Neuroleptic Malignant Syndrome: Pathophysiology, Recognition, Atypical Variants, and Distinction from Serotonin Syndrome

Scope

This review covers adult neuroleptic malignant syndrome (NMS): its mechanism, the agents that cause it, predisposing factors, the classic and atypical clinical spectrum, evidence-based treatment, and the clinical and laboratory features that separate it from serotonin syndrome (SS) and other hyperthermic toxidromes. A recurring theme is that both entities are clinical diagnoses without a pathognomonic test, and that the physical examination, particularly the neuromuscular findings, carries more discriminating weight than any laboratory value (Boyer & Shannon, 2005; Wijdicks & Ropper, 2024).

Pathophysiology

NMS is a rare, idiosyncratic reaction to dopamine-blocking (or dopamine-depleting) agents driven by central dopamine D2 receptor blockade across several circuits (Chun et al., 2016; Wijdicks & Ropper, 2024). Hypothalamic D2 blockade raises the thermoregulatory set point and impairs heat dissipation; nigrostriatal and spinal D2 antagonism produces rigidity and tremor; and loss of tonic dopaminergic inhibition of the sympathetic nervous system produces autonomic instability (Chun et al., 2016; Wijdicks & Ropper, 2024). At the muscle level, sustained rigidity drives excess heat generation and calcium release from the sarcoplasmic reticulum, causing rhabdomyolysis and CK elevation, but there is no primary skeletal muscle defect, which distinguishes NMS mechanistically from malignant hyperthermia (Chun et al., 2016; Oruch et al., 2017; Wijdicks & Ropper, 2024). Supporting evidence includes reduced CSF homovanillic acid during acute episodes and the fact that abrupt dopamine-agonist withdrawal reproduces the syndrome (Guinart et al., 2021). Because clozapine, which has weak D2 affinity, can still cause NMS, pure D2 blockade is an incomplete explanation, and many experts now regard NMS as a form of malignant catatonia precipitated by dopamine antagonism, given shared features and shared response to benzodiazepines and ECT (Kuhlwilm et al., 2020; Sachdev et al., 1995; Wilson et al., 2025).

Incidence is roughly 0.01–0.04% of antipsychotic-treated patients, and mortality has fallen from historical rates near 76% to under 10–15% with modern recognition and intensive care, though it remains 10–20% when the diagnosis is missed (Chun et al., 2016; Jeste et al., 2022; Kuhlwilm et al., 2020).

Causative Agents

High-potency first-generation antipsychotics (haloperidol, fluphenazine, pimozide) carry the greatest risk (incidence ~0.2%, mortality 10–20%) (Factor et al., 2019; Wijdicks & Ropper, 2024). Second-generation agents (clozapine, olanzapine, risperidone, quetiapine, aripiprazole) cause NMS less often (~0.006%) and with lower mortality (3–5.5%) (Factor et al., 2019; Trollor et al., 2012; Wijdicks & Ropper, 2024). Critically, non-psychiatric dopamine blockers used in general medicine are frequently overlooked culprits: metoclopramide, prochlorperazine, droperidol, promethazine, and domperidone, plus the dopamine-depleter tetrabenazine (Jeste et al., 2022; Le Quang et al., 2024; Robottom et al., 2011; Wijdicks & Ropper, 2024). Finally, abrupt withdrawal of dopaminergic therapy (levodopa, amantadine) precipitates a clinically identical picture termed parkinsonism-hyperpyrexia syndrome (Chun et al., 2016; Factor et al., 2019; Kuhlwilm et al., 2020).

Clinical Features and Diagnostic Criteria

The classic tetrad is hyperthermia, "lead-pipe" rigidity, autonomic instability, and altered mental status (Chun et al., 2016; Jeste et al., 2022; Wijdicks & Ropper, 2024). Temperature commonly exceeds 38°C and can surpass 41°C; rigidity is uniform ("lead pipe") and typically unresponsive to antiparkinsonian agents; autonomic signs include tachycardia, labile blood pressure, diaphoresis, and sialorrhea; and mental status ranges from agitated delirium to alert mutism and stupor (Chun et al., 2016; Jeste et al., 2022; Wijdicks & Ropper, 2024). A clinically important point is the temporal sequence: altered consciousness and extrapyramidal signs are often the earliest manifestations, with fever, CK elevation, and dysautonomia following, and severity peaking over 48–72 hours (Jeste et al., 2022; Schneider et al., 2020; Wijdicks & Ropper, 2024). Onset is typically 1–3 days after drug initiation or dose change (median ~4 days), with nearly all cases within 30 days and generally within 72 hours of exposure per DSM-5 (Jeste et al., 2022; Kuhlwilm et al., 2020; Wijdicks & Ropper, 2024).

