloft) • Citalopram (Celexa) • Escitalopram (Lexapro) • Fluvoxamine ( Luvox)

7. Mechanism of action • All SSRIs inhibit reuptake of 5HT by presynaptic neurons

8. SSRI Therapeutic Indications • Depression • OCD (give higher doses) • Panic Disorder • PTSD (help with intrusive and avoidant sx) • GAD • Premenstrual Dysphoric disorder • Social Anxiety disorder • Eating disorders (Fluoxetine)

9. SSRI ½ lives and metabolites • Fluoxetine : longest ½ life 4-6 days! • Active Metabolite: 7-9 days • Sertraline : 26h • Active Metabolite: 3-5 days • No active metabolites • Citalopram : 35h • Escitalopram : 27-32h • Paroxetine : 21h • Fluvoxamine : 15h (most likely to cause withdrawal reaction)

10. SSRIs • Plasma Protein binding • Highly bound • Fluoxetine, Sertraline and Paroxetine • Least bound • Escitalopram • CYP 450 • Fluvoxamine: marked effect on CYP • 1A2, 2C and 3A • Fluoxetine and Paroxetine • 2D6 • Least likely to cause problems • Citalopram, Sertraline and Escitalopram

11. SSRIs - General Side Effects • Restlessness, psychomotor retardation, mild parkinsonism and dystonic movements (5HT-2A in basal ganglia) • Myoclonus, sleep disturbance and nocturnal awakening (2A in brainstem) • Sexual dysfunction, apathy and decreased libido (2A and 2C in spinal cord) • N/V (5HT-3 in hypothalamus and brainstem) • Increased bowel motility, GI cramps and diarrhea (5HT3 and 4 in GI tract) GI Sx  Most common SE leading to discontinuation

12. SSRIs - General Side Effects • Suicide • increased thoughts/actions in children, adolescents and young adults <25 • Closely monitor first few weeks when starting SSRI • Pregnancy • Small increase in anencephaly, craniosynostosis and omphalocele (as per population registries) • Hematologic • Prolonged bleeding time - functional impairment of platelet aggregation • Endocrine • Can decrease glucose concentrations acutely

13. SSRIs - General Side Effects • Most common SE associated with long term treatment: • Sexual Dysfunction – continues as long as the drug is taken • Sleep disturbances • Extremely vivid dreams or nightmares • Bruxism, restless legs, nocturnal myoclonus • Yawning • Not associated with fatigue – effect of SSRI on hypthalamus

14. Citalopram and Escitalopram • Most selective inhibitors of serotonin reuptake • Citalopram may have some sedative effects (H1) Citalopram Escitalopram

15. Fluoxetine • 5HT2C receptor block • NE and DA release • Increased energy • Activation/anxiety • Antibulimic/anorexic effects • Boosts antidepressant action of Olanzapine in Bipolar Depression • NE reuptake blockade

16. Fluoxetine • Of the SSRIs, most likely to cause headaches • Can cause anxiety, specially during 1st weeks of use  on the long run decrease anxiety • SSRI most likely to cause insomnia

17. Sertraline Atypical Depression Overeating and oversleeping Extreme sensitivity with interpersonal loss or rejection Severe psychomotor retardation Mood reactivity • Sigma 1 action  anxiolytic • weak DA and NE reuptake inhibition • Improves energy, motivation and concentration • Helps with atypical depression • Fist line in Panic d/o (also Paroxetine)

18. Paroxetine • Anticholinergic (M1) • calming/sedating • Good for anxiety sx • weak NE reuptake inhibition • antidepressant effects • Nitric Oxide Synthetase (NOS) and 2D6 • Sexual dysfunction

19. Paroxetine • Withdrawal reaction with sudden d/c • Anticholinergic rebound • Substrate and inhibitor for 2D6 • Rapid decline in plasma when d/c • First line in Panic disorder (also Zoloft) • Anticholinergic activity • Dry mouth, constipation, sedation

20. Paroxetine • Fetal abnormalities • Cardiac malformation (R Ventricular outflow obstruction) • Pulmonary hypertension • Seen with doses >25mg in 1st trimester • More frequent and pronounced weight gain than other SSRIs

21. Fluvoxamine • Not normally used as antidepressant • Used for OCD, Panic d/o, PDD, Aggression in autism • SSRI with the most DDI of all

22. Serotonin Syndrome • Constellation of sx composed, in order of appearance, by • Diarrhea • Restlessness • Extreme agitation, hyperreflexia, autonomic instability with fluctuation of vital signs • Myoclonus, seizure, hyperthermia, rigidity, shivering • Delirium, coma, status epilepticus, cardiovascular collapse • Death

23. Serotonin Syndrome • SSRI + MAOI, MAOB Inhibitors, L-Tryptophan, Lithium, SSRIs, SNRIs, TCAs, Buspirone, Meperidine, Nefazodone, Trazodone, Linezolid • may raise SSRI to toxic levels • Treatment • Remove offending agent • Supportive care • nitroglycerine, methysergide, cooling blankets, chlorpromazide, dantrolene, benzodiazepines, anticonvulsants, mechanical ventilation, paralyzing agents

24. Serotonin Syndrome • May resemble NMS • Serotonin Syndrome more likely to have • Myoclonus • Hyperreflexia • GI symptoms • NMS more likely to have • Muscular rigidity

25. SSRI Discontinuation Syndrome • Abrupt discontinuation of SSRI • Especially Fluvoxamine and Paroxetine • Shorter ½ lives • Least likely: Fluoxetine • Longer ½ life • Symptoms • Dizziness, weakness, nausea, h/a, anxiety, rebound depression, poor concentration, upper respiratory sx, paresthesias.

