Serotonin Syndrome

AUTHORS: Nathan Stanford, MD and Alan Taylor, MD

Definition

Serotonin syndrome (SS) is an iatrogenic medical condition resulting from excessive serotonergic stimulation of 5-HT_1A and 5-HT_2a receptors ¹ in the central nervous system (CNS) and peripheral nervous system (PNS). SS is a disorder that is classically characterized by a constellation of various symptoms that are classically defined by the triad of mental status changes, neuromuscular hyperactivity, and autonomic dysfunction.¹^,²

Synonyms

Hyperserotonemia

Serotonergic syndrome

Serotonin toxicity

ICD-10CM CODES
Y49		Adverse effects due to psychotropic drugs
Y49.0		Adverse effects due to tricyclic and tetracyclic antidepressants
Y49.1		Adverse effects due to monoamine-oxidase-inhibitor antidepressants
Y49.2		Adverse effects due to other and unspecified antidepressants
Y49.3		Adverse effects due to phenothiazine antipsychotics and neuroleptics
G25.89		Other specified extrapyramidal and movement disorders

Epidemiology & Demographics

While the exact incidence of SS is not known, as clinical manifestations may go unnoticed or be attributed to another condition, the overall incidence is known to be rising in the face of increased use of serotonergic medications.¹
SS is seen in all age groups.
SS classically occurs in patients receiving two or more serotonergic drugs, but it can also occur occasionally with monotherapy.
Selective serotonin reuptake inhibitor (SSRI) is the most commonly implicated medication associated with SS.
Concomitant use of an SSRI with a monoamine oxidase inhibitor (MAOI) poses the greatest risk of developing severe SS.
Combination of SSRIs with other serotonergic drugs (e.g., tryptophan, illicit drugs like cocaine and MDMA, “Ecstasy”) or drugs with serotonergic properties (e.g., methylene blue, lithium, meperidine, triptans, linezolid) may also lead to SS.

Physical Findings & Clinical Presentation

Findings of clonus and tremor with hyperreflexia in the setting of recent use of serotonergic agents strongly suggest the diagnosis of SS.
Symptoms can manifest within minutes to hours after starting a new psychopharmacologic treatment, increasing the dose of a serotonergic drug, or administering a second serotonergic drug. Nearly all patients develop symptoms within 24 h of exposure.
Clonus (inducible, spontaneous, and ocular) is the key finding in establishing a diagnosis of SS.
Classic triad of clinical features:
1. Neuromuscular excitation: Hyperreflexia, myoclonus, muscle rigidity, tremor, ocular clonus, bilateral Babinski signs
2. Autonomic nervous system excitation: Nausea/vomiting, diarrhea, hypertension, tachycardia, diaphoresis, fever >38° C (100° F) to severe hyperthermia, dilated pupils, dry mucous membranes, flushed skin
3. Altered mental status: Anxiety, agitation, confusion, coma

Etiology

Hyperstimulation of the brain stem and spinal cord serotonin receptors leading to the neuromuscular and autonomic symptoms.¹^,²
Psychopharmacologic drugs-in particular, fluoxetine and sertraline taken with MAOI (e.g., tranylcypromine and phenelzine)-have been cited as a common cause of SS. Triptans (serotonin-receptor agonists used in the treatment of migraines) may also precipitate the SS when used in combination with SSRIs and serotonin-norepinephrine reuptake inhibitors. Box 1 describes classes of medications that produce SS.

BOX 1 Classes of Medications That Produce Serotonin Syndrome in Psychiatric Patients

Selective serotonin reuptake inhibitors

Monoamine oxidase inhibitors

Atypical antipsychotics

Heterocyclic antidepressants

Trazodone

Dual-uptake inhibitors

Psychostimulants

Buspirone

Mood stabilizers

Analgesics

Antiemetics

Cough suppressants

Dietary supplements

Linezolid

From Goldman L, Schafer AI: Goldman-Cecil medicine, ed 24, Philadelphia, 2012, Saunders.

