US Pharm. 2007;32(11):20-23.
One of the many ways that
pharmacists make a difference in the care of their patients is through
educating themselves about, monitoring for, and raising awareness of
preventable medication-related conditions. Serotonin syndrome, also referred
to as serotonin toxicity, is one such condition that, in some cases,
may be fatal. Medications with serotonergic activity, some even available OTC (
TABLE 1), are the culprits of this potentially preventable complex of
symptoms. The incidence of serotonin syndrome is increasing with the expanded
use of serotonergic agents and, specifically, with polypharmacy.1
The FDA recently asked the manufacturers of these medications to include
warning labels on their products informing patients about the potential risk
of serotonin syndrome.2
The most common drug combinations
associated with serotonin syndrome involve the monoamine oxidase inhibitors
(MAOIs), selective serotonin reuptake inhibitors (SSRIs), and the tricyclic
antidepressants (TCAs).3 While there are several mechanisms that
result in excess serotonin, severe, life-threatening serotonin toxicity occurs
only with combinations of medications acting at different sites, most
frequently including an MAOI and an SSRI.4-6 The less-severe cases
occur with other combinations and overdoses and may even present as a result
of single-drug therapy in a susceptible individual.5 This condition
is more likely to occur when a medication is initially introduced into the
regimen or when the dosage is increased.2
Due to the current widespread use of SSRIs for a variety of conditions (e.g.,
depression, obsessive-compulsive disorder, panic disorder, generalized anxiety
disorder, premenstrual dysphoric disorder, and bulimia nervosa) and across the
spectrum of patient populations (e.g., pediatric, teens, adults, and the
elderly), it is potentially likely that serotonin syndrome will be more
frequently encountered than in previous years. A revealing 2002 Toxic Exposure
Surveillance System report indicated that of 26,733 individuals receiving
SSRIs, 27% developed significant morbidity and 93 expired.7 While
age and gender are not related to the incidence of or predisposition to
serotonin syndrome, many of the medications with the potential to cause this
condition are commonly used in the geriatric population.8,9 For
instance, SSRIs are the drugs of choice for depression in the elderly since
they have relatively few cardiovascular and anticholinergic effects compared
with other classes of antidepressants (e.g., tricyclic antidepressants).
Pharmacists should become familiar with the underlying principles and
characteristics of this syndrome to assist with its recognition, treatment,
and prevention.
Recognition and Diagnosis of Serotonin Toxicity
Serotonin syndrome is a potentially preventable, drug-related complication
that occurs from increased serotonin activity in the central nervous system
through a variety of mechanisms including an increase in serotonin synthesis,
a decrease in serotonin metabolism, an increase in serotonin release,
inhibition of serotonin uptake, direct serotonin receptor stimulation, and a
nonspecific increase in serotonin activity.3,10 The toxicity is
characterized by an altered mental status (e.g., anxiety, agitation,
confusion), neuromuscular excitation, and autonomic stimulation. The patient's
medication history is positive for serotonergic drugs. Presentation is
described as a sudden onset of altered consciousness, muscle rigidity (usually
in the lower extremities), hyperreflexia, clonus, myoclonus, diaphoresis,
flushing, and tremor. Vital signs reflect hypertension, tachycardia,
tachypnea, and hyperthermia.4,9
Serotonin toxicity can be classified as mild (serotonergic features that may
or may not concern the patient), moderate (toxicity that causes significant
distress and deserves treatment, but is not life threatening), or severe (a
medical emergency characterized by rapid onset of severe hyperthermia, muscle
rigidity, and multiple organ failure).5 Serotonin syndrome is
diagnosed only after all other potential causes of symptoms have been ruled
out. The differential diagnosis includes, but is not limited to, neuroleptic
malignant syndrome (NMS), infection, intoxication (e.g., anticholinergic
agents), metabolic problems, delirium tremors, malignant hyperthermia, and
drug withdrawal, all based on the patient's history and presentation.9
Some symptoms may even mimic those secondary to an overdose of cocaine,
lithium, or an MAOI. In NMS, the medication history is positive for dopamine
antagonists, the onset is gradual (within seven days), the muscle rigidity is
"lead pipe" in all extremities, and there is bradyreflexia; NMS usually
resolves in about nine days.9 Making the distinction between NMS
and serotonin syndrome is important since dopamine agonists, such as
bromocriptine, are commonly used to treat NMS but may exacerbate the symptoms
of serotonin syndrome.9 Clonus has been found to be more specific
to serotonin toxicity.5 Tests to assist with ruling out other
causes of symptomatology may include complete blood count, thyroid function
tests, drug screen, and electrocardiogram.2
Case Reports in Seniors
In an elderly patient, a change in mental status may indicate a variety of
conditions and needs to be addressed and evaluated carefully. Potential causes
or conditions need to be ruled out so the appropriate treatment, if necessary,
may be implemented. Published case reports warn that clinicians treating
patients with a combination of serotonergic antidepressants and atypical
antipsychotics for psychotic depression should be aware of the potential for
serotonin syndrome.11 For example, one 69-year-old male treated for
depression with psychosis with trazodone, risperidone, and sertraline
developed myoclonus, tremor, cogwheel rigidity, and diaphoresis; another
patient, a 72-year-old female who was receiving phenelzine and quetiapine,
presented with increased confusion, lethargy, slurred speech, and a fever of
101.5.11 In both cases, all symptoms resolved within 24 hours of
discontinuation of the psychotropics. The conditions reported in these
individuals were attributed to serotonin syndrome as a result of a combination
of an antidepressant and an atypical antipsychotic.11 Similar
combinations of antidepressant and atypical antipsychotic agents have been
associated with case reports of serotonin syndrome.