26. Tricyclic and Tetracyclic Antidepressants (TCAs)

27. Tricyclics

28. Which of the following is a secondary TCA? • Protriptyline • Clomipramine • Maprotiline • Amitriptyline • Doxepine

29. Available TCAs • Tertiary Amines • Clomipramine • Imipramine • Trimipramine • Amitriptyline • Doxepin • Secondary Amines • Desipramine • Protriptyline • Nortriptyline • Tetracyclics • Maprotyline • Amoxapine

30. Pharmacologic Actions • Significant metabolism - 1st pass effect • CYP450 • 2D6 (many meds may rise levels to toxic) • Half-lives from 10-70 hours • Longer • Nortriptyline, Maprotiline and Protriptyline

31. Pharmacologic Actions • TCA’s block reuptake pumps • NE and/or5HT • Most 5HT selective  Clomipramine • Most NE selective  Desipramine

32. TCA Receptor Structure

33. Serotonin reuptake block

34. NE reuptake block

35. SIDE EFFECTS

36. SIDE EFFECTS Histamine 1 receptor block Weight gain most antihistaminergic of the TCAs Doxepin

37. SIDE EFFECTS Muscarinic (M1) receptor block Tx Bethanecol urinary retention

38. (M1) Anticholinergic SE • Can aggravate Narrow Angle Glaucoma • Avoid TCAs in this condition – Amitriptyline • Can cause Anticholinergic Delirium • Especially if TCA used with dopamine receptor antagonist or anticholinergics • Treatment: IM or IV physostigmine Amoxapine, Nortriptyline Desipramine, Maprotiline Least Anticholinergic

39. SIDE EFFECTS Alpha-1 adrenergic receptor block Most common cause of TCA d/c Orthostatic Hypotension

40. Overdose with TCAs • TCAs – block voltage-sensitive Na channels • Brain – coma, seizures • Heart – arrhythmia, death • OD –monitored with EKG • Most frequent cause of death: arrhythmia • EKG changes: PR, QRS, QTc prolongation • Very common cause for discontinuation: Tachycardia

41. Uses in Depression Melancholic Features Depressed mood Severe anhedonia Early morning awakening Weight loss Profound guilt • Very effective • More likely to induce mania than bupropion or SSRIs • Better response • Melancholic features, prior major depressive episodes, family hx • In the US • Clomipramine only approved for OCD

42. TCAs have caused SUDDEN DEATH in children and adolescents! Other Uses • Panic disorder • Imipramine – most studied drug • GAD • Doxepin – FDA approved • OCD • Only Clomipramine – use first SSRIs • Pain and Migraine prophylaxis • Amitriptyline – used most often • Childhood enuresis • Imipramine

43. Special Considerations • Amoxapine • May cause Parkinsonian sx • Avoid in Parkinson’s Disease • Blood levels of 4 TCAs can be monitored • Nortriptyline, Desipramine, Clomipramine and Imipramine • Nortriptyline: THERAPEUTIC WINDOW • TCAs have low risk for inducing seizures • Except for Maprotiline • May cause seizures when dose increased too fast or kept at hight doses • Clomipramine and Amoxapine • May lower seizure threshold DO NOT give TCAs during ECT!  serious cardiac effects

44. Special Considerations • Nortriptyline • least likely to cause orthostatic hypotention • Desipramine and Protriptyline • most activating of the TCAs • Relative contraindication for TCA use • Bundle branch block • Cardiac disease or age >40 • Do EKG prior to TCA use

45. Drug Interactions • CYP 1A2, 2D6 and 3A4  dirty drugs • Birth control pills and nicotine decrease TCA levels • Fluoxetine, Fluvoxamine and Paroxetine increase TCA levels x4!!(CYP 2D6) • If used together  use lower dose of TCA • Antipsychotics and Methylphenidate increase TCA levels

46. Monoamine Oxidase Inhibitors (MAOIs)

47. Therapeutic Indications • Depression • Atypical Depression • Panic Disorder • Bulimia • PTSD • Migraine • ADD

48. Available MAOIs • Irreversible • Phenelzine • Tranylcypromine • Isocarboxazid • Reversible/Selective MAO-A (RIMA) • Moclobemide (not in the US) • Selective MAO-B • Selegiline (transdermal patch)

49. Pharmacokinetics • MAOIs inhibit MAO A and B • Stops MAO from destroying • NE, 5HT and DA • Increasing these neurotransmitters • Irreversible • MAO enzyme synthesized again in 2 weeks • Need for dietary restrictions • Washout period needed when starting a new antidep. • Reversible • MAO enz synthesized again in 24-48h • Flexible dietary restrictions

50. MAOI Irreversible MAOIs MAOI