Psychiatric Annals

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Atypical Antipsychotics and Neuroleptic Malignant Syndrome

Stanley N Caroff, MD; Stephan C Mann, MD; E Cabrina Campbell, MD

Abstract

Since the original description of neuroleptic malignant syndrome (NMS) 40 years ago, clinical studies have enhanced awareness and understanding of this rare but potentially lethal disorder.1 In several reports, investigators have concluded that the incidence of NMS may correlate with D2-receptor blockade, reflected in the potency, dose, and rate of increase of antipsychotics associated with cases of NMS. These findings supported recommendations for the selective and conservative use of typical antipsychotics for patients susceptible to NMS. They also raised expectations that new, atypical antipsychotics would not be associated with NMS. The reduced D2-receptor potency of these drugs, in addition to their effect on other neurotransmitter systems, suggested to us and others that they would be less likely to cause NMS.2

Contrary to expectations, however, cases of NMS associated with atypical antipsychotics have been reported. In a review of reported cases, Sachdev et al.3 concluded that NMS does occur with clozapine, but may present with fewer motor manifestations and milder creatine kinase (CK) elevations. Hasan and Buckley4 concurred that NMS may develop with clozapine and risperidone, but suggested that the occurrence of atypical forms of NMS with these drugs was unproven.

In view of additional reports of NMS with clozapine, risperidone, olanzapine, and quetiapine, we decided to exarnine the following five critical questions of significance to practicing clinicians:

1. Is there a risk of classic NMS developing when atypical antipsychotics are used?

2. Are there atypical forms of NMS associated with atypical drugs?

3. Is the risk or incidence of NMS reduced with atypical drugs?

4. Is the risk of recurrence reduced for patients with previous episodes of NMS if rechallenged with atypical rather than typical antipsychotics?

5. Can the occurrence of NMS associated with atypical antipsychotics enhance our understanding of the pathophysiology of NMS?

METHODS

Cases of NMS reported in English were collected through MEDLINE by cross-referencing NMS with each atypical drug marketed in the United States. Article references were scanned for additional reports. Cases were added from the Neuroleptic Malignant Syndrome Information Service (NMSIS) database. This is a nonprofit consultation service providing telephone hotline consultations to physicians in the United States and Canada. Data on NMSIS cases were obtained by phone report and written case report forms.

All cases were diagnosed retrospectively using Levenson,5 DSM-TV, and Caroff and Mann1 criteria. Levenson criteria allow the diagnosis of NMS even if rigidity or fever is absent. Both DSM-IV and Caroff and Mann criteria require both rigidity and fever, whereas Caroff and Mann additionally require temperatures exceeding 38°C and more detailed evidence of neurologic and autonomic dysfunction.

Table

Incidence

Using a centralized database in Australia, Sachdev et al.3 reported the frequency of reports of NMS in patients treated with clozapine to be 3 in 1,250 (0.24%). Williams and Macpherson,20 using a database in England, estimated the frequency of reports of NMS in patients treated with clozapine as 9 in 9,l>00 (0.1%). According to prescribing information, quetiapine was associated with 2 possible cases of NMS in 2,387 patients (0.1%) in premarketing clinical trials.473

In published clinical trials of atypical antipsychotics, neither olanzapine nor haloperidol induced NMS in 1,336 and 660 patients, respectively48; neither risperidone nor haloperidol induced NMS in 348 and 87 patients, respectively49; and neither quetiapine nor haloperidol induced NMS in 250 and 52 patients, respectively.50 In the study of clozapine in treatment-refractory patients, no cases of NMS were reported in 126 patients treated with clozapine or 139 patients treated with chlorpromazine.51 In contrast, Kozaric-Kovacic et al.52 reported that no cases of NMS occurred in 866 treatment episodes of patients with schizophrenia receiving clozapine, whereas 17 episodes (0.6%) of NMS occurred in…

Since the original description of neuroleptic malignant syndrome (NMS) 40 years ago, clinical studies have enhanced awareness and understanding of this rare but potentially lethal disorder.1 In several reports, investigators have concluded that the incidence of NMS may correlate with D2-receptor blockade, reflected in the potency, dose, and rate of increase of antipsychotics associated with cases of NMS. These findings supported recommendations for the selective and conservative use of typical antipsychotics for patients susceptible to NMS. They also raised expectations that new, atypical antipsychotics would not be associated with NMS. The reduced D2-receptor potency of these drugs, in addition to their effect on other neurotransmitter systems, suggested to us and others that they would be less likely to cause NMS.2

Contrary to expectations, however, cases of NMS associated with atypical antipsychotics have been reported. In a review of reported cases, Sachdev et al.3 concluded that NMS does occur with clozapine, but may present with fewer motor manifestations and milder creatine kinase (CK) elevations. Hasan and Buckley4 concurred that NMS may develop with clozapine and risperidone, but suggested that the occurrence of atypical forms of NMS with these drugs was unproven.

