Savvy Psychopharmacology

How to prevent serotonin syndrome

from drug-drug interactions
Jeffrey R. Bishop, PharmD, BCPP, and Danielle L. Bishop, PharmD, BCPP

s. B, age 22, is brought to the emergency

department (ED) by her roommate for
evaluation of confusion. Ms. B has a history of
migraines and major depressive disorder and
has been taking fluoxetine, 40 mg/d, for 1 year.
A week ago, she started amitriptyline, 50 mg/d,
when her migraines became more frequent.
According to her roommate, Ms. B experienced
a migraine early in the morning and had taken
2 doses of sumatriptan, 50 mg. She later complained of nausea and vomiting, and when her
roommate returned from work that evening
Ms. B was disoriented and her leg muscles
would not stop twitching.
In the ED, Ms. B is diaphoretic and increasingly agitated. Blood alcohol and urine
drug screens are negative. Blood glucose is
95 mg/dL. Complete blood count, basic metabolic panel, liver function, and kidney function
tests are within normal limits. Her physical
examination reveals a blood pressure of
130/85 mm Hg, heart rate of 130 beats per
minute, respiratory rate of 21 breaths per minute, and body temperature of 38.6C (101.4F).
Myoclonus and hyperreflexia affect her lower
extremities. Ms. B is admitted with a preliminary diagnosis of serotonin (5-HT) syndrome.

Serotonin syndrome: What is it?

Serotonin syndrome is a rare but potentially serious adverse event resulting from
excess serotonergic activity at central and
Dr. Jeffrey R. Bishop is Assistant Professor, Department
of Pharmacy Practice, University of Illinois at Chicago College
of Pharmacy. Dr. Danielle L. Bishop is Clinical Pharmacy
Specialist, Department of Pharmacy, Rush University Medical
Center, Chicago, IL.

Table 1

Characteristics of serotonin
syndrome*
Recent addition or dose increase of a
serotonergic agent
Tremor plus hyperreflexia
Muscle rigidity plus fever plus clonus
Spontaneous clonus
Ocular clonus plus agitation or diaphoresis

Vicki L. Ellingrod,
PharmD, BCPP, FCCP
Series Editor

Inducible clonus plus agitation or diaphoresis

*A combination of these characteristics may indicate
serotonin syndrome
Source: References 1-3

peripheral 5-HT2A and 5-HT1A receptors.

Serotonin syndrome toxicity ranges from
relatively mild to severe, and may be lethal. Symptoms develop rapidlywithin
hoursand may include altered mental status, clonus, tremor, hyperthermia,
diaphoresis, tachycardia, mydriasis, and
akathisia (Table 1).1-3 Fortunately, if recog-

Practice Points
Know which drugs are associated with
serotonin syndrome.
Understand the types of drug interactions
that may precipitate serotonin syndrome
and use drug information resources such
as Micromedex, Lexicomp, Physicians Desk
Reference, AHFS Drug Information, and
Facts and Comparisons.
Know what prescription medications your
patient is receiving from other providers
as well as any over-the-counter and illicit
drugs they may be using.

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Savvy Psychopharmacology

Table 2

Drugs associated with serotonin syndrome

Drugs that increase
5-HT release

Amphetamine, cocaine, MDMA (ecstasy), mirtazapine, phentermine, reserpine

Drugs that inhibit

5-HT reuptake

Amitriptyline, amphetamine, bupropion, citalopram, clomipramine, cocaine,

desipramine, dextromethorphan, doxepin, duloxetine, escitalopram, fentanyl,
fluoxetine, fluvoxamine, Hypericum perforatum (St. Johns wort), imipramine,
MDMA, meperidine, nefazodone, nortriptyline, paroxetine, protriptyline,
sertraline, tramadol, trazodone, venlafaxine