Laboratory findings are supportive but nonspecific: CK often >4× ULN and frequently >16,000 IU/L, leukocytosis (15,000–30,000/mm³), elevated transaminases and LDH, metabolic acidosis, and characteristically low serum iron (Chun et al., 2016; Guinart et al., 2021; Jeste et al., 2022; Su et al., 2014). Complications include rhabdomyolysis with AKI (up to 30%), aspiration, respiratory failure, DIC, and venous thromboembolism (Chun et al., 2016; Kuhlwilm et al., 2020; Wijdicks & Ropper, 2024).

DSM-5 criteria require dopamine-blocker exposure plus rigidity and fever, with at least two additional features (diaphoresis, dysphagia, tremor, incontinence, altered consciousness, mutism, tachycardia, labile BP, leukocytosis, elevated CK) (Kuhlwilm et al., 2020; Wijdicks & Ropper, 2024). The 2011 international Delphi consensus instead uses weighted priority points out of 100: dopamine antagonist exposure/agonist withdrawal (20), hyperthermia (18), rigidity (17), mental status change (13), CK ≥4× ULN (10), sympathetic lability (10), hypermetabolism (5), and negative alternative workup (7), reinforcing that no single feature is mandatory (Chun et al., 2016; Gurrera et al., 2011).

Predisposing and Risk Factors

Risk is multiplied by both pharmacologic and patient-related factors. The strongest and most consistent modifiable factor is dehydration (Chun et al., 2016; Jeste et al., 2022; Kuhlwilm et al., 2020; Wijdicks & Ropper, 2024).

Category	Specific Factors	References
Pharmacologic	High-potency FGAs; high doses and rapid titration; parenteral/IM administration; depot formulations; antipsychotic polypharmacy; concomitant lithium	(Berardi et al., 1998; Chun et al., 2016; Jeste et al., 2022; Kuhlwilm et al., 2020; Wijdicks & Ropper, 2024)
Patient-related	Dehydration; psychomotor agitation/exhaustion; preexisting catatonia; male sex (~2:1); age <40; organic brain disease/dementia; iron deficiency; prior NMS episode; postpartum state	(Berardi et al., 1998; Chun et al., 2016; Jeste et al., 2022; Kuhlwilm et al., 2020; Schneider et al., 2020; Su et al., 2014)
Heightened sensitivity states	Dementia with Lewy bodies, intellectual disability, anti-NMDA receptor encephalitis ("neuroleptic intolerance" in ~47%)	(Su et al., 2014; Wijdicks & Ropper, 2024)
Genetic	DRD2 TaqI A1 allele and −141C Del polymorphism (Japanese cohorts); CYP2D6 variants (inconsistent)	(Kato et al., 2007; Kishida et al., 2004; Suzuki et al., 2001; Wijdicks & Ropper, 2024)

Notably, NMS occurs within the therapeutic dose range and is not related to overdose or duration of exposure, and prior episodes recur in 15-20%, suggesting individual vulnerability (Chun et al., 2016; Jeste et al., 2022). Genetic associations derive from small, predominantly Japanese cohorts and are inconsistently replicated; the 2024 NEJM review concluded that CYP2D6 slow-metabolizer variants apparently do not confer increased risk overall (Wijdicks & Ropper, 2024).

