Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Putting MAOIs Into Practice:
A Case-Based Approach (Part 1)
Handout for the Neuroscience Education Institute (NEI) online activity:
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Learning Objectives
• Explain the role of monoamine oxidase in the
neurobiology, etiology, and presentation of
psychiatric illnesses, including depression
• Identify foods and medications that interact with
MAO inhibitors
• Implement safe management strategies when
switching between MAO inhibitors and serotonin
reuptake inhibitors
• Integrate MAO inhibitors into clinical practice
according to best practices standards
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
The Case: 54-year-old man admitted for
symptoms of infection who then develops
neurological symptoms
The Question: What is the cause of these
symptoms?
The Dilemma: How to make the diagnosis
in order to manage patients as quickly as
possible
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Patient Intake
• 54-year-old married man admitted for symptoms of
infection 2 weeks after slicing his finger in a work-
related accident
– Workup reveals swinging pyrexia and neutrophilia
– Swab of his injured finger grows methicillin-resistant
Staphylococcus aureus (MRSA); a blood culture grows
MRSA as well
– Oral antibiotics are started
• Over the next 2 days, the patient becomes
increasingly agitated and confused; pyrexia persists
(~39°C) and he develops hypertonicity, tachycardia,
hypertension, tremor, and inducible clonus
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Medical History
• Borderline hypertension currently managed with diet
and exercise
• Major depressive disorder, in recovery; treated for
the last 10 years with citalopram 20 mg/day and
bupropion SR 300 mg/day
• Moderate alcohol use (2–3 beers/day, most days of
the week)
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Poll Question 1
Which of the following would you most likely
suspect for this patient?
A. Delirium tremens (DT) due to alcohol withdrawal
B. Neuroleptic malignant syndrome (NMS)
C. Sepsis-associated encephalopathy (SAE)
D. Serotonin toxicity (ST)
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Attending Physician's Mental Notes
DT NMS SAE ST
Onset 2–3 days after
last alcohol
Often ≤7 days
after start of DA
drug
Slower Rapid after start
of 5HT drug
Symptoms
and signs
Confusion,
agitation, tremor,
hyperpyrexia,
tachycardia,
hypertension
Hypersalivation,
incontinence,
rigidity,
rhabdomyolysis,
bradykinesia
Agitation,
confusion,
altered sleep/
wake, impaired
attention, coma,
hemodynamic
instability, loss of
deep tendon
reflexes, rigidity,
myoclonus,
septic blood
picture
Spontaneous
clonus, inducible
clonus, agitation,
diaphoresis,
ocular clonus,
tremor,
hyperreflexia,
hypertonia,
pyrexia
Shaikh ZS et al. Ann R Coll Surg Engl 2011;93:569-72;
Dunkley EJC et al. Q J Med 2003;96(9):635-42.
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Attending Physician's Mental Notes
• The patient’s symptoms and onset are consistent
with both delirium tremens and serotonin toxicity
• DT: The patient may have misled his physician with
respect to his alcohol intake
• ST: The antibiolitc is linezolid, which turns out to be
a reversible MAOI
– There are numerous case reports in the literature of
serotonin toxicity in patients who take linezolid plus
an SSRI
• Brain CT scan is ordered and is negative for
ischemic or hemorrhagic lesions
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Case Outcome
• Interview with the patient’s wife affirms that he usually
has a couple of drinks a night, a few times a week—not
an amount likely to produce dependence that results in
severe alcohol withdrawal
• The differential diagnosis of serotonin toxicity is made
• All serotonergic drugs are discontinued, and
management is purely supportive
• Clindamycin is prescribed for his infection
• The patient makes a full recovery from ST within a week
• His infection also resolves, and he is discharged
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Switching:
From a Serotonergic Drug to an MAOI
**Titration schedule for MAOI may differ depending on the individual agent
Stahl SM. Prescriber’s Guide. 4th ed. Cambridge University Press; 2011.
MAOI** 5HT Drug
Half-Lives*
1 2 3 4 5
*5–7 days for most drugs;
5 weeks for fluoxetine
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Take-Home Points
• Serotonin toxicity can present in hospital settings in which medications are added for different conditions
• Depending on the reason for hospitalization, differential diagnosis for patients with symptoms of ST can include:
– Delirium tremens (if patient has history of alcohol use)
– Neuroleptic malignant syndrome (if an agent that can increase DA levels is added)
– SAE (if patient has infection)
– Malignant hyperpyrexia (if patient had surgery)
• If ST is determined, 5HT drugs should be discontinued; management is generally supportive
• Quick diagnosis is essential to patient recovery
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
The Case: 64-year-old male with
treatment-resistant depression who needs
a kidney transplant
The Question: Should an MAOI be
discontinued in the face of major surgery?
