Antipsychotic Rechallenge After NeurolepticMalignant Syndrome with Catatonic Features

Item Type Thesis

Authors Bond, Alicia Giuffrida

Rights Copyright © is held by the author. Digital access to this materialis made possible by the College of Medicine - Phoenix, Universityof Arizona. Further transmission, reproduction or presentation(such as public display or performance) of protected items isprohibited except with permission of the author.

Download date 20/04/2018 23:33:25

Link to Item http://hdl.handle.net/10150/170529

1

Antipsychotic Rechallenge After Neuroleptic Malignant Syndrome with Catatonic Features

A Thesis submitted to The University of Arizona College of Medicine- Phoenix in partial fulfillment of the requirements for the

Degree of Doctor of Medicine

Alicia Giuffrida Bond

2011

2

This project is dedicated to Mr.S

and the many other West Tower 6 patients

who sparked my interest in research and compassion for those

suffering from psychiatric illness

3

Acknowledgements Dr. Christian Cornelius and Dr. Richard Gerkin, faculty at Banner Good Samaritan Medical Center, contributed to this thesis and will be listed as co-authors when it is submitted for publication. Dr. Sandra McDonald and Dr. Courtney Kekich at Banner Good Samaritan Medical Center took excellent care of Mr. S and contributed to the case report. Kathleen Shepler, librarian at Banner Good Samaritan Medical Center, was an invaluable resource who tracked down many difficult-to-find publications for this project.

4

Abstract Neuroleptic malignant syndrome (NMS) is a life-threatening condition that can occur in patients who require long-term antipsychotic therapy, and who therefore must be rechallenged with antipsychotics after their NMS episode. Current guidelines are based on limited data and recommend that rechallenge be undertaken by titrating from low doses of low-potency antipsychotics, after a period of two weeks following resolution of symptoms. We present the case of a patient with an NMS course complicated by residual catatonia course and a literature review with analysis to determine whether time to rechallenge, potency of rechallenge drug, and dose of rechallenge drug are independent predictors of NMS recurrence in patients. One hundred thirteen instances of neuroleptic rechallenge in non-catatonic NMS cases and 29 cases of rechallenge in NMS with catatonic features were identified through broad Medline and PsycInfo database searches and were analyzed by a single reviewer for rechallenge data. Fifty-five cases involved female patients, and 87 male patients; patients ranged in age from 12 to 86, with a mean of 37. There was no statistically significant relationship found between rate of NMS recurrence and time elapsed before rechallenge, either for all cases or by subgroup. Although the recurrence rate for patients rechallenged with highest-potency antipsychotics was found to be higher than those rechallenged with lowest-potency drugs,the relationship was not significant. The maximum antipsychotic dose reached during rechallenge was significantly lower among patients with recurrence of NMS than those who did not recur, likely due to recurrences early in dose titration. There was no statistically significant relationship between starting dose and recurrence. Based on our analysis, time between resolution of symptoms and rechallenge may have no bearing on risk of recurrence, in contrast to current recommendations. Dose of rechallenge drug is also unlikely to be an independent predictor of recurrence. Several studies, including ours, have shown a statistically insignificant but consistent positive relationship between potency of rechallenge drug and risk of recurrence.

5

Table of Contents Introduction 6 Case Report 7 Method 10 Results 11 Discussion 12 Limitations of the Study 15 Revisiting Mr. S 16 Conclusions 16 References 18 Poster 28

6

Introduction Neuroleptic malignant syndrome (NMS) is an uncommon but life-threatening complication of antipsychotic pharmacotherapy characterized by hyperpyrexia, muscle rigidity, autonomic instability, and elevation of serum creatine phosphokinase (CPK). NMS carries a mortality rate of 10-20 percent. In many cases, it occurs in patients who would benefit from long-term antipsychotic therapy, and who therefore must be rechallenged with an antipsychotic after NMS has resolved. However, little evidence is available to guide safe rechallenge, particularly with second-generation antipsychotics. Based on several small studies in the 1980s that demonstrated conflicting results1-7, it is generally recommended that rechallenge be undertaken with careful monitoring, preferably by titrating from low doses of low-potency antipsychotics, after a period of 2 weeks following resolution of symptoms8-9. The symptoms of NMS generally resolve within two weeks of withdrawal of the inducing agent. However, numerous cases of residual catatonia following NMS have been reported10-12. The relationship between NMS and catatonia has been conceptualized in various ways. Recently, Carroll and Lee et al have described NMS as an entity with three subtypes: NMS without catatonic features; NMS with catatonia preceding NMS development; and NMS followed by catatonia13. For those cases in which catatonic features persist after the resolution of fever and rigidity, it is unclear when the illness can be considered “resolved”, and therefore difficult to interpret the existing guidelines on safe reintroduction of antipsychotics. We present a case report describing a patient who suffered a prolonged course of NMS with catatonic features and required subsequent antipsychotic therapy, followed by a literature review of NMS cases with rechallenge information. Data were gathered from published NMS case reports to evaluate whether time to rechallenge, dose of rechallenge drug, and potency of rechallenge drug were independent predictors of NMS recurrence, both in non-catatonic NMS and NMS with residual catatonia.

