Antipsychotics and Neuroleptic Malignant Syndrome

Release Date: November 1, 2015

Expiration Date: November 30, 2017

FACULTY:

Mark H. J. Litzinger, BSc, BSc Pharm, RPh
Clinical Instructor of Pharmacy Practice,
School of Pharmacy, Philadelphia College of
Osteopathic Medicine–Georgia, Suwanee, Georgia
Assistant Clinical Professor, Loma Linda
University School of Pharmacy,
Loma Linda, California
Regional Health and Wellness Director,
Walmart Stores, Inc.

Vivian Nguyen, PharmD
Pharmacy Manager, Walmart Stores, Inc.,
Anaheim, California

Katelyn E. Horne, PharmD
Pharmacist, Walmart Stores, Inc.,
Suisun City, California

Larry Rutebuka, PharmD
Pharmacy Manager, Walmart Stores, Inc.
Assistant Clinical Professor, Loma Linda
University School of Pharmacy
Loma Linda, California

Deanna Seiler, PharmD
Senior Manager of Quality Improvement
Walmart Stores, Inc., Chicago, Illinois

Joan Marie Ordonez, PharmD
Pharmacy Manager, Walmart Stores, Inc.
Ontario, California

Rebecca Kiani, PharmD
Pharmacist, Walmart Stores, Inc.
Loma Linda, California
Monica Litzinger, BSc, BSc Pharm, RPh

FACULTY DISCLOSURE STATEMENTS:

The authors have no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
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UAN: 0430-0000-15-053-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

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TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL:

To enhance pharmacists' knowledge on the epidemiology, pathophysiology, and clinical presentation of neuroleptic malignant syndrome (NMS), ultimately increasing awareness of risk factors and symptoms.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Understand the epidemiology and pathophysiology of NMS.
  2. Discuss the clinical features of NMS.
  3. Describe medications that may contribute to the etiology of NMS.
  4. Identify pharmacologic therapies in the treatment of NMS.
  5. Educate pharmacists to counsel patients and caregivers on the risk factors and symptoms of NMS to raise awareness.

ABSTRACT: Neuroleptic malignant syndrome (NMS) is a life-threatening, idiosyncratic condition that often occurs as a complication of the use of antipsychotic drugs. The onset of NMS is often acute, presenting with atypical symptoms and therefore impeding the process of differential diagnosis. NMS is characterized by hyperthermia, muscle rigidity, dysautonomia, and mental status changes. Although the etiology of NMS has not been identified, most studies suggest that NMS is a result of dopamine receptor antagonism in the central nervous system. Dopamine blockade most often occurs in patients treated with neuroleptic medications or selected antiemetic agents or by withdrawal of dopaminergic agents. Treatment involves the discontinuation of the offending agent and supportive therapy. Pharmacists play a crucial role in advising physicians on recognition of early symptoms and therapeutic options or alternatives in NMS treatment.

Neuroleptic malignant syndrome (NMS) was first described in 1960 by French clinicians studying adverse drug reactions associated with haloperidol.1 NMS presents with symptoms of hyperthermia, severe muscle rigidity, and autonomic and mental status changes. It is thought to be linked to dopamine blockade and is often associated with the use of antipsychotics, antidopaminergic drugs, and the abrupt withdrawal of dopaminergic agents. While NMS is statistically insignificant, occurring in only 0.01% to 0.02% of patients treated with antipsychotics, the 10% mortality rate is a major concern for these patients. The mortality rate associated with NMS generally results from dysautonomic manifestations and systemic complications. The U.S. Agency for Healthcare Research and Quality indicates that approximately 2,000 cases of NMS are diagnosed annually in the United States, resulting in an annual healthcare cost of $70 million. Determination of NMS by differential diagnosis and aggressive intervention are key to decreasing the mortality rate.2

PATHOPHYSIOLOGY

Case reports and clinical manifestations support the theory that dopamine-receptor blockade is the central mechanism in NMS.2-5 The dopamine-receptor blockade theory hypothesizes that antipsychotic-induced blockage of dopamine receptors in the hypothalamic, substantia nigrostriatal, and midbrain cortical pathways results in clinical symptoms including hyperthermia, dysautonomia, muscle rigidity, and tremor.3,6,7 Data suggest that other neurotransmitter systems (epinephrine, serotonin, and acetylcholine) may also be directly or indirectly associated with NMS.