In view of additional reports of NMS with clozapine, risperidone, olanzapine, and quetiapine, we decided to exarnine the following five critical questions of significance to practicing clinicians:

1. Is there a risk of classic NMS developing when atypical antipsychotics are used?

2. Are there atypical forms of NMS associated with atypical drugs?

3. Is the risk or incidence of NMS reduced with atypical drugs?

4. Is the risk of recurrence reduced for patients with previous episodes of NMS if rechallenged with atypical rather than typical antipsychotics?

5. Can the occurrence of NMS associated with atypical antipsychotics enhance our understanding of the pathophysiology of NMS?

METHODS

Cases of NMS reported in English were collected through MEDLINE by cross-referencing NMS with each atypical drug marketed in the United States. Article references were scanned for additional reports. Cases were added from the Neuroleptic Malignant Syndrome Information Service (NMSIS) database. This is a nonprofit consultation service providing telephone hotline consultations to physicians in the United States and Canada. Data on NMSIS cases were obtained by phone report and written case report forms.

All cases were diagnosed retrospectively using Levenson,5 DSM-TV, and Caroff and Mann1 criteria. Levenson criteria allow the diagnosis of NMS even if rigidity or fever is absent. Both DSM-IV and Caroff and Mann criteria require both rigidity and fever, whereas Caroff and Mann additionally require temperatures exceeding 38°C and more detailed evidence of neurologic and autonomic dysfunction.

Table

TABLE 1Comparison of Cases Meeting Diagnostic Criteria for Neuroleptic Malignant Syndrome

TABLE 1

Comparison of Cases Meeting Diagnostic Criteria for Neuroleptic Malignant Syndrome

By using the three criteria, we expected to capture atypical or partial forms of NMS detected by Levenson criteria and to subject reports to a more rigorous and specific definition of NMS (Caroff and Mann criteria). All cases meeting Caroff and Mann criteria also met DSM-IV and Levenson criteria, and all cases, except one, that met DSM-IV criteria also met Levenson criteria. Cases were excluded from analysis if typical antipsychotics were coadniinistered with atypical antipsychotics, if other etiologies for clinical symptoms could not be ruled out, or if they failed to meet any of the three criteria sets.

To compare clinical features of NMS due to atypical drugs with clinical features of NMS caused by typical drugs, we used data from a literature review by Addonizio et al.6 as a historical control group for typical antipsychotics. Clinical findings were expressed as a percentage of all cases, or as a percentage of only those cases in which the presence or absence of a symptom or variable was specifically described, to allow for comparison with data as reported by Addonizio et al. For comparison between rates of recurrent NMS following antipsychotic rechallenge, data reported by Wells et al.7 on recurrence with typical antipsychotics were used as a control. According to Wells et al., recurrence was defined as definite if complete diagnostic criteria for NMS were fulfilled, or as possible if only partial criteria were met, and if antipsychotic drugs were discontinued as a result of recurrent symptoms.

Ordinal data for cases of NMS were compared among groups of patients treated with clozapine, risperidone, or olanzapine and tested for statistical significance of any differences by analysis of variance (ANOVA) with Bonferroni correction for a P value of .05 or less. Differences in proportional distributions between treatment groups, including typical antipsychotics, were tested using Fisher's exact test (two-tailed).

RESULTS

Clinical Manifestations

We found 30 cases of NMS associated with clozapine in the literature. Eleven cases were excluded because typical drugs were coadministered, other diagnoses could not be ruled out, or they failed to meet any diagnostic criteria for NMS. Nineteen remaining cases8"22 met Levenson criteria and 15 met DSM-IV criteria; only 7 met Caroff and Mann criteria due to limited temperature elevations or insufficient detail of symptoms (Table 1).

There were no significant differences in age between treatment groups (Table 2). Although there were more men in the clozapine group, this was significant only in comparison to the group treated with risperidone. Compared with cases of NMS associated with other atypical and typical antipsychotics, cases of NMS induced by clozapine showed a similar course and distribution of findings except for a significant decrease in the frequency with which tremor was described (P < .05). Only one patient treated with clozapine was described as tremulous. Abnormalities of CK were similar across all four treatment groups. Collectively, atypical drugs were significantly less likely than typical drugs to be associated with temperatures exceeding 380C (P < .05), or 400C (P < .01), although this effect was most pronounced for risperidone.