7

Case Report Mr. S is a very pleasant 44-year-old man with a history of schizophrenia and panic attacks who presented to the emergency department after three days of feeling ill with increased auditory hallucinations, panic attacks, anxiety, and agitation. His illness had been well-controlled on clozapine 100 mg per day for the last four months. Due to worsening symptoms the week of presentation, his outpatient provider added lorazepam 1 mg twice daily three days prior to admission, followed by fluphenazine 5 mg daily and benztropine mesylate 1 mg twice daily the day prior to admission. His only other outpatient medication was docusate 250 mg twice daily. In the emergency department, he was confused with nonsensical speech, tachycardia ranging from 102-122 beats per minute, and tachypnea up to 26 breaths per minute. His blood pressure ranged from 112/68 to 145/97, and his temperature was 36.9. Physical examination, CBC, electrolytes, TSH, CPK, urinalysis, CT head without contrast, and chest X-ray were all unremarkable. Urine drug screen was positive for benzodiazepines only. Because his tachycardia did not resolve with IV fluid administration or lorazepam, and out of concern for possible anticholinergic toxicity, he was admitted to telemetry for monitoring. CT angiography of the chest was performed to rule out pulmonary embolus. Mr. S was continued on benztropine 1 mg twice daily and fluphenazine 5 mg daily. Notably, clozapine was not identified by any of his physicians as a current outpatient medication and was not continued. On hospital day two, his temperature rose to 38.6, and he was diagnosed with pneumonia based on a nonspecific left upper lobe opacity found on CT. He was treated with levofloxacin, albuterol, and ipratropium; other non-psychotropic inpatient medications were docusate, enoxaparin, and famotidine. Over the next four days, his fever, tachycardia, and mental status improved, and discharge was planned for hospital day seven. However, on day seven, Mr. S’ mental status declined, and he developed slow speech, bilateral involuntary movements, and significant cogwheeling in the upper extremities. On day eight, psychiatric consultation identified the inadvertent discontinuation of clozapine and recommended discontinuation of fluphenazine and benztropine out of concern for neuroleptic malignant syndrome. At that

8

time, Mr. S was found to be tachycardic (109), with diaphoresis, tremor, bilateral upper extremity cogwheel rigidity and moderate lower extremity rigidity. Blood pressure ranged from 117/76 to 162/104, and his temperature rose to 37.5. Labs included CPK 857, white blood cell count 13.7, AST 86, ALT 100, and CO2 17. He was transferred to the intensive care unit and treated with 45 mg IV diazepam in seven doses over the next 36 hours with mild relief in tremor and rigidity. Over the next several days, Mr. S became increasingly somnolent and mute, and was sedated and intubated on hospital day 13 for increased respiratory secretions and inability to protect his airway. Despite treatment with dantrolene and diazepam, his rigidity continued to wax and wane, his CPK fluctuated between 589 and 1906, his pulse and blood pressure remained labile, and his temperature ranged from 37.0 to 37.7. He developed posturing, stupor, and staring, and on hospital day 19 he was started on lorazepam 2 mg IV every 4-8 hours. His tremor and rigidity decreased; he awoke and was able to follow commands, and he was extubated on hospital day 21. His CPK began to trend down and his temperature dropped below 37. However, he demonstrated mutism, posturing, rigidity, immobility, staring, withdrawal, and ongoing autonomic instability with a Bush-Francis catatonia rating scale score of 14 (out of possible 69 points) performed on hospital day 22. His primary team planned to taper lorazepam and pursue electroconvulsive therapy for residual catatonia; however, his mental status improved over the next several days, and he began talking and eating, though slow speech and flat affect persisted. He was transferred from the ICU to a medical floor on hospital day 29. His rigidity gradually decreased, and he received inpatient physical therapy for weakness. His CPK returned to normal (191) on hospital day 35. His lorazepam was tapered and discontinued over the next three days, and he was transferred to the psychiatric inpatient unit with increasing complaints of auditory hallucinations on hospital day 39. Although the primary team indicated a resolution of all extrapyramidal symptoms, the admitting psychiatrist noted persistent cogwheeling on examination. He was restarted on lorazepam 2 mg every 6 hours. Over the next four days, he also developed tachycardia (114), diaphoresis, and a mild leukocytosis (11.7). Out of concern for

