An Overview of Neuroleptic Malignant Syndrome (NMS)

A rare syndromic side effect of psychiatric and other drugs

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Neuroleptic malignant syndrome (NMS) is a rare and life-threatening condition that can occur after changes in specific medications, most commonly after increases in psychiatric drugs.

The central nervous system contains many neurons that respond to the neurotransmitter dopamine. Many different medical conditions are characterized by alterations in dopamine systems in the brain. For example, in schizophrenia, certain areas of the brain show changes in dopamine response. This is thought to contribute to such problems as hallucinations.

Conditions such as Parkinson’s disease have other, different problems with dopamine production and stimulation. Both of these conditions are sometimes treated with drugs that affect the dopamine system. In rare circumstances, sudden changes in medications that either block or stimulate dopamine receptors can lead to the symptoms of NMS.

The syndrome was first characterized in the 1960s, soon after the introduction of the first antipsychotic drugs. Fortunately, NMS is less common than it used to be. This is partly due to the introduction of newer “second-generation” antipsychotic drugs, which are less likely to cause the syndrome.

NMS can occur in people of all ages, and it seems to be more common in males than in females.

Symptoms

The symptoms of NMS may start out gradually and worsen over a few days. Two of the classic symptoms of NMS are muscular rigidity and extremely elevated body temperature. Some other potential symptoms include:

  • Tremor
  • Muscle cramps
  • Agitation
  • Disorientation (and other mental symptoms)
  • Unstable blood pressure
  • Increased heart rate
  • Increased rate of breathing
  • Increased sweating
  • Skin flushing or paleness
  • Incontinence
  • Unusual physical movements
  • Kidney failure (from the breakdown of muscle tissue)
  • Coma (if the condition continues untreated)

Not everyone with NMS will have all of these symptoms, however. For example, muscle rigidity and elevated body temperature may not occur in someone with NMS from an “atypical” antipsychotic drug. NMS may be more difficult to diagnose in someone without these classic symptoms.

Unfortunately, if not diagnosed and treated promptly, NMS can be fatal (from respiratory failure, heart rhythm abnormalities, or other problems).

Causes

Neuroleptic malignant syndrome is an unusual side effect from particular drugs that affect the dopamine system. Researchers still aren’t sure why only a small percentage of people taking these drugs ever develop NMS.

Most commonly, NMS occurs after a person is given a drug that blocks dopamine receptors. An example is the drug haloperidol, used to help treat schizophrenia and some other psychiatric conditions. Drugs like haloperidol can have positive effects, such as reducing hallucinations. However, in NMS, something triggers a potentially devastating side effect from the drug.

NMS is more likely to occur after sudden changes in these drugs. For example, a person given a rapid increase in a dopamine-blocking drug may be more likely to experience NMS. Long-acting drugs and high-dose drugs may also be more likely to trigger NMS. NMS may also be more likely for people taking more than one of these types of drugs. Less commonly, NMS can occur when a person is on a long-term stable dose of a drug such as haloperidol.

NMS is more common with older “typical” antipsychotics like haloperidol. However, more recently developed anti-psychotic drugs (sometimes called “atypical” antipsychotics) may also trigger NMS in certain situations.

Other types of drugs that affect dopamine receptors can also cause NMS. For example, certain drugs to prevent vomiting (such as metoclopramide) also block certain dopamine receptors. Sometimes increasing these drugs can lead to NMS as well.

In other cases, NMS can occur after a drug is stopped or dramatically decreased. Drugs such as levodopa can be given to help increase dopamine stimulation. For example, levodopa can be used to treat someone with Parkinson’s disease. If a person stops, steps down, or switches these types of medications, NMS might occur.

In other words, NMS has its greatest potential risk when increasing the dose of a dopamine-blocking drug (like haloperidol) or decreasing the dose of a dopamine-stimulating drug. In both cases, a person is receiving less dopamine stimulation than before.

Exactly why this can trigger NMS is still not completely clear. It probably involves a complex series of physiological events. The abrupt change in stimulation to dopamine receptors seems to dysregulate the autonomic nervous system (part of your body that regulates many unconscious bodily functions). This is what leads to problems such as increased pulse and breathing rate. Changes in dopamine may also lead to unexpected effects on muscle cells, triggering muscular rigidity.