Distinguishing NMS from Serotonin Syndrome

The two syndromes overlap in hyperthermia, autonomic instability, and altered mentation, but differ fundamentally in mechanism, tempo, and, most usefully at the bedside, the neuromuscular examination. SS reflects excess serotonergic activity (principally 5-HT2A stimulation) and is a dose-dependent, predictable phenomenon, whereas NMS is idiosyncratic (Boyer & Shannon, 2005; Chun et al., 2016; Gillman, 2005). SS is precipitated by SSRIs, SNRIs, MAOIs, TCAs, opioids (tramadol, fentanyl, meperidine, methadone), triptans, linezolid, methylene blue, dextromethorphan, MDMA, and St. John's wort; the most dangerous combinations involve an MAOI with any serotonin reuptake inhibitor (Bai et al., 2022; Blyzniuk et al., 2026; Boyer & Shannon, 2005; Gillman, 2005).

Feature	NMS	Serotonin Syndrome	Malignant Hyperthermia	Anticholinergic Toxicity	References
Trigger	Dopamine blocker / agonist withdrawal	Serotonergic agent(s)	Volatile anesthetic / succinylcholine	Antimuscarinic agent	(Boyer & Shannon, 2005; Evans et al., 2010; Wijdicks & Ropper, 2024)
Onset	1–3 days	Minutes–hours (<24 h)	Minutes–hours	<12 h	(Chun et al., 2016; Evans et al., 2010)
Muscle tone	Lead-pipe rigidity, all groups	Increased tone, lower-limb predominant	Rigor-like rigidity	Normal	(Boyer & Shannon, 2005; Evans et al., 2010; Wijdicks & Ropper, 2024)
Reflexes	Normal / decreased	Hyperreflexia, clonus	Hyporeflexia	Normal	(Evans et al., 2010; Wijdicks & Ropper, 2024)
Pupils	Normal	Mydriasis	Normal	Mydriasis	(Evans et al., 2010; Kawai et al., 2017)
Bowel sounds	Normal / decreased	Hyperactive	Decreased	Absent	(Boyer & Shannon, 2005; Evans et al., 2010)
Skin	Pallor, diaphoresis	Diaphoresis	Mottled	Hot, dry, red	(Boyer & Shannon, 2005; Evans et al., 2010)
CK / leukocytosis	Markedly elevated	Less prominent	Elevated	Normal	(Chun et al., 2016; Perry & Wilborn, 2012; Wijdicks & Ropper, 2024)

Diagnosis of SS rests on the Hunter Serotonin Toxicity Criteria (sensitivity 84%, specificity 97%), which require a serotonergic agent plus any of: spontaneous clonus; inducible clonus with agitation/diaphoresis; ocular clonus with agitation/diaphoresis; tremor with hyperreflexia; or hypertonia with temperature >38°C and ocular/inducible clonus (Chun et al., 2016; Dunkley et al., 2003).

Two caveats deserve emphasis. First, in severe SS, extreme hypertonicity can mask clonus and hyperreflexia, rendering it clinically indistinguishable from NMS (Boyer & Shannon, 2005; Factor et al., 2019). Second, some agents (e.g., metoclopramide) have both antidopaminergic and serotonergic activity, and simultaneous NMS and SS has been reported (Wijdicks & Ropper, 2024). When a patient is taking both classes, the laboratory profile (pronounced CK elevation, leukocytosis, transaminitis, and low serum iron) favors NMS (Perry & Wilborn, 2012). Malignant hyperthermia is separated by its anesthetic context, rising end-tidal CO2, and rigor-like rigidity, and anticholinergic toxicity by dry skin, absent bowel sounds, and normal reflexes (Boyer & Shannon, 2005; Evans et al., 2010; Wijdicks & Ropper, 2024).

Atypical Presentations

NMS is best conceptualized as a dimensional spectrum rather than an all-or-none diagnosis; roughly half the cases in the AMSP pharmacovigilance program followed an "abortive course" not meeting full ICD-10/DSM-IV criteria, and DSM-5 deliberately softened the criteria to capture early or partial forms (Schneider et al., 2020). Recognizing these variants is where the diagnosis is most often missed.

Second-generation antipsychotics produce a largely similar picture to FGAs with one key exception: less rigidity and fewer extrapyramidal signs, a difference driven predominantly by clozapine, and considerably lower mortality (3.0% vs 16.3%) (Trollor et al., 2012). Clozapine-associated NMS characteristically presents with tachycardia, mental-status change, and diaphoresis while fever, rigidity, and CK elevation are attenuated or absent (Gurrera et al., 2022; Karagianis et al., 1999; Shin et al., 2025; Wijdicks & Ropper, 2024). Aripiprazole, a partial D2 agonist, has caused afebrile NMS and even a "brief" form lasting only hours, and quetiapine frequently presents without rigidity (Chen & Bae, 2025; Mizumura et al., 2017; Szota et al., 2022). Among SGAs, an FAERS analysis found ziprasidone carried the strongest signal and lurasidone the weakest (He et al., 2025).

