Neuroleptic malignant syndrome (NMS) is a rare condition that develops in response to the use of psychiatric medications. The development of NMS is unpredictable and the cause not clearly defined, though research shows abnormal brain chemistry plays an important role. Symptoms of the syndrome are acute, and life-threatening complications can develop if medical attention is delayed. People with NMS require prompt diagnosis and treatment to make a full recovery with no lasting effects.

The Development of Neuroleptic Malignant Syndrome

Nearly all cases of neuroleptic malignant syndrome develop within 30 days of beginning the offending medication, most within several days or a week. The development of NMS occurs with nearly all types of a specific class of medications. All instances of NMS develop in a predictable pattern, regardless of the specific prescription, with the same symptoms and complications. Symptoms usually peak within three days.

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Neuroleptics are used in the treatment of schizophrenia, schizoaffective disorder, and, occasionally, bipolar disorder and severe depression. Neuroleptics treat symptoms of psychosis, primarily hallucinations and delusions; they are antidopaminergics, psychiatric drugs that inhibit the activity of nerves by blocking dopamine receptors. Neuroleptics are designated first-generation, or typical, and second-generation, or atypical.

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Causes and the Role of Dopamine

Other medications are also linked to the development of neuroleptic malignant syndrome, including anti-nausea and anti-vomiting drugs and those that treat involuntary muscle movement. Additionally, abruptly discontinuing medications that act on dopamine receptors can lead to NMS. Why NMS develops in some and not others is still a topic of study, but researchers know that inhibition of the D2 dopamine receptor in the brain and spinal cord is a contributor. Dopamine is a neurotransmitter instrumental in relaying information in the central nervous system (CNS). Blocked receptors in structures of the CNS underlie the acute symptoms and complications of NMS.

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Symptoms of Neuroleptic Malignant Syndrome

Muscle rigidity and high fever are the hallmark symptoms of neuroleptic malignant syndrome. Mood, mental status, and the autonomic nervous system (ANS), which regulates involuntary functions such as blood pressure and heart rate, may also be affected. Symptoms include

  • Agitation
  • Confusion
  • Paranoia
  • Erratic blood pressure
  • Abnormally high heart and respiratory rates
  • Increased sweating and saliva production

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The most common complication of neuroleptic malignant syndrome is kidney damage or failure due to musculature effects. When a muscle is injured, it releases cellular contents into the bloodstream, namely myoglobin and creatine phosphokinase (CPK). High levels of myoglobin and CPK in the bloodstream can lead to complications of the kidney, including acute renal failure. Muscle injury can also lead to the development of blood clots in the vessels. Other critical complications include aspiration pneumonia, cardiopulmonary failure, heart attack, and sepsis.

neuroleptic NMS complications kidney muscle Pichitchai Chanpen / Getty Images


Risk Factors

Several factors increase one's risk of developing neuroleptic malignant syndrome. Taking a neuroleptic in high doses or taking multiple neuroleptics puts a person at higher risk. Certain non-antidopaminergic drugs taken in combination with a neuroleptic may lead to the development of NMS. Instability in dosing and noncompliance are also contributing factors. Case studies in NMS have revealed additional risk factors, including

  • Having a structural or functional brain disorder
  • Trauma
  • Physical exhaustion
  • Use of psychoactive substances or alcohol
  • Malnutrition and iron deficiency

Underlying genetic causes can also raise the risk of NMS, suggesting there are hereditary links.

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A doctor diagnoses neuroleptic malignant syndrome based primarily on symptoms and a person's history of prescription drug use. Symptoms of NMS are similar to those of other conditions, including meningitis and sepsis, so the physician will often eliminate these diseases first. A doctor may perform a urine or blood test to check for signs of complications.

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Treating Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome can quickly turn critical, so immediate treatment is crucial. Stopping the use of the offending drug is the first priority, followed by intensive supportive care, including fever reduction, hydration, and restoration of nutrients.Doctors will treat complications individually. In cases of acute NMS, the physician may prescribe a dopamine receptor agonist and muscle relaxant to increase dopamine activity in the brain and reduce muscle rigidity.

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Treatment Outcomes

Delayed medical care in neuroleptic malignant syndrome may lead to a longer recovery period, long-term complications, or death. Immediate and intensive treatment, however, significantly reduces this risk. If diagnosed and treated within 14 days of symptom development, a person with NMS is typically expected to make a full recovery with no lasting effects. Repeated episodes are not uncommon, though doctor and patient can significantly reduce the chance of recurrence by delaying re-administration of the neuroleptic drug for at least two weeks following the episode. This lowers the chance of recurrence from 60% to 30%.

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Medical Advancements

Since the identification of neuroleptic malignant syndrome in the 1950s, increased awareness in the medical field, dedicated research, and the development of new neuroleptics continue to improve the prevention and treatment of the condition. The prevalence of NMS has decreased from 3.2% to .02% in the last fifty years. The rate of mortality, too, has decreased from 30% to 10%.

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