Neuroleptic Malignant Syndrome vs Serotonin Syndrome

Neuroleptic malignant syndrome (NMS) and serotonin syndrome (SS) are drug-induced crises that affect the central nervous system (CNS).¹ Neuroleptic malignant syndrome is a rare, potentially fatal idiosyncratic reaction to dopamine antagonists that leads to reduced dopamine activity and a cascade of serious symptoms.¹ Serotonin syndrome is a reaction characterized by increased serotonin activity, usually as the result of the concurrent use of medications that directly or indirectly increase serotonin levels in the brain.² These 2 syndromes can be challenging to differentiate because they share certain symptoms, such as altered mental status, hyperthermia, and muscle rigidity.³ However, because their treatments are distinct, an accurate diagnosis is essential.¹ This article explores the similarities and differences between NMS and SS, including their causes, clinical features, and management strategies. 

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome is caused by pharmacological inhibition of dopamine activity in the CNS.⁴ Although patients usually develop symptoms of NMS within 72 hours of receiving a dopamine antagonist, the condition can arise at any time, including within 24 hours of the initiation of therapy or after years of receiving a stable, therapeutic dose.^2,5,6 Neuroleptic malignant syndrome requires immediate intervention to prevent death.² The estimated mortality rate of NMS ranges from 5.6% to 10%.^5,7

Causes

Dopamine is required for the initiation of movement and inhibition of unwanted movement. It also plays a role in stimulating the hypothalamus, a brain region involved in temperature regulation and autonomic nervous system functioning. Dysregulation of dopamine receptors in some brain regions can result in psychiatric symptoms, including symptoms of schizophrenia. Because they block dopamine receptors, many antipsychotic medications have the potential to cause NMS.³ This includes older, first-generation antipsychotic medications such as haloperidol as well as the more commonly prescribed second-generation (atypical) antipsychotics.⁴ 

In addition to antipsychotic use, cessation of levodopa (L-dopa) for Parkinson’s treatment has resulted in NMS.³ Because dopamine is synthesized from L-dopa, decreasing L-dopa can lead to a decrease in dopamine in the CNS.

Symptoms of Neuroleptic Malignant Syndrome

The symptoms of NMS usually develop slowly within a few days to 2 weeks of starting a new antipsychotic medication or increasing the dose.^4,7 The most common symptoms of NMS include the following^3,5-7:

• Muscle rigidity (“lead pipe” rigidity, meaning the muscles resist passive motion);
• Hyperthermia (greater than 100.4 °F or 38.0 °C on at least 2 occasions);
• Autonomic dysfunction (diaphoresis, tachycardia, tachypnea, and labile blood pressure); and
• Altered mental status (delirium, agitation, mutism, somnolence, coma).

Neuroleptic Malignant Syndrome Diagnosis

The diagnosis of NMS is mainly clinical, and primarily involves taking a thorough history, evaluating the timing and characteristics of symptoms, and excluding other possible conditions.⁵ A gradual onset of symptoms that starts with mental status changes and proceeds to muscle rigidity, hyperthermia, and autonomic dysfunction is a common pattern of NMS.⁵ Although there is no single laboratory finding that is specific to NMS, patients may exhibit leukocytosis, metabolic acidosis, hypoxia, decreased serum iron concentrations, and elevations in serum muscle enzymes and catecholamines.⁶

Treatment of Neuroleptic Malignant Syndrome

The first-line treatment for patients with NMS is to stop the triggering dopaminergic medication and provide aggressive supportive care to stabilize the patient’s vital signs.^2,4,7 Cooling blankets and ice packs can be used to address hyperthermia.⁷ In many cases, NMS resolves within a few days to 2 weeks of discontinuing the triggering medication.^1,2

For patients with moderate to severe NMS, a dopamine agonist such as bromocriptine or the muscle relaxant dantrolene may be helpful.^1,2,4,5 Benzodiazepines can be used to alleviate muscle rigidity and sympathetic overactivity.^4,7 If muscle rigidity affects the airways, intubation may be necessary.¹ Electroconvulsive therapy has been used to treat patients with moderate to severe NMS, but evidence supporting its efficacy is limited.¹

One challenge in treating NMS is that many patients who develop NMS will require ongoing treatment with an antipsychotic medication. Once NMS has subsided, clinicians should wait at least 2 weeks before starting a patient on a different antipsychotic.¹ In these situations, a low dose of a second-generation antipsychotic should be slowly titrated, and the patient should be monitored closely during reintroduction.

