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 SABSMDeputy Psychiatrist in Chief- UHN

Director, C/L Service, TWHDeputy Clerkship DirectorDirector Psychiatry UME

University of Toronto

Disclosure

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

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

Outline

General Approach to Psychopharmacology in the Patient with Co-Morbid Medical Illness:

Heart FailureCOPDBariatric Surgery Q & A

Basic Principles of Psychopharmacology in the Medically Ill

KUWAIT CONFERENCE

The Context: Increasing Rates of Polypharmacy in Mental Health Care

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

Principles of Psychopharmacology

• Pharmacodynamics

• Pharmacokinetics

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

Proportion of Drugs Metabolized by Phase I Enzymes (CYP450)

Wynn GH. Clinical Manual of Drug Interaction Principles for Medical Practice 2009

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

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

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

Harnessing Antidepressant Profiles: Prescribing Parsimony

• Pain –TCA, duloxetine, venlafaxine (desvenlafaxine)• Sleep – mirtazapine, TCA, trazodone• Nausea / poor appetite – mirtazapine, olanzapine• Constipation – SSRIs• Fatigue – Bupropion, SNRI

CARDIAC DISEASE AND PSYCHOPHARMACOLOGY

CARDIOVASCULAR DISEASE AND DEPRESSION 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

DEPRESSION IN CARDIAC DISEASE

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)

DEPRESSION AND HEART FAILURE 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

ANXIETY AND CARDIAC DISEASE 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

DEPRESSION AND CARDIOVASCULAR DISEASE LINKS 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.)

NEUROTRANSMITTER 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

SSRIS- CARDIAC TRIALSStudy Design ResultsSADHAT Open label; evaluate

safety, efficacy, tolerability of Sertraline post- MI

Improved depressionNo adverse cardiac events

SADHART Randomized, 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-CHF Randomized, db, Sertraline Vs. placebo cont. in CHF

No impact depression or cardiacIn those w. remission- improved health status (social, physical, symptoms, qol, 6min walk). ***

SSRIS- CARDIAC TRIALSStudy Design ResultsENRICHD Randomized, 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 eventsCBT- small but sig. effect

CREATE Randomized, controlled, 2x2 (IPT/Clin. Mgmt., placebo/citalopram) in depressed CAD

Citalopram > placeboNo increase over placebo in cardiac adverse eventsNo benefit IPT

SSRIS- CYP450 SSRIs inhibit P450 (CYP1A2, CYP3A4, CYP

2D6) Can increase levels of antiarrhythmics, β-

blockers, antihistamines, and Ca2+ 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

SSRIS 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 %

SSRIS 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

TCAS 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*

MIXED 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)

QT AND TORSADES DE POINTES 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

BENZODIAZEPINES 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

TYPICAL ANTIPSYCHOTICS Low potency typicals (chlorpromazine)-

significant orthostatic hypotension, QT, HR avoid where possible

High potency typicals (haloperidol)- QT prolongation (esp. IV); moderated 2D6 inhibitor

ATYPICAL ANTIPSYCHOTICS 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.)

ATYPICAL 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

MOOD 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)

SLEEP MEDICATIONS Zopiclone- generally safe; rare tachycardia or

arrhythmia elderly Trazodone- orthostatic hypotension;

uncommon conduction abnormalities

PSYCHOTHERAPY CBT IPT Collaborative supportive care f/u- eg. post

cardiac event

EXERCISE! ! ! 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!

SUMMARY 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

Breathless: Psychopharmacology in COPD

COPD: The Context

Pulmonary Diseases

Airway

Alveoli

InterstitialVascular

Chest Wall

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

COPD Management: CTS Guidelines

O’Donnell et al., Can Resp J, 2008 15(SupplA)

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

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

Psychiatric Side Effects of Common Drugs used to treat COPD

Drug NameBronchodilators (cont’d)Theophylline

Psychiatric Side Effects

Anxiety, insomnia, tremor, restlessness, rare seizures Drug levels may require monitoring (narrow therapeutic window)

Psychiatric Side Effects of Common Drugs used to treat COPD

DrugCorticosteroidsInhaled

Oral (systemic absorption)

Psychiatric Side Effects

Uncommon

Depression, mania, mood lability, anxiety, insomnia, psychosis, personality changes

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

High Risk Drug Choices in COPD

Drugs that decrease respiratory drive especially with CO2 retention• Barbiturates • Benzodiazepines with caution