Drugs that decrease

5-HT metabolism

Isocarboxazid, linezolid, phenelzine, selegiline, tranylcypromine

Drugs that are direct

5-HT agonists

Almotriptan, buspirone, dihydroergotamine, eletriptan, frovatriptan, LSD,

naratriptan, rizatriptan, sumatriptan, zolmitriptan

Others

L-tryptophan, carbamazepine, carisoprodol, droperidol, levodopa, lithium,

metoclopramide, pentazocine, phenylpropanolamine

5-HT: serotonin; LSD: lysergic acid; MDMA: methylenedioxymethamphetamine

Clinical Point
A drugs serotonergic
activity can be
increased as a result
of a pharmacokinetic
interaction, a
pharmacodynamic
interaction, or both

Source: Reference 1

nized promptly and offending agents are

discontinued, serotonin syndrome often
resolves within a couple of days.
The differential diagnosis includes neuroleptic malignant syndrome (NMS), anticholinergic toxicity, and malignant hyperthermia.1 Differentiating serotonin syndrome
from NMS can be difficult. NMS results
from dopamine blockade; however, many
NMS symptoms are similar to those experienced with serotonin syndrome. Obtaining
a history of recent medication and/or illicit
drug use, conducting a physical exam, and
evaluating the patients clinical course help
clarify a likely diagnosis. NMS generally has
a slower onsetwithin daysand patients
demonstrate neuromuscular rigidity and
bradykinesia rather than the neuromuscular
hyperreactivity (myoclonus, hyperreflexia)
seen with serotonin syndrome.

Interactions that increase risk

82

Current Psychiatry
March 2011

A drug interaction is a pharmacologic or

clinical response to a combination of medications that differs from the agents known
effects if given on their own. In the context of
serotonin syndrome, the serotonergic activity of a drug can be increased as a result of
a pharmacokinetic (PK) interaction, a pharmacodynamic (PD) interaction, or a combination of both.
PK interactions may result from the coadministration of a drug that alters absorption,

distribution, metabolism, or elimination

parameters of 1 other drugs. Serotonergic
antidepressants usually are metabolized by
cytochrome P450 (CYP450) enzymes. Any
drug that inhibits a CYP450 enzyme responsible for biotransformation of 1 of these antidepressants may increase exposure to the
antidepressant and raise the risk of serotonin
syndrome. CYP450 inhibitors include prescription medications as well as seemingly
benign over-the-counter (OTC) drugs.
PD interactions may result from an additive or synergistic pharmacologic effect
caused by coadministration of 2 agents
that produce the same or similar end result. In Ms. Bs case, agents inhibiting 5-HT
reuptake (fluoxetine and amitriptyline)
were combined with a direct 5-HT agonist
(sumatriptan). The resulting potentiation of
5-HT via 2 distinct mechanisms increased
Ms. Bs risk of serotonin syndrome. Similarly, simultaneous use of 2 agents potentiating 5-HT through identical mechanisms,
such as combining 2 serotonin reuptake inhibitors, also may increase the risk of serotonin syndrome (Table 2).1
A combination of PK and PD interactions also may increase the risk of serotonin syndrome. For example, Ms. B is
taking fluoxetine and amitriptyline for
different therapeutic reasons. Both of these
agents inhibit 5-HT reuptake, potentiating 5-HT. In addition, amitriptyline is a
substrate for CYP2D6 and fluoxetine is a

Savvy Psychopharmacology
robust CYP2D6 inhibitor. The coadministration of fluoxetine with tricyclic antidepressants (TCAs) results in a 4- to 5-fold
increase in TCA exposure, which may increase the risk of serotonin syndrome and
other sequelae from TCA toxicity.4,5

Preventing serotonin syndrome

The warnings highlighted in drug interaction references or pharmacy databases often mean that clinicians have to evaluate
whether the risk of combining medications
outweighs the therapeutic benefits. It is unknown why some patients tolerate multiple
agents potentiating 5-HT, and practitioners
cannot predict when and in whom serotonin
syndrome may occur. However, the following strategies may help minimize these risks:

Know which drugs are associated with

serotonin syndrome. Concomitant use of
these drugs and agents that inhibit metabolism of these drugs increases risk.