Serotonin Syndrome

Serotonin syndrome is a pharmacologically induced condition driven by excessive serotonin in the brain.² It produces a combination of neuropsychiatric symptoms, autonomic system dysfunction, and neuromuscular abnormalities. The onset of symptoms usually occurs quickly, within hours of a medication change, overdose, or new drug exposure.^2,5 Serotonin syndrome can be life-threatening, but this is rare.²

Causes

Serotonin syndrome usually is caused by the use of a drug or combination of drugs that trigger increased serotonergic activity in the CNS.² This includes medications with the following mechanisms related to serotonin¹:

• Inhibition of serotonin uptake (selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], and tricyclic antidepressants [TCAs]);
• Inhibition of serotonin metabolism (monoamine oxidase inhibitors [MAOIs]);
• Increased serotonin synthesis (stimulants);
• Increased serotonin release (stimulants and opiates);
• Activation of serotonin receptors (lithium); and
• Inhibition of certain cytochrome P450 (CYP450) enzymes (ciprofloxacin, fluconazole). 

Serotonin syndrome also can be induced by the use of illicit drugs such as 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) and lysergic acid diethylamide (LSD), as well as over-the-counter supplements such as St. John’s wort.^1,3,5 The condition can be the result of monotherapy with a serotonergic medication, polypharmacy, drug interactions, or overdose.¹

Symptoms of Serotonin Syndrome

The 3 hallmarks of SS are mental status changes, autonomic dysfunction, and neuromuscular abnormalities.⁵ The following are the most common symptoms of SS^2,4,5:

• Anxiety; 
• Agitation;
• Confusion;
• Delirium;
• Hallucinations;
• Hyperthermia;
• Diaphoresis;
• Hypertension;
• Clonus;
• Muscle rigidity;
• Hyperreflexia;
• Pupil dilations;
• Tachypnea;
• Tachycardia; and
• Tremor.

Less common but more serious symptoms can include the following:

• Coma;
• Multi-organ failure;
• Seizures; and
• Rhabdomyolysis.

Serotonin Syndrome Diagnosis

Because there is no laboratory test to conclusively diagnose SS, diagnosis depends on the patient’s clinical presentation, known drug exposures, and the differential diagnosis.² Two sets of criteria are used to establish the diagnosis: Sternbach’s diagnostic criteria for SS, and the Hunter serotonin toxicity criteria.¹ Sternbach’s criteria require the presence of at least 3 of 10 common SS symptoms, as well as inclusion and exclusion criteria based on previous medication use.¹ 

Because Sternbach’s criteria strongly emphasize the patient’s mental state, the Hunter criteria are considered to be more accurate.¹ The Hunter criteria require the patient to be taking a serotonergic agent (of any kind) and take into account the presence of coinciding neuromuscular and autonomic abnormalities. According to these criteria, SS would be diagnosed in a patient taking a serotonergic medication who exhibits any of the following¹:

• Spontaneous clonus;
• Inducible clonus with agitation or diaphoresis;
• Ocular clonus with agitation or diaphoresis;
• Tremor and hyperreflexia; or
• Hypertonia, temperature above 100.4 °F (38.0 °C), and ocular or inducible clonus.

Treatment of Serotonin Syndrome

Treatment begins with discontinuing the triggering serotonergic agent(s).¹ Mild cases can be treated with supportive care and often resolve within 24 to 72 hours after the causative agent is stopped.^1,2 For patients with moderate or severe SS, the serotonin 2A antagonist cyproheptadine may be used, and/or benzodiazepines for symptom management.^2,4

NMS vs Serotonin Syndrome: Key Differences

Neuroleptic malignant syndrome and SS can be challenging to differentiate because their symptoms overlap.^1,3 In addition, patients with psychiatric disorders frequently are treated with a combination of medications, including antipsychotics (which can block dopamine) and antidepressants (which can increase serotonin activity).⁵ However, a careful medication history and evaluation of symptoms can detect notable differences in the triggering agents, rate of onset of symptoms, and presence and characteristics of specific symptoms.¹