Table

TABLE 2Comparison of Clinical Findings in Patients With Neuroieptic Malignant Syndrome Induced by Typical and Atypical Antlpsychotic Drugs

TABLE 2

Comparison of Clinical Findings in Patients With Neuroieptic Malignant Syndrome Induced by Typical and Atypical Antlpsychotic Drugs

We found 26 cases of NMS due to risperidone, 21 from the literature and 5 from the NMSIS database. Two cases failed to meet criteria and 3 were excluded because of coadministration of typical drugs. Of the 21 remaining cases,23"39 20 met Levenson criteria, 18 met DSM-IV criteria, and 8 met Caroff and Mann criteria. There were no significant differences in clinical findings among cases of NMS due to risperidone, olanzapine, or typical antipsychotics, except that fewer risperidone cases had extreme temperatures compared with cases associated with typical drugs.

Eight reported cases of NMS with olanzapine and 5 from the database were obtained for analysis. Three failed to meet criteria and 1 was excluded because of concomitant typical drug use. Nine met Levenson criteria, 8 met DSM-IV criteria, and 6 fulfilled Caroff and Mann criteria for NMS.40"46 There were no significant differences in demographic variables or clinical presentation of NMS compared with typical drugs, except for the infrequency of extreme temperatures.

We found one reported case of NMS associated with quetiapine that met Levenson and DSM-TV criteria, but not Caroff and Mann criteria.47

Table

TABLE 3Recurrence of Definite or Possible Neuroleptic Malignant Syndrome Symptoms After Rechailenge With Typkai and Atypical Antipsychotic Drugs

TABLE 3

Recurrence of Definite or Possible Neuroleptic Malignant Syndrome Symptoms After Rechailenge With Typkai and Atypical Antipsychotic Drugs

Incidence

Using a centralized database in Australia, Sachdev et al.3 reported the frequency of reports of NMS in patients treated with clozapine to be 3 in 1,250 (0.24%). Williams and Macpherson,20 using a database in England, estimated the frequency of reports of NMS in patients treated with clozapine as 9 in 9,l>00 (0.1%). According to prescribing information, quetiapine was associated with 2 possible cases of NMS in 2,387 patients (0.1%) in premarketing clinical trials.473

In published clinical trials of atypical antipsychotics, neither olanzapine nor haloperidol induced NMS in 1,336 and 660 patients, respectively48; neither risperidone nor haloperidol induced NMS in 348 and 87 patients, respectively49; and neither quetiapine nor haloperidol induced NMS in 250 and 52 patients, respectively.50 In the study of clozapine in treatment-refractory patients, no cases of NMS were reported in 126 patients treated with clozapine or 139 patients treated with chlorpromazine.51 In contrast, Kozaric-Kovacic et al.52 reported that no cases of NMS occurred in 866 treatment episodes of patients with schizophrenia receiving clozapine, whereas 17 episodes (0.6%) of NMS occurred in 2,897 hospitalizations of patients with schizophrenia treated with haloperidol or fluphenazine (P < .05).

Rechallenge and Recurrence

We found that 5 of 19 patients with clozapineindrced NMS had a previous NMS episode w hile receiving typical antipsychotics. Taking these 5 cases, together with subsequent attempts at rechallenge in the cases reviewed here, and including other published reports of rechallenge with clozapine,52-61 we found that in 9 of 31 cases (29%), clozapine was discontinued because of recurrence of definite or possible symptoms of NMS (IJAe 3). Only 1 of 21 patients with risperidone-induced NMS had a prior NMS episode. We found a total of 7 instances of rechallenge using risperidone; 5 (71 Y0) resulted m possible or definite recurrence of NMS. Among cases attributed to olanzapine, 3 involved previous NMS episodes. There were 6 rechallenge attemptc wth olanzapine, and 4 (67%) led to recurrent NMS symptoms. One patient who recoven. ' from olanzapine-induced NMS had possible recurrent symptoms following quetiapine administration.

DISCUSSION

We found a total of 44 published cases that fulfilled diagnostic criteria for NMS, and were attributed to clozapine, risperidone, or olanzapine. An additional 5 cases associated with olanzapine or risperidone were obtained from the NMCIS database. Although we found only 1 case report of NMS due to quetiapine, and 2 possible cases cited by the manufacturer, additional cases may be reported over time as quetiapine becomes more widely prescribed.

