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Selective Serotonin Reuptake Inhibitor Toxicity Clinical Presentation

  • Author: Tracy A Cushing, MD, MPH, FACEP, FAWM; Chief Editor: Asim Tarabar, MD  more...
Updated: Oct 21, 2015


Serotonin toxicity is most likely to develop following the initiation of a new serotonergic medication or the increase in dosage of a previously prescribed SSRI.[12]

Symptom onset from SSRI toxicity presents within 2-8 hours after acute ingestion, or it may occur over several days if serotonin syndrome (SS) develops from the initiation of a new therapy or the addition of a second serotonergic agent.

A history of mental illness, particularly affective disorders, and prior suicide attempts should be elicited.

Serotonin syndrome diagnostic criteria

Diagnostic criteria for SS were developed in 1991 by Sternbach et al to assist in diagnosis.[1] The Sternbach criteria include the following:

  • Symptoms coincide temporally with the addition of a serotonergic agent to a patient's regimen or with an increase in the dose of a previously prescribed serotonergic agent
  • At least 3 of the following physical findings are present: agitation, ataxia, diaphoresis, diarrhea, hyperreflexia, mental status changes, myoclonus, shivering, tremor, or hyperthermia
  • A neuroleptic agent has not been recently added to the patient's regimen or increased in dose, if previously prescribed
  • Other etiologies, such as infection, intoxication, metabolic derangements, substance abuse, and withdrawal, have been ruled out

These criteria have been modified over time to account for symptoms associated with more mild cases, but they provide a framework for the history and physical examination to aid in diagnosis.

Newer diagnostic criteria include the Hunter Serotonin Toxicity Criteria, which were established based on single-agent SSRI overdoses, as well as on combinations of serotonergic drugs. This decision rule is based more on the presence of neuromuscular findings (clonus, hyperreflexia, tremor, diaphoresis, hyperthermia) than on altered mental status and was found to have a sensitivity of 84% and a specificity of 97% in predicting SS.[21]

Mild cases of SS, due to vague symptomatology, may often go unrecognized.


Physical Examination

Signs of excess serotonin can range from subtle tremor to frank coma.[22] Mental status changes, autonomic instability, and neuromuscular agitation are the primary findings used to delineate Sternbach's criteria. However, more specific signs and physical findings have become recognized as reliable predictors of serotonin toxicity; several decision rules have been established to help clinicians identify patients with possible SS.

Neuromuscular findings

Neuromuscular findings, such as clonus, hyperreflexia, muscular rigidity, and ataxia, may be present, as well as myoclonic jerks, teeth chattering, and resting tremor. The clonus is spontaneous, inducible, or ocular. Hyperreflexia is often more pronounced in the lower extremities. Muscular rigidity may mask clonus. Among these findings, clonus is the most useful in diagnosing SS.

Mental status findings

Mental status findings may be subtle, including such symptoms as pressured speech, restlessness, and confusion. More severe cases may manifest with agitation, hypomania, coma, or seizures.

Autonomic findings

Autonomic instability includes diaphoresis; hyperthermia, which is exacerbated by prolonged muscular rigidity or seizure activity; tachycardia; mydriasis; and blood pressure lability including hypertension and hypotension. Electrocardiographic changes such as QTc prolongation have been reported specifically in citalopram ingestions.

Peripheral findings

Peripheral findings may include increased gastrointestinal motility (eg, diarrhea or hyperactive bowel sounds), coagulopathy (disseminated intravascular coagulation in severe cases), and increased vascular tone.

Serotonin toxicity versus other toxicities

Physical examination findings are helpful in distinguishing serotonin toxicity from other toxic ingestions (although ingestion of multiple agents in suicide attempts can make physical findings less reliable).

Neuroleptic malignant syndrome, associated with dopamine antagonists, has a slower onset of symptoms than SS and is associated with bradykinesia and "lead-pipe" muscular rigidity, rather than hyperkinesias and tremors.

Anticholinergic toxicity involves dry, erythematous skin; enlarged pupils (mydriasis); decreased bowel sounds; and normal reflexes, in contrast to serotonin toxicity, which includes diaphoresis, increased bowel sounds, diarrhea, and hyperreflexia.

Contributor Information and Disclosures

Tracy A Cushing, MD, MPH, FACEP, FAWM Assistant Professor and Attending Physician, Department of Emergency Medicine, University of Colorado School of Medicine

Tracy A Cushing, MD, MPH, FACEP, FAWM is a member of the following medical societies: American College of Emergency Physicians, Society for Academic Emergency Medicine, Wilderness Medical Society

Disclosure: Nothing to disclose.


Theodore I Benzer, MD, PhD Assistant Professor in Medicine, Harvard Medical School; Director of the ED Observation Unit, Director of Toxicology, Chair of Quality and Safety, Department of Emergency Medicine, Massachusetts General Hospital

Theodore I Benzer, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Emergency Physicians

Disclosure: Nothing to disclose.

Monica Noori, MD Resident Physician, Department of Emergency Medicine, Denver Health

Monica Noori, MD is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, Emergency Medicine Residents' Association

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Additional Contributors

Howard Kim, MD Resident Physician, Department of Emergency Medicine, Denver Health Medical Center

Disclosure: Nothing to disclose.


John G Benitez, MD, MPH Associate Professor, Department of Medicine, Medical Toxicology, Vanderbilt University Medical Center; Managing Director, Tennessee Poison Center

John G Benitez, MD, MPH is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Medical Toxicology, American College of Preventive Medicine, Society for Academic Emergency Medicine, Undersea and Hyperbaric Medical Society, and Wilderness Medical Society

Disclosure: Nothing to disclose.

Miguel C Fernandez, MD, FAAEM, FACEP, FACMT, FACCT Associate Clinical Professor, Department of Surgery/Emergency Medicine and Toxicology, University of Texas School of Medicine at San Antonio; Medical and Managing Director, South Texas Poison Center

Miguel C Fernandez, MD, FAAEM, FACEP, FACMT, FACCT is a member of the following medical societies: American Academy of Emergency Medicine, American College of Clinical Toxicologists, American College of Emergency Physicians, American College of Medical Toxicology, American College of Occupational and Environmental Medicine, Society for Academic Emergency Medicine, and Texas Medical Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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