Med/Psych Update

Differentiating serotonin syndrome and neuroleptic malignant syndrome

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Symptoms can overlap, but accurate diagnosis is critical because treatments are distinct.



Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are each rare psychiatric emergencies that can lead to fatal outcomes. Their clinical presentations can overlap, which can make it difficult to differentiate between the 2 syndromes; however, their treatments are distinct, and it is imperative to know how to identify symptoms and accurately diagnose each of them to provide appropriate intervention. This article summarizes the 2 syndromes and their treatments, with a focus on how clinicians can distinguish them, provide prompt intervention, and prevent occurrence.

Serotonin syndrome

Mechanism. The decarboxylation and hydroxylation of tryptophan forms serotonin, also known as 5-hydroxytryptamine (5-HT), which can then be metabolized by monoamine oxidase-A (MAO-A) into 5-hydroxyindoleacetic acid (5-HIAA).1Medications can disrupt this pathway of serotonin production or its metabolism, and result in excessive levels of serotonin, which subsequently leads to an overactivation of central and peripheral serotonin receptors.1 Increased receptor activation leads to further upregulation, and ultimately more serotonin transmission. This can be caused by monotherapy or use of multiple serotonergic agents, polypharmacy with a combination of medication classes, drug interactions, or overdose. The wide variety of medications often prescribed by different clinicians can make identification of excessive serotonergic activity difficult, especially because mood stabilizers such as lithium,2 and non-psychiatric medications such as ciprofloxacin and fluconazole, can also contribute. Table 13 lists medications that can cause SS. The pathways that increase serotonin transmission, potentially causing SS, include:

  • inhibition of serotonin uptake (seen with selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], and tricyclic antidepressants [TCAs])
  • inhibition of serotonin metabolism (seen with monoamine oxidase inhibitors [MAOIs])
  • increased serotonin synthesis (seen with stimulants)
  • increased serotonin release (seen with stimulants and opiates)
  • activation of serotonin receptors (seen with lithium)
  • inhibition of certain cytochrome P450 (CYP450) enzymes (seen with ciprofloxacin, fluconazole, etc.).
Medications that can cause serotonin syndrome

It is important to recognize that various serotonergic agents are involved in the CYP450 system. Inhibition of the CYP450 pathway by common antibiotics such as ciprofloxacin, or antifungals such as fluconazole, may result in an accumulation of serotonergic agents and place patients at increased risk for developing SS.

Clinical presentation. The clinical presentation of SS can range from mild to fatal. There is no specific laboratory test for diagnosis, although an elevation of the total creatine kinase (CK) and leukocyte count, as well as increased transaminase levels or lower bicarbonate levels, have been reported in the literature.4

Symptoms of SS generally present within 24 hours of starting/changing therapy and include a triad of mental status changes (altered mental status [AMS]), autonomic instability, and abnormalities of neuromuscular tone. Examples of AMS include agitation, anxiety, disorientation, and restlessness. Symptoms of autonomic instability include hypertension, tachycardia, tachypnea, hyperthermia, diaphoresis, flushed skin, vomiting, diarrhea, and arrhythmias. Symptoms stemming from changes in neuro­muscular tone include tremors, clonus, hyperreflexia, and muscle rigidity.1 The multiple possible clinical presentations, as well as symptoms that overlap with those of other syndromes, can make SS difficult to recognize quickly in a clinical setting.

Sternbach’s diagnostic criteria for serotonin syndrome

Diagnostic criteria. Sternbach’s diagnostic criteria for SS are defined as the presence of 3 or more of the 10 most common clinical features (Table 25). Due to concerns that Sternbach’s diagnostic criteria overemphasized an abnormal mental state (leading to possible confusion of SS with other AMS syndromes), the Hunter serotonin toxicity criteria6 (Figure6) were developed in 2003, and were found to be more sensitive and specific than Sternbach’s criteria. Both tools are often used in clinical practice.

Hunter serotonin toxicity criteria

Treatment. Treatment of SS begins with prompt discontinuation of all sero­tonergic agents. The intensity of treatment depends on the severity of the symptoms. Mild symptoms can be managed with supportive care,3 and in such cases, the syndrome generally resolves within 24 hours.7 Clinicians may use supportive care to normalize vital signs (oxygenation to maintain SpO2 >94%, IV fluids for volume depletion, cooling agents, antihypertensives, benzodiazepines for sedation or control of agitation, etc.). Patients who are more ill may require more aggressive treatment, such as the use of a serotonergic antagonist (ie, cyproheptadine) and those who are severely hyperthermic (temperature >41.1ºC) may require neuromuscular sedation, paralysis, and possibly endotracheal intubation.3

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