Drugs That Cause Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome is a life-threatening neurological disorder most often caused by neuroleptic (antipsychotic) medications, which are used to treat schizophrenia and certain other psychiatric disorders, among other things.[1] The syndrome also can be caused by certain other drugs used to treat nausea and depression, as well as by the sudden discontinuation of a dopamine agonist (drugs that are used most commonly to treat Parkinson’s disease).

Patients taking any drugs associated with neuroleptic malignant syndrome need to watch vigilantly for the symptoms of the disorder and seek immediate medical attention if they experience such symptoms.

Neuroleptic malignant syndrome overview

Signs and symptoms of neuroleptic malignant syndrome include the following:

• high fever
• excessive sweating
• stupor (impaired consciousness and markedly decreased responsiveness)
• muscle rigidity or stiffness
• unstable blood pressure, which may lead to dizziness and fainting upon standing
• irregular heart rate or pulse
• [2]

In most cases, the syndrome occurs within the first two weeks of treatment with the causative drug. However, patients may develop the disorder at any time during therapy: It may occur after a single dose of a causative drug[3] or after taking the same dose of the drug for years.

Treatment for neuroleptic malignant syndrome usually requires management in an intensive care unit.[4] The most important elements of therapy are discontinuation of the causative drug and aggressive fever control. In some cases, a muscle relaxant may be used.

Common major acute complications of neuroleptic malignant syndrome include rhabdomyolysis (muscle breakdown), respiratory failure and kidney injury, which may require dialysis treatment.[5]

The unstable blood pressure seen with neuroleptic malignant syndrome, as well as acute complications of the disorder, can lead to death.[6] Early studies from the 1960s reported that more than 75% of patients with the syndrome died.[7] The death rate has declined substantially since then, with one U.S. study published in 2016 showing an in-hospital death rate of less than 10% from 2002 to 2011.[8]

Antipsychotics

The first case of neuroleptic malignant syndrome was reported in 1956 in a patient taking chlorpromazine,[9] a first-generation (typical) antipsychotic that was approved by the Food and Drug Administration (FDA) in 1957 and marketed originally under the brand name THORAZINE and is now available in generic forms only.

The risk of neuroleptic malignant syndrome is greatest with the high-potency first-generation antipsychotics (for example, fluphenazine [available in generic only] and haloperidol [HALDOL]), but the syndrome can be caused by any of the FDA-approved antipsychotics (see Table 1, below, for a list).[10] Depending on the drug, the reported incidence rates of the syndrome have ranged from 0.02% to 3% of patients taking antipsychotic medications.[11]

The exact mechanism by which antipsychotic drugs cause neuroleptic syndrome is not well understood. It may be related to the ability of these drugs to block the activity of dopamine, a chemical in the brain known as a neurotransmitter that sends signals from one nerve cell to another.[12]

Table 1: List of FDA-Approved Antipsychotics

*Designated as Limited Use by Worst Pills, Best Pills News
**Not evaluated by Worst Pills, Best Pills News
***Designated as Do Not Use by Worst Pills, Best Pills News
†Brand-name product that contains another active ingredient.

Other drugs

Table 2 below lists examples of other medications by drug category that are associated with the development of neuroleptic malignant syndrome. In general, these drugs are much less likely to cause this syndrome than antipsychotics.

Table 2: Examples of Other Drugs Associated With Neuroleptic Malignant Syndrome

*Designated as Limited Use by Worst Pills, Best Pills News
**Not evaluated by Worst Pills, Best Pills News
***Designated as Do Not Use by Worst Pills, Best Pills News
†Brand-name product that contains another active ingredient.

Drugs for nausea

Several drugs that are used to treat or prevent nausea can cause neuroleptic malignant syndrome.[13] Similar to antipsychotic medications, these anti-nausea drugs work, in part, by blocking the activity of dopamine.[14],[15],[16]

Although metoclopramide (REGLAN) often is used to treat nausea, the FDA has not approved it for this use.[17] The FDA has approved it for treatment of diabetic gastroparesis, a condition that occurs in patients with diabetes and causes nausea, vomiting, loss of appetite, heartburn and a feeling of fullness after meals. The drug also is approved to treat patients with gastroesophageal reflux (a condition in which the stomach contents flow backward into the esophagus, causing heartburn) who have failed first-line therapies like antacids and drugs that suppress stomach acid.