Afebrile NMS (~8% of cases) and NMS without rigidity or with normal/mildly elevated CK are well described, particularly with SGAs, since CK may be normal at outset and rise only days into the illness (Jurawan & Eachnie, 2026; Picard et al., 2008; Szota et al., 2022; Wijdicks & Ropper, 2024). CK is inherently nonspecific; up to 70% of psychosis inpatients have elevated CK without NMS (Scott et al., 2024). The practical rule from Picard et al. is to not prematurely exclude NMS when severe rigidity or hyperthermia is absent, as these may be early or impending forms (Picard et al., 2008).

Parkinsonism-hyperpyrexia syndrome (PHS) is the mirror-image mechanism: an NMS-identical crisis triggered by abrupt reduction or cessation of dopaminergic therapy in Parkinson disease (non-compliance, perioperative withholding, dysphagia/malabsorption, DBS battery failure, amantadine withdrawal) (Dos Santos et al., 2021; Factor et al., 2019; Hocker et al., 2013; Pötter-Nerger et al., 2024; Wijdicks & Ropper, 2024). It occurs in 0.3–3.6% of PD patients with 4–15% mortality, and, critically, its treatment is rapid reintroduction of dopaminergic therapy rather than dopamine blockade withdrawal (Factor et al., 2019; Newman et al., 2009; Robottom et al., 2011). In a dementia clinic series, levodopa discontinuation caused 12 of 19 NMS episodes (Isik et al., 2023).

Antiemetic-induced NMS (metoclopramide, prochlorperazine, droperidol, promethazine) is especially treacherous because the offending drug is not being used for psychosis and clinicians may not recognize its dopamine-blocking properties; these cases occur even at standard doses and often lack typical lab abnormalities (Robottom et al., 2011; Tee, 2024; Wijdicks & Ropper, 2024; Wittmann et al., 2016). Older adults with dementia are highly vulnerable, with atypical presentations in ~67% and frequent concurrent infection that confounds a diagnosis of exclusion (Isik et al., 2023).

Treatment

No randomized controlled trials exist for any NMS-specific therapy; all recommendations derive from case series, retrospective cohorts, and expert consensus (Schönfeldt-Lecuona et al., 2020; Suekane et al., 2026). Management is severity-guided, and the foundation for both syndromes is immediate withdrawal of the offending agent plus aggressive supportive care. For NMS, the essential steps are: (1) stop the dopamine blocker (or, in PHS, reinstate the dopaminergic agent); (2) supportive care, including IV fluids targeting urine output ~200–300 mL/h for rhabdomyolysis, cooling and acetaminophen for hyperthermia, correction of electrolytes and acidosis, DVT and stress-ulcer prophylaxis, and ICU-level airway/autonomic support (clonidine, calcium-channel blockers, or dexmedetomidine to avoid reintroducing antipsychotics); and (3) severity-tiered pharmacotherapy (Chen & Bae, 2025; Chun et al., 2016; Wijdicks & Ropper, 2024).

Agent	Role / Severity	Dosing	Notes	References
Lorazepam	First-line, mild–moderate	1–2 mg IM/IV q4–6h	Also treats catatonia; safe	(Chen & Bae, 2025; Chun et al., 2016; Wijdicks & Ropper, 2024)
Dantrolene	Moderate–severe rigidity/hyperthermia	1 mg/kg IV, then 0.25–0.75 mg/kg q6h; max 10 mg/kg/day	Hepatotoxic; mixed mortality data	(Chun et al., 2016; Kuhlwilm et al., 2020; Le Quang et al., 2024; Wijdicks & Ropper, 2024)
Bromocriptine	Dopamine agonist, moderate–severe	2.5 mg q6–8h, up to 40 mg/day	Contraindicated in SS	(Boyer & Shannon, 2005; Chen & Bae, 2025; Chun et al., 2016)
Amantadine	Dopaminergic alternative	100 mg PO, up to 200 mg q12h	Also anticholinergic	(Chen & Bae, 2025; Chun et al., 2016)
ECT	Refractory / life-threatening	Bitemporal, daily if severe	Lowest mortality in severe NMS series	(Kuhlwilm et al., 2020; Wijdicks & Ropper, 2024; Wilson et al., 2025)

