Fever, Rigidity, and Raised CK on Haloperidol and Fluoxetine
Mr E is a 58-year-old man with schizophrenia and obsessive-compulsive symptoms. He takes haloperidol 10 mg/day and fluoxetine 40 mg/day. Over 36 hours he becomes confused and mute, with fever 39.2°C, BP 160/100 mmHg, pulse 120/min, lead-pipe rigidity, coarse tremor, and profuse sweating. He has no clonus or diarrhea. CK is 1,800 U/L, creatinine rises from 80 to 130 µmol/L, and WBC is 14 × 10^9/L. He was given intramuscular haloperidol 10 mg in the emergency department 2 days ago for agitation. A junior doctor suspects serotonin syndrome and plans cyproheptadine. The nursing staff ask whether lorazepam would help. There is no clear history of catatonia, but he is mute and holds his arm in the air for several minutes. His family asks if the antipsychotic caused this. The medical team needs a working diagnosis and immediate management plan.
1. What is the most likely diagnosis, and what features argue for and against the alternatives?
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Neuroleptic malignant syndrome is the most likely diagnosis. The key features are dopamine antagonist exposure, including a recent intramuscular haloperidol dose, followed by confusion, fever, lead-pipe rigidity, autonomic instability, raised CK, and leukocytosis. Fluoxetine inhibits CYP2D6 and can raise haloperidol levels, increasing risk.
Serotonin syndrome is less likely: there is no clonus, hyperreflexia, or diarrhea, and the onset is over 36 hours rather than hours. Cyproheptadine would not be the first treatment. Catatonia is a real differential because he is mute and holds his arm in the air; malignant catatonia can resemble NMS. However, the antipsychotic exposure, rigidity, high CK, and autonomic instability favor NMS. Delirium from infection or metabolic disturbance must be excluded, but it does not fully explain the rigidity and CK rise. The family should be told that the antipsychotic is a likely contributor.
2. What immediate management steps are required?
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Stop haloperidol and fluoxetine immediately. Admit for close monitoring, preferably with critical-care support if autonomic instability or renal impairment progresses. Give supportive care: cooling, intravenous fluids, electrolyte correction, monitoring of CK, renal function, coagulation, and temperature. Treat agitation and rigidity with benzodiazepines such as lorazepam; this is reasonable and may also help if there is a catatonic component.
For severe NMS, dantrolene or bromocriptine may be used according to local protocol, with specialist input. Do not give cyproheptadine unless serotonin syndrome becomes the working diagnosis. Avoid all antipsychotics during the acute episode. If the condition is refractory or malignant catatonia is suspected, ECT should be considered early. The team should also look for complications such as rhabdomyolysis, acute kidney injury, aspiration, and venous thrombosis.
3. How should antipsychotic treatment be handled after recovery, given his schizophrenia and OCD?
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After recovery, the priority is to prevent recurrence. Wait until the CK has normalized, fever and rigidity have resolved, and renal function is stable before considering antipsychotic rechallenge. Avoid high-potency typical antipsychotics such as haloperidol, especially with fluoxetine, because of the pharmacokinetic interaction and the previous severe reaction.
If antipsychotic treatment is essential, use the lowest effective dose of a different agent, start slowly, monitor temperature, CK, and mental state, and ensure hydration. Clozapine may be considered in some NMS histories, but it carries its own risks and requires specialist decision-making. ECT is an alternative for severe psychosis or catatonia and may be safer in selected cases.
His OCD treatment also needs review: fluoxetine and haloperidol interacted, and the overall regimen should be simplified where possible. The plan should be documented and shared with the patient and family, with clear advice to seek urgent review for fever, rigidity, confusion, or reduced urine output.