Know which drugs your patient is taking. Patients may see several prescribers,
which makes it essential to ask what they
are receiving from other practitioners. Also
inquire about OTC and illicit drug use.

Related Resource
MedWatch: The FDA Safety Information and Adverse Event
Reporting Program. www.fda.gov/Safety/MedWatch.
Drug Brand Names
Almotriptan Axert
Amitriptyline Elavil
Bupropion Wellbutrin,
Zyban
Buspirone BuSpar
Carbamazepine Carbatrol,
Equetro, others
Carisoprodol Soma
Citalopram Celexa
Desipramine Norpramin
Dihydroergotamine
Migranal
Doxepin Adapin, Silenor
Droperidol Inapsine
Duloxetine Cymbalta
Eletriptan Relpax
Escitalopram Lexapro
Fentanyl Sublimaze,
others
Fluoxetine Prozac
Fluvoxamine Luvox
Frovatriptan Frova
Imipramine Tofranil
Isocarboxazid Marplan
Levodopa Dopar,
Larodopa, others
Linezolid Zyvox
Lithium Eskalith, Lithobid

Meperidine Demerol
Metoclopramide Reglan,
Metozol
Mirtazapine Remeron
Naratriptan Amerge
Nefazodone Serzone
Nortriptyline Aventyl,
Pamelor
Paroxetine Paxil
Pentazocine Talwin
Phenelzine Nardil
Phentermine
Fastin, Adipex-P
Protriptyline Vivactil
Reserpine Serpasil
Rizatriptan Maxalt
Selegiline Carbex,
Eldepryl, others
Sertraline Zoloft
Sumatriptan
Imitrex, Alsuma
Tramadol Ultram, Ultracet,
others
Tranylcypromine Parnate
Trazodone Desyrel, Oleptro
Venlafaxine Effexor
Zolmitriptan Zomig

Disclosures
Dr. Jeffrey Bishop receives grant/research support from
Ortho-McNeil-Janssen.

Clinical Point
Educate patients
about symptoms
to look for and
instruct them to call
you if they show
signs consistent with
serotonin syndrome

Dr. Danielle Bishop reports no financial relationship with

any company whose products are mentioned in this article, or
with manufacturers of competing products.

Check for interactions. If you are unfamiliar with a new drug or drug-drug combination, check multiple resources for potential
interactions. The potential severity of an interaction and the detail in which interactions
are describedsuch as class effects vs documented cases or studiesdiffers among
drug interaction resources, which means a
potential interaction may be flagged in 1
source but not another. Electronic resources
such as Micromedex and Lexicomp often
have detailed literature summaries and citations so clinicians can review primary literature that lead to the categorization of an
interaction. Using multiple sources is helpful when trying to translate warnings in the
context of a clinical scenario.

Weigh the risks and benefits. Prescribers

know that not all treatments are benign, but
not treating a condition also may be detrimental. Identify potential alternative phar-

macologic or nonpharmacologic treatments

when possible. Discuss the risks and benefits
of drug therapy with patients.

Counsel your patients. Although it is not

possible to predict who may experience
serotonin syndrome, educate patients on
what symptoms to look for. Instruct them
to call their prescriber or pharmacist if they
show symptoms that may be consistent
with serotonin syndrome.
References
1. Boyer EW, Shannon M. The serotonin syndrome. N Engl J
Med. 2005;352:1112-1120.
2. Dunkley EJ, Isbister GK, Sibbritt D, et al. The Hunter Serotonin
Toxicity Criteria: simple and accurate diagnostic decision
rules for serotonin toxicity. QJM. 2003;96:635-642.
3. Sternbach H. The serotonin syndrome. Am J Psychiatry.
1991;148:705-713.
4. Preskorn SH, Beber JH, Faul JC, et al. Serious adverse effects
of combining fluoxetine and tricyclic antidepressants. Am J
Psychiatry. 1990;147:532.
5. Preskorn SH, Alderman J, Chung M, et al. Pharmacokinetics
of desipramine coadministered with sertraline or fluoxetine. J
Clin Psychopharmacol. 1994;14:90-98.

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