These are some of the other drugs that can cause NMS when increased:

  • Other “typical” antipsychotic drugs (e.g., fluphenazine and chlorpromazine)
  • “Atypical" Antipsychotic drugs (e.g., olanzapine and risperidone)
  • Other antiemetic drugs (like promethazine)
  • Certain antidepressants (like citalopram and desipramine)
  • Lithium salts (for mood stabilization)
  • Valproate (anticonvulsant drug)

Other drugs that stimulate dopamine (like amantadine) may also trigger NMS when decreased or removed.

Diagnosis

The diagnosis of NMS is sometimes difficult, as it can resemble other conditions. For example, doctors must rule out medical problems that may have some similar symptoms, like heat stroke, central nervous system infection, or drug intoxication. Other drug-induced syndromes, like serotonin syndrome, also must be eliminated as possibilities. Serotonin syndrome can cause symptoms quite similar to NMS. However, it is triggered by a different type of drug: selective serotonin reuptake inhibitors.

The clinical exam and medical history provide important starting points. Critically, NMS is only a possibility if the individual was taking one of the medications that can lead to NMS.

A number of laboratory tests can aid with diagnosis, partly by eliminating other diagnostic possibilities. These tests also may help in monitoring potential complications. Some potentially helpful tests might include:

  • Lumbar puncture (to check for infection)
  • Blood tests of creatinine phosphokinase (product of muscle breakdown often elevated in NMS)
  • Brain imaging (to assess other potential causes)
  • Basic blood work to assess electrolytes, blood acid levels, immune response, organ functioning, etc.
  • Electroencephalogram (EEG, to assess for seizures)

Fortunately, due to greater awareness of the condition, people tend to be diagnosed more quickly than they were in the past. This has reduced long-term problems and death rate from the syndrome.

Treatment

Neuroleptic malignant syndrome is a medical emergency and it must be treated as quickly as possible. Affected individuals need close monitoring in an intensive care unit.

The initial step is stopping the dopamine-blocking drug that triggered the problem. If the NMS was instead triggered by stopping a dopamine-stimulating drug (like for Parkinson’s disease), the drugs should be restarted. Other supportive treatments may include:

  • Intravenous fluids and electrolytes
  • Cooling treatments (such as cooling blankets) to lower body temperature
  • Dopamine-stimulating drugs (like bromocriptine mesylate)
  • Muscle relaxants (like dantrolene sodium)
  • Benzodiazepine drugs (to control agitation)
  • Anti-arrhythmic drugs (for heart rhythm problems, if needed)
  • Mechanical ventilation, if needed

In the large majority of cases, NMS can be managed successfully and the affected person will recover within a couple of weeks with no long-term consequences. However, sometimes there are permanent problems related to NMS, such as kidney failure.

NMS is fatal in roughly 10 percent of cases (with higher rates in the elderly and in people with other significant medical conditions, like congestive heart failure).

Monitoring for NMS

Unfortunately, there is not now a way to predict which people who start these types of drugs will experience NMS. Genetic factors may play a role, but these are not yet known.

It is important to be aware of the condition if you or someone you care about is taking a medication with a risk of triggering NMS. It is important to monitor people who have recently started dopamine-blocking drugs for early symptoms. This is especially important for people who have started injectable, long-acting medications.

It is also important to monitor people with Parkinson’s who are stopping medication or changing their treatment regimen. This careful monitoring can lead to early diagnosis and treatment.

After Neuroleptic Malignant Syndrome

Although most people who experience NMS never have another episode, some people may, especially if proper precautions are not followed.

If a person experiences NMS, it is important not to restart a similar drug too soon. Generally speaking, one needs to wait at least a couple of weeks before resuming treatment. Then your physician can slowly reintroduce a drug using careful monitoring. Typically, people are started on a related drug that is not the same one originally associated with triggering NMS.

What to Do

If you are concerned about NMS or a recurrence of NMS, talk to your doctor. Don’t stop taking medications without first consulting with your treatment team—that might lead to other major problems. But you may be able to use another medication with a lower risk of NMS. For example, you might be able to switch from an older drug to a newer “atypical” antipsychotic drug. Or you might be able to use a lower dose of the drug you are taking, lowering the risk of NMS. Don’t hesitate to bring up all your concerns with your healthcare team.

A Word From Verywell

Neuroleptic malignant syndrome is a rare but very serious potential syndrome that can result from certain medications—particular certain psychiatric medications. Talk to your healthcare provider about whether NMS is a potential risk in your situation. Learn about the condition so you know how best to be aware of it. Watch for early signs and symptoms, and get help right away if you have concerns. If you or a loved one does experience NMS, know that there are a team of health care professionals available to help you through this crisis. 

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Article Sources
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