Linezolid and Some Lesser-Known MAOIs
As mentioned above, it is the combination of serotonergic drugs, acting by
different mechanisms, that is capable of raising intrasynaptic serotonin to a
level that is life threatening.4 Complications can occur, such as
uncontrolled muscle spasms causing severe muscle breakdown and resulting in
renal damage, if not recognized and treated appropriately.2 The
combination that most commonly does this is an MAOI drug combined with any
serotonin reuptake inhibitor (SRI). A number of lesser-known agents are
MAOIs, such as the antibiotic linezolid. After linezolid was released to the
U.S. market, several case reports of serotonin syndrome emerged.12
This antimicrobial agent, used to treat resistant gram-positive bacteria, is a
weak MAOI and has been reported to interact with SSRIs.13
Controversy exists regarding whether linezolid and SSRIs can be given
concomitantly.14 Caution should be used when linezolid is used in
patients receiving an SSRI.13 Researchers from the Department of
Pharmacy, Mayo Clinic, Rochester, Minnesota, based on a recently published
retrospective study, report that if the clinical situation warrants use of
linezolid in a patient receiving an SSRI, linezolid may be used concomitantly
with the SSRI, without a 14-day washout period and with careful monitoring for
signs and symptoms of serotonin syndrome.14 Serotonergic agents
should be promptly discontinued if serotonin syndrome is suspected. Clark et
al. recommend that other antibiotic options be considered first, and linezolid
be reserved as the last resort if possible.13
The analgesics meperidine, methadone, propoxyphene, and tramadol and the OTC
cough-suppressant dextromethorphan appear to be weak SSRIs that have all been
associated with serotonin toxicity reactions with MAOIs, including some
fatalities.4 The alternative analgesics morphine, codeine,
oxycodone, and buprenorphine are not known SRIs and do not
precipitate serotonin toxicity with MAOIs.4 Understanding the
mechanisms involved in these interactions and raising awareness of their
properties will therefore help to ensure that problems can be avoided in most
clinical situations and that appropriate treatment will be provided if
problems do occur.4
Treatment
Treatment involves removal of the causative agents and may also include the
use of serotonin antagonists (i.e., cyproheptadine). Immediate supportive care
should be directed toward symptom management (e.g., therapy for hypertension,
tachycardia, hyperthermia, and respiratory distress).3,6,9 Symptoms
typically resolve within 24 hours after withdrawal of the serotonergic
medication. Benzodiazepines, such as diazepam or lorazepam, are often utilized
to decrease agitation, myoclonus, and muscle rigidity; the addition of
nondepolarizing paralyzing agents may be necessary as second-line therapy.
9 It has been recommended that patients with serotonin syndrome stay in
the hospital for at least 24 hours for close observation.2 In
life-threatening cases, artificial ventilation is necessary.2 Case
reports of serotonin syndrome indicate that cyproheptadine reduced the
severity of signs and symptoms but did not alter the time required for
resolution.15 Additionally, cyproheptadine lacks dopamine
antagonist activity and therefore can safely be administered in situations in
which NMS cannot be differentiated from serotonin syndrome.16
Prevention of Serotonin Toxicity
Clinicians should obtain complete medication histories to identify patients at
risk, strictly monitor medication therapy including concomitant agents, and
receive education about serotonin syndrome.12 Prescribers should
reconsider the use of two or more serotonergic medications and/or consider
switching to less-serotonergic alternatives, if appropriate.3
Pharmacists should monitor
medication regimens for interactions between serotonergic agents and counsel
patients and caregivers about the avoidance of OTC products that may elevate
serotonin levels (e.g., dextromethorphan and St. John's wort). Educating
patients at risk for potential adverse effects from serotonergic agents (e.g.,
confusion, muscle spasms, shaking, shivering, sweating) should be an integral
part of counseling.
Summary
Serotonin syndrome is a potentially preventable, medication-related
complication that occurs from increased serotonin activity in the central
nervous system, usually secondary to the use of one or more serotonergic
agents. Early diagnosis and prompt treatment are important in the resolution
of this condition. Treatment involves removal of the causative agents and may
also include the use of serotonin antagonists (i.e., cyproheptadine) and other
interventions. Symptoms typically resolve within 24 hours after withdrawal of
the offending medication. Pharmacists can make a difference in the lives of
their patients by identifying individuals at risk for serotonin syndrome,
recommending changes or alternatives to therapy, counseling patients to avoid
prescription and OTC interactions, raising awareness among health care
professionals regarding the potential for negative outcomes, and potentially
preventing unnecessary human suffering, elevated health care costs, and
possibly preventable deaths.
References
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12. Huang V, Gortney JS. Risk of serotonin syndrome with concomitant administration of linezolid and serotonin agonists. Pharmacotherapy. 2006;26:1784-1793.
13. Clark DB, Andrus MR, Byrd DC. Drug interactions between linezolid and selective serotonin reuptake inhibitors: case report involving sertraline and review of the literature. Pharmacotherapy. 2006;26:269-276.
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Geriatric Dosage Handbook. 12th ed. Hudson, OH: Lexi-Comp, Inc; 2007.
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