pSYCHIATRY

Neuroleptic malignant syndrome: Don’t let your guard down yet

88 case reports indicate newer antipsychotics may cause atypical presentations

hen second-generation antipsychotics® Dowden (SGAs) Health Media were introduced, clinicians hoped the drugs W would not have the potential to cause neu- roleptic malignant syndromeCopyright (NMS).1For Since then,personal how- use only ever, case reports have made it clear that SGAs—like first-generation antipsychotics (FGAs)—can precipitate this life-threatening neurologic emergency. To help you protect your patients receiving SGAs, this article explains how to: • identify those at risk • recognize the different NMS presentations associated with each SGA • continue antipsychotic treatment for a patient

with a history of NMS. VEER.COM 2007 © CASE STUDY A drug-induced disorder Fahd A. Zarrouf, MD Mrs. Z, age 39, has a history of multiple hospitalizations for Medicine/psychiatry resident schizoaff ective disorder complicated by poor compliance Veena Bhanot, MD Associate professor and a history of abuse. This time she Psychiatry program was admitted with increased auditory hallucinations and paranoid delusions of her family trying to poison her. West Virginia University Despite multiple injections (5 mg IM q4h prn), Charleston Mrs. Z continued to have hallucinations and remained agitated. Haloperidol was discontinued and ziprasidone (20 mg IM q4h prn) was started. After 3 days, Mrs. Z became less agitated and had fewer hallucinations. The IM route was discontinued and oral ziprasidone was started at 40 mg bid, then titrated to 80 mg bid after 2 days. On the third Current Psychiatry day after titration, Mrs. Z fell twice. She hit her head in one Vol. 6, No. 8 89

For mass reproduction, content licensing and permissions contact Dowden Health Media. Table 1 NMS is believed to be caused by re- DSM-IV-TR defi nition of NMS* duced activity in the brain associated with dopamine antagonists, Hyperthermia (>38° C) and interruptions in nigrostriatal dopamine Muscle rigidity and pathways, or withdrawal of dopaminer- gic medications.3 However, dopamine D2 At least 2 of the following: receptor blocking potential is not directly • diaphoresis 6 Neuroleptic • dysphagia linked to the occurrence of NMS. Other malignant • incontinence mechanisms include genetic susceptibil- syndrome • changes in level of consciousness ity and different CNS neurotransmitter ranging from confusion to coma disturbances.7 • mutism NMS develops in an estimated 0.02% • elevated or labile blood pressure • CPK elevation to 2.5% of patients treated with antipsy- 8-10 • chotics. The syndrome appears to occur • tachycardia slightly less frequently with SGAs than 6,10 * Symptoms must be associated with the use of with FGAs. Clinical Point neuroleptic medication, and other central and systemic causes of hyperthermia must be excluded. Risk factors. NMS appears to CPK: creatine phosphokinase; NMS: neuroleptic NMS can develop at any age, occur slightly less malignant syndrome in men and women, and in patients with Source: DSM-IV-TR psychiatric or medical illness.11,12 In addi- frequently with SGAs tion to antipsychotics, other medications— than with FGAs fall, but a brain CT to rule out bleeding was including antiemetics and sedatives—can normal. cause NMS. The syndrome has been trig- The next day, Mrs. Z became more gered when Parkinson’s disease patients confused and developed fever, tremor, stop taking or reduce the dose of a dopa- urinary incontinence, and a severe . mine agonist or switch from 1 dopamine She became obtunded, was intubated, and agonist to another.13,14 was transferred to the intensive care unit of Symptoms usually develop during the a tertiary care center. first 2 weeks of pharmacotherapy but On admission, her temperature was 103° F (39.4° C); she had severe muscle rigidity and blood pressure of 85/60 mm Hg. Creatine Promising New Investigator phosphokinase (CPK) was 2,559 U/L (normal 24 to 170 U/L). Liver enzymes were elevated: Fahd A. Zarrouf, MD alanine transaminase was 202 U/L (normal 13 to 50 U/L), and aspartate transaminase (AST) This paper was among those entered in was 190 U/L (normal 15 to 46 U/L). At 140 the 2007 Promising New Investigators μg/dL, Mrs. Z’s serum iron was within normal competition sponsored by the Neuroleptic Malignant Syndrome Information limits (40 to 150 μg/dL). Service (NMSIS). The theme of this year’s competition was “New insights on psychotropic drug safety and side effects.” Neuroleptic malignant syndrome CURRENT PSYCHIATRY is honored to publish Clinical manifestations of NMS range from this peer-reviewed, evidenced-based article typical—as defi ned by the DSM-IV-TR on a clinically important topic for practicing (Table 1)2,3—to atypical, without: psychiatrists. • fever4 NMSIS is dedicated to reducing morbidity • rigidity5 and mortality of NMS by improving medical • CPK elevation. and psychiatric care of patients with Many conditions resemble NMS (Table 2). heat-related disorders; providing support information for medical professionals, Because NMS can be fatal without emer- patients, and families; and improving gent diagnosis and treatment, maintain a scientifi c understanding of these conditions high index of suspicion for this condition Current Psychiatry through research. 90 August 2007 whenever you prescribe antipsychotics. may start after the initial dose or dur- Table 2 15 ing long-term stable therapy. Although NMS diff erential diagnosis pSYCHIATRY some studies found NMS development Primary CNS disorders to be dose-independent, multiple cases CurrentPsychiatry.com have demonstrated an association with CNS vasculitis Infarctions dose changes. Death occurs from dys- Infections autonomic manifestations and systemic Parkinson’s disease complications. An elevated risk for NMS may exist in pa- Trauma tients with: Tumors • mood disorders Systemic disorders • preexisting catatonia16 Acute porphyria • complicated medical and neurologic Autoimmune disorders disorders, such as or men- Dehydration Heat tal retardation17 Hyperthyroidism • poor functional and physiologic status3 Infections Clinical Point • concurrent lithium treatment Pheochromocytoma • IM injection of an antipsychotic Tetanus Reports suggest • use of a high-potency antipsychotic, Psychiatric disorders that parenteral such as haloperidol Idiopathic lethal catatonia • . antipsychotic Other potential risk factors include Medication-related disorders administration may dehydration, adolescent age, male gen- Anticholinergic syndrome increase NMS risk der, low serum iron concentrations, rela- Drug intoxication Levodopa syndrome tively high antipsychotic dosages, and Malignant hyperthermia mental retardation or prior structural brain injury.18-20