The Dilemma: Managing physical needs
without compromising mental health
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Patient Intake
• 64-year-old male
• Diagnosed with major depressive disorder at age 29
• Attempted suicide at age 34 and again at age 40
• Diagnosed with autosomal dominant polycystic
kidney disease at age 37
• Is currently in end-stage renal failure; requires a
kidney transplant as soon as possible
– Fortunately, his niece is a compatible and willing
donor
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Medication History
• Between ages 29 and 35, the patient failed trials with
various SSRIs, SNRIs, TCAs, and bupropion
• At age 35, the patient started oral selegiline (30 mg/day)
and attained remission from depressive symptoms (most
notably, suicidal ideation)
• At age 40, the patient discontinued the use of selegiline.
Two months following discontinuation, he was
hospitalized for attempted suicide
• Oral selegiline (60 mg/day) was reinitiated following
suicide attempt
• The patient has been switched to transdermal selegiline
and is being successfully treated with 12 mg/24 hours
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In light of the impending transplant surgery, how
would you adjust this patient’s treatment regimen?
A. Decrease selegiline dose
B. Discontinue selegiline prior to surgery
C. Switch to a different MAOI
D. Switch to a different antidepressant (non-MAOI)
Poll Question 2
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Attending Physician's Mental Notes
• Transdermal selegiline is an irreversible inhibitor of
both MAO-A and MAO-B in the brain and
predominantly MAO-B in the gut
• Following discontinuation of an irreversible MAOI,
MAO function is restored only after new MAO
enzymes have been made
– MAO enzyme function slowly recovers 2-3 weeks
following discontinuation of transdermal selegiline
The MAOI Handbook. NEI Press; Carlsbad, CA; 2011.
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Attending Physician's Mental Notes
• Reversible MAOIs can be displaced by other MAO
substrates and consequently can be discontinued
the day before surgery
– Moclobemide is a reversible selective inhibitor of
MAO-A but is not available in the United States
• Hypotension is not uncommon with general
anesthesia
– Selection of a pressor agent must be carefully done
by the anesthesiologist when the patient is taking an
MAOI
Doak GJ. Can J Anaesth 1997;44:R112-7; McFarlane HJ. Anaesthesia 1994;49:597-9;
Pavy TPG et al. Can J Anaesth 1995;47(7):618-20.
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Attending Physician's Mental Notes Potential Drug Interactions of MAOIs and Anesthesia
• Sympathomimetic drugs (e.g., ephedrine)
– Mechanism: norepinephrine overactivity
– Consequence: hypertensive crisis
• Narcotic Type I excitatory reaction (e.g., meperidine)
– Mechanism: serotonergic overactivity (serotonin syndrome)
– Consequence: agitation, hypo- or hypertension, convulsions, hyperthermia, coma
• Narcotic Type II depressive reaction (e.g., morphine)
– Mechanism: possible increased opioid levels due to blockade of hepatic enzymes by MAOI
– Consequence: hypotension, respiratory depression, coma
Doak GJ. Can J Anaesth 1997;44(5 Pt 2):R112-23; Huyse FJ et al. Psychosomatics 2006;47(1):8-22.
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Use of Anesthetics in Patients Taking an
MAOI
Local anesthetic Elective surgery Urgent or elective
surgery when patient is
still taking an MAO
inhibitor
Choose an agent that
does not contain
vasoconstrictors
Wash out the MAO
inhibitor 10 days prior to
surgery
Cautiously use a
benzodiazepine,
mivacurium,
rapacuronium, morphine,
or codeine
The MAOI Handbook. NEI Press; Carlsbad, CA; 2011.