It is clear from these cases that NMS can result from treatment with atypical antipsychotics, and that it often presents with the classic features and cou: Je of illness reported previously in association with typical antipsychotics. At least one-third of the cases met even stringent criteria for NMS. The similarity of these cases to the potentially life-threatening picture of NMS described in the past is further strengthened by reports of four deaths among these cases associated with atypical drugs.

Although all of these cases associated with atypical antipsychotics met broad criteria for NMS, some patients presented with only partial or incomplete pictures of NMS, lacking rigidity or other features. Compared with patients treated with typical and other atypical drugs, patients treated with clozapine presented more often with fever in the absence of rigidity or tremors, although this reached statistical significance only for tremors. Temperatures exceeding 380C or 400C were less often observed in NMS induced by all three atypical drugs than in NMS induced by typical drugs.

Despite these differences, the question as to whether atypical drugs are more likely to produce atypical forms of NMS remains moot. Even with typical drugs, the presentation of NMS has often been variable and heterogeneous, with some patients diagnosed without rigidity, fever, or other features. This has become even more common, as increased awareness promotes earlier recognition of NMS in mild or partial forms regardless of which antipsychotic is used.62'63 For example, the reduced frequency of patients with extreme temperatures found among those treated with atypicals is not surprising because more recent cases of NMS are diagnosed earlier with less chance of progression to the fulminant state reported in the past.

Furthermore, milder, partial, or atypical forms may be less specific for NMS, and difficult to distinguish from other more common and benign side effects. This is particularly true for clozapine, which has been associated with benign temperature elevations without extrapyramidal signs in 25% to 50% of patients, and tachycardia in 25% of patients.64 Hence, it is unclear whether these atypical forms of NMS represent the expected variability in presentation of NMS, an early stage of NMS, a spectrum of benign extrapyramidal and autonomic side effects that may or may not be related to NMS, or a result of the unique properties of newer drugs.

In addition, reliance on anecdotal case reports may lead to spurious differences between groups because of variability in the extent of clinical descriptions. The absence of a symptom, such as tremors in patients receiving clozapine, could mean it did not occur, it occurred but was not observed, or it was observed but not reported. Standardized descriptive detail in case reports consistent with diagnostic criteria is essential in comparing clinical presentations of NMS.

Although atypical antipsychotics have been shown to trigger NMS in rare cases, the possibility remains that the incidence of NMS will be reduced with their use. However, this has been difficult to demonstrate. Previously, combining data from several large studies, we estimated the incidence of NMS with typical antipsychotics to be approximately 0.2%. 1 Based on this figure, an impractical number of patients would be required for comparative trials - at least 500 patients on average to detect a single case. Hence, most published clinical trials that revealed no difference in the risk of NMS with either typical or atypical drugs have been too small to reveal cases of NMS.4*"51 Using a larger sample of patients with schizophrenia, KozaricKovacic et al.52 found that clozapine was significantly less likely to cause NMS than were haloperidol and fluphenazine. However, the unexpectedly high rate of NMS (0.6%) observed with typical drugs used in combinations at high dosages may have biased the results of this study.

Furthermore, studies based on postmarketing reports from physicians3,4'20 reflect a rate of reporting cases rather than an actual prospective incidence of occurrence in a population. In these studies, reports of NMS with atypical drugs may be disproportionate and incidence rates overestimated, because clinicians are more likely to report NMS with new drugs and because patients who received atypical drugs may have been more susceptible to the development of NMS. Until recently, these patients comprised a group at high risk for NMS for the same reasons they were switched to atypical drugs. For instance, 18% of the patients we reviewed were switched to atypical drugs because of a prior NMS episode while taking typical drugs, only to have a recurrent NMS episode while taking the new drug. The risk of recurrent NMS in patients with prior episodes may be 30%, compared with an incidence of 0.2% in an unselected population.1 In addition to prior episodes of NMS, patients may have received atypical drugs and thereby comprised a group at high risk for NMS because of the previous development of intolerable extrapyramidal side effects, tardive dyskinesia, or treatment resistance to typical drugs.

Finally, the process of switching, or stopping and restarting antipsychotics, which has frequently preceded the adrninistration of atypical drugs, may constitute an overlooked risk factor that biases studies in favor of finding a higher incidence of NMS with atypical drugs. First, it is possible that the lingering effect of recent treatment with typical drugs may be a factor in the development of NMS with atypical drugs. Second, the period after discontinuation of antipsychotics may represent a period of instability in dopaminergic systems. This may account for the occurrence of withdrawal dyskinesias and the increased risk of psychotic relapse during this period. Furthermore, reports of NMS occurring after discontinuation of antipsychotics indicate that this also represents a period of heightened risk for NMS; most of the reported cases of atypical drug-induced NMS in the literature and the NMSIS database followed the discontinuation of typical drugs.