(Figure 2, page 92). The reason is not clear. NMS and SGAs One hypothesis suggests that men are We reviewed 88 reports of NMS cases as- more likely to present with severe agita- sociated with 6 SGAs: , clozap- tion that requires aggressive antipsychotic ine, risperidone, ziprasidone, quetiapine, treatment.14,22 and aripiprazole. In this article, we cite Previous reports suggested that paren- representative cases only; readers inter- teral antipsychotic administration might ested in the full literature search can fi nd increase NMS risk. Most NMS cases in this evidence and its references in the Case our review involved oral administration, Reports Table that appears with this article perhaps because parenteral SGAs have on CurrentPsychiatry.com. become available only recently. In the NMS cases were fairly evenly distrib- future, increased use of parenteral SGAs uted across all age groups (Figure 1, page might increase the incidence of NMS. 92). SGAs were implicated in NMS when The NMS mortality rate associated with used as monotherapy in 9 cases (10%) and SGAs was lower than that linked to FGAs.6 in combination with other psychotropics This fi nding, however, may be infl uenced in 41 cases (47%). We could not fi nd medi- by increasing awareness of NMS among cation regimen data for 38 cases (43%). physicians, resulting in earlier diagnosis Our review suggests that a history of and treatment.6 NMS is a risk factor for developing anoth- er episode. Twenty cases showed a clear history of NMS, and 2 cases reported 3 dif- Findings for specifi c SGAs ferent NMS episodes in each patient.19,21 Aripiprazole. Because aripiprazole is the In the cases we reviewed, NMS devel- newest SGA, data on its association with Current Psychiatry oped more often among men than women NMS are limited. Our review looked at Vol. 6, No. 8 91 Figure 1 drug or restarted it after discontinuation. NMS incidence across age groups NMS has developed in patients receiving chronic steady doses of clozapine, after dosage increases, and after other medica- 100 % of all age group tions have been added. 80 Clozapine-treated patients need to be