Antidepressants

Numerous drugs from different classes of antidepressants have been linked to neuroleptic malignant syndrome, including certain older tricyclic antidepressants (for example, nortriptyline [PAMELOR]) and newer selective serotonin reuptake inhibitors (for example, citalopram [CELEXA]). There is evidence that several of these drugs block dopamine activity.[18],[19],[20],[21]

Parkinson’s disease drugs

In contrast to all the other medications discussed in this article, the dopamine agonist drugs that are routinely used to treat Parkinson’s disease can lead to neuroleptic malignant syndrome when they are discontinued suddenly or their dosage is reduced rapidly.[22] Such discontinuation of these drugs leads to a rapid decrease in brain dopamine levels. Some of these drugs, including pramipexole (MIRAPEX) and ropinirole (REQUIP), also are used to treat restless legs syndrome.

Lithium

Use of the mood-stabilizing drug lithium (LITHOBID), which is used to treat bipolar disorder, has been associated with neuroleptic malignant syndrome, but usually when taken in combination with antipsychotics.[23]

What You Can Do

If you are taking any of the drugs discussed in this article (or discontinuing any dopamine agonists for Parkinson’s disease or restless legs syndrome), you should seek immediate medical attention if you develop the symptoms associated with neuroleptic malignant syndrome that are listed above.
 

References

[1] National Institute of Neurological Disorders and Stroke. Neuroleptic malignant syndrome information page. March 27, 2019. https://www.ninds.nih.gov/Disorders/All-Disorders/Neuroleptic-Malignant-Syndrome-Information-Page. Accessed March 10, 2021.

[2] Ibid.

[3] Wijdicks EF. Neuroleptic malignant syndrome. UpToDate. May 31, 2019.

[4] National Institute of Neurological Disorders and Stroke. Neuroleptic malignant syndrome information page. March 27, 2019. https://www.ninds.nih.gov/Disorders/All-Disorders/Neuroleptic-Malignant-Syndrome-Information-Page. Accessed March 10, 2021.

[5] Modi S, Dharaiya D, Schultz L, Varelas P. Neuroleptic malignant syndrome: Complications, outcomes, and mortality. Neurocrit Care. 2016;24(1):97-103.

[6] Wijdicks EF. Neuroleptic malignant syndrome. UpToDate. May 31, 2019.

[7] Ibid.

[8] Modi S, Dharaiya D, Schultz L, Varelas P. Neuroleptic malignant syndrome: Complications, outcomes, and mortality. Neurocrit Care. 2016;24(1):97-103.

[9] Berman BD. Neuroleptic malignant syndrome: A review for neurohospitalists. Neurohospitalist. 2011;1(1):41-47.

[10] Wijdicks EF. Neuroleptic malignant syndrome. UpToDate. May 31, 2019.

[11] Ibid.

[12] Ibid.

[13] Wijdicks EF. Neuroleptic malignant syndrome. UpToDate. May 31, 2019.

[14] National Library of Medicine. Droperidol. February 20, 2020. https://pubchem.ncbi.nlm.nih.gov/compound/Droperidol. Accessed March 10, 2021.

[15] ANI Pharmaceuticals. Label: metoclopramide (REGLAN). August 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/017854s062lbl.pdf. Accessed March 10, 2021.

[16] Din L, Preuss CV. Prochlorperazine. February 17, 2021. https://www.ncbi.nlm.nih.gov/books/NBK537083/. Accessed March 10, 2021.

[17] ANI Pharmaceuticals. Label: metoclopramide (REGLAN). August 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/017854s062lbl.pdf. Accessed March 10, 2021.

[18] Hellings JA, Arnold LE, Han JC. Dopamine antagonists for treatment resistance in autism spectrum disorders: review and focus on BDNF stimulators loxapine and amitriptyline. Expert Opin Pharmacother. 2017;18(6):581-588.

[19] Actavis Pharma, Inc. Label: amoxapine. February 2015. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=a16297df-3158-48db-85e5-5cd506885556&type=display. Accessed March 10, 2021.

[20] Suhara T, Inoue O, Kobayasi K. Effect of desipramine on dopamine receptor binding in vivo. Life Sci. 1990;47(23):2119-2126.

[21] Gross G, Xin X, Gastpar M. Trimipramine: pharmacological reevaluation and comparison with clozapine. Neuropharmacology. 1991;30(11):1159-1166.

[22] Wijdicks EF. Neuroleptic malignant syndrome. UpToDate. May 31, 2019.

[23] Patil V, Gupta R, Verma R, Balhara YP. Neuroleptic malignant syndrome associated with lithium toxicity. Oman Med J. 2016;31(4):309-311.