9

residual catatonia or recurrent NMS, his lorazepam was increased to 3 mg every 6 hours on hospital day 43 and benztropine 1 mg every 8 hours was added. His cogwheeling, tachycardia, and leukocytosis resolved within 24 hours. Over the same time period, Mr. S complained of increasing paranoia, auditory hallucinations, and delusions of thought broadcasting. He expressed distress about his symptoms and repeatedly requested to have his antipsychotic medications restarted; however, there was much concern about recurrence given the severity of his clinical course. Toxicology recommendations and a literature search on neuroleptic rechallenge after NMS suggested a trial two weeks after “resolution of NMS symptoms”; however, because of his prolonged course, it was unclear how to define “resolution of symptoms”. His fever resolved on hospital day 22 and CPK normalized on day 35; however, his most recent extrapyramidal signs were noted on day 42, and ongoing extrapyramidal symptoms might be masked by lorazepam and benztropine. After discussing options with the patient, including the possibility of ECT, it was decided to restart antipsychotics on hospital day 56, 14 days after cogwheeling was last noted. Quetiapine was chosen for rechallenge due to its low potency and short half-life. It was started at 25 mg twice daily on day 56 and increased in increments of 25 mg per day to 700 mg per day in divided doses over the next 30 days. Additionally, divalproex sodium extended release 1000 mg every night was started on hospital day 53 and increased to 2000 mg every night after 10 days. Mr. S remained on lorazepam 3 mg every 6 hours and benztropine 1 mg every 8 hours, and levocarnitine 330 mg every 8 hours was added on hospital day 63. Physical exam, CPK, and vital signs were carefully monitored with no signs of NMS recurrence. Mr. S experienced some improvement in symptoms over the month, but had persistent auditory hallucinations and delusions of thought broadcasting. Ninety-one days after admission, Mr S was transferred to another facility for consideration of ECT to address his persistent psychotic symptoms at the request of his primary insurance carrier.

10

Method Through broad MEDLINE and PsycInfo database searches and from reference lists of published literature and review articles on NMS over 500 cases of NMS published since 1984 were identified. Each full-text case report was reviewed by a single investigator for information about antipsychotic rechallenge. Included in the final analysis were cases that met Levenson criteria for NMS (Table 1)14, which are the most inclusive of several proposed sets of diagnostic criteria15-18; these criteria were chosen due to the high variability in diagnostic parameters reported in the cases. Cases were identified as catatonic or non-catatonic based upon the presence or absence of catatonic features such as posturing, prolonged mutism, waxy flexibility, refusal of food and drink, catalepsy, and immobility described during or following the NMS episode. Multiple instances of rechallenge in a single patient were treated as separate rechallenge cases. The full text of each case was reviewed to extract data including (1) antipsychotic drug, potency, and dose at onset of NMS; (2) concurrent psychotropic medications; (3) drug, potency, and initial and maximum dose at rechallenge; and (4) time between resolution of symptoms and rechallenge. Doses were converted to chlorpromazine (CPZ) equivalents as defined by Davis, Woods, Andreasen, and others19-23. Analysis of drug potency was based on relative chlorpromazine equivalents; drugs with a CPZ equivalent of 2 or less (including risperidone and haloperidol) were included in the “highest potency” category, and those with a CPZ equivalent 95 or greater, (including clozapine, quetiapine, and chlorpromazine), were included in the “lowest potency” category. “Resolution of symptoms” was defined for the non-catatonic patients as resolution of fever and rigidity and return of CPK to normal limits (< 130); for the catatonic patients, it was defined as resolution of the persistent catatonic features. The time-frame parameters analyzed for rechallenge were based on the time frames found to be significant in past studies: 5 days from resolution of symptoms5 and 2 weeks from resolution of symptoms2.We also included an analysis comparing rechallenge before vs. after resolution of symptoms. Recurrence of NMS was defined to include both repeat NMS episodes meeting Levenson criteria and milder recurrences of NMS signs such as elevations in temperature or CPK.