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Case Outcome
• Transdermal selegiline is discontinued 10 days prior
to surgery
• The patient reports a mild increase in depressive
symptoms 6 days after discontinuation of selegiline
but no suicidal ideation
• The kidney transplant is successfully completed with
no immediate complications
• The patient resumes transdermal selegiline as soon
as he is hemodynamically stable and able to drink
fluids
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Take-Home Points
• When possible, it is prudent to discontinue the use
of an irreversible MAOI prior to elective surgery
• When surgery must be performed on a patient
taking an MAOI, there are several anesthetic agents
that may be used with caution
• The surgeon, anesthesiologist, and psychiatrist must
collaborate to determine which options are best for
the patient’s physical and mental health
• It is essential that the anesthesiologist be informed
of MAOI use so that appropriate measures can be
taken to ensure patient safety
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
The Case: 35-year-old cancer patient with
major depressive disorder
The Question: What is the best option for
treating depression in a patient taking an
opiate?
The Dilemma: How to manage both
depressive symptoms and chronic pain
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Patient Intake
• 35-year-old married mother of 1 (age 5)
• At age 33, she was diagnosed with Stage III breast
cancer
• She was treated with surgery, chemotherapy, and
radiation and is currently in remission from her cancer
• For the last 6 months, she has been taking morphine
to treat ongoing chronic pain that is moderate to
severe
• She currently presents with a major depressive
episode that has been unresponsive to several trials of
antidepressant medications
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Patient History
• Age 25: MDE characterized by depressed mood,
hypersomnia, psychomotor retardation
– Remitted with sertraline
• Age 30: postpartum episode characterized by
depressed mood, lack of motivation, hypersomnia,
suicidal ideation
– Had stopped treatment during pregnancy
– Unresponsive to sertraline, sertraline + bupropion,
venlafaxine, amitriptyline
– Responded to tranylcypromine; stopped treatment
after 1 year
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Current Episode (Age 35)
• Characterized by depressed mood, lack of
motivation, hypersomnia, suicidal ideation
• Unresponsive to venlafaxine + bupropion,
amitriptyline, lamotrigine, lamotrigine + aripiprazole
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Poll Question 3
Would you prescribe an MAOI for this patient?
A. Yes
B. No
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Poll Question 4
If you would prescribe an MAOI for this patient,
would you change her opiate medication?
A. Yes
B. No
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Myth #6:
The Painkiller Interaction
Use With MAOIs
Should Be Cautious
acetaminophen
aspirin
buprenorphine
butorphanol
codeine
hydrocodone
nalbuphine
NSAIDs
pentazocine
Use With MAOIs May
Sometimes Be Done
By Experts
hydromorphone
morphine*
oxycodone*
oxymorphone
Use With MAOIs
Strictly Prohibited
fentanyl
meperidine
methadone
tapentadol
tramadol
*Not all experts agree that these drugs require more caution than those in the left-hand column.
Grady MM, Stahl SM. CNS Spectr 2012;In press; Gillman PK. Br J Anaesth 2005;95(4):434-41.
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Attending Physician's Mental Notes
Opioids
Commonly
Used For
Cancer Pain*
Potency
(relative to
morphine)
Onset Duration Addiction
Potential
Morphine 1
(benchmark)
~20 min after
injection
Elimination
half-life ~2 hrs
High
Oxycodone 1.5–2 ~60 min after
ingestion
Large
interindividual
differences
Fairly high;
less than with
morphine
Buprenorphine 25–30 Not given PO
Transdermal:
12–24 hrs
Elimination
half-life 37 hrs
Typically mild
withdrawal
after short-
term use
Hydromorphone 8–10 Slightly faster
than
morphine
Elimination
half-life 2–3
hrs
Fairly high;
less than with
morphine
*Not contraindicated with MAOIs Plante GE, VanItallie TB. Metab Clin Exp 2010;59(suppl 1):S47-52.
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Case Outcome
• The treatment team agrees to initiate an MAOI for the
patient’s depression after switching morphine to
transdermal buprenorphine
• After the opioid switch is complete, tranylcypromine is
initiated at 30 mg/day
• The patient’s pain is managed adequately with the
switch to buprenorphine (20 mcg/h; 7-day patch)
• The patient experiences improvement in mood,
hypersomnia, and suicidal ideation following the initiation
of tranylcypromine
• She continues to have some residual depressive
symptoms
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Take-Home Points
• It is common for cancer survivors to suffer from both chronic pain that requires opioid treatment and depression
• MAOIs can be an option for patients with treatment-resistant depression who require opioid treatment; however, some opioids are absolutely contraindicated, and others need to be used with caution
• A risk-benefit assessment must be made for each patient to determine if MAOI treatment would necessitate changing the opioid
• Close alliance with the rest of the treatment team is essential
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
The Case: 32-year-old female with
treatment-resistant depression
The Question: How can genetic
information be used to guide treatment?