TREATMENT^1-3

Once a diagnosis of SS is established, consultation with a medical toxicologist, clinical pharmacologist, and/or poison control center should be considered.
Management includes:
1. Discontinue use of all potential precipitating drugs.
2. Provide supportive management.
3. Control agitation.
4. Administer serotonin antagonists.
5. Control autonomic instability.
6. Control hyperthermia.
7. Reassess the need to resume the use of the serotonergic agent once the symptoms have resolved.

Diagnosis ⬆ ⬇

SS is a clinical diagnosis. There are no specific laboratory tests for SS. A high index of suspicion along with a detailed medication history is the mainstay of diagnosis.⁴
Diagnostic criteria: Most accurate is Hunter Serotonin Toxicity Criteria (sensitivity 84%, specificity 97%, confirmation by toxicologist). Sternbach diagnostic criteria (Table E1) are also commonly used with statistics of sensitivity 75% and specificity 96%.⁴

TABLE E1 Criteria to Determine Serotonin Syndrome and Toxicity

Sternbach diagnostic criteria for serotonin syndrome		Recent addition or increase of proserotonergic medication At least three of the following: Agitation Ataxia Diaphoresis Diarrhea Hyperreflexia Hyperthermia Mental status changes Myoclonus Shivering Tremor Neuroleptic agent not added or dose increased before the onset of symptoms Diagnosis of infections, withdrawal, and other poisoning or metabolic disruptions excluded
Hunter criteria for serotonin toxicity (context of serotonergic medications)		If patient has spontaneous clonus, serotonin toxicity present If no spontaneous clonus, one of the following needed for a diagnosis of serotonin toxicity: Inducible clonus and agitation or diaphoresis Ocular clonus and agitation or diaphoresis Tremor and hyperreflexia Temperature >38° C and ocular clonus or inducible clonus

From Adams JG et al: Emergency medicine, clinical essentials, ed 2, Philadelphia, 2013, Elsevier.

Differential Diagnosis

Medical: Neuroleptic malignant syndrome, malignant hyperthermia, infection (e.g., meningitis, encephalitis), hyperthyroidism, tetanus.¹^,²
Toxins: Anticholinergic, amphetamines, cocaine, lithium, LSD, PCP, salicylates.
Classic features in differentiation of NMS from SS are that SS develops over 24 h, involves neuromuscular hyperactivity (hyperreflexia, myoclonus), and begins to resolve within 24 h with appropriate therapy, whereas NMS develops gradually over days to weeks, involves sluggish neuromuscular response, and resolves over an average period of 1 wk to 10 days.⁵

Workup

Because SS is a clinical diagnosis, there is no laboratory test that confirms the diagnosis, and serum serotonin concentration does not correlate with the clinical picture.³
However, patients with SS may develop leukocytosis, elevated creatinine phosphokinase, and decreased sodium bicarbonate levels.
Patients with severe SS may develop complications including disseminated intravascular coagulation, rhabdomyolysis, metabolic acidosis, renal failure, myoglobinuria, and acute respiratory distress syndrome.
All patients should receive more extensive workup to evaluate for other life-threatening illnesses.¹^,²^,⁵

(Used to Narrow Differential Diagnosis)¹ ³

CBC with differential when considering sepsis
Urine and blood cultures
Electrolytes, blood urea nitrogen, and creatinine to rule out acidosis and renal failure
Coagulation studies to rule out disseminated intravascular coagulation
Blood and urine toxicology screen, including acetaminophen and salicylate levels if overdose was intentional to rule out complicating co-ingestions
It should be noted that urine drug screening is of limited utility due to its lack of sensitivity for many drugs
Thyroid function tests
Creatine-phosphokinase (CPK) with isoenzymes
ECG because ventricular rhythm disturbance is a potentially fatal complication
Cerebrospinal fluid studies to rule out meningitis

Imaging Studies (Used to Narrow Differential Diagnosis)

Plain chest x-ray examination
Head computed tomography

Pearls & Considerations ⬆ ⬇

The combined use of SSRIs and MAOIs is contraindicated.