Medication History

A thorough review of the patient’s medication use can help identify drugs or drug combinations that could cause NMS or SS.¹ In addition to first- and second-generation antipsychotics, other dopamine antagonists that could cause NMS include antiemetic agents (domperidone, droperidol, metoclopramide, prochlorperazine, promethazine), and certain antidepressants and mood stabilizers, particularly when they are used in combination with other medications that affect dopamine.¹

Serotonin syndrome can be triggered by any drug that enhances serotonergic activity. This includes several common classes of antidepressants (SSRIs, SNRIs, TCAs, and MOAIs), bupropion, stimulants, opiates, lithium, metoclopramide, valproate, carbamazepine, sibutramine,

dextromethorphan, cyclobenzaprine, and illicit drugs such as MDMA and LSD.¹ 

Onset of Symptoms

The onset of symptoms usually is much quicker in SS than in NMS. Serotonin syndrome tends to occur within 24 to 72 hours of starting or changing a medication, and the symptoms are rapidly progressive.^1,4,5 The symptoms of NMS typically develop slowly over days.^1,4,5

NMS vs Serotonin Syndrome: Differences in Symptoms

While both NMS and SS can cause autonomic nervous system dysfunction and impaired cognition, there are some differences in the patient’s presentation. The most notable difference is the specific motor symptoms. Neuroleptic malignant syndrome is a hypokinetic condition, and patients present with a sluggish motor response.^1,5 In contrast, SS is a hyperkinetic condition, and patients present with neuromuscular hyperactivity (clonus, hyperreflexia).^1,5 In addition, patients with NMS may exhibit normal pupil size and normal bowel sounds, whereas patients with SS present with dilated pupils and hyperactive bowel activity.³

NMS and Serotonin Syndrome Differential Diagnosis 

In addition to being differentiated from each other, NMS and SS need to be distinguished from other malignant syndromes that can cause similar symptoms. These conditions include the following²:

• Malignant hyperthermia;
• Malignant catatonia;
• Acute akinesia;
• Withdrawal syndromes;
• Anticholinergic syndrome; and
• Anticholinergic syndrome.

These potentially life-threatening malignant syndromes result in rapid systemic dysfunction, including hyperthermia, altered mental status, autonomic instability, and severe muscle rigidity or spasms.² Despite these shared features, these syndromes have distinct pathophysiological mechanisms and require highly targeted treatments.²

Prevention of NMS and Serotonin Syndrome

Clinicians who prescribe antipsychotics and/or antidepressants need to have a thorough knowledge of the risks of these medications. They also should be familiar with the symptoms of NMS and SS, educate patients about these symptoms, and closely monitor patients when starting or changing any medication.

To prevent SS, a prescribing clinician should take care to fully understand the patient’s medical and personal history. Do they use illicit substances? What over-the-counter supplements do they take? Is the patient already taking a medication that enhances serotonin activity? For NMS, does the patient require an antipsychotic? If so, can they be started on a lower dose? 

References

1. Turner AH, Kim JJ, McCarron RM. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry. 2019;18(2):30-36.
2. Cuccarelli M, Zampogna A, Suppa A. The broad spectrum of malignant syndromes. Neurobiol Dis. 2024;203:106734. doi:10.1016/j.nbd.2024.106734
3. Sweileh WM. Neuroleptic malignant syndrome and serotonin syndrome: A comparative bibliometric analysis. Orphanet J Rare Dis. 2024;19(1):221. doi:10.1186/s13023-024-03227-5
4. Maktabi L, Shipman D, Reinert JP. Serotonin syndrome and neuroleptic malignant syndrome: A case report of intersecting symptomatology. Ment Health Clin. 2024;14(1):23-27. doi:10.9740/mhc.2024.02.023
5. Tormoehlen LM, Rusyniak DE. Neuroleptic malignant syndrome and serotonin syndrome. Handb Clin Neurol. 2018;157:663-675. doi:10.1016/B978-0-444-64074-1.00039-2
6. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR). American Psychiatric Association Publishing. Published February 2022. Accessed May 29, 2025. https://www.appi.org/dsm5tr
7. Tan CM, Kumachev A. Neuroleptic malignant syndrome. CMAJ. 2023;195(43):E1481. doi:10.1503/cmaj.221763