1. Psychopharmacology in the Psychiatric Patient with Co-Morbid Medical Illness- The Heart, The lung & The Gut Clinical Pearls for the General Adult Psychiatrist/ GPs R Hawa MD FRCPC DABPN SABSM Deputy Psychiatrist in Chief- UHN Director, C/L Service, TWH Deputy Clerkship Director Director Psychiatry UME University of Toronto

2. Disclosure No financial disclosures or conflict of interest to be declared for the development and presentation of this session

3. Learning Objectives At the end of this course the participant will be able to: Describe an organized approach to the psychopharmacological management of the psychiatric patient with co-morbid medical illness List sources of information to help navigate clinically challenging situations List drugs that require modification in use (e.g. dosing, dosing timing, etc.) because of co-morbid medical conditions

4. Outline General Approach to Psychopharmacology in the Patient with Co-Morbid Medical Illness: Heart Failure COPD Bariatric Surgery Q & A

5. Basic Principles of Psychopharmacology in the Medically Ill KUWAIT CONFERENCE

6. The Context: Increasing Rates of Polypharmacy in Mental Health Care

7. An Approach to Psychopharmacology in the Medically Ill Diagnostic clarity is paramount Identify target symptoms Consider drug-drug interactions Practice pharmacological parsimony when possible Start low & go slow – BUT give it a “good” trial Consult available psychopharmacology resources when challenged Sockalingam, S, Tan A, Abbey S. Chapter 4 in Psychopharmacology in the Medically Ill 2010

8. Principles of Psychopharmacology Pharmacodynamics Pharmacokinetics

9. Pharmacokinetics & Pharmacodynamics Dose of drug administered Drug in systemic circulation Drug in tissues of distribution Drug metabolized or excreted Drug at site of action Pharmacological Effect Pharmacokinetics: What the body is doing to the drug Pharmacodynamics: What the drug is doing to the body Adapted from Ferrando SJ et al. 2010

10. Proportion of Drugs Metabolized by Phase I Enzymes (CYP450) Wynn GH. Clinical Manual of Drug Interaction Principles for Medical Practice 2009

11. Pathways of Metabolism and Excretion Phase I Metabolism (Oxidation) Most Psychiatric Medications CYP450 Phase II Metabolism (Glucuronidation) Lorazepam, oxazepam, temazepam Desvenlafaxine, paliperidone Renal & Biliary Excretion Exclusively renally excreted (no hepatic metabolism): Lithium Gabapentin Pregabalin Topiramate Ferrando SJ et al. 2010

12. P-glycoprotein Pump – Efflux Transporters Can be inhibited or induced If inhibit or induce CYP3A4, in most cases will do the same for p- gp Examples: MDR1sub- type (intestine), Blood- brain-barrier Adapted from Ferrando S et al. 2011

13. CANMAT 2009 Guidelines for Major Depressive Disorder. J Affect Disord 2009. Potential Drug-Drug Interactions Among 1st-Line Antidepressants Minimal or low potential Citalopram Desvenlafaxine Escitalopram Venlafaxine Moderate potential Agomelatine (1A2 substrate) Bupropion (2D6) Duloxetine (2D6; 1A2 substrate) Higher potential Fluoxetine (2D6, 2C19) Fluvoxamine (1A2, 2C19, 3A4) Moclobemide (MAO inhibitor precautions) Paroxetine (2D6; p-glycoprotein) Selegiline (MAO inhibitor precautions) Sertaline (2D6; p-glycoprotein) Cytochrome P450 isoenzyme or p-glycoprotein inhibition noted in brackets

14. Harnessing Antidepressant Profiles: Prescribing Parsimony Pain –TCA, duloxetine, venlafaxine (desvenlafaxine) Sleep – mirtazapine, TCA, trazodone Nausea / poor appetite – mirtazapine, olanzapine Constipation – SSRIs Fatigue – Bupropion, SNRI

15. C ARDIAC D ISEASE AND P SYCHOPHARMACOLOGY

16. C ARDIOVASCULAR D ISEASE AND D EPRESSION Leading health problems 85 % of cardiac deaths occur in >65 yrs Bidirectional relationship Depression + 1 or more chronic diseases= worst functional health score across all disease states across 20 countries