11

Continuous variables were reported as means and standard errors. Categorical variables were reported as percentages. Categorical variables were analyzed using chi-square testing. Continuous variables were analyzed using the t-test; when continuous variables were not normally distributed, the Wilcoxon rank sum test was used. Logistic regression was used to determine independent predictors of recurrence. A two-tailed p < 0.05 was considered significant. Due to variability in reporting by case authors, not every parameter was available for analysis in each instance; for example, some authors report only initial dose of rechallenge drug, some report only maximum dose reached over time, and some report both. Results One hundred thirteen instances of neuroleptic rechallenge in non-catatonic NMS cases and 29 cases of rechallenge in NMS with catatonic features were included in our analysis5,11,14,24-104. Fifty-five cases involved female patients, and 87 male patients. Diagnoses requiring antipsychotic treatment included schizophrenia, acute psychosis, bipolar disorder with psychosis, and dementia. Of these 142 cases, 55 (39%) resulted in recurrence of NMS and 87 resulted in no recurrence. The recurrence rate was slightly higher in the non-catatonic NMS subgroup (45 cases, 40%) than the catatonic subgroup (10 cases, 35%). Rates of recurrence for all cases and for catatonic and non-catatonic subgroups are summarized in Tables 2-4. There was no statistically significant relationship found between rate of NMS recurrence and either of our evaluated parameters for time elapsed before rechallenge, either for all cases or by subgroup, However, a higher recurrence rate for rechallenges greater than two weeks from resolution of symptoms (53%) vs. less than two weeks (35%) approached statistical significance with a p value of 0.053. Additionally, there was no statistically significant relationship found between recurrence rates if antipsychotics were reintroduced before vs. after resolution of symptoms. Although the recurrence rate for patients rechallenged with highest-potency antipsychotics was found to be higher (43% overall) than those rechallenged with lowest-potency drugs (36% overall), the relationship was not significant (p = 0.518). An additional chi-square

12

analysis that evaluated second-generation drugs independently of first-generation antipsychotics also showed no significant difference. Most of the rechallenges we identified were with different antipsychotics than those that precipitated the initial NMS episodes; however, we identified 24 instances in which patients were rechallenged with the same drug. Fourteen of those, seven of which were with clozapine, were successful (58%) and did not result in re-emergence of NMS. However, there were too few such cases to analyze for significance. Most rechallenge drugs were started at lower doses and gradually increased to therapeutic doses. The maximum antipsychotic dose reached during rechallenge was significantly lower among patients with recurrence of NMS than those who did not recur (p = .0026); however, there was no statistically significant relationship between starting dose and recurrence. Reported starting doses ranged from 11 CPZ equivalents to 800, with a mean of 150 and median of 100, while maximum doses ranged from 11 to 3000, with a mean of 296 and median of 210. Discussion The overall rate of recurrence found in our analysis is higher than rates estimated by previous prospective studies2,4 and is likely not representative of the actual recurrence rate upon rechallenge of patients after a single NMS episode given our inclusion of multiple recurrences in single patients as separate instances. Furthermore, it is possible that rechallenge information may be included more often in case reports when the rechallenge has been unsuccessful. Time Frame Although several past studies have suggested a significant relationship between time frame and likelihood of recurrence, that relationship was not borne out by the analysis performed here. Wells5 reported among 44 patients a 64 percent recurrence rate in rechallenges before five days after resolution of symptoms vs. a 30 percent recurrence rate after five days. In smaller series, Rosebush2 and Susman and Addonizio6 found that rechallenge before two weeks increased risk of recurrence.

13

While it is possible that our study did not include enough case reports to identify a significant trend, our findings suggested that recurrence is in fact more likely when rechallenge is undertaken greater than two weeks after resolution of symptoms. This may be due to our inclusion of several reports of patients in whom initial rechallenge was successful, but who then experienced recurrences months or years after their initial episode, often in the context of a change to a stable antipsychotic regimen. It is also possible that past studies may have underestimated the rate of recurrence after the two-week waiting period due to inadequate follow-up periods. We identified in the literature numerous instances in which antipsychotics were re-introduced before the resolution of NMS symptoms, most commonly after improvement of fever and rigidity but before normalization of laboratory values. We were surprised to find that in our analysis, these patients were not at higher risk of recurrence than those in whom the recommended waiting period was observed. This was the case for both the non-catatonic and catatonic subtypes. Again, it is possible that our study was underpowered to find a significant trend. Discontinuing the precipitating medication is the well-supported mainstay of treatment for NMS, and it therefore remains prudent to withhold antipsychotics while fever and rigidity persist; however, our data suggest that antipsychotics may be safely reintroduced earlier than is generally recommended. Potency of Rechallenge Drug Our findings, although statistically insignificant, were consistent with past literature reviews suggesting a higher risk of recurrence with higher-potency antipsychotics. Rosebush et al2 found a similar insignificant relationship in their prospective series, and literature reviews by Addonizio et al1, Shalev and Munitz3 both suggested higher rates of recurrence with haloperidol vs. chlorpromazine or thioridazine. Analyses by Caroff and Mann7 and Gelenberg4 have similar results. Unlike the older studies, our analysis included second-generation antipsychotics, including multiple instances of rechallenge with quetiapine, clozapine, olanzapine, and risperidone. Given the low rate of extrapyramidal symptoms experienced with the low-potency second-generation antipsychotics relative to chlorpromazine, we generally recommend choosing a lower-

