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Brief Report   |    
Novel Antipsychotics and the Neuroleptic Malignant Syndrome: A Review and Critique
Samia Hasan, M.D.; Peter Buckley, M.D.
Am J Psychiatry 1998;155:1113-1116.
Abstract

OBJECTIVE: The authors' goal was to analyze reported cases of neuroleptic malignant syndrome in patients given clozapine and risperidone. METHOD: They assessed 19 cases of clozapine-induced neuroleptic malignant syndrome and 13 cases of risperidone-induced neuroleptic malignant syndrome against three criteria sets and against extent of exclusionary workup and then designated them as high or low probability of being neuroleptic malignant syndrome. RESULTS: Nine of the 19 cases of clozapine-related neuroleptic malignant syndrome and eight of the 13 cases of risperidone-related neuroleptic malignant syndrome were designated as having high probability of being neuroleptic malignant syndrome. The remainder were designated as having low probability because presentations were not linked to treatment or failed to meet criteria for the syndrome. CONCLUSIONS: Neuroleptic malignant syndrome can occur in patients given atypical antipsychotics and resembles "classical" neuroleptic malignant syndrome. However, side effect profiles overlap considerably with neuroleptic malignant syndrome criteria, and atypical antipsychotics may cause neurotoxicities unrelated to (but misattributed as) neuroleptic malignant syndrome. Insufficient evidence exists for "atypical" neuroleptic malignant syndrome with novel antipsychotics. (Am J Psychiatry 1998; 155:1113–1116)

Abstract Teaser
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Two reviews (R1558231, R1558232) found insufficient evidence for neuroleptic malignant syndrome attributable to clozapine. Another (R1558233) proposed a causal relationship, advocating the concept of "atypical" neuroleptic malignant syndrome as well as the disputed spectrum concept (R1558234). Incorrectly diagnosing neuroleptic malignant syndrome during clozapine or risperidone therapy may deprive patients of potentially more efficacious and safer medications; however, clinicians must be alert for neuroleptic malignant syndrome with novel antipsychotics. This review, by critically examining reported cases against established diagnostic criteria, addresses this conundrum.

Cases of neuroleptic malignant syndrome related to clozapine or risperidone reported in English were collected (by means of a MEDLINE literature search and contacting pharmaceutical companies as well as authors when necessary) and analyzed against three sets of criteria that represent a continuum of formulations of neuroleptic malignant syndrome: most stringent (Caroff and Mann [5]), intermediary (DSM-IV), and least stringent (Levenson [6]). All criteria sets require adequate workup for exclusion of other etiologies; importantly, the extent of workup is unspecified.

Cases were categorized as high or low probability of being neuroleptic malignant syndrome according to criteria sets, agreement across these criteria, and documentation of adequate, exclusionary workup. For cases designated as having high probability of being neuroleptic malignant syndrome, potential predisposing, precipitating, or contributing factors (use of concomitant medications, rapid titration, age, use of depot neuroleptics, and previous neuroleptic malignant syndrome) were identified.

We identified 19 reports of clozapine-induced neuroleptic malignant syndrome and 13 reports of risperidone-induced neuroleptic malignant syndrome (T1) with variability in ascribed diagnostic certainty. When we applied the criteria of Caroff and Mann (R1558235), we identified four of the clozapine cases and five of the risperidone cases as being neuroleptic malignant syndrome; when we applied DSM-IV criteria, 10 of the clozapine cases and 10 of the risperidone cases were so identified; when we applied Levenson's criteria (R1558236), 14 of the clozapine cases and 11 of the risperidone cases were so identified. All of the cases identified as being neuroleptic malignant syndrome when we applied Caroff and Mann guidelines were also identified by DSM-IV and Levenson's criteria. All but one (a risperidone case reported by Singer et al. [26]) of the cases identified by DSM-IV also met Levenson's criteria. Four clozapine cases (3 [patients 1 and 2], 9, 13) and two risperidone cases (R15582321, R15582327) met Levenson's criteria alone. There was consensus for nine clozapine cases (3 [patients 3 and 4], 10, 12, 14, 16, 17 [patient 1], 18, 20) and six risperidone cases (R15582322, R15582324, R15582325, R15582328, R15582330, R15582332); of these, five clozapine cases (3 [patients 3 and 4], 16, 18, 20) and one risperidone case (R15582324) failed to fulfill any criteria.