17. D EPRESSION IN C ARDIAC D ISEASE 3x risk of depression in cardiac disease 15-20% at any one time have MDD 17-36% of hospitalized CAD patients (HF higher) 2.0-2.5 RR of poor cardiac outcome if depressed (esp. in first 30 days)

18. D EPRESSION AND H EART F AILURE Heart Failure: 10 per 1000 >65 yrs Depression: 20 % of Heart failure patients HF Mortality 2X if depressed Increases incident HF, worsens quality of life and functional status Outpatients = inpatients

19. A NXIETY AND C ARDIAC D ISEASE 25-30% of cardiac patients have anxiety symptoms GAD and PTSD (more common if depressed) Increased risk of cardiac mortality in anxious medically healthy individuals Anxiety and depression in cardiac disease additive 1= 2X mortality 2= 3X mortality

20. D EPRESSION AND CARDIOVASCULAR DISEASE L INKS Inflammation (CRP, TNF-α, IL-6, IL-1) Endothelial dysfunction and atherogenesis Platelet activation and aggregation HPA axis (  HR,  HRV,  cortisol,  epi.) Behavioral (diet, exercise, cardiac rehab.)

21. N EUROTRANSMITTER EFFECTS ON CARDIOVASCULAR FUNCTION NE- binds to peripheral α and β adreneric receptors: orthostatic hypotension, hypertension, conduction abnormalities, increased HR and contractility and conduction velocity (ischemia, cp, bp, arrhythmias) DA (converted to NE) 5-HT- platelet aggregation, vasodilatation vasoconstriction

22. SSRI S - CARDIAC TRIALS StudyDesignResults SADHATOpen label; evaluate safety, efficacy, tolerability of Sertraline post- MI Improved depression No adverse cardiac events SADHARTRandomized, db., Sertraline Vs placebo post. MI or unstable angina Sertraline superior on CGI but not HAM-D. Superior in recurrent dep. Lower adverse events than placebo (platelets?) SADHART-CHFRandomized, db, Sertraline Vs. placebo cont. in CHF No impact depression or cardiac In those w. remission- improved health status (social, physical, symptoms, qol, 6min walk). ***

23. SSRI S - C ARDIAC TRIALS StudyDesignResults ENRICHDRandomized, not db, early CBT + SSRI- usually Sertraline (HAM-D>24) vs. usual care post. MI (major, minor, dysthymia) SSRI- lower mortality; no increase cardiac adverse events CBT- small but sig. effect CREATERandomized, controlled, 2x2 (IPT/Clin. Mgmt., placebo/citalopram) in depressed CAD Citalopram > placebo No increase over placebo in cardiac adverse events No benefit IPT

24. SSRI S - CYP450 SSRIs inhibit P450 (CYP1A2, CYP3A4, CYP 2D6) Can increase levels of antiarrhythmics, β- blockers, antihistamines, and Ca 2+ channel blockers e.g. CYP2D6 inhibition by fluoxetine, paroxetine, sertraline (weak) may cause metoprolol and carvediolol accumulation and bradycardia e.g. CYP2C19 inhibition by fluoxetine inhibits clopidogrel’s effect by inhibiting conversion to active metabolite Escitalopram and citalopram (1A2,2D6,2C19) weak inhibitors

25. SSRI S Increased risk of G.I. bleeding through antiplatelet activity and increased gastric acidity Hazard Ratio of combining SSRI with: aspirin- 1.42 clopidogrel 1.54 aspirin and clopidogrel-2.35 Use PPI to decrease bleeding risk Note PPI inhibition of CYP2C19 (clopidogrel)- avoid omeprazole and esomeprazole Pantoprazole is weak inhibitor Note other medications can affect INR through P450 (2C9 most significant; 1A2, 3A4): reduce dose by ~ 25 %

26. SSRI S AND QT INTERVAL Health Canada- don’t Rx above 40mg Citalopram (20mg- 8.5ms; 40mg- 12.6ms; 60mg- 18.5ms). Dose max >65yrs: 20mg <65: 40mg Escitalopram (10mg- 4.3ms; 30mg- 10.7ms) Dose max >65 yrs: 10mg note tdp associated qt>60msΔ