60 closely monitored for agranulocytosis Neuroleptic symptoms, so any other adverse effects— malignant 40 such as initial symptoms of NMS—likely syndrome 20 26.9 28.5 will be detected early. Some reports sug- 22.2 19 3.2 gested that clozapine-induced NMS may 0 feature fewer extrapyramidal side effects 20 < >80 21-40 41-60 61-80 and a lower-than-typical increase in CPK. Age In the cases we reviewed, however, NMS presentations ranged from typical—with Incidence is dispersed fairly evenly; elderly patients may be less likely to be prescribed an antipsychotic a highly elevated CPK—to mild with no Clinical Point than other age groups. rigidity and mild or no CPK elevation. Source: Reference 5 Compared with Two of 28 cases reported neurologic se- NMS triggered by quelae, including severe truncal and . Figure 2 other antipsychotics, Clozapine has been used to treat pa- clozapine-induced NMS: More common in men tients with a history of NMS who expe- NMS may occur rience psychotic relapse. In several cases, sooner after starting 100 however, NMS recurred after clozapine was started. In 1 case, a third rechallenge 80 the drug with slow titration of clozapine was 72 60 successful. 40 Percent Olanzapine. Some studies have found 20 28 olanzapine-induced NMS to be rare (rate 0 ≤0.01%), but our review found 36 such Male Female cases. Ten patients (30%) had a history of Men may be at higher risk because they are more NMS. Olanzapine dosing did not corre- likely to present with severe agitation and receive late with NMS—in 11 cases NMS occurred larger doses of potent antipsychotics. Source: References 14,22 with daily doses ≤10 mg. As with clozapine, the presentation of olanzapine-induced NMS varies widely. 2 cases. Both patients had atypical NMS Onset from within 8 hours of starting features, including absence of fever and olanzapine to after 2½ years of stable mild CPK elevation. In 1 case, aripipra- olanzapine dosing has been reported. zole was used to treat agitation in a 13- Some cases have featured a typical NMS year-old girl with history of NMS. This presentation. Atypical presentations have resulted in a mild increase in tachycardia included: and brief worsening of serum CPK but • extremely elevated serum sodium did not significantly affect temperature, • absence of rigidity respiratory rate, or blood pressure. • normal CPK • generalized tonic-clonic pre- Clozapine. Several NMS cases have been ceding NMS onset connected to clozapine monotherapy (6 • anterograde amnesia cases) or combination therapy (22 cases). • defi cits in learning verbal information. Compared with NMS caused by other Olanzapine challenge for patients with antipsychotics, clozapine-induced NMS a history of NMS often has triggered re- Current Psychiatry 92 August 2007 occurred sooner after patients started the curring NMS. Quetiapine. NMS has been reported in pa- Table 3 tients receiving quetiapine monotherapy Treating NMS: Where to start pSYCHIATRY and combination therapy. Patients who pre- viously experienced NMS after taking an Stop offending agent(s) CurrentPsychiatry.com FGA have developed quetiapine-induced Provide intensive hemodynamic and NMS, as have some with a history of Lewy supportive care: body disease. Two patients treated with • Correct dehydration quetiapine developed CPK elevations to al- • Correct hyperpyrexia • Correct electrolyte imbalance most 9,000 U/L (normal <171 U/L)—with- • Correct acute renal failure associated out other NMS features—that improved with rhabdomyolysis and other organ after discontinuing the medication. dysfunction