Clozapine cases were designated as having low probability of being neuroleptic malignant syndrome if 1) presentations were not causally linked to clozapine because important differential diagnoses were not clearly excluded and concomitant medical illness (3 [patient 1], 18), and concomitant psychotropic medications (R15582315) were present or 2) they did not fulfill neuroleptic malignant syndrome criteria but were suggestive of possible neurotoxicity of clozapine alone (R1558239, R15582313, R15582316) or with polypharmacy (3 [patient 4], 8, 20). Risperidone cases were designated as having low probability if the presentations were attributable to infection (R15582326), neurotoxicity from polypharmacy (R15582331), benzodiazepine withdrawal (R15582321, R15582331), serotonin syndrome (R15582331), and risperidone-induced extrapyramidal side effects (R15582324, R15582327).

Nine of 19 clozapine cases were designated as having a high probability of being neuroleptic malignant syndrome, with consensus across criteria sets for four cases (10, 12, 14, 17 [patient 1]). The remaining five cases were close in presentation to typical neuroleptic malignant syndrome, and this was the most parsimonious diagnosis (2 [patient 2], 7, 11, 17 [patient 2], 19). Diagnostic ambiguity remained for three patients (3 [patient 2], 12, 14) with infections of unclear temporal sequence. Eight of 13 risperidone cases were designated as having high probability of being neuroleptic malignant syndrome, with consensus for five cases (R15582322, R15582325, R15582328, R15582330, R15582332). Most cases had both fever and rigidity, except two (3 [patient 1], 22) with minimal rigidity and two (R1558237, R15582329) with fevers around 99°F.

Notwithstanding methodological limitations, the following tentative conclusions appear justified: 1) Neuroleptic malignant syndrome can occur during clozapine or risperidone monotherapy. 2) A proportion of published cases of neuroleptic malignant syndrome appear to have implicated clozapine or risperidone inappropriately. 3) The diagnostic conundrum inherent to neuroleptic malignant syndrome is further complicated when atypical antipsychotics are used because side effects are likely to be misattributed to neuroleptic malignant syndrome or because diagnoses of concomitant infection or neurotoxic drug effects may be consistent with the clinical presentation. 4) Insufficient evidence exists currently to support the concept of "atypical" neuroleptic malignant syndrome with novel antipsychotics.

The potential for diagnostic confusion is considerable because of overlap between features of neuroleptic malignant syndrome and adverse effects of atypical antipsychotics. Approximately 3% of patients receiving clozapine develop benign hyperthermia, and approximately 25% have autonomic instability during initial titration of clozapine or risperidone therapy (R15582333). Also, massive creatine phosphokinase elevations with atypical antipsychotics may occur in the absence of other features of neuroleptic malignant syndrome (R15582334). These observations suggest that clinicians should be particularly judicious in ascribing a diagnosis of neuroleptic malignant syndrome (especially early or "incipient" forms) at the initiation of atypical antipsychotic therapy.