Evidence for specific pharmacotherapy is genuinely conflicting: a 405-patient case-series analysis found no overall mortality benefit for dantrolene but a significant benefit for specific therapy (dantrolene, bromocriptine, or ECT) in severe NMS (10% vs 30% mortality), whereas a nationwide Japanese cohort and a VA analysis found higher mortality with dantrolene, almost certainly confounding by indication (Kuhlwilm et al., 2020; Suekane et al., 2026). After recovery, antipsychotics should be resumed only after at least 2 weeks, using a different, lower-potency agent at low dose with slow titration; premature rechallenge is the principal recurrence risk, though documented recurrence rates are low (~4%) (Lally et al., 2019; Susman & Addonizio, 1988; Wijdicks & Ropper, 2024).

For serotonin syndrome, treatment is likewise tiered: discontinue serotonergic agents, give benzodiazepines at every severity level (essential for agitation and the hyperadrenergic component), and add cyproheptadine, a 5-HT2A antagonist, for moderate-to-severe cases at 12 mg initially, then 2 mg q2h as needed, maintenance 8 mg q6h (max ~32 mg/day) (Boyer & Shannon, 2005; Pande et al., 2019). Severe SS with temperature >41.1°C requires sedation, nondepolarizing neuromuscular paralysis (avoid succinylcholine), and intubation, because the hyperthermia is muscle-generated and antipyretics have no role (Boyer & Shannon, 2005; Chun et al., 2016). Physical restraints should be avoided as they worsen isometric muscle activity and lactic acidosis (Boyer & Shannon, 2005). Several NMS therapies are actively contraindicated or unhelpful in SS: bromocriptine (may worsen serotonergic signs), dantrolene, and propranolol (Boyer & Shannon, 2005).

Feature	NMS	Serotonin Syndrome	References
Onset / resolution	Days to weeks / 7–11 days	Hours / usually <24 h	(Boyer & Shannon, 2005; Chun et al., 2016; Wijdicks & Ropper, 2024)
Benzodiazepines	First-line mild–moderate	Essential at all levels	(Boyer & Shannon, 2005; Wijdicks & Ropper, 2024)
Specific antidote	Dantrolene / bromocriptine / amantadine	Cyproheptadine	(Boyer & Shannon, 2005; Chun et al., 2016)
ECT	Refractory cases	Not indicated	(Boyer & Shannon, 2005; Wijdicks & Ropper, 2024)
Antipyretics	May help (central hyperthermia)	No role (muscular heat)	(Boyer & Shannon, 2005; Wijdicks & Ropper, 2024)
Mortality	5–15%	~5%	(Factor et al., 2019; Wijdicks & Ropper, 2024)

Evidence Gaps

The pathophysiology remains incompletely explained: the low recurrence rate on rechallenge and the occurrence of NMS with low-D2-affinity clozapine both argue against a simple D2-blockade model (Sachdev et al., 1995; Wijdicks & Ropper, 2024). No RCTs guide NMS pharmacotherapy, optimal dosing and duration are undefined, and observational mortality data on dantrolene are heavily confounded (Kuhlwilm et al., 2020; Suekane et al., 2026). The evidence for cyproheptadine in SS is very low quality, limited to case reports (King & Rotella, 2025; Nguyen et al., 2019). Whether atypical/abortive NMS represents early disease or a distinct entity, and precisely where NMS ends and malignant catatonia begins, remain unresolved (Kuhlwilm et al., 2020; Szota et al., 2022; Wilson et al., 2025).