14

potency second-generation drug for rechallenge. However, given that numerous studies have failed to show a significant relationship between potency and recurrence risk, individual cases may warrant other choices. For example, if a patient were stable on a higher-potency medication before an acute change that precipitated NMS, it may be reasonable to consider gradually resuming that stable regimen. Dose of Rechallenge Drug The significant inverse relationship found between maximum dose and risk of rechallenge can be explained by the fact that NMS recurred at subtherapeutic doses in many patients, and antipsychotics were discontinued early in the dose titration. Patients who were successfully rechallenged were able to have their doses increased further to therapeutic levels. The lack of significant relationship between starting dose and recurrence risk is consistent with findings from past studies2. We encountered one case report in which a patient was successfully rechallenged with a very low dose of a drug that had triggered NMS multiple times in the past at higher doses; however, starting dose did not predict recurrence in any of our analyses. Antipsychotic drugs should always be started at low doses and increased to the lowest possible therapeutic dose to minimize side effects, but there do not appear to be special considerations for most NMS patients. Medication dose was a difficult variable to standardize, given the existence of several formulas for calculating chlorpromazine equivalence and the fact that each medication has a unique mechanism of action, half-life, and side effect profile. These characteristics should also be taken into account when choosing the appropriate rechallenge medication for an individual patient. Residual Catatonia Although the conceptualization of NMS as an entity with catatonic and non-catatonic subtypes was consistent with the types of cases encountered during our broad literature search, none of the variables evaluated in this study were significantly different in patients with catatonic features. However, as we reviewed the cases with an eye toward differentiating subtypes, we believe there may be

15

other variables that may differ significantly between the subtypes, particularly in the area of treatment. As Lee105 has suggested, this is an area that deserves further exploration. Limitations of the Study The data for this study was gathered and coded by a single researcher, which risks introducing that researcher’s bias in choosing which cases to include. This is especially true with regard to evaluating the presence of catatonic features, which were often poorly described in case studies. In addition to the variables analyzed here, there were many other factors that could contribute to recurrence risk and confound our findings, including the patient’s diagnosis, history of antipsychotic use, NMS recurrence history, and use of other psychotropic medications. Electroconvulsive therapy was used successfully to resolve residual symptoms in a majority of the catatonic patients before the reintroduction of antipsychotics, and may also have impacted recurrence risk. In order to maximize the power of the analysis, we chose to include multiple instances of rechallenge in a single patient as separate cases. It has been proposed that individual predisposition may play a role in recurrence risk8, and therefore may be a confounding factor in our analysis. However, most of these patients were ultimately rechallenge successfully, potentially contributing relevant information about ideal rechallenge circumstances. Furthermore, clinicians encountering NMS may not know whether a patient has had an episode in the past, and a study sample that includes high-risk patients is more likely to apply to clinical practice.

We used a broad definition of NMS in choosing our cases, and although cases were reviewed carefully, it is possible that individual cases may have been misdiagnosed by the authors. The case reports included varied greatly in terms of level of detail and length of follow-up, and therefore the data is inherently subject to error. A larger, prospective study including NMS data from multiple hospitals, along with long-term follow-up, would allow for continued improvement of our understanding of NMS recurrence.

16

Revisiting Mr. S Mr. S had been stable on clozapine for several months before the addition of fluphenazine and subsequent inadvertent discontinuation of clozapine. Using the existing guidelines for rechallenge, we chose to restart him on quetiapine at low doses, which was ineffective at controlling his psychotic symptoms. This is not surprising, given that clozapine is generally prescribed when a patient has failed extensive trials of several other medications. Furthermore, more than two weeks elapsed after he began complaining of hallucinations before antipsychotics were reintroduced. While Mr. S had a severe and prolonged course of NMS complicated by residual catatonia, the findings from our analysis suggest that we might safely have restarted him much sooner, used clozapine instead of quetiapine, and increased his does to therapeutic levels more quickly, potentially providing him with greater relief from his psychotic symptoms. Notably, we encountered three other cases in which NMS was precipitated by a change in medication regimen that included withdrawal of clozapine31,77,79; in two of these cases, rechallenge with clozapine was successful, and in the third, rechallenge with risperidone was successful. Conclusions NMS is a syndrome whose onset is difficult to predict and which may recur; however, many patients are successfully restarted on antipsychotic medication. Based on our analysis, time between resolution of symptoms and rechallenge may have no bearing on risk of recurrence, in contrast to current recommendations. Dose of rechallenge drug is also unlikely to be an independent predictor of recurrence. Several studies, including ours, have shown a statistically insignificant but consistent positive relationship between potency of rechallenge drug and risk of recurrence. Clinicians should consider the severity of patient symptoms and the patient’s past responses to different medications when choosing the appropriate time and drug for rechallenge, and always reintroduce antipsychotics with careful monitoring of vital signs and laboratory values. Further study of

17

recurrence risk, as well as NMS with catatonic features, will improve our ability to make the best choices for our patients.