Some reports were most likely drug-drug interactions occurring during polypharmacy with lithium, benzodiazepines, antidepressants, or other neuroleptics (R1558238, R15582315, R15582321, R15582331). In several cases (3 [patients 3 and 4], 8, 9, 16, 20, 21, 24, 27), neurotoxicity related to initiation or discontinuation of neuroleptics seemed a more apt explanation. Clarifying risk factors and mechanisms for such adverse reactions and distinguishing these from neuroleptic malignant syndrome is particularly important because treatment of neurotoxicity differs from that of neuroleptic malignant syndrome. Among the high-probability neuroleptic malignant syndrome cases, seven of the nine clozapine-treated patients had schizophrenic or schizoaffective diagnoses and four of the eight risperidone cases had schizoaffective or affective disorders. Concomitant diagnoses of mental retardation were also prominent. This is consistent with findings of high rates of comorbidity and affective disorder in neuroleptic malignant syndrome from typical neuroleptics (R15582335). Three of the nine patients given clozapine (but none given risperidone) had a history of neuroleptic malignant syndrome from typical antipsychotics; there may be a selection bias for clozapine treatment in such patients. Although neuroleptic malignant syndrome patients may tolerate clozapine without recurrence, this clinical practice may over time accrue cases of clozapine-induced neuroleptic malignant syndrome. Four of the clozapine-treated and four of the risperidone-treated patients received concomitant psychotropics; three of the clozapine-treated patients were receiving decanoate preparations before clozapine treatment (with washout periods of 3 weeks to 11 months). Notably, substantial dopamine receptor blockade occurs even at 16 weeks after discontinuation of depot neuroleptics (R15582336). Three of the four patients with clozapine-induced neuroleptic malignant syndrome were rechallenged with clozapine and one with risperidone without subsequent problems. Both patients with risperidone-induced neuroleptic malignant syndrome developed some signs and symptoms short of neuroleptic malignant syndrome when rechallenged with antipsychotics: one had creatine phosphokinase elevation (3293 IU/liter); another had rigidity, fever (99.1°F), and creatine phosphokinase elevation (220 IU/liter). It is important to evaluate carefully whether neuroleptic malignant syndrome can occur with other novel antipsychotics. This process will be advanced by reporting based on recognized diagnostic criteria and by meticulous attention to alternative medical diagnoses and possible neurotoxicities.

 

Received June 3, 1997; revision received March 9, 1998; accepted March 24, 1998. From the Department of Psychiatry, Case Western Reserve University and University Hospitals of Cleveland; and the Northcoast Behavioral Healthcare System, Cleveland. Address reprint requests to Dr. Buckley, Department of Psychiatry, Case Western Reserve University, 2040 Abington Rd., Cleveland, OH 44106; buckleyp@mhmail.mh.state.oh.us (e-mail).

Weller M, Kornhuber J: Does clozapine cause neuroleptic malignant syndrome? J Clin Psychiatry  1993; 54:70–71
 
Thornberg SA, Ereshefsky L: Neuroleptic malignant syndrome associated with clozapine monotherapy. Pharmacotherapy  1993; 13:510–514
[PubMed]
 
Sachdev P, Kruk J, Kneebone M, Kissane D: Clozapine-induced neuroleptic malignant syndrome: review and report of new cases. J Clin Psychopharmacol  1995; 15:365–371
[PubMed]
[CrossRef]
 
Nierenberg D, Disch M, Manheimer E, Patterson J, Ross J, Silvestri G, Summerhill E: Facilitating prompt diagnosis and treatment of the neuroleptic malignant syndrome. Clin Pharmacol Ther  1991; 50:580–586
[PubMed]
[CrossRef]
 
Caroff SN, Mann SC: Neuroleptic malignant syndrome. Med Clin North Am  1993; 77:185–202
[PubMed]
 
Levenson JL: Neuroleptic malignant syndrome. Am J Psychiatry  1985; 142:1137–1145
[PubMed]
 
Pope HG Jr, Cole JO, Choras PT, Fulwiler CE: Apparent neuroleptic malignant syndrome with clozapine and lithium. J Nerv Ment Dis  1986; 174:493–495
[PubMed]
[CrossRef]
 
Muller T, Becker T, Fritze J: Neuroleptic malignant syndrome after clozapine plus carbamazepine (letter). Lancet  1988; 2:8626–8627
 
Nopoulos P, Flaum M, Miller DD: Atypical neuroleptic malignant syndrome with an atypical neuroleptic: clozapine-induced NMS without rigidity. Ann Clin Psychiatry  1990; 2:251–253
[CrossRef]
 
Miller DD, Sharafuddin MJA, Kathol RG: A case of clozapine-induced NMS wihtout rigidity. Ann Clin Psychiatry  1990; 2:251–253
[CrossRef]
 