Summary

NMS is a dopamine-blockade–driven hyperthermic emergency defined by lead-pipe rigidity, fever, dysautonomia, and altered mentation evolving over days, with markedly elevated CK (Chun et al., 2016; Wijdicks & Ropper, 2024). It is most reliably separated from serotonin syndrome by its slower tempo and its hypokinetic, hyporeflexic motor picture, versus the rapid-onset clonus, hyperreflexia, and myoclonus of SS (Boyer & Shannon, 2005; Wijdicks & Ropper, 2024). Clinicians should maintain a low threshold for the diagnosis in atypical presentations (clozapine/aripiprazole cases lacking rigidity or fever, antiemetic-induced cases, and parkinsonism-hyperpyrexia from dopaminergic withdrawal) because these are where recognition most often fails (Picard et al., 2008; Robottom et al., 2011; Trollor et al., 2012). Treatment for both syndromes begins with drug withdrawal and supportive care, then diverges: dantrolene/dopaminergics/ECT and benzodiazepines for NMS, versus benzodiazepines and cyproheptadine for SS, with several NMS drugs contraindicated in SS (Boyer & Shannon, 2005; Wijdicks & Ropper, 2024).

References

• Bai, A. D., McKenna, S., Wise, H., Loeb, M., & Gill, S. S. (2022). Association of linezolid with risk of serotonin syndrome in patients receiving antidepressants. JAMA Network Open, 5(12), e2247426.
• Berardi, D., Amore, M., Keck, P. E., Troia, M., & Dell'Atti, M. (1998). Clinical and pharmacologic risk factors for neuroleptic malignant syndrome: A case-control study. Biological Psychiatry, 44(8), 748-754.
• Blyzniuk, B., Danukalo, M., Gastaldon, C., et al. (2026). Precipitants and clinical features of serotonin syndrome: A systematic review with patient-level analysis of published case reports and series. European Journal of Clinical Pharmacology, 82(8), 210.
• Boyer, E. W., & Shannon, M. (2005). The serotonin syndrome. The New England Journal of Medicine, 352(11), 1112-1120.
• Chen, A., & Bae, M. (2025). Lorazepam in managing atypical neuroleptic malignant syndrome: A systematic review of case reports. The Western Journal of Emergency Medicine, 26(5), 1446-1453.
• Chun, T. H., Mace, S. E., Katz, E. R., et al. (2016). Evaluation and management of children with acute mental health or behavioral problems. Part II: Recognition of clinically challenging mental health related conditions presenting with medical or uncertain symptoms. Pediatrics, 138(3), e20161573.
• Dos Santos, D. T., Imthon, A. K., Strelow, M. Z., Pille, A., & Schumacher-Schuh, A. F. (2021). Parkinsonism-hyperpyrexia syndrome after amantadine withdrawal: Case report and review of the literature. The Neurologist, 26(4), 149-152.
• Dunkley, E. J., Isbister, G. K., Sibbritt, D., Dawson, A. H., & Whyte, I. M. (2003). The Hunter serotonin toxicity criteria: Simple and accurate diagnostic decision rules for serotonin toxicity. QJM, 96(9), 635-642.
• Evans, R. W., Tepper, S. J., Shapiro, R. E., Sun-Edelstein, C., & Tietjen, G. E. (2010). The FDA alert on serotonin syndrome with use of triptans combined with selective serotonin reuptake inhibitors or selective serotonin-norepinephrine reuptake inhibitors: American Headache Society position paper. Headache, 50(6), 1089-1099.
• Factor, S. A., Burkhard, P. R., Caroff, S., et al. (2019). Recent developments in drug-induced movement disorders: A mixed picture. The Lancet Neurology, 18(9), 880-890.
• Gillman, P. K. (2005). Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. British Journal of Anaesthesia, 95(4), 434-441.
• Guinart, D., Misawa, F., Rubio, J. M., et al. (2021). A systematic review and pooled, patient-level analysis of predictors of mortality in neuroleptic malignant syndrome. Acta Psychiatrica Scandinavica, 144(4), 329-341.