Risperidone. NMS among patients tak- ing risperidone occurs more frequently in those with history of NMS or who restart CASE CONTINUED risperidone after discontinuation. Time to A complicated illness NMS occurrence after starting risperidone Mrs. Z was diagnosed with NMS. Ziprasidone Clinical Point varies from hours to months. Atypical was discontinued, and supportive treat- Dopamine agonists ment, bromocriptine (2.5 mg po qid), and presentations include delayed fever, de- can reduce the layed muscle rigidity, massive intestinal lorazepam (2 mg IV qid) were started. Tem- bleeding, massive CPK elevation (such as peratures of 101º to 103º F (38.3º to 39.4º duration and 46,420 U/L), and hyponatremia instead of C) persisted for the next 2 days. This hyper- mortality of NMS hypernatremia. thermia was difficult to control because of but might worsen suspected . psychotic symptoms Ziprasidone. Administering IM ziprasi- The team started ceftriaxone (2 gm IV done or combining any form of the drug q12h) while awaiting lumbar puncture re- with other psychotropics increases NMS sults. CSF showed mild white blood cell el- risk. Although most cases featured typical evation of 20/cu mm (normal 0 to 5/cu mm) presentations, 1 case reported absence of with 62% neutrophils (normal 0 to 6%), nor- muscle rigidity, which is present in >90% mal protein, normal glucose, and negative of patients with NMS associated with cultures. After 2 days of antibiotic therapy, FGAs. the patient developed diarrhea and was di- agnosed with Clostridium diffi cile-associated colitis, a side eff ect of the antibiotic. NMS sequelae related to SGAs Brain injury following NMS can cause , limb ataxia, , Treatment is mainly supportive , dysmetria, dysarthria, Recognizing NMS signs is the fi rst and sensory function problems, balance prob- most important step to quick diagnosis lems, persistent amnesia, diffi culties and early medical intervention. Recom- comprehending commands, attention mendations for medical treatment of NMS problems, and electroencephalograph or vary widely, but most stress stopping the MRI abnormalities.23,24 Postmortem stud- triggering drug and initiating supportive ies of patients with NMS have revealed care (Table 3).27-29 cerebellar degeneration, reduction of Several medications have been used Purkinje and granule cells, and in off-label to treat NMS based on anecdotal the dentate nucleus.25,26 clinical reports. such as Why some patients develop sequelae parenteral lorazepam, 1 to 2 mg every 6 to after NMS while others recover is un- 8 hours, have been used to treat catatonic known. Sustained hyperpyrexia, preex- symptoms.30 Dopamine agonists—includ- isting medical or neurologic disorders, ing bromocriptine, 2.5 mg every 8 hours— polypharmacy, prolonged courses, and have reduced the duration and mortality Current Psychiatry delayed diagnosis may play a role. 25-27 of NMS but have the potential to worsen Vol. 6, No. 8 93 psychotic symptoms and cause hypoten- sion and emesis.30 Related Resources • Neuroleptic Malignant Syndrome Information Service. http://nmsis.org. CASE CONTINUED • National Institute of Neurological Disorders and Stroke. Resuming antipsychotic Tx Neuroleptic malignant syndrome information page Five days after intubation, Mrs. Z started to www.ninds.nih.gov/disorders/neuroleptic_syndrome/ neuroleptic_syndrome.htm. improve and was extubated successfully. Neuroleptic However, she developed severe truncal Drug Brand Names Aripiprazole • Abilify Lorazepam • Ativan malignant ataxia, upper extremity (resting and Benztropine • Cogentin Olanzapine • Zyprexa syndrome intentional), athetosis, hemiballismus, dys- Bromocriptine • Parlodel Quetiapine • Seroquel metria, and . She continued to ex- Ceftriaxone • Rocephin Risperidone • Risperdal Clozapine • Clozaril Ziprasidone • Geodon perience hallucinations after transfer back to Haloperidol • Haldol the psychiatric fl oor. Disclosure Oral olanzapine challenge was started at The authors report no fi nancial relationship with any 2.5 mg/d and titrated up to 10 mg/d over company whose products are mentioned in this article, or the next 7 days. Her psychotic symptoms with manufacturers of competing products. Clinical Point showed mild improvement but her ataxic movements worsened and she fell frequent- Wait 1 or 2 weeks 2. Thornberg SA, Ereshefsky L. Neuroleptic malignant syndrome ly. Benztropine, 1 mg po bid, was added to associated with clozapine monotherapy. Pharmacotherapy before restarting 1993;13:510-4. her regimen and helped with the tremor. 3. Caroff SN, Mann SC. Neuroleptic malignant syndrome. Med any antipsychotic in She was transferred for rehabilitation and Clin North Am 1993;77:185-202. 4. Rodriguez OP, Dowell MS. A case report of neuroleptic a patient who has eventually discharged home. malignant syndrome without fever in a patient given aripiprazole. J Okla State Med Assoc 2006;9(7):435-8. developed NMS 5. Kogoj A, Velikonja I. Olanzapine induced neuroleptic malignant syndrome—a case review. Hum Psychopharmacol If a patient needs antipsychotics 2003;18(4):301-9. 