Polypharmacy in Psychiatry: Why Do We Do It and When Should We Avoid It?

1. Polypharmacy in Psychiatry: Why Do We Do It and When Should We Avoid It? Stacy Miller, PharmD, BCPS, BCPP Assistant Professor, Pharmacy Practice Gatton College of Pharmacy East Tennessee State University Johnson City, Tennessee April 27, 2012

2. Relevant Disclosures • Consulting fees/honoraria: None • Speaker’s bureau: None • Ownership/partnership/principal: None • Research grants: None • Salary: None

3. Objectives Upon completion of this session, the learner will be able to: • Define the term polypharmacy • Describe instances of rational and irrational polypharmacy • Summarize causes and consequences of polypharmacy in psychiatry • Recommend potential alternatives to irrational polypharmacy in psychiatry

5. Polypharmacy, Defined Hoffman et al. Neuropsych Dis Treat 2001; 7: 639. Kingsbury et al. Psychiatr Serv 2001; 52: 1033.

6. Polypharmacy, Prevalence in Bipolar Depression Greil et al. J Affect Disord 2012; 136: 534.

7. Rational versus Irrational Polypharmacy Hoffman et al. Neuropsych Dis Treat 2001; 7: 639.

8. Polypharmacy in Psychiatry

9. Polypharmacy in Psychiatry

10. Extrapyramidal Symptoms > 80% D2 occupancy  EPS Kapur et al. Am J Psychiatr 2000; 157: 514. Gomberg. J Clin Psychopharmacol 1999; 19: 272. Koreen et al. Am J Psychiatr 1995; 152: 1690.

11. QTc Prolongation Pfizer Briefing Document for Zeldox® Capsule (2000). Marino et al. Ann Pharmacother 2010; 44: 863-870. Reilly et al. Lancet 2000; 355: 1048-1052.

12. Orthostasis with SGAs Asenapine Iloperidone Paliperidone Richelson E. J Clin Psychiatr 2010; 71(9): 1243. Stahl. J Clin Psych PCC 2003; 5 (suppl 3): 9.

13. Orthostasis with FGAs High Potency Low Potency

14. Neuroleptic Malignant Syndrome Ananth et al. Acta Neuropsychiatr 2004; 16: 219. Margetić et al. Pharmacoepidemiol Saf 2010; 19: 429.

15. Serotonin Syndrome - Very High-Risk Combinations: Irreversible Monoamine Oxidase Inhibitors • Avoid combination with or within 2 weeks of: • SSRIs (wait 5 weeks for fluoxetine) • Amphetamine • Illicit substances – methamphetamine or MDMA (ecstasy) Sun-Edelstein et al. Expert Opin Drug Saf 2008; 7: 587. Sola et al. Mayo Clin Proc 2006; 81: 330.

16. Serotonin Syndrome - High-Risk Combinations: Irreversible Monoamine Oxidase Inhibitors Sun-Edelstein et al. Expert Opin Drug Saf 2008; 7: 587.

17. Serotonin Syndrome - High-Risk Combinations: Zyvox® (Linezolid) • Reversible monoamine oxidase inhibitor (MAO-I) • Contraindicated with SSRI/SNRI unless patient is advised of risk • Contraindicated with irreversible MAO-I • Nardil® (phenelzine) • Parnate® (tranylcypromine) • Marplan® (isocarboxazid) Sola et al. Mayo Clin Proc 2006; 81: 330. Micromedex.

18. Drug-Drug Interactions - Antidepressants Micromedex Healthcare Series: Thompson Reuters Healthcare, Inc.

19. Drug-Drug Interactions - Antidepressants Fluoxetine inhibits CYP 2D6 and 2C9 Decreased metabolism of: Tricyclic antidepressants Clozapine Phenytoin Warfarin Tamoxifen (decreased efficacy) Micromedex Healthcare Series: Thompson Reuters Healthcare, Inc.

20. Drug-Drug Interactions - Antidepressants Paroxetine inhibits CYP 2D6 Decreased metabolism of: Tricyclic antidepressants Tamoxifen (decreased efficacy) Micromedex Healthcare Series: Thompson Reuters Healthcare, Inc.

21. Drug-Drug Interactions - Antidepressants Fluvoxamine inhibits CYP 1A2, 2C19, 2C9 and 3A4 Decreased metabolism of: Tricyclic antidepressants Clozapine Methadone Theophylline Warfarin Micromedex Healthcare Series: Thompson Reuters Healthcare, Inc.

22. Drug-Drug Interactions – Mood Stabilizers • Divalproex Sodium inhibits metabolism of lamotrigine via glucuronidation • Can increase risk of toxic side effects of lamotrigine • Will impact how lamotrigine is dosed Micromedex Healthcare Series: Thompson Reuters Healthcare, Inc.

23. Drug-Drug Interactions: Mood Stabilizers - Carbamazepine • CYP 3A4 Auto-induction* • Causes its own metabolism • Occurs after each dose increase or initiation • May need higher doses to reach goal serum concentration after first month of treatment • Also induces 1A2, 2C9/10 • Increases metabolism of oral contraceptives • Be cautious when combining with clozapine (risk for agranulocytosis) Micromedex Healthcare Series: Thompson Reuters Healthcare, Inc.

24. Drug-Drug Interactions – First Generation Antipsychotics Micromedex Healthcare Series: Thompson Reuters Healthcare, Inc.

