putting maois into practice: a case-based...

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:


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


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


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


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)


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)


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.



• 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


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


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


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


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


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


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


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



• 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.



• 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.


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.


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.


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


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


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


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


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


Current Episode (Age 35)

• Characterized by depressed mood, lack of

motivation, hypersomnia, suicidal ideation

• Unresponsive to venlafaxine + bupropion,

amitriptyline, lamotrigine, lamotrigine + aripiprazole


Poll Question 3

Would you prescribe an MAOI for this patient?

A. Yes

B. No


Poll Question 4

If you would prescribe an MAOI for this patient,

would you change her opiate medication?

A. Yes

B. No


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.



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.


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


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


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


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


Medication History

• Previous unsuccessful trials of:

– SSRIs

• Sertraline; citalopram

– SNRI

• Venlafaxine

– NDRI

• Bupropion

– TCA

• Doxepin

– Atypical antipsychotics

• Quetiapine; aripiprazole



• 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


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.


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.


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)


Response to Fluoxetine in Females:

Effect of MAOA-uVNTR Genotype

Yu YWY et al. Neuropsychopharmacology 2005;30:1719-23.

* p=0.024


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


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


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)

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