Disrupted modulation of the sympathetic nervous system has also been associated with NMS. Patients with NMS often present with a heightened sympathetic nervous system, manifesting as increased muscle tone and metabolism, ineffective heat dissipation, and labile blood pressure and heart rate.2,5,8 It is also thought that antipsychotic medications peripherally promote the release of calcium from the sarcoplasmic reticulum, leading to increased contractility, uncontrolled muscle rigidity, and increased metabolism.1,4 This results in diaphoresis, hyperthermia, rigidity, and muscle cell breakdown.2,5 The true cause is likely complex, involving a cascade of dysregulation in multiple neurochemical and neuroendocrine systems.1

CLINICAL MANIFESTATION

The clinical manifestation of NMS is often heterogeneous and usually occurs within 2 weeks of therapeutic initiation; nearly all cases occur within 30 days.2 Symptoms involve a tetrad of distinctive clinical features, including muscle rigidity, hyperthermia, autonomic instability, and mental status changes.9 Extrapyramidal reactions are due to dopaminergic blockade in the nigrostriatal pathway. Affected patients may experience cogwheel tremor, dystonia, and other dyskinesias.8,9 Hyperthermia arising from dopaminergic blockage in the hypothalamus may lead to temperatures higher than 105.8°F.9 Autonomic instability, caused by dopamine-receptor blockade in the hypothalamus, includes tachycardia, labile or high blood pressure, dysrhythmia, profuse diaphoresis, and tachypnea.9 Mental status changes often manifest as agitated delirium with confusion and may evolve to encephalopathy or coma. More subtle symptoms include peripheral neuropathy, mutism, and seizure activity.

Elevated serum creatine phosphokinase (CPK) due to rhabdomyolysis and leukocytosis is commonly present in patients with NMS, with profound elevation in those with severe rigidity. Although mild-to-moderate elevated CPK is nonspecific for NMS, CPK levels greater than 1,000 IU/L are probably more specific for NMS.9,10 Normal CPK levels can be seen at early onset of the syndrome if rigidity is not well developed. Other nonspecific laboratory abnormalities that are common in NMS include elevated WBC count, electrolyte abnormalities, and elevated lactate dehydrogenase, alkaline phosphatase, and liver transaminases. Brain imaging studies (MRI and CT) and lumbar puncture are required to exclude structural brain disease and infection. Brain imaging studies and lumbar puncture are usually normal in NMS.10

DIAGNOSIS

There is lack of consensus about the diagnostic criteria for NMS, but the most commonly used criteria are provided by the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and are listed in TABLE 1.2,7,11 NMS is difficult to distinguish from extrapyramidal side effects of antipsychotics and from other disorders with similar presentation. DSM-IV diagnostic criteria require that both severe muscle rigidity and hyperthermia be present after recent administration of a neuroleptic agent as well as two associated signs, symptoms, or laboratory findings that are not better accounted for by a substance-induced, neurologic, or general medical condition.2,11 The symptoms include diaphoresis, dysphagia, tremor, incontinence, altered mental status (from mild confusion to coma), mutism, tachycardia, elevated or unstable blood pressure, raised leukocyte level, or laboratory evidence of muscle damage (such as increased CPK).2,11


table1

DIFFERENTIAL DIAGNOSIS

NMS is a diagnosis of exclusion requiring differential diagnosis, as symptoms can resemble those seen in other conditions, which are listed in TABLE 2. Many medical conditions mimic the presentation of NMS, including serotonin syndrome, lethal catatonia, heat stroke, central nervous system infection, status epilepticus, and drug-induced extrapyramidal symptoms.6.10 Laboratory investigations are essential to exclude other disorders or complications. A number of tests should be completed upon evaluating a patient with suspected NMS, including CPK concentration, WBC count, renal function, EEG, CT scan, lumbar puncture, and serum lithium concentration.6,10


table2

RISK FACTORS

The greatest risk factors for developing NMS are use of high-potency antipsychotics, recent or rapid dose escalation, and use of long-acting or intramuscular depot forms.9,10,12,13 Rapid dose escalation has not been systematically defined or universally observed, but it remains an important risk factor.13 The risk for NMS development lasts for 10 to 20 days after oral neuroleptics are discontinued and even longer when depot forms are administered.6 Although some studies demonstrate an increased risk with higher doses, multiple case studies found NMS development to be dose-independent.2 NMS is less likely to occur in patients who have been stable on their dose of antipsychotic medication or who have good long-term compliance.10,13

Concurrent use of multiple neuroleptics or predisposing drugs, such as lithium, monoamine oxidase inhibitors, and tricyclic antidepressants, also appear to confer an increased risk.7,9 Lithium, which has synergistic effects with neuroleptic drugs, may increase risk in conjunction with other causative factors including neuroleptic drug use or levodopa withdrawal.14 Reports also suggest that lithium triggers NMS by reducing the synthesis of dopamine when taken on a long-term basis.15 A review of case studies found that NMS associated with antidepressants alone is a rare occurrence, suggesting that antidepressants may increase levels of antipsychotics, leading to an increased risk of NMS due to the antipsychotic itself.16