Anderson ES, Powers PS: Neuroleptic malignant syndrome associated with clozapine use. J Clin Psychiatry  1991; 52:102–104
[PubMed]
 
DasGupta K, Young A: Clozapine-induced neuroleptic malignant syndrome. J Clin Psychiatry  1991; 52:105–107
[PubMed]
 
Goates MG, Escobar JI: An apparent neuroleptic malignant syndrome without extrapyramidal symptoms upon initiation of clozapine therapy: report of a case and results of a clozapine rechallenge (letter). J Clin Psychopharmacol  1992; 12:139–140
[PubMed]
[CrossRef]
 
Reddig S, Minnema AM, Tandon R: Neuroleptic malignant syndrome and clozapine. Ann Clin Psychiatry  1993; 5:25–27
[PubMed]
[CrossRef]
 
Nemecek D, Rastogi-Cruz D, Csernansky JG: Atropinism may precipitate neuroleptic malignant syndrome during treatment with clozapine (letter). Am J Psychiatry  1993; 150:1561; correction, 150:1910
 
Viner MW, Escobar JI: An apparent neurotoxicity associated with clozapine (letter). J Clin Psychiatry  1994; 55:38–39
 
Tsai G, Crisostomo G, Rosenblatt ML, Stern TA: Neuroleptic malignant syndrome associated with clozapine treatment. Ann Clin Psychiatry  1995; 7:91–95
[PubMed]
[CrossRef]
 
Lowy A, Wilson A, Sachdev P, Lindeman R: Disseminated intravascular coagulopathy and thrombocytopenia associated with clozapine-induced neuroleptic malignant syndrome (letter). Aust NZ J Med  1995; 25:368
[CrossRef]
 
Ganelin L, Lichtenberg PS, Marcus EL, Munter RG: Suspected neuroleptic malignant syndrome in a patient receiving clozapine. Ann Pharmacother  1996; 30:248–250
[PubMed]
 
Illing M, Ancill R: Clozapine-induced neuroleptic malignant syndrome: clozapine monotherapy rechallenge in a case of previous NMS (letter). Can J Psychiatry  1996; 41:258
 
Tomsic J, Chatt PL, Chandarana P: Neuroleptic malignant syndrome caused by risperidone (poster). 25th Annual Professional Practice Conference of the Canadian Society of Hospital Pharmacists 1994:N10314/1
 
Lee H, Ryan J, Mullett G, Lawlor BA: Neuroleptic malignant syndrome associated with the use of risperidone, an atypical antipsychotic agent. Hum Psychopharmacol 1994: 9:303–305
 
Webster P, Wijeratne C: Risperidone-induced neuroleptic malignant syndrome (letter). Lancet  1994; 344:1228–1229
 
Raitasuo V, Vataja R, Elomaa E: Risperidone-induced neuroleptic malignant syndrome in a young patient [letter). Lancet  1994; 344:1705
 
Dave M: Two cases of risperidone-induced neuroleptic malignant syndrome (letter). Am J Psychiatry  1995; 152:1233–1234
 
Singer S, Richards C, Boland RJ: Two cases of risperidone-induced neuroleptic malignant syndrome (letter). Am J Psychiatry  1995; 152:1234
 
Murray S, Haller E: Risperidone and NMS? (letter). Psychiatr Serv  1995; 46:951
 
Najara JE, Enikeev ID: Risperidone and neuroleptic malignant syndrome: a case report (letter). J Clin Psychiatry  1995; 56:534–535
[PubMed]
 
Meterissian GB: Risperidone-induced neuroleptic malignant syndrome: a case report and review. Can J Psychiatry  1996; 41:52–54
[PubMed]
 
Tarsy D: Risperidone and neuroleptic malignant syndrome (letter). JAMA  1996; 275:446
[PubMed]
[CrossRef]
 
Kern JL, Cernek PK: Delayed risperidone-induced neuroleptic malignant syndrome (letter). Ann Pharmacother  1996; 30:300
 
Levin GM, Lazowick AL, Powell HS: Neuroleptic malignant syndrome with risperidone (letter). J Clin Psychopharmacol  1996; 16:192–193
[PubMed]
[CrossRef]
 