18

References 1 Addonizio G, Susman VL, Roth SD. Neuroleptic malignant syndrome: Review and analysis of 115 cases. Biol Psychiatry. 1987;22:1004-1020 2 Rosebush PI, Stewart TD, Gelenberg AJ. Twenty neuroleptic rechallenges after neuroleptic malignant syndrome in 15 patients. J Clin Psychiatry. 1989;50:295-298. 3 Shalev A & Munitz H. The neuroleptic malignant syndrome: Agent and host interaction. Acta Psychiatrica Scandinavia.1986;73:337-347 4 Gelenberg AJ, Bellinghausen B, Wojcik JD, Falk WE, Farhadi AM. Patients with neuroleptic malignant syndrome histories: What happens when they are rehospitalized? J Clin Psychiatry. 1989;50:178-180 5 Wells AJ, Sommi RW, Crismon ML. Neuroleptic rechallenge after neuroleptic malignant syndrome: Case report and literature review. Drug Intell and Clin Pharm. 1988;22:475-479 6 Susman VL & Addonizio G. Recurrence of neuroleptic malignant syndrome. J Nerv Ment Dis. 1988;176:234-241 7 Caroff SN & Mann SC. Neuroleptic malignant syndrome. Psychopharmacol Bull. 1988;24:25-29 8 Caroff SN. Neuroleptic malignant syndrome, in Neuroleptic Malignant Syndrome and Related Conditions, 2nd ed. Edited by Mann SC, Caroff SN, Keck PE Jr, Lazarus A. Washington, DC, American Psychiatric Publishing, 2003, pp 1-44 9 Strawn JR, Keck PE Jr, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry. 2007;164:870-876 10 Caroff SN, Mann SC, Keck PE Jr, Francis A. Residual catatonic state following neuroleptic malignant syndrome. J Clin Psychopharm. 2000;20:257-259 11 Trollor JN & Sachdev PS. Electroconvulsive treatment of neuroleptic malignant syndrome: A review and report of cases. Aust N Z J Psychiatry. 1999;33:650-659 12 Lee JWY. Catatonic and non-catatonic neuroleptic malignant syndrome. Aust N Z J Psychiatry. 2000;34:877 13 Carroll BT, Lee JWY, Graham KT, Thalassinos A, Thomas C, Kirhart R. Diagnosing subtypes of neuroleptic malignant syndrome: An introduction to the Lee-Carroll Scale. Annals Clin Psychiatry. 2008;20:47-48

19

14 Levenson JL. Neuroleptic malignant syndrome. Am J Psychiatry. 1985;142:1137-1145 15 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC, American Psychiatric Association, 1994. 16 Pope HG, Keck PE Jr, McElroy SL. Frequency and presentation of neuroleptic malignant syndrome in a large psychiatric hospital. Am J Psychiatry. 1986;143:1227-1233 17 Addonizio G, Susman VL, Roth SD. Symptoms of neuroleptic malignant syndrome in 82 consecutive inpatients. Am J Psychiatry. 1986;143:1587-1590 18 Caroff SN & Mann SC. Neuroleptic malignant syndrome. Med Clin North Am. 1993;77:185-202 19 Davis JM. Dose equivalence of the antipsychotic drugs. J Psychiatric Res. 1974;11:65-69 20 Woods SW. Chlorpromazine equivalent doses for the newer atypical antipsychotics. J Clin Psychiatry. 2003;64:663-667 21 Andreasen NC, Pressler M, Nopoulos P, Miller D, Ho BC. Antipsychotic dose equivalents and dose-years: A standardized method for comparing exposure to different drugs. Biol Psychiatry. 2010;67:255-262 22 Atkins M, Burgess A, Bottomley C, Riccio M. Chlorpromazine equivalents: A consensus of opinion for both clinical and research applications. Psychiatric Bulletin. 1997;21:224-226 23 Wyatt RJ & Torgow JS. A comparison of equivalent clinical potencies of neuroleptics as used to treat schizophrenia and affective disorders. J Psychiatric Res. 1976;13:91-98 24 Abbott RJ & Loizou LA. Neuroleptic malignant syndrome. J Psychiatry. 1986;148:47-51 25 Adityanjee, Singh S, Singh G, Ong S. Spectrum concept of neuroleptic malignant syndrome. Br J Psychiatry. 1988;153:107-111 26 Aizenberg D, Shalev A, Munitz H. The aftercare of the patient with the neuroleptic malignant syndrome. Br J Psychiatry. 1985;146:317-318 27 Anderson ES & Powers PS. Neuroleptic malignant syndrome associated with clozapine use. J Clin Psychiatry. 1991;52:102-104 28 Baker RW & Chengappa KNR. Further study of neuroleptic malignant syndrome. Am J Psychiatry 1995;152:1831