For similar reasons, the expected reduction in the recurrence of NMS when atypical antipsychotics are used for patients with prior episodes of NMS has not been consistently observed. Although several investigators advocate clozapine as the therapy of choice for psychotic patients with a history of NMS,52-57 we found that 19 of 45 rechallenges using atypical drugs resulted in suspected recurrence of NMS symptoms, prompting discontinuation of the drugs. Wells et al.7 reported recurrence using similar criteria in 17 of 44 patients rechallenged with typical drugs. There was no significant difference between typical and atypical drugs in the rate of recurrence of NMS in these cases. However, this comparison is also confounded by reporting biases; we do not know how many patients were re-treated with either class of antipsychotic and did not experience NMS, as these successful cases are unlikely to be reported. This bias is illustrated by our findings of high recurrence rates among the few patients rechallenged with olanzapine and risperidone; data on a larger number of patients successfully rechallenged would undoubtedly reduce the recurrence rates with these drugs to the levels observed with clozapine and typical drugs (Table 3).

The rechallenge data also indicate that NMS symptoms from both classes of drugs occur in the same patients, reflecting the same risks and underlying pathophysiology. In 17 cases, patients had episodes of NMS due to both typical and atypical drugs on separate occasions. In 1 patient who had NMS without rigidity while taking clozapine, a prior episode while taking remoxipride and haloperidol manifested typical signs of NMS, including mild rigidity.3 Three patients diagnosed as having NMS, in the absence of fever, due to atypicals had prior episodes of NMS diagnosed with typical drugs.3-57,59

Theoretically, the fact that NMS occurs at all with the atypical drugs suggests that their reduced D2-receptor potency and other neurotransmitter effects are not sufficient to prevent all cases of NMS. This is most surprising for clozapine, which shows D2-receptor occupancy that is significantly lower than that of typical and other atypical antipsychotics at therapeutically effective doses.65 In keeping with the hypodopaminergic hypothesis of NMS, this suggests that NMS can occur even with relatively weak dopamine antagonists in susceptible patients, who have genetically determined, structural, or stress-related reductions in baseline dopamine activity. It is possible that NMS can be triggered by druginduced D2-receptor occupancy lower than that associated with common extrapyramidal side effects, and perhaps lower than that required for therapeutic antipsychotic effect. If true, this would imply that the risk of NMS cannot be entirely disassociated from efficacy. However, given the méthodologie limitations of current data on the risk of NMS with atypicals, it may yet prove to be the case that the novel properties of these drugs result in fewer or milder cases of NMS in future studies.

CONCLUSION

The atypical drugs represent a significant advance in the treatment of psychoses, offering enhanced efficacy in refractory patients, treating a broader range of symptoms associated with schizophrenia, and reducing the potential for extrapyramidal side effects and tardive dyskinesia. Nevertheless, clozapine, risperidone, and olanzapine can induce typical NMS in susceptible patients. NMS without significant rigidity or tremors is more likely to be observed with clozapine than with other drugs. Further data are required on quetiapine and NMS. Cases of NMS with atypical drugs are reported disproportionately in the recent literature, and have generally involved patients who are highly susceptible because of prior NMS episodes, extrapyramidal symptoms, treatment failures, and risks associated with switching drugs. As a result, the relative risk of NMS occurring and recurring in association with the use of atypical antipsychotics, especially in more generalized populations, remains unclear. In patients with prior NMS episodes, the use of atypicals is a logical choice, although there appears to be a risk of recurrence of NMS symptoms even with these drugs. As atypical antipsychotics are more widely used as first-line agents in the treatment of psychosis, more broad-based, prospective data on NMS with these drugs may become available.

Currently, the mainstay in the management of NMS in patients receiving atypical as well as typical antipsychotics remains a high index of suspicion, careful monitoring of psychotic patients during the initial stages of treatment, and a clear awareness of the symptoms of NMS, allowing for early recognition and rapid intervention if NMS occurs.

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TABLE 1

Comparison of Cases Meeting Diagnostic Criteria for Neuroleptic Malignant Syndrome

TABLE 2

Comparison of Clinical Findings in Patients With Neuroieptic Malignant Syndrome Induced by Typical and Atypical Antlpsychotic Drugs

TABLE 3

Recurrence of Definite or Possible Neuroleptic Malignant Syndrome Symptoms After Rechailenge With Typkai and Atypical Antipsychotic Drugs

10.3928/0048-5713-20000501-09

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