27. TCA S Orthostatic hypotension (20%) and tachycardia Nortriptyline most favorable cardiac profile Act as class I antiarrhythmic- prolong interventricular conduction; prolong QT Can cause heart block, asystole, **lethal in overdose *Avoid- many other options*

28. M IXED ACTION AGENTS Limited studies Venlafaxine: dose dependent  BP and  HRV; minimal interaction potential (weak 2D6) Duloxetine: possible hypertension; moderate CYP 2D6 Mirtazapine:  weight and body mass. MIND- IT (negative): no significant changes in cardiovascular indices; minimal interaction potential (weak 1A2, 2D6, 3A4) Bupropion: May  HR (higher doses). Used widely in smoking cessation in this population with no adverse cardiac events. Moderate interaction (2D6)

29. QT AND T ORSADES DE P OINTES QT modestly associated with TdP (syncope, seizure, sudden death) Health QTc 400ms, Upper M=450ms F=460ms >500ms or Δ60ms risk for TdP RFs: Congenital long QT (1/1000), fam. Hx of sudden death, structural heart disease, bradycardia, reduced renal function,  potassium/magnesium/calcium, proarrhythmic agents, reduced renal/hepatic

30. B ENZODIAZEPINES Generally safe at therapeutic doses Can cause  BP and  HR Hepatic and renal impairment can affect clearance- increasing BP and HR effects (reduce dose in these groups) Elderly at higher risk

31. T YPICAL A NTIPSYCHOTICS Low potency typicals (chlorpromazine)- significant orthostatic hypotension, QT,  HR avoid where possible High potency typicals (haloperidol)- QT prolongation (esp. IV); moderated 2D6 inhibitor

32. A TYPICAL A NTIPSYCHOTICS 2-3 x mortality from CV disease;  risk of stroke (role of glucose and lipids?) Increased risk of venous thromboembolism Orthostatic hypotension (worse in  vol) Tachycardia (olanzapine least) QTc prolongation: ziprasidone>quetiapine/risperidone>aripiprazole (not assoc.)

33. A TYPICAL ANTIPSYCHOTICS Interactions (Quetiapine best due to limited effect on hepatic oxidation) Weight and WC- Histamine and Serotonin antagonism, increased leptin sectretion (Olanzapine,clozapine>quetiapine>risperidone> ziprasidone,aripiprazole) Lipid Profile/Glucose (Olanzapine worst); disease vs. medication vs both? Clozapine- cardiomyopathy, myocarditis (0.3%) Avoid Ziprasidone in recent MI, QT, or uncompensated HF

34. M OOD STABILIZERS Lithium- generally safe; interactions w. thiazide diuretics, ACE inhibitors, calcium channel blockers, NSAIDs- toxicity Valproic acid- safe; rare peripheral edema Carbamazepine- contraindicated in A/V block; hyponatremia; interaction with calcium channel blockers (inhibit metabolism)

35. S LEEP M EDICATIONS Zopiclone- generally safe; rare tachycardia or arrhythmia elderly Trazodone- orthostatic hypotension; uncommon conduction abnormalities

36. P SYCHOTHERAPY CBT IPT Collaborative supportive care f/u- eg. post cardiac event

37. E XERCISE ! ! ! Exercise effective in depression in cardiac disease; also reduces relapse! Benefits on cardiac health and metabolic profile Reduces fatal cardiac events by 25% Should be part of regimen for every depressed patient!

38. S UMMARY Risk/benefit favors treatment Consider interactions, comorbidities, age Collaborate with cardiology, GP, pharmacy Monitor metabolic, EKG, and bleeding profiles Consider psychotherapy/supportive care Exercise for all of our patients

39. Breathless: Psychopharmacology in COPD

40. COPD: The Context Pulmonary Diseases AirwayAlveoliInterstitialVascularChest Wall

41. COPD Largely caused by smoking Persistent inflammation of airways, lung parenchyma, vasculature Cardinal symptom = dyspnea Associated medical comorbidity – Ischemic heart disease, osteopenia, cachexia and malnutrition, anemia, peripheral muscle dysfunction, cancer, metabolic syndrome