Despite serotonin syndrome being relatively rare, it is worth consideration in a differential even if common supporting elements to the diagnosis are absent such as meeting Hunter criteria, MAOI involvement, rapid onset, and hyperthermia.⁴

Studies have suggested that genetic polymorphisms at the sites of CYP2D6 and T102C may contribute to individuals developing serotonin syndrome.³

Comments

The use of SSRIs and other serotonergic agents is not an absolute contraindication; however, prompt withdrawal of the medication is recommended if any symptoms suggesting SS occur.
SS is usually found in patients being treated for depression, bipolar disorders, obsessive-compulsive disorder, attention deficit disorder, and Parkinson disease.
SS can occur without an elevation of body temperature.
Absence of MOAI does not exclude SS from one’s differential; any other combinations of SSRIs or serotoninergic modulating drugs can precipitate SS.

NONPHARMACOLOGIC THERAPY

Discontinuation of the drug is the mainstay of therapy.¹
Supportive treatment aimed at normalizing vital signs.
Patients who are severely hyperthermic with temperatures >41° C (106° F) should be given intravenous (IV) sedation, paralyzed, and intubated. Cooling blankets can be used for patients with mild to moderate hyperthermia. There is no role for acetaminophen. (This lack of utility is due to the etiology of the hyperthermia; Tylenol focuses the thermoregulatory nature of the hypothalamus whereas SS hyperthermia is entirely derived from muscle activity.)³^,⁴
Intubation is recommended for patients who are unable to protect their airways as a result of mental status changes or seizures.³

ACUTE GENERAL Rx

Benzodiazepines for control of agitation are preferred to physical restraints.¹
1. Lorazepam 2 to 4 mg IV every 30 min has been used effectively in treating agitation, muscle rigidity, myoclonus, and seizure complications, but while that is a good starting point, effective treatment often requires escalating to much higher doses.
2. Diazepam 5 to 10 mg is an alternative choice.
Patients may have rapid changes in blood pressure and heart rate. Hypertensive patients should be treated with short-acting titratable agents (e.g., esmolol or nitroprusside). Hypotensive patients may require both IV fluids and vasopressor therapy.
Serotonin antagonists should be titrated to clinical effectiveness in patients for whom nonpharmacologic therapy and benzodiazepines are not achieving adequate response. Although, limited evidence is available for these treatments.
1. Cyproheptadine (4 mg tablet or 2 mg/5 ml syrup available)-widely accepted as standard of care
  1. Adults: 12 mg initially followed by 2 mg every 2 h until therapeutic response (up to 32 mg/day)
  2. Children (ages 7 to 14): 4 mg every 6 h (up to 16 mg/day)
  3. Children (ages 2 to 6): 2 mg every 6 h (up to 12 mg/day)
  4. Children (younger than 2 yr): 0.06 mg/kg every 6 h (up to 0.25 mg/kg/day)
2. Atypical antipsychotic agents with serotonin antagonist properties (e.g., olanzapine 10 mg sublingual [SL]) have been tried with some success, but efficacy is unproven. It also has been reported in some instances to cause SS.³
3. Chlorpromazine 50 to 100 mg intramuscularly may be considered in severe cases, but intravenous fluid loading is essential to prevent hypotension. This may also increase the likelihood of the patient seizing.
4. Dantrolene and Bromocriptine which is used in treating NMS have no role in treating SS.³^,⁵

CHRONIC Rx

For patients not requiring hospital admission, lorazepam can be given in an oral dose on a prn basis with close follow-up.

DISPOSITION²^,³

SS is a potentially life-threatening condition if not recognized early, although it does exist on a spectrum.
Prompt diagnosis and withdrawal of the medication results in improvement of symptoms within 24 h.
Seizures, rhabdomyolysis, hyperthermia, ventricular arrhythmia, respiratory arrest, and coma are all complicating features of SS.

REFERRAL

All cases of SS secondary to psychotropic medications should be referred to a psychiatrist.

PREVENTION

Modify prescription practices by avoiding multidrug regimens.

Detailed pharmacy review before starting high risk drugs (see Box 1).

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Basic Information ⬇

Diagnosis ⬆ ⬇

Pearls & Considerations ⬆ ⬇

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