20

29 Beauchemin MA, Millaud F, Nguyen KA. A case of neuroleptic malignant syndrome with clozapine and risperidone. Can J Psychiatry. 2002;47:886 30 Benazzi F. Clozapine-induced neuroleptic malignant syndrome not recurring with olanzapine, a structurally and pharmacologically similar antipsychotic. Hum Psychopharmacol. 1999;14:511-513 31 Bottlender R, Jaeger M, Hofschuster E, Dobmeier P, Moeller HJ. Neuroleptic malignant syndrome due to atypical neuroleptics: Three episodes in one patient. Pharmacopsychiatry. 2002;35:119-121 32 Bourgeois JA, Babine S, Meyerovich M, Doyle J. A case of neuroleptic malignant syndrome with quetiapine. J Neuropsychiatry Clin. 2002;14:87 33 Boyarsky BK, Fuller M, Early T. Malignant catatonia-induced respiratory failure with response to ECT. J ECT. 1999;15:232-236 34 Boyd RD. Recurrence of neuroleptic malignant syndrome via an inadvertent rechallenge in a woman with mental retardation. Ment Retard. 1992;30:77-79 35 Brieger P & Reinelt Y. No recurrence of neuroleptic malignant syndrome under quetiapine. Aust N Z J Psychiatry. 2003;37:627 36 Brown TM. Clozapine, neuroleptic malignant syndrome, and pancerebellar syndrome. Psychosomatics. 1999;40:518-520 37 Chandran GJ, Mikler JR, Keegan DL. Neuroleptic malignant syndrome: Case report and discussion. CMAJ. 2003;169:439-442 38 Chandran M & El-Shazly M. Catatonia, neuroleptics and brain damage: A case report. J Psychopharmacol. 2009;23:223 39 Chungh DS, Kim BN, Cho SC. Neuroleptic malignant syndrome due to three atypical antipsychotics in a child. J Psychopharmacol. 2005;19:422-425 40 Conlon P. The spectrum concept of neuroleptic toxicity. Am J Psychiatry. 1986;143:811 41 Dalkilic A & Grosch WN. Neuroleptic malignant syndrome following initiation of clozapine therapy. Am J Psychiatry. 1997;153:881-882 42 Dassa D, Drai-Moog D, Samuelian JC. Neuroleptic malignant syndrome with the addition of aripriprazole to clozapine. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:427-428 43 Doan RJ & Callahan WD. Clozapine treatment and neuroleptic malignant syndrome. Can J Psychiatry. 2000;45:394-395

21

44 Duggal HS & Nizamie SH. Neuroleptic malignant syndrome precipitated by promethazine and lorazepam. Aust N Z J Psychiatry. 2001;35:250-251 45 Duggal HS. Possible neuroleptic malignant syndrome associated with paliperidone. J Neuropsychiatry Clin Neurosci. 2007;19:477-478 46 Duggal HS & Singh I. Neuroleptic malignant syndrome presenting with acute renal failure. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:1074-1075 47 Ferioli V, Manes A, Melloni C, Nanni S, Boncompagni G. Atypical neuroleptic malignant syndrome caused by clozapine and venlafaxine: Early brief treatment with dantrolene. Can J Psychiatry. 2004;49:497-498 48 Fitzgerald B, Middleton JK, Cooper SA. Adverse effects of summer amongst people with learning disabilities: neuroleptic malignant syndrome. J Intellect Disabil Res. 1997;41:273-277 49 Frances A & Susman VL. Managing an acutely manic 17-year-old girl with neuroleptic malignant syndrome. Hosp Community Psychiatry. 1986;37:771-772 50 Ghaziuddin N, Alkhouri I, Champine D, Quinlan P, Fluent T, Ghaziuddin M. ECT treatment of malignant catatonia/NMS in an adolescent: A useful lesson in delayed diagnosis and treatment. J ECT. 2002;18:95-98 51 Gheorghiu S, Knobler HY, Drumer D. Recurrence of neuroleptic malignant syndrome with olanzapine treatment. Am J PsychiatryAm J Psychiatry. 1999;156:1836 52 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. J Clin Psychopharmacol. 1992;12:139-140 53 Goenner F, Baumgartner R, Schuepbach D, Merlo MCG. Neuroleptic malignant syndrome during low dosed neuroleptic medication in first-episode psychosis: A case report. Psychopharmacol. 1999;144:416-418 54 Goldwasser HD, Hooper JF, Spears NM. Concomitant treatment of neuroleptic malignant syndrome and psychosis. Br J Psychiatry. 1989;154:102-104 55 Gray NS. Ziprasidone-related neuroleptic malignant syndrome in a patient with Parkinson’s disease: a diagnostic challenge. Hum Psychopharmacol. 2004;19:205-207