42. COPD Management: CTS Guidelines O’Donnell et al., Can Resp J, 2008 15(SupplA)

43. Psychopathology and COPD Anxiety and depression most common Depression and anxiety rates vary based on disease severity – 10% (stable disease) to 60-70% (severe disease) Nicotine dependence, cognitive impairment, sleep disturbances Maurer et al., 2008

44. Psychiatric Side Effects of Common Drugs used to treat COPD Drug Name(s) Bronchodilators Beta-agonists (e.g. short acting – salbutamol, long acting salmeterol) Anticholinergics (e.g. short acting- ipratropium, long- acting-tiotropium) Psychiatric Side Effects Anxiety, insomnia, tremor, palpitations, rare paranoia, hallucinations No significant psychiatric side- effects (vs. atropine), often given in combination with beta agonists

45. Psychiatric Side Effects of Common Drugs used to treat COPD Drug Name Bronchodilators (cont’d) Theophylline Psychiatric Side Effects Anxiety, insomnia, tremor, restlessness, rare seizures Drug levels may require monitoring (narrow therapeutic window)

46. Psychiatric Side Effects of Common Drugs used to treat COPD Drug Corticosteroids Inhaled Oral (systemic absorption) Psychiatric Side Effects Uncommon Depression, mania, mood lability, anxiety, insomnia, psychosis, personality changes

47. Pharmacokinetic Considerations in COPD Nil in general related to COPD – Consider co-morbidities (e.g. chronic renal failure) – Consider pharmacokinetic and pharmacodynamic changes with ongoing cigarette smoking Bronchoconstriction Induction of CYP1A2, 2B6, 2D6

48. High Risk Drug Choices in COPD Drugs that decrease respiratory drive especially with CO 2 retention Barbiturates Benzodiazepines with caution

49. Dosage Alterations in COPD No specific data Start low, go slow Parsimony in prescribing – Drug-drug interactions, patient reticence to take another medication

50. Antidepressants In general safe to use Caution in combining sedating antidepressants with other sedative/hypnotic drugs due to additive potential for respiratory depression

51. Anxiolytics - Benzodiazepines Risk-benefit analysis May increase respiratory efficiency Start low, go slow Low dose, short-acting LOT –lorazepam, oxazepam, temazepam Consult with respirologist – ABGs, communication about management of COPD and psychiatric symptoms/disorder

52. Anxiolytics – Other Choices Buspirone for anxiety Low dose antipsychotic

53. Mood Stabilizers Theophylline may increase lithium clearance (decrease Li levels)

54. Antipsychotics Most first and second generation can be safely used ?Bronchodilating effects of antipsychotics with anticholinergic properties Caution with drugs that can increase QTc (e.g. ziprasidone) Rare acute dystonic reaction – laryngeal dystonia

55. Sleep Medications Consider nonbenzodiazepine sedative/hypnotics (zolpidem, zopiclone) which may have less potential to cause respiratory depression ?Trazodone

56. Cholinesterase Inhibitors & Memantine Caution with cholinesterase inhibitors – bronchoconstriction No significant respiratory effects reported with memantine

57. Clinical Pearls Communication/collaboration with primary care or respirologist to manage psychiatric disorder/symptoms and COPD Benzodiazepines – Risk/benefit analysis – Low dose, short acting “LOT” 1 st choice – May increase respiratory efficiency and help with pulmonary rehab Consider low dose antipsychotic to manage anxiety and insomnia

58. Bariatric Pharmacotherapy

59. Contemporary Surgical Options Roux-en-Y GBSleeve GastrectomyLap Band (Jackson, Adv Surg, 2012)

60. High Prevalence of Psychiatric Comorbidity in Bariatric Surgery Candidates Sockalingam S et al. Current Psychiatry Reviews 2011;7:226-233

61. Effects of Malabsorptive Bariatric Surgery (Roux- en-Y) on Psychotropic Absorption Malabsorptive procedures (Roux-en-Y) result in decreased surface area pH alterations can occur due to decreased gastric acid exposure Enteric-coated or extended release formulations of psychotropic medications have decreased absorption post-surgery = decreased bioavailability Padwal R et al. Obesity Reviews 2009;11:41-50 Miller AR et al. Am J Health-Syst Pharm 2006; 63: 1852-7