6. Ananth J, Parameswaran S, Gunatilake S, et al. Neuroleptic If a patient who has experienced NMS malignant syndrome and atypical antipsychotic drugs. J Clin Psychiatry 2004;65(4):464-70. continues to need pharmacotherapy for 7. Caroff SN, Mann SC, Campbell EC. Atypical antipsychotics psychosis, wait 1 or 2 weeks after NMS and neuroleptic malignant syndrome. Psychiatric Annals 2000;30:314-21. symptoms resolve before restarting any 8. Levenson, JL. Neuroleptic malignant syndrome. Am J antipsychotic.31 Although most patients Psychiatry 1985;142:1137. 9. Addonizio G, Susman VL, Roth SD. Symptoms of neuroleptic can be treated safely with an antipsychot- malignant syndrome in 82 consecutive inpatients. Am J ic after having NMS, clearly document Psychiatry 1986;143:1587-90. 10. Pope HG, Keck PE, McElroy SL. Frequency and presentation the indications and your discussions with of neuroleptic malignant syndrome in a large psychiatric the patients and their families. hospital. Am J Psychiatry 1986;143:1227–33. 11. Chungh DS, Kim BN, Cho SC. Neuroleptic malignant No conclusive evidence indicates which syndrome due to three atypical antipsychotics in a child. J Psychopharmacol 2005;19(4):422-5. antipsychotic might lower a patient’s risk 12. Suh H, Bronson B, Martin R. Neuroleptic malignant syndrome of recurrent NMS. Using an FGA in pa- and low-dose olanzapine. Am J Psychiatry 2003;160(4):796. 13. Shalev A, Hermesh H, Munitz H. Mortality from neuroleptic tients who recover from NMS carries a 30% malignant syndrome. J Clin Psychiatry 1989;50:18. risk of recurrent episodes.3 Data on the re- 14. Velamoor, VR. Neuroleptic malignant syndrome. Recognition, prevention and management. Drug Saf 1998;19:73. currence of NMS with SGAs are inconclu- 15. Pope HG Jr, Aizley HG, Keck PE Jr, McElroy SL. Neuroleptic sive. No relationship was found between malignant syndrome: long-term follow-up of 20 cases. J Clin Psychiatry 1991;52:208. 32 relapse rate and patients’ age or sex. 16. White DAC, Robins AH. Catatonia: harbinger of the neuroleptic Regardless of which drug you choose, malignant syndrome. Br J Psychiatry 1991;158:419-21. 17. Caroff SN, Mann SC, McCarthy M, et al. Acute infectious start with a low dosage and titrate slowly. encephalitis complicated by neuroleptic malignant syndrome. You also can protect patients by reducing J Clin Psychopharmacol 1998;18:349-51. 18. Apple JE, Van Hauer G. Neuroleptic malignant syndrome risk factors for NMS, such as dehydration, associated with olanzapine therapy. Psychosomatics and considering alternate therapies such 1999;40(3):267-8. 19. Margolese HC, Chouinard G. Olanzapine-induced neuroleptic as electroconvulsive therapy, when ap- malignant syndrome with mental retardation. Am J Psychiatry 1999;156(7):1115-6. propriate. 20. Boyd RD. Neuroleptic malignant syndrome and mental retardation: review and analysis of 29 cases. Am J Ment Retard References 1993;98:143–55. 1. Delay J, Pichot P, Lemperiere T, et al. Un neuroleptique majeur 21. Malyuk R, Gibson B, Procyshyn RM, Kang N. Olanzapine non-phenothiazine et non reserpinique, l’haloperidol, dans associated weight gain, and neuroleptic Current Psychiatry le traitement des psychoses. Annales Medico-Psychologique malignant syndrome: case report. Int J Geriatr Psychiatry 94 August 2007 1960;118:145-52. 2002;17(4):326-8. 22. Zun LS. A prospective study of the complication rate of use 27. Gratz SS, Levinson DF, Simpson GM. The treatment and of patient restraint in the emergency department. J Emerg Med management of neuroleptic malignant syndrome. Prog 2003;24(2):119-24. Neuropsychopharmacol Biol Psychiatry 1992;16(4):425-43. pSYCHIATRY 23. Labuda A, Cullen N. Brain injury following neuroleptic 28. Scheftner WA, Shulman RB. Treatment choice in neuroleptic malignant syndrome: case report and review of the literature. malignant syndrome. Convuls Ther 1992;8:267-79. Brain Inj 2006;20(7):775-8. CurrentPsychiatry.com 29. Harsch HH. Neuroleptic malignant syndrome: physiological 24. Manto M, Goldman S, Hildebrand J. Cerebellar gait ataxia and laboratory fi ndings in a series of nine cases. J Clin following neuroleptic malignant syndrome. J Neurol Psychiatry 1987;48:328-33. 1996;243(1):101-2. 30. Caroff SN. Neuroleptic malignant syndrome: still a risk, but 25. Lee S, Merriam A, Kim TS, et al. Cerebellar degeneration in which patients may be in danger? Current Psychiatry 2003;2:36- neuroleptic malignant syndrome: neuropathologic fi ndings and 42. review of the literature concerning heat-related injury. J Neurol Neurosurg Psychiatry 1989;52(3):387-91. 31. Wells AJ, Sommi RW, Crismon ML. Neuroleptic rechallenge 26. Naramoto A, Koizumi N, Itoh N, Shigematsu H. An autopsy after neuroleptic malignant syndrome: case report and case of cerebellar degeneration following lithium intoxication literature review. Drug Intell Clin Pharm 1988;22:475-80. with neuroleptic malignant syndrome. Acta Pathol Jpn 32. Susman VL, Addonizio G. Recurrence of neuroleptic 1993;43(1-2):55-8. malignant syndrome. J Nerv Ment Dis 1988;176:234-41. Bottom Line Patients who develop NMS as a result of an SGA may lack the hallmark fever, muscle rigidity, or elevated CPK. Early diagnosis and treatment depend on recognizing the NMS signs associated with each SGA. Discontinue the triggering agent, provide supportive therapy, and use medications such as benzodiazepines to address catatonia.

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