14th February 2025

Neuroleptic malignant syndrome and serotonin syndrome

Overview of neuroleptic malignant syndrome (NMS)

Rather than a psychiatric presentation, NMS is an uncommon iatrogenic condition resulting from the medications used to treat psychiatric conditions. It is a medical emergency and requires rapid intervention.

The single most important diagnostic factor is the presence of relevant psychotropic drug treatment:

• Presence of dopamine modulator therapy, especially if started or increased in the last 10 days: 
  • Antipsychotics, especially first generation, e.g. haloperidol
  • Antidepressants, especially tricyclic antidepressants, e.g. amitriptyline, imipramine
  • Metoclopramide, lithium, amantadine, tolcapone
• Cessation of dopamine agonists, usually Parkinson’s treatments, e.g. levodopa, bromocriptine, ropinirole

Risk factors include male sex and pre-existing brain pathology, e.g. Parkinson’s, dementia, delirium, traumatic injury.

Diagnosis of NMS

Examination in NMS

Typical features on examination include:

• Altered conscious level, e.g. agitation, confusion, coma
• Autonomic instability, e.g. hyperthermia (sweating), tachycardia, tachypnoea, labile blood pressure, drooling
• Respiratory distress
• Muscle rigidity*: lead-pipe rigidity, dysphagia

Presentation of NMS is very similar to SS, and some drugs can cause both. The main discriminators are the longer onset time in NMS from drug initiation or dose change, and features marked with *.

Investigations in NMS

NMS is a clinical diagnosis with no specific test, although the below support diagnosis and screen for complications.

Bedside tests:

• ECG: NMS and associated metabolic changes and autonomic instability can trigger cardiac issues
• Urinalysis: myoglobinuria indicates poor prognosis

Blood tests:

• FBC, U&Es, LFTs, clotting, blood cultures: for AKI, electrolyte abnormalities, infection, liver failure
• Creatine kinase (CK): 4x above upper limit of normal range due to muscle damage (non-specific)
• Blood gas: screen for respiratory failure
• Blood glucose: rule out hypoglycaemia

Tests to rule out infection or other causes of confusion should be considered, e.g. CXR, CT head, LP.

Management of NMS

The most important step is to stop the psychotropic drug trigger or, in cases triggered by cessation of dopamine agonists, to restart the dopamine agonist.

Supportive care includes IV or oral rehydration, NGT insertion if dysphagia is limiting food, fluid and medication intake, and cooling. Physical cooling measures must be used as antipyretics are ineffective. Invasive measures might be required in severe hyperthermia, such as cold fluid gastric lavage or intravascular cooling.

Rhabdomyolysis should be treated if present.

Pharmacological treatment may include:

• Sedation: with agitation, severe hyperthermia or poor toleration of therapy consider a benzodiazepine
• Dopamine agonist (bromocriptine or amantadine) or dantrolene (postsynaptic muscle relaxant)

Escalation to ICU (intensive care unit) is required with severe hyperthermia >38.5℃, ineffective ventilation due to muscle rigidity, AKI or coma.

After recovery from the acute illness psychotropic drugs should not be started for 2 weeks, and the causative agent should be avoided.

Overview of serotonin syndrome

As with NMS, this is an iatrogenic toxicity condition resulting from the medications used to treat psychiatric conditions. It shows a spectrum of severity and can be a medical emergency.

Diagnosis of SS

The single most important diagnostic factor is the presence of serotonergic drugs, particularly if started or increased in the past 24 hours. This might be in the form of:

• Serotonergic drug therapy
  • Selective serotonin reuptake inhibitors (SSRI), e.g. fluoxetine, paroxetine, sertraline, citalopram
  • Serotonin and norepinephrine reuptake inhibitors (SNRI), e.g. duloxetine, venlafaxine
  • Other antidepressants: imipramine
  • Opioids: tramadol, fentanyl
  • Monoamine oxidase inhibitors (MAO-I)
  • Others: lithium, lamotrigine, tryptophan
  • Drug interactions: multiple serotonergic drug therapy increases the likelihood of SS
• Illicit drug use, e.g. amphetamines, methamphetamine, ecstasy, cocaine
• Deliberate or accidental overdose of the above

Examination in SS

Typical features may include the following, but anywhere along the spectrum of severity:

• Altered conscious level: anxiety, agitation, confusion, coma
• Autonomic instability: hyperthermia, tachycardia, hyper/hypotension, sweating, mydriasis*
• Respiratory distress
• Neuromuscular excitability*: clonus, progression to spontaneous clonus (can appear similar to muscle rigidity or a generalised tonic-clonic seizure), tremor, hyperreflexia

Presentation of SS is very similar to NMS, and some drugs can cause both SS and NMS. The main discriminators are the shorter onset time in SS from drug initiation or dose change and features marked with *.

Investigations in SS

NMS is a clinical diagnosis with no specific test, although the below support diagnosis and screen for complications.

Bedside tests:

• ECG: autonomic instability can trigger cardiac issues
• Urine toxicology screen: for illicit drug causes of SS

Blood tests:

• FBC, U&Es, LFTs, clotting, blood cultures: screen for infection
• Blood glucose: rule out hypoglycaemia
• Consider CK if NMS is a differential diagnosis

Tests to rule out infection or other causes of confusion should be considered, e.g. CXR, CT head, LP.

Management of SS

The most important step is to stop the serotonergic drug trigger. In mild cases of SS, dose reduction is another option, and none of the below may be required.

Supportive care includes rehydration and cooling. The latter requires physical measures as antipyretics are ineffective; invasive measures for severe hyperthermia include cold fluid gastric lavage and intravascular cooling.

Pharmacological treatment may include:

• Sedation (one of the following options, from low to high SS severity): cyproheptadine (antihistamine), benzodiazepine ± morphine, propofol
• Activated charcoal: if overdose taken in preceding 1 hour
• Chlorpromazine: first-generation antipsychotic with serotonin antagonist properties (limited evidence)

Escalation to ICU may be required in severe SS for airway management and sedation.

Differential diagnosis of NMS and SS

Key differentials to consider and potentially rule out for both NMS and SS include:

• Sepsis
• Malignant hyperthermia
• Non-convulsive status epilepticus
• Hypoglycaemia
• Delirium

References

• Mitchell J, Jenkins-Welch M, Gurrera R. Neuroleptic malignant syndrome [Internet]. BMJ Best Practice. 2021 [cited 2022 Jan 15]. Available from: https://bestpractice.bmj.com/topics/en-gb/3000227
• Benzer T. Neuroleptic Malignant Syndrome: Practice Essentials, Background, Pathophysiology [Internet]. eMedicine. 2021 [cited 2022 Feb 28]. Available from: https://emedicine.medscape.com/article/816018-overview
• Isbister G. Serotonin syndrome [Internet]. BMJ Best Practice. 2019 [cited 2022 Feb 28]. Available from: https://bestpractice.bmj.com/topics/en-gb/991
• Khan SS, Kattan A. Serotonin Syndrome: Practice Essentials, Problem, Management [Internet]. eMedicine. 2019 [cited 2022 Feb 28]. Available from: https://emedicine.medscape.com/article/2500075-overview