62. Seamen et al. Psychosomatics 2005 Weights of Dissolved Portions of Psychiatric Medications in Standardized Dissolution Test Models of the Gastrointestinal Environments of Preoperative and Postoperative Roux-en-Y Geriatric Bypass (RYGB) Patients Preoperative (Control) EnvironmentPost-RYGB Environment Medication Dose (mg/day) Median Wt. of Dissolved Portion (mg) %1%1 %1%1 p2p2 ANTIDEPRESSANTS Amitriptyline 7580286021<0.04 Bupropion 1003205245073<0.05 Citalopram 2070278031n.s. Fluoxetine 20110304011<0.04 Paroxetine 2030091003<0.04 Sertraline 10050163010<0.04 Venlafaxine 751805918059n.s. ANXIOLYTICS, Sedative Buspirone101205912059n.s. Clonazepam0.5100579052<0.05 Diazepam5106 6n.s. Lorazepam110800n.s. Trazodone1003305933059n.s. Zolpidem5100829074n.s. ANTIPSYCHOTICS/Miscellaneous Clozapine 1001905415043<0.05 Haloperidol 2107 7n.s. Lithium carbonate 3001303528075<0.05 Methylphenidate 2070488054n.s. Olanzapine 101904516038<0.05 Oxcarbazepine 300205102n.s. Quetiapine 2002705312023<0.05 Risparidone 21306410049<0.05 Ziprasidone 8028077210270.05 1.Relative to original pill weight 2.Mann-Whitney U test

63. Duloxetine Absorption Post-Surgery Duloxetine Post-Surgery Roerig JL et al. J Clin Psychopharmacol 2013;33: 479-84

64. Psychiatric Treatment Post Weight Loss Surgery DrugAbsorption SiteManagement LamotrigineStomach/Proximal small intestine Monitor for decreased efficacy OlanzapineStomachMonitor for decreased efficacy- Switching to Zydis does not increase absorption QuetiapineStomach/DuodenumMonitor for decreased efficacy ZolpidemAbsorption impacted by food; absorbed rapidly Increased absorption time with delay in effect; take on empty stomach Am J Health-Sys Pharm, 2006

65. PreWeekly lithium levels Drink 2.5-3 L per day (includes Optifast) Consider lithium dose decrease if lithium levels approach 1.2mmol/L or increase by > 25% from baseline Hold and reassess dose if signs of lithium toxicity Monitor depressive or manic symptoms Post 0-6 weeks Weekly lithium levels as fluid intake will increase gradually over initial months post surgery*** Ask about food intolerance and vomiting as it can impact fluid intake Consider lithium dose decrease if lithium levels approach 1.2mmol/L or increase by > 25% from baseline Hold and reassess dose if signs of lithium toxicity Monitor depressive or manic symptoms (consider standardized scales) Post > 6 weeks Monitor lithium levels q2weeks until 6 months post-surgery and then proceed to monthly lithium levels until 1 year post-surgery Ask about food intolerance and vomiting as it can impact fluid intake After 1 year post-surgery, resume routine lithium monitoring Lithium S Sockalingam and R Hawa

66. PRE- 0-6 months > 6 months K Bingham, S Sockalingam and R Hawa Valproic Acid

67. Potential for Depression Relapse Due to Poor Antidepressant Absorption Early Post-Op 1.Optimize pharmacological treatment of psychiatric symptoms pre-surgery 2.Educate the patient about possible worsening symptoms post-surgery 3.Pay close attention to symptoms immediately during the first 6 months post-surgery Hamad J et al. Am J Psychiatry 2012;169:256-263

68. Tindle HA et al. Am J Med 2010; 123:1036-42; Adams TD et al. N Engl J Med 2007; 357: 753-61 Suicide Rate = 4x general population (4.1 suicides / 10 000 persons years)

69. Psychopharmacological Pearls with Malabsorptive Bariatric Surgery Significant weight loss may require dose reduction in lipophilic drugs (most psychotropic agents) Lithium should be monitored while on Optifast (meal replacement used pre-surgery) and post-surgery due to fluid changes RYGB patients ( post-surgery ) show reduced bioavailability in SSRIs compared to non-surgical controls Roerig JL et al. Surg Obes Rel at Dis 2012;8:62-6

70. Questions

71. Thanks Drs Tait, Abbey, Sockalingam, and Tan C/L Team- University Health Network