Dosage Alterations in COPD

• No specific data• Start low, go slow• Parsimony in prescribing

– Drug-drug interactions, patient reticence to take another medication

Antidepressants

• In general safe to use • Caution in combining sedating antidepressants

with other sedative/hypnotic drugs due to additive potential for respiratory depression

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

Anxiolytics – Other Choices

• Buspirone for anxiety • Low dose antipsychotic

Mood Stabilizers

• Theophylline may increase lithium clearance (decrease Li levels)

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

Sleep Medications

• Consider nonbenzodiazepine sedative/hypnotics (zolpidem, zopiclone) which may have less potential to cause respiratory depression

• ?Trazodone

Cholinesterase Inhibitors & Memantine

• Caution with cholinesterase inhibitors – bronchoconstriction

• No significant respiratory effects reported with memantine

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” 1st choice – May increase respiratory efficiency and help with

pulmonary rehab• Consider low dose antipsychotic to manage anxiety

and insomnia

Bariatric Pharmacotherapy

Contemporary Surgical OptionsRoux-en-Y GB Sleeve Gastrectomy Lap Band

(Jackson, Adv Surg, 2012)

High Prevalence of Psychiatric Comorbidity in Bariatric Surgery Candidates

Sockalingam S et al. Current Psychiatry Reviews 2011;7:226-233

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;11:41-50Miller AR et al. Am J Health-Syst Pharm 2006; 63: 1852-7

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) Environment Post-RYGB Environment

Medication Dose (mg/day)

Median Wt. of Dissolved Portion (mg) %1 Median Wt. of Dissolved

Portion (mg) %1 p2

ANTIDEPRESSANTSAmitriptyline 75 80 28 60 21 <0.04Bupropion 100 320 52 450 73 <0.05Citalopram 20 70 27 80 31 n.s.Fluoxetine 20 110 30 40 11 <0.04Paroxetine 20 30 09 10 03 <0.04Sertraline 100 50 16 30 10 <0.04Venlafaxine 75 180 59 180 59 n.s.ANXIOLYTICS, SedativeBuspirone 10 120 59 120 59 n.s.Clonazepam 0.5 100 57 90 52 <0.05Diazepam 5 10 6 10 6 n.s.Lorazepam 1 10 8 0 0 n.s.Trazodone 100 330 59 330 59 n.s.Zolpidem 5 100 82 90 74 n.s.ANTIPSYCHOTICS/MiscellaneousClozapine 100 190 54 150 43 <0.05Haloperidol 2 10 7 10 7 n.s.Lithium carbonate 300 130 35 280 75 <0.05Methylphenidate 20 70 48 80 54 n.s.Olanzapine 10 190 45 160 38 <0.05Oxcarbazepine 300 20 5 10 2 n.s.Quetiapine 200 270 53 120 23 <0.05Risparidone 2 130 64 100 49 <0.05Ziprasidone 80 280 77 210 27 0.05

1. Relative to original pill weight2. Mann-Whitney U test

Duloxetine Absorption Post-Surgery

Duloxetine Post-Surgery

Roerig JL et al. J Clin Psychopharmacol 2013;33: 479-84

Psychiatric Treatment Post Weight Loss Surgery

Drug Absorption Site ManagementLamotrigine Stomach/Proximal

small intestineMonitor for decreased efficacy

Olanzapine Stomach Monitor for decreased efficacy- Switching to Zydis does not increase absorption

Quetiapine Stomach/Duodenum Monitor for decreased efficacy

Zolpidem Absorption impacted by food; absorbed rapidly

Increased absorption time with delay in effect; take on empty stomach

Am J Health-Sys Pharm, 2006

Pre Weekly lithium levelsDrink 2.5-3 L per day (includes Optifast) Consider lithium dose decrease if lithium levels approach 1.2mmol/L or increase by > 25% from baselineHold 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 intakeConsider 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-surgeryAsk about food intolerance and vomiting as it can impact fluid intakeAfter 1 year post-surgery, resume routine lithium monitoring

Lithium

S Sockalingam and R Hawa

PRE-

0-6 months

> 6 months

K Bingham, S Sockalingam and R Hawa

Valproic Acid

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

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)

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

Questions

Thanks

• Drs Tait, Abbey, Sockalingam, and Tan• C/L Team- University Health Network