• Gurrera, R. J., Caroff, S. N., Cohen, A., et al. (2011). An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method. The Journal of Clinical Psychiatry, 72(9), 1222-1228.
• Gurrera, R. J., Gearin, P. F., Love, J., et al. (2022). Recognition and management of clozapine adverse effects: A systematic review and qualitative synthesis. Acta Psychiatrica Scandinavica, 145(5), 423-441.
• He, J., Luo, X., Li, C., et al. (2025). Investigation into neuroleptic malignant syndrome triggered by atypical antipsychotics: Insights from FDA Adverse Event Reporting System Database. Journal of Affective Disorders, 386, 119481.
• Hocker, S., Kenney, D. L., & Ramar, K. (2013). Parkinsonism-hyperpyrexia syndrome: Broadening our differential diagnosis in the ICU. Neurology Clinical Practice, 3(6), 535-538.
• Isik, A. T., Kaya, D., Ontan, M. S., et al. (2023). Neuroleptic malignant syndrome in patients with dementia: Experiences of a single memory clinic. Clinical Neuropharmacology, 46(6), 209-213.
• Jeste, D. V., Lieberman, J. A., Fassler, D., et al. (2022). Diagnostic and statistical manual of mental disorders. American Psychiatric Association.
• Jurawan, K. T., & Eachnie, N. M. (2026). EP16.184: Atypical neuroleptic malignant syndrome in early pregnancy. Ultrasound in Obstetrics & Gynecology, 68(Suppl 1), 415-416.
• Karagianis, J. L., Phillips, L. C., Hogan, K. P., & LeDrew, K. K. (1999). Clozapine-associated neuroleptic malignant syndrome: Two new cases and a review of the literature. The Annals of Pharmacotherapy, 33(5), 623-630.
• Kato, D., Kawanishi, C., Kishida, I., et al. (2007). Effects of CYP2D6 polymorphisms on neuroleptic malignant syndrome. European Journal of Clinical Pharmacology, 63(11), 991-996.
• Kawai, Y., DeMonbrun, A. G., Chambers, R. S., et al. (2017). A previously healthy adolescent with acute encephalopathy and decorticate posturing. Pediatrics, 139(1), e20153779.
• King, E., & Rotella, J. A. (2025). Review article: Efficacy of cyproheptadine in the management of serotonin toxicity following deliberate self-poisoning: a systematic review. Emergency Medicine Australasia, 37(1), e14554.
• Kishida, I., Kawanishi, C., Furuno, T., et al. (2004). Association in Japanese patients between neuroleptic malignant syndrome and functional polymorphisms of the dopamine D(2) receptor gene. Molecular Psychiatry, 9(3), 293-298.
• Kuhlwilm, L., Schönfeldt-Lecuona, C., Gahr, M., et al. (2020). The neuroleptic malignant syndrome: a systematic case series analysis focusing on therapy regimes and outcome. Acta Psychiatrica Scandinavica, 142(3), 233-241.
• Lally, J., McCaffrey, C., O'Murchu, C., et al. (2019). Clozapine rechallenge following neuroleptic malignant syndrome: A systematic review. Journal of Clinical Psychopharmacology, 39(4), 372-379.
• Le Quang, M., Solé, G., Martin-Négrier, M. L., & Mathis, S. (2024). Clinical and pathological aspects of toxic myopathies. Journal of Neurology, 271(9), 5722-5745.
• Mizumura, N., Uematsu, M., Ito, A., et al. (2017). "Brief" aripiprazole-induced neuroleptic malignant syndrome with symptoms that only lasted a few hours. Internal Medicine, 56(22), 3089-3092.
• Newman, E. J., Grosset, D. G., & Kennedy, P. G. (2009). The parkinsonism-hyperpyrexia syndrome. Neurocritical Care, 10(1), 136-140.
• Nguyen, H., Pan, A., Smollin, C., Cantrell, L. F., & Kearney, T. (2019). An 11-year retrospective review of cyproheptadine use in serotonin syndrome cases reported to the California Poison Control System. Journal of Clinical Pharmacy and Therapeutics, 44(2), 327-334.
• Oruch, R., Pryme, I. F., Engelsen, B. A., & Lund, A. (2017). Neuroleptic malignant syndrome: An easily overlooked neurologic emergency. Neuropsychiatric Disease and Treatment, 13, 161-175.