Several studies of risk factors for NMS suggest that age, sex, and time of year do not significantly correlate with risk of developing the condition.2 Although no genetic link has been discovered, a polymorphism of the dopamine D2 receptor gene may increase susceptibility.9 Genetic studies indicate that NMS patients commonly display a specific allele of the dopamine D2 receptor gene, which is associated with reduced density and function of dopamine receptors.17 Coexisting medical conditions including nutritional deficiencies, electrolyte imbalances, organic brain syndrome, and dehydration may confer a higher risk.9,13 Dehydration during neuroleptic use may induce peripheral vasoconstriction and impair heat dissipation.18 Nearly all case studies of NMS patients have reported physical exhaustion and dehydration prior to the onset of NMS, although some experts question whether dehydration is a cause or effect of the syndrome.9

MEDICATIONS ASSOCIATED WITH NMS

NMS is attributed to the suppression of dopamine receptor activation and primarily results from the use of neuroleptic drugs or other dopamine-depleting agents or the abrupt withdrawal of levodopa or dopamine receptor agonists. Although NMS is most commonly associated with typical high-potency antipsychotics, atypical antipsychotics and antiemetic drugs have also been implicated. The phenomenon has been rarely associated with other medications such as lithium, phenelzine, and dosulpine (dothiepin).10 Dopamine-depleting agents such as reserpine and tetrabenazine may also cause NMS.19,20 TABLE 3 lists medications associated with NMS.


table3

Typical and Atypical Antipsychotics

Both typical and atypical antipsychotics have dopamine receptor–blocking properties, which have the potential to produce NMS. Symptoms often develop within the first 2 weeks of antipsychotic therapy but may start after the initial dose or during long-term stable therapy with the same agent and dose.21 Typical antipsychotics such as haloperidol, fluphenazine, and chlorpromazine have been most frequently associated with NMS. Atypical antipsychotics appear to have reduced risk of NMS development, but a significant number of cases have been reported.22 Newer atypical antipsychotics inhibit serotonin receptors to a greater extent than dopamine receptors and show an increased affinity for D1, D3, and D4 receptors than for D2 receptors.23 While some studies suggest that atypical antipsychotic–induced NMS may be distinct from NMS produced by typical antipsychotic drugs, other reviews report that NMS associated with atypical and typical antipsychotics manifest in a similar manner.21,24,25 There is some evidence of an atypical presentation, particularly following the use of clozapine.13,25 Extrapyramidal symptoms including rigidity and tremor generally occur less in NMS associated with clozapine.21,25

Antiemetic Agents

Droperidol, metoclopramide, prochlorperazine, and promethazine are agents that exhibit dopamine receptor–blocking effects in the chemoreceptor trigger zone. Although these agents are commonly used as antiemetics, their dopaminergic activity can trigger NMS. The use of a serotonin antagonist, including ondansetron, dolasetron, or granisetron, is recommended for nausea and vomiting in NMS-susceptible patients.9

Antiparkinson Agents

NMS is also present in patients treated for Parkinson’s disease during abrupt medication cessation, dose reduction, or a switch from one dopamine agonist to another. Withdrawal of L-dopa and dopamine agonists, including bromocriptine and amantadine, mimics the action of dopamine antagonists and reduces the amount of available dopamine, which is believed to be part of the pathogenesis of NMS.6,9

TREATMENT

Treatment for NMS involves immediate withdrawal of causative agents including antipsychotic medications and dopamine (D2) receptor antagonists. Once NMS has been diagnosed and antipsychotic drugs are discontinued, NMS is self-limiting in most cases.2 The average recovery time after discontinuing the offending agent is 7 to 10 days, with 63% of patients recovering within 7 days and nearly all within 30 days.2 However, the duration of NMS episodes may be prolonged when long-acting depot antipsychotics are used.

Supportive Care

Supportive care is crucial, as complications are common and may be fatal. Supportive care includes correction of hypotension and volume depletion with IV fluids. Volume resuscitation should be aggressive, since most patients with NMS are dehydrated in the acute phase of the illness.2 Correction of electrolyte abnormalities is critical, and use of alkalinized fluids or bicarbonate loading may be beneficial in preventing renal failure.2,10 Hyperthermia should be treated with cooling blankets, ice packs, cooled IV fluids, and antipyretics, although some researchers believe antipyretics are ineffective because hyperthermia in NMS is not mediated by pyrogens.26 In addition, IV fluids and parenteral nutrition are recommended for patients in respiratory distress or those unable to tolerate oral intake.26 Maintaining cardiorespiratory stability via mechanical ventilation, antiarrhythmic agents, or pacemakers may be required. Other complications including cardiorespiratory failure, thrombocytopenia, renal or hepatic failure, and sepsis also need to be corrected immediately before they become fatal.