Buckley PF, Meltzer HY: Treatment of schizophrenia, in A Textbook of Psychopharmacology. Edited by Schatzberg A, Nemeroff CD. Washington, DC, American Psychiatric Press, 1995, pp 615-639
 
Scelsa SN, Simpson DM, McQuistion HL, Fineman A, Ault K, Reichler B: Clozapine-induced myotoxicity in patients with chronic psychotic disorders. Neurology  1996; 47:1518–1523
[PubMed]
 
Addonizio G, Susman VL, Roth SD: Neuroleptic malignant syndrome: review and analysis of 115 cases. Biol Psychiatry  1987; 22:1004–1020
[PubMed]
[CrossRef]
 
Nyberg S, Farde L, Halldin C: Delayed normalization of central D2 dopamine receptor availability after discontinuation of haloperidol decanoate. Arch Gen Psychiatry  1997; 54:953–958
[PubMed]
 
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References

Weller M, Kornhuber J: Does clozapine cause neuroleptic malignant syndrome? J Clin Psychiatry  1993; 54:70–71
 
Thornberg SA, Ereshefsky L: Neuroleptic malignant syndrome associated with clozapine monotherapy. Pharmacotherapy  1993; 13:510–514
[PubMed]
 
Sachdev P, Kruk J, Kneebone M, Kissane D: Clozapine-induced neuroleptic malignant syndrome: review and report of new cases. J Clin Psychopharmacol  1995; 15:365–371
[PubMed]
[CrossRef]
 
Nierenberg D, Disch M, Manheimer E, Patterson J, Ross J, Silvestri G, Summerhill E: Facilitating prompt diagnosis and treatment of the neuroleptic malignant syndrome. Clin Pharmacol Ther  1991; 50:580–586
[PubMed]
[CrossRef]
 
Caroff SN, Mann SC: Neuroleptic malignant syndrome. Med Clin North Am  1993; 77:185–202
[PubMed]
 
Levenson JL: Neuroleptic malignant syndrome. Am J Psychiatry  1985; 142:1137–1145
[PubMed]
 
Pope HG Jr, Cole JO, Choras PT, Fulwiler CE: Apparent neuroleptic malignant syndrome with clozapine and lithium. J Nerv Ment Dis  1986; 174:493–495
[PubMed]
[CrossRef]
 
Muller T, Becker T, Fritze J: Neuroleptic malignant syndrome after clozapine plus carbamazepine (letter). Lancet  1988; 2:8626–8627
 
Nopoulos P, Flaum M, Miller DD: Atypical neuroleptic malignant syndrome with an atypical neuroleptic: clozapine-induced NMS without rigidity. Ann Clin Psychiatry  1990; 2:251–253
[CrossRef]
 
Miller DD, Sharafuddin MJA, Kathol RG: A case of clozapine-induced NMS wihtout rigidity. Ann Clin Psychiatry  1990; 2:251–253
[CrossRef]
 
Anderson ES, Powers PS: Neuroleptic malignant syndrome associated with clozapine use. J Clin Psychiatry  1991; 52:102–104
[PubMed]
 
DasGupta K, Young A: Clozapine-induced neuroleptic malignant syndrome. J Clin Psychiatry  1991; 52:105–107
[PubMed]
 
Goates MG, Escobar JI: An apparent neuroleptic malignant syndrome without extrapyramidal symptoms upon initiation of clozapine therapy: report of a case and results of a clozapine rechallenge (letter). J Clin Psychopharmacol  1992; 12:139–140
[PubMed]
[CrossRef]
 
Reddig S, Minnema AM, Tandon R: Neuroleptic malignant syndrome and clozapine. Ann Clin Psychiatry  1993; 5:25–27
[PubMed]
[CrossRef]
 
Nemecek D, Rastogi-Cruz D, Csernansky JG: Atropinism may precipitate neuroleptic malignant syndrome during treatment with clozapine (letter). Am J Psychiatry  1993; 150:1561; correction, 150:1910
 