The Dilemma: Optimizing the treatment of
depression based on the sex and genotype
of the patient
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Patient Intake
• 32-year-old female
• Diagnosed with major depressive disorder at age 22
• She has been hospitalized 4 times for attempted
suicide over the past 5 years
• Genetic testing reveals the following polymorphisms
in the gene for MAO-A:
– Homozygosity for the G allele of T941G
– Homozygosity for the 4-repeat (long) allele of the
upstream variable tandem repeat (MAOA-uVNTR)
region
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Medication History
• Previous unsuccessful trials of:
– SSRIs
• Sertraline; citalopram
– SNRI
• Venlafaxine
– NDRI
• Bupropion
– TCA
• Doxepin
– Atypical antipsychotics
• Quetiapine; aripiprazole
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Attending Physician's Mental Notes
• The MAO-A polymorphisms in this patient suggest
that treatment to boost monoamine levels (e.g.,
SSRIs, TCAs) may not actually be treating the
primary issue: too much MAO-A
• Recent data suggest that the treatment of
depression is influenced by polymorphisms in MAO-
A as well as by patient sex and age
• By taking a patient’s sex, age, and any available
genetic information into account, the treatment of
many psychiatric disorders, including MDD, can be
improved
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
T941G Polymorphism
• T allele
– Lower enzyme activity
• G allele
– Greater enzyme activity
• The G/G genotype is associated with:
– 75% greater MAO-A activity
– A greater number of depressive episodes
– Worse response to mirtazapine in females
Pitychoutis PM et al. Curr Pharm Design 2010;16:2214-23;
Tadić A et al. Am J Med Genetics B Neuropsychiatr Genetics 2007;144B(3):325-31.
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
T941G Polymorphism
• Females with a G allele have less chance of responding to mirtazapine
% o
f p
atie
nts
re
sp
on
din
g to
mirta
za
pin
e
Tadić A et al. Am J Med Genetics B Neuropsychiatr Genetics 2007;144B(3):325-31.
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
MAOA-uVNTR
• The long allele is:
– A risk factor for MDD
– Linked to worse outcomes in adult females exposed
to severe childhood stress
– Associated with suicide in males with depression
– Predictive of worse response to fluoxetine treatment
in females
Du L et al. Neuroreport 2002;13(9):1195-8; Fan M et al. Psychiatr Genetics 2010;20:1-7;
Gutiérrez B et al. Psychiatr Genetics 2004;14:203-8; Kinnally EL et al. Psychiatr Genetics 2009;19:126-33;
Lung F-W, BMC Med Genetics 2011;12(74):1-11; Pitychoutis PM et al. Curr Pharm Design 2010;16:2214-23;
Schulze TG et al. Am J Med Genetics 2000;96(6):801-3; Xu Z et al. J Affective Dis 2011;133:165-73.
• Short 3-repeat allele (lower expression of MAO-A)
• Long 4-repeat allele (higher expression of MAO-A)
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Response to Fluoxetine in Females:
Effect of MAOA-uVNTR Genotype
Yu YWY et al. Neuropsychopharmacology 2005;30:1719-23.
* p=0.024
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Treatment of Major Depressive Disorder:
Response Rates by Gender
57 62
0
10
20
30
40
50
60
70
Women Men
Resp
on
ders
(%
)
Sertraline
Imipramine
Kornstein SG et al. J Clin Psychiatry 2001;62(suppl 16):18-25.
46 *
45 **
*p=.012
**p=.043
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Case Outcome
• The patient is prescribed transdermal selegiline, 6
mg/day
• She experiences partial response, and the dose is
increased to 12 mg/day
• She experiences further improvement and is currently
doing fairly well, with a few residual symptoms but no
current suicidal ideation or plans
• Future options, if she worsens, would include
augmentation of the MAOI (e.g., with a stimulant or
atypical antipsychotic)
• ECT may also be considered
Copyright © 2012 Neuroscience Education Institute. All rights reserved.
Posttest Question 1
Which of the following antidepressants would
you recommend for this patient?
A. Fluoxetine (SSRI)
B. Mirtazapine (alpha-2 antagonist)
C. Selegiline (MAOI)
D. Imipramine (TCA)