• Pande, C. K., O'Halloran, A., Stewart, R. W., Nguyen, A., & Canares, T. (2019). Case 2: Agitation and abnormal movements in a 14-year-old boy. Pediatrics in Review, 40(10), 532-534.
• Perry, P. J., & Wilborn, C. A. (2012). Serotonin syndrome vs neuroleptic malignant syndrome: A contrast of causes, diagnoses, and management. Annals of Clinical Psychiatry, 24(2), 155-162.
• Picard, L. S., Lindsay, S., Strawn, J. R., et al. (2008). Atypical neuroleptic malignant syndrome: Diagnostic controversies and considerations. Pharmacotherapy, 28(4), 530-535.
• Pötter-Nerger, M., Löhle, M., Höglinger, G., & German Parkinson's Guideline Group. (2024). Akinetic crisis and withdrawal syndromes: Guideline "Parkinson's disease" of the German Society of Neurology. Journal of Neurology, 271(10), 6485-6493.
• Robottom, B. J., Weiner, W. J., & Factor, S. A. (2011). Movement disorders emergencies part 1: Hypokinetic disorders. Archives of Neurology, 68(5), 567-572.
• Sachdev, P., Kruk, J., Kneebone, M., & Kissane, D. (1995). Clozapine-induced neuroleptic malignant syndrome: Review and report of new cases. Journal of Clinical Psychopharmacology, 15(5), 365-371.
• Schneider, M., Regente, J., Greiner, T., et al. (2020). Neuroleptic malignant syndrome: Evaluation of drug safety data from the AMSP program during 1993–2015. European Archives of Psychiatry and Clinical Neuroscience, 270(1), 23-33.
• Schönfeldt-Lecuona, C., Kuhlwilm, L., Cronemeyer, M., et al. (2020). Treatment of the neuroleptic malignant syndrome in international therapy guidelines: A comparative analysis. Pharmacopsychiatry, 53(2), 51-59.
• Scott, F. A. M., Butler, M., & Rogers, J. P. (2024). The limited clinical utility of a routine creatine kinase (CK) on admission to a psychiatric inpatient unit. BMC Psychiatry, 24(1), 908.
• Shin, M. H., Jeong, J. W., & Yu, T. Y. (2025). Concurrence of clozapine-induced diabetic ketoacidosis and neuroleptic malignant syndrome: A case report. Medicine, 104(34), e44172.
• Su, Y. P., Chang, C. K., Hayes, R. D., et al. (2014). Retrospective chart review on exposure to psychotropic medications associated with neuroleptic malignant syndrome. Acta Psychiatrica Scandinavica, 130(1), 52-60.
• Suekane, A., Senda, A., Morishita, K., & Fushimi, K. (2026). Clinical outcomes of dantrolene in neuroleptic malignant syndrome: A nationwide retrospective study. Acta Psychiatrica Scandinavica, 153(6), 627-635.
• Susman, V. L., & Addonizio, G. (1988). Recurrence of neuroleptic malignant syndrome. The Journal of Nervous and Mental Disease, 176(4), 234-241.
• Suzuki, A., Kondo, T., Otani, K., et al. (2001). Association of the TaqI a polymorphism of the dopamine D(2) receptor gene with predisposition to neuroleptic malignant syndrome. The American Journal of Psychiatry, 158(10), 1714-1716.
• Szota, A. M., Radajewska, I., & Araszkiewicz, A. S. (2022). Atypical neuroleptic malignant syndrome: Case reports and diagnostic challenges. Journal of Psychoactive Drugs, 54(3), 284-293.
• Tee, Z. J. (2024). Prochlorperazine-induced neuroleptic malignant syndrome. The American Journal of Emergency Medicine, 81, 160.e1-160.e2.
• Trollor, J. N., Chen, X., Chitty, K., & Sachdev, P. S. (2012). Comparison of neuroleptic malignant syndrome induced by first- and second-generation antipsychotics. The British Journal of Psychiatry, 201(1), 52-56.
• Wijdicks, E. F. M., & Ropper, A. H. (2024). Neuroleptic malignant syndrome. The New England Journal of Medicine, 391(12), 1130-1138.
• Wilson, J. E., Oldham, M. A., Francis, A., et al. (2025). Resource document on catatonia. American Psychiatric Association.
• Wittmann, O., Sadot, E., Bisker-Kassif, O., et al. (2016). Neuroleptic malignant syndrome associated with metoclopramide use in a boy: Case report and review of the literature. American Journal of Therapeutics, 23(5), e1246-1249.