25. Drug-Drug Interactions – Second Generation Antipsychotics

26. Additional Issues

27. What did I miss?What other risks of polypharmacy have you considered?

28. Polypharmacy in Psychiatry

29. Treatment Resistance TIMA Depression Algorithm 2000.

30. Treatment Resistance - Schizophrenia TIMA Schizophrenia 2000.

31. Multiple Prescribers Tamblynet al. CMAJ 1996; 154: 1177.

32. Additional Causes

33. What Did I Miss?What Other Causes of Polypharmacy Have You Considered?

34. Solutions for Avoiding Irrational Polypharmacy

35. Patient Case #1 • SC is a 37 year old female with treatment resistant major depressive disorder. She is prescribed paroxetine 10 mg daily, lithium 600 mg HS and aripiprazole 2.5 mg daily. She has never reported adverse effects from her medications. Is this rational or irrational polypharmacy and why? What could be done to avoid this?

36. Patient Case #2 • Sally Jo is a 26-year-old female with a diagnosis of major depressive disorder. Her HAM-D score before treatment was 23 and now, on her current regimen, her score is 10. Her medications include fluoxetine 60 mg daily and venlafaxine XR 150 mg daily. Is this regimen appropriate? What can be done to improve it?

37. Patient Case #3 • Zach is a 42 year old male with a long history of schizophrenia. He is being hospitalized for the fourth time this year for his symptoms of psychosis. • His current medications are citalopram 40 mg, lithium 600 mg BID, olanzapine 20 mg HS, aripiprazole 10 mg daily.

38. Patient Case #3 Continued • Zach’s past medical history is significant for psoriasis, and his condition worsened when lithium was started. • Zach is also complaining of cogwheel rigidity, over-sedation and akathisia. • What should be done for Zach?

39. Case #3, Continued • Critically evaluate the need for every psychotropic medication • Consider a washout? Hoffman et al. Neuropsych Dis Treat 2001; 7: 639.

40. The Cost of Polypharmacy Libby Zion 1965-1984

41. Psychiatrist Mohammed Saaed stopped haloperidol 16 days before Yates killed her children. The Cost of Wash-Out http://articles.cnn.com/2002-03-04/justice/yates.trial_1_andrea-yates-suicide-defense-attorneys?_s=PM:LAW Andrea Yates

42. Objectives Upon completion of this session, the learner will be able to: • Define the term polypharmacy • Describe instances of rational and irrational polypharmacy • Summarize causes and consequences of polypharmacy in psychiatry • Recommend potential alternatives to irrational polypharmacy in psychiatry

43. Questions

44. References • Ananth, J, Aduri K, Parameswaran S, et al. Neuroleptic malignant syndrome: Risk factors, pathophysiology, and treatment. Acta Neuropsychiatr 2004; 16: 219-228. • FDA Psychopharmacological Drugs Advisory Committee. Briefing document for Zeldox® Capsules (Ziprasidone). 19 July 2000. • Gomberg RF. Interaction between olanzapine and haloperidol. J Clin Psychopharm 1999; 19(3): 272-273. • Greil W, Häberle A, Haueis P, et al. Pharmacotherapeutic trends in 2231 psychiatric inpatients with bipolar depression from the International AMSP Project between 1994 and 2009. J Affect Disord 2012; 136: 534-542. • Hoffman DA, Schiller M, Greenblatt JM, Iosifescu DV. Polypharmacy or medication washout: An old tool revisited. Neuropsych Dis Treat 2011; 7: 639-648. • Kapur S, Zipursky R, Jones C. Relationship between Dopamine D2 occupancy, clinical response, and side effects: A double-blind PET student of first episode schizophrenia. Am J Psychiatr 2000; 157: 514-520.

45. References • Kingsbury SJ, Yi D, Simpson GM. Psychopharmacology: rational and irrational polypharmacy. Psychiatr Serv 2001; 52(8): 1033-1036. • Koreen AR, Lieberman JA, Kronig M, Cooper TB. Cross-tapering clozapine to risperidone. Am J Psychiatr 1995; 152(11): 1690. • MargetrićB, Margetrić BA. Neuroleptic malignant syndrome and its controversies. Pharmacoepidemiol Saf 2010; 19: 429-435. • Marino J, Caballero J. Iloperidone for the treatment of schizophrenia. Ann Pharmacother 2010; 44: 863-870. • Reilly JG, Aiyas SA, Ferrier IN, et al. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 2000; 355 (9209): 1048-1052. • Richelson E. New antipsychotic drugs: How do their receptor-binding profiles compare? J Clin Psychiatr 2010; 71(9): 1243-1244. • Sola CL, Bostwick JM, Hart DA, Lineberry TW. Anticipating potential linezolid-SSRI interactions in the general hospital setting: An MAOI in disguise. Mayo Clin Proc 2006; 81: 330-334.

46. References • Stahl SM. Describing an atypical antipsychotic: Receptor binding and its role in pathophysiology. J Clin Psych Primary Care Companion 2003; 5 (suppl 3): 9-13. • Sun-Edelstein C, Tepper SJ, Shapiro RE. Drug-induced serotonin syndrome: A review. Expert Opin Drug Saf 2008; 7: 587-596. • Tamblyn RM, McLeod PJ, Abrahamowicz M, Laprise R. Do too many cooks spoil the broth? Multiple physician involvement in medical management of elderly patients and potentially inappropriate drug combinations. CMAJ 1996; 154(8): 1177-1184. • Trivedi MH, Shon S, Crismon ML, Key T. Texas Implementation of Medical Algorithms (TIMA): Guidelines for treating major depressive disorder. 2000.