Viner MW, Escobar JI: An apparent neurotoxicity associated with clozapine (letter). J Clin Psychiatry  1994; 55:38–39
 
Tsai G, Crisostomo G, Rosenblatt ML, Stern TA: Neuroleptic malignant syndrome associated with clozapine treatment. Ann Clin Psychiatry  1995; 7:91–95
[PubMed]
[CrossRef]
 
Lowy A, Wilson A, Sachdev P, Lindeman R: Disseminated intravascular coagulopathy and thrombocytopenia associated with clozapine-induced neuroleptic malignant syndrome (letter). Aust NZ J Med  1995; 25:368
[CrossRef]
 
Ganelin L, Lichtenberg PS, Marcus EL, Munter RG: Suspected neuroleptic malignant syndrome in a patient receiving clozapine. Ann Pharmacother  1996; 30:248–250
[PubMed]
 
Illing M, Ancill R: Clozapine-induced neuroleptic malignant syndrome: clozapine monotherapy rechallenge in a case of previous NMS (letter). Can J Psychiatry  1996; 41:258
 
Tomsic J, Chatt PL, Chandarana P: Neuroleptic malignant syndrome caused by risperidone (poster). 25th Annual Professional Practice Conference of the Canadian Society of Hospital Pharmacists 1994:N10314/1
 
Lee H, Ryan J, Mullett G, Lawlor BA: Neuroleptic malignant syndrome associated with the use of risperidone, an atypical antipsychotic agent. Hum Psychopharmacol 1994: 9:303–305
 
Webster P, Wijeratne C: Risperidone-induced neuroleptic malignant syndrome (letter). Lancet  1994; 344:1228–1229
 
Raitasuo V, Vataja R, Elomaa E: Risperidone-induced neuroleptic malignant syndrome in a young patient [letter). Lancet  1994; 344:1705
 
Dave M: Two cases of risperidone-induced neuroleptic malignant syndrome (letter). Am J Psychiatry  1995; 152:1233–1234
 
Singer S, Richards C, Boland RJ: Two cases of risperidone-induced neuroleptic malignant syndrome (letter). Am J Psychiatry  1995; 152:1234
 
Murray S, Haller E: Risperidone and NMS? (letter). Psychiatr Serv  1995; 46:951
 
Najara JE, Enikeev ID: Risperidone and neuroleptic malignant syndrome: a case report (letter). J Clin Psychiatry  1995; 56:534–535
[PubMed]
 
Meterissian GB: Risperidone-induced neuroleptic malignant syndrome: a case report and review. Can J Psychiatry  1996; 41:52–54
[PubMed]
 
Tarsy D: Risperidone and neuroleptic malignant syndrome (letter). JAMA  1996; 275:446
[PubMed]
[CrossRef]
 
Kern JL, Cernek PK: Delayed risperidone-induced neuroleptic malignant syndrome (letter). Ann Pharmacother  1996; 30:300
 
Levin GM, Lazowick AL, Powell HS: Neuroleptic malignant syndrome with risperidone (letter). J Clin Psychopharmacol  1996; 16:192–193
[PubMed]
[CrossRef]
 
Buckley PF, Meltzer HY: Treatment of schizophrenia, in A Textbook of Psychopharmacology. Edited by Schatzberg A, Nemeroff CD. Washington, DC, American Psychiatric Press, 1995, pp 615-639
 
Scelsa SN, Simpson DM, McQuistion HL, Fineman A, Ault K, Reichler B: Clozapine-induced myotoxicity in patients with chronic psychotic disorders. Neurology  1996; 47:1518–1523
[PubMed]
 
Addonizio G, Susman VL, Roth SD: Neuroleptic malignant syndrome: review and analysis of 115 cases. Biol Psychiatry  1987; 22:1004–1020
[PubMed]
[CrossRef]
 
Nyberg S, Farde L, Halldin C: Delayed normalization of central D2 dopamine receptor availability after discontinuation of haloperidol decanoate. Arch Gen Psychiatry  1997; 54:953–958
[PubMed]
 
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