Psychopharmacology in the Psychiatric
Patient with Co-Morbid Medical IllnessThe 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
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 Failure
COPD
Bariatric Surgery
Q&A
KUWAIT CONFERENCE
Basic Principles of
Psychopharmacology in the
Medically Ill
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
Pharmacokinetics:
Pharmacodynamics:
What the body is doing to the drug
What the drug is doing to the body
Drug in tissues of
distribution
Dose of drug
administered
Drug in systemic
circulation
Drug metabolized
or excreted
Adapted from Ferrando SJ et al. 2010
Drug at
site of
action
Pharmacological
Effect
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
Ferrando SJ et al. 2010
• Exclusively renally excreted
(no hepatic metabolism):
• Lithium
• Gabapentin
• Pregabalin
• Topiramate
P-glycoprotein Pump
– Efflux Transporters
• Can be inhibited or
induced
• If inhibit or induce
CYP3A4, in most cases
will do the same for pgp
• Examples: MDR1subtype (intestine), Bloodbrain-barrier
Adapted from Ferrando S et al. 2011
Potential Drug-Drug Interactions Among 1st-Line
Antidepressants
Cytochrome P450 isoenzyme or p-glycoprotein inhibition noted in brackets
Minimal or low potential
Moderate potential
Higher potential
•
•
•
•
Citalopram
Desvenlafaxine
Escitalopram
Venlafaxine
• Agomelatine (1A2 substrate)
• Bupropion (2D6)
• Duloxetine (2D6; 1A2 substrate)
•
•
•
•
•
•
Fluoxetine (2D6, 2C19)
Fluvoxamine (1A2, 2C19, 3A4)
Moclobemide (MAO inhibitor precautions)
Paroxetine (2D6; p-glycoprotein)
Selegiline (MAO inhibitor precautions)
Sertaline (2D6; p-glycoprotein)
CANMAT 2009 Guidelines for Major Depressive Disorder. J Affect Disord 2009.
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 TRIALS
Study
Design
Results
SADHAT
Open label; evaluate
safety, efficacy,
tolerability of
Sertraline post- MI
Improved depression
No 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,
No impact depression
Sertraline Vs. placebo or cardiac
cont. in CHF
In those w. remissionimproved health
status (social,
physical, symptoms,
qol, 6min walk). ***
SSRIS- CARDIAC TRIALS
Study
Design
Results
ENRICHD
Randomized, not db,
early CBT + SSRIusually 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
CREATE
Randomized,
controlled, 2x2
(IPT/Clin. Mgmt.,
placebo/citalopram)
in depressed CAD
Citalopram > placebo
No increase over
placebo in cardiac
adverse events
No benefit IPT
SSRIS- CYP450
SSRIs inhibit P450 (CYP1A2, CYP3A4, CYP
2D6)
 Can increase levels of antiarrhythmics, βblockers, 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; 60mg18.5ms).



Escitalopram (10mg- 4.3ms; 30mg- 10.7ms)


Dose max >65yrs: 20mg <65: 40mg
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
Airway
Chest Wall
Alveoli
Pulmonary
Diseases
Vascular
Interstitial
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)
Psychiatric Side Effects
Anticholinergics
(e.g. short actingipratropium, longacting-tiotropium)
No significant psychiatric sideeffects (vs. atropine), often given in
combination with beta agonists
Anxiety, insomnia, tremor,
palpitations, rare paranoia,
hallucinations
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)
Psychiatric Side Effects of Common
Drugs used to treat COPD
Drug
Corticosteroids
Inhaled
Psychiatric Side Effects
Oral
(systemic
absorption)
Depression, mania, mood lability,
anxiety, insomnia, psychosis,
personality changes
Uncommon
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 Options
Roux-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 (Rouxen-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
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
Medication
Dose
(mg/day)
Median Wt. of Dissolved
Portion (mg)
Post-RYGB Environment
%1
Median Wt. of Dissolved
Portion (mg)
%1
p2
ANTIDEPRESSANTS
Amitriptyline
75
80
28
60
21
<0.04
Bupropion
100
320
52
450
73
<0.05
Citalopram
20
70
27
80
31
n.s.
Fluoxetine
20
110
30
40
11
<0.04
Paroxetine
20
30
09
10
03
<0.04
Sertraline
100
50
16
30
10
<0.04
Venlafaxine
75
180
59
180
59
n.s.
Buspirone
10
120
59
120
59
n.s.
Clonazepam
0.5
100
57
90
52
<0.05
Diazepam
5
10
6
10
6
n.s.
Lorazepam
1
10
8
0
0
n.s.
Trazodone
100
330
59
330
59
n.s.
5
100
82
90
74
n.s.
100
190
54
150
43
<0.05
2
10
7
10
7
n.s.
Lithium carbonate
300
130
35
280
75
<0.05
Methylphenidate
ANXIOLYTICS, Sedative
Zolpidem
ANTIPSYCHOTICS/Miscellaneous
Clozapine
Haloperidol
20
70
48
80
54
n.s.
Olanzapine
10
190
45
160
38
<0.05
Oxcarbazepine
300
20
5
10
2
n.s.
Quetiapine
200
270
53
120
23
<0.05
Risparidone
2
130
64
100
49
<0.05
Ziprasidone
80
280
77
210
27
0.05
Seamen et al. Psychosomatics 2005
1. Relative to original pill weight
2. 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
Lamotrigine
Absorption Site
Stomach/Proximal
small intestine
Management
Monitor for
decreased efficacy
Olanzapine
Stomach
Quetiapine
Stomach/Duodenum
Monitor for
decreased
efficacy- Switching
to Zydis does not
increase
absorption
Monitor for
decreased efficacy
Zolpidem
Absorption impacted
by food; absorbed
rapidly
Increased
absorption time
with delay in
Lithium
Pre
Weekly 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
S Sockalingam and R Hawa
Valproic Acid
PRE0-6
months
> 6 months
K Bingham, S Sockalingam and R Hawa
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
Suicide Rate = 4x general population
(4.1 suicides / 10 000 persons years)
Tindle HA et al. Am J Med 2010; 123:1036-42; Adams TD et al. N Engl J Med 2007; 357: 753-61
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