Pharmacologic Treatment

Owing to the rarity of NMS, clinical trials are difficult to perform and pharmacologic treatment remains somewhat controversial because no large, randomized, controlled trials have shown clear benefit to support its use. General treatment guidelines, however, have been developed through the review of case reports. In patients who present with CK elevation or hyperthermia, or who do not respond to withdrawal of medication and supportive care, the use of dantrolene, bromocriptine, or amantadine should be considered. Dantrolene, a direct-acting skeletal muscle relaxant, is dosed at 1 to 2.5 mg/kg and may be repeated to a maximum dose of 10 mg/kg/day. Dantrolene has a rapid onset of action, reducing hyperthermia and rigidity within minutes of administration. However, dantrolene is hepatotoxic, so it should be used with caution in patients with hepatic impairment.27 Some case studies show that administration of dantrolene alone or in addition to other medications is effective initially but may increase mortality. Dantrolene can be combined with benzodiazepines or dopamine agonists, but it should not be coadministered with calcium channel blockers, as cardiovascular collapse can occur.2 Slow tapering of dantrolene is recommended after 10 days of treatment to reduce the risk of relapse.

Case studies and meta-analyses report that dopaminergic agents may reverse parkinsonism in NMS and reduce recovery and mortality rates.2 Bromocriptine, a centrally acting dopamine agonist, restores lost dopaminergic tone in moderate to severe NMS. Bromocriptine is initiated at a dose of 2.5 mg every 6 to 8 hours and may be titrated to a maximum dose of 40 mg daily.28 An alternative to bromocriptine is amantadine, which exhibits both dopaminergic and anticholinergic effects. Amantadine is dosed 100 mg every 8 hours and is titrated upward as needed to a maximum dose of 200 mg every 12 hours. With stimulation of the D2 receptors in the brain, clinical manifestations benefit; however, psychosis may worsen.2,29 Premature discontinuation of these agents may result in rebound symptoms.2

Oral or IV benzodiazepines are sometimes used to treat agitation, and these may also provide benefit with fever and rigidity. Although benzodiazepines do not have a preventive effect, use may hasten recovery.2 More specifically, clinical benefits have been seen with clonazepam and lorazepam.6 Benzodiazepines may be a reasonable first-line intervention in patients with acute NMS; however, monitoring respiratory status is critical.

Duration of Pharmacologic Treatment: Duration of NMS treatment is recommended for 10 days after symptoms have resolved; however, some studies suggest treating for an additional 2 to 3 weeks to decrease recurrence if the neuroleptic agent is a long-acting formulation.30 Pharmacologic treatment is most commonly used owing to the benefit shown in case report studies and clinical experience. It is difficult to compare specific treatments for NMS and define an exact duration of treatment because of the heterogeneous and unpredictable nature of the disorder.

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) may be effective if symptoms are refractory to supportive care and pharmacotherapy. ECT is a reasonable treatment option in NMS; however, there are no prospective, randomized, controlled data supporting its efficacy. A review of published cases found a lower mortality rate in ECT-treated patients compared with those receiving supportive care alone (10.3% vs. 21%).31 In another comprehensive literature review, clinical response to ECT occurred after an average of 4.1 treatments.32 However, interpretation of these study results is confounded by the variable timing of ECT in relation to symptom onset.24 Owing to safety concerns, ECT is generally reserved for patients who do not respond to other treatments or who require nonpharmacologic psychotropic treatment.

Restarting Neuroleptics

Recurrent NMS is idiosyncratic, and relapse rates are reported anywhere between 10% and 90%.8 The risk of restarting neuroleptic agents is difficult to quantify, as patients may or may not have a recurrent NMS episode. Risk factors for recurrence include early resumption of neuroleptic agents, use of high-potency or parenteral neuroleptics, and concomitant use of lithium.8 Recommendations suggest waiting at least 2 weeks before resuming neuroleptic therapy, as well as choosing low-potency agents at low doses with a slow titration in order to minimize the risk of recurrence.

CONCLUSION

NMS is a neurologic emergency characterized by a distinctive clinical syndrome. While the incidence of NMS associated with antipsychotic use is statistically rare, the public health impact is great. Both typical and atypical antipsychotics have been implicated in NMS, and clinicians must be aware of its idiosyncratic nature and be vigilant in detecting early signs. Specific treatment for NMS should be individualized and based on the severity of the clinical signs and symptoms. For mild cases, supportive care and clinical monitoring may be sufficient, whereas in severe cases, more aggressive therapy may be necessary. Pharmacists have the opportunity to counsel patients on the risk factors and symptoms of NMS to raise awareness. Pharmacists also play a critical role in assisting physicians with therapeutic options and alternatives in NMS treatment.

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