22

56 Greenberg LB & Gujavarty K. The neuroleptic malignant syndrome: Review and report of three cases. Comp Psychiatry. 1985;26:63-70 57 Hanin B & Lerner Y. Neuroleptic malignant syndrome: Neuroleptic rechallenge after electroconvulsive therapy. Convuls Ther. 1993;9:198-204 58 Hatch CD, Lund BC, Perry PJ. Failed challenge with quetiapine after neuroleptic malignant syndrome with conventional antipsychotics. Pharmacotherapy. 2001;21:1003-1006 59 Hermesh H, Huberman M, Radvan H, Kott E. Recurrent neuroleptic malignant syndrome due to tiapride and haloperidol: The possible role of D-2 dopamine receptors. J Nerv Ment Dis. 1984;172:692-695 60 Hickey C, Stewart C, Lippmann S. Olanzapine and NMS. Psychiatr Serv. 1999;50:836-837 61 Illing M & Ancill R. Clozapine-induced neuroleptic malignant syndrome: Clozapine monotherapy rechallenge in a case of previous NMS. Can J Psychiatry. 1996;41:258 62 Jessee SS & Anderson GF. ECT in the neuroleptic malignant syndrome: Case report. J Clin Psychiatry. 1983;44:186-188. 63 Johnson V & Bruxner G. Neuroleptic malignant syndrome associated with olanzapine. Aust N Z J Psychiatry. 1998;32:884-886 64 Kemperman CJF. Zuclopenthixol-induced neuroleptic malignant syndrome at rechallenge and its extrapyramidal effects. Br J Psychiatry. 1989;154:562-563 65 Knific J & Kogoj A. Amisulpiride-induced neuroleptic malignant syndrome. Acta Neuropsychiatrica. 2008;20:108-109 66 Koponen H, Repo E, Lepola U. Neuroleptic malignant syndrome. Biol Psychiatry. 1988;24:943-944 67 Kumar RR. Neuroleptic rechallenge following neuroleptic malignant syndrome. Aust N Z J Psychiatry. 1998;32:700 68 Lazarus A. Treatment of neuroleptic malignant syndrome with electroconvulsive therapy. J Nerv Ment Dis. 1986;174:47-49 69 Lazarus A & Rosenberg H. Treatment of rehospitalized NMS patients. J Clin Psychiatry. 1990;51:84 70 Lee H, Ryan J, Mullett G, Lawlor B. Neuroleptic malignant syndrome associated with the use of risperidone, an atypical antipsychotic agent. Hum Psychopharmacol. 1994;9:303-305 71 Leung SK. Catatonia and neuroleptic malignant syndrome. Hong Kong J Psychiatry. 2001;11:22-24

23

72 Levenson JL & Fisher JG. Long-term outcome after neuroleptic malignant syndrome. J Clin Psychiatry. 1988;49:154-156 73 Lewis AL & Kahn DA. Malignant catatonia in a patient with bipolar disorder, B12 deficiency, and neuroleptic malignant syndrome: One cause or three? J Psychiatr Prac. 2009;15:415-422 74 Mahendran R, Winslow M, Lim D. Recurrent neuroleptic malignant syndrome. Aust N Z J Psychiatry. 1998;32:699-700 75 Mall GD, Hake L, Benjamin AB, Adityanjee A. Catatonia and mild neuroleptic malignant syndrome after initiation of long-acting injectable risperidone. J Clin Psychopharmacol. 2008;28:572 76 Mantas C, Kalabokis G, Tourlakopoulos A, Hyphantis T, Mavreas V. Possible neuroleptic malignant syndrome during paliperidone administration. J Clin Psychopharmacol. 2010;30:89 77 Margetic B & Aukst-Margetic B. Neuroleptic malignant syndrome and clozapine withdrawal at the same time? Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:145-147 78 Margolese HC & Chouinard G. Olanzapine-induced neuroleptic malignant syndrome with mental retardation. Am J Psychiatry. 1999;156:1115-1116 79 Mendhekar DN & Jiloha RC. Neuroleptic malignant syndrome precipitated by haloperidol following clozapine discontinuation. Aust N Z J Psychiatry. 2005;39:947-948 80 Miller DD, Sharafuddin MJA, Kathol RG. A case of clozapine-induced neuroleptic malignant syndrome. J Clin Psychiatry. 1991;52:99-101 81 Moltz DA & Coeytaux RR. Case report: Possible neuroleptic malignant syndrome associated with olanzapine. J Clin Psychopharmacol. 1998;18:485-486 82 Nemets B, Geller V, Grisaru N, Belmaker RH. Olanzapine treatment of clozapine-induced NMS. Hum Psychopharmacol. 2000;15:77-78 83 Newman M, Adityanjee, Jampala C. Atypical neuroleptic malignant syndrome associated with risperidone treatment. Am J Psychiatry. 1997;154:1475 84 Nisijima K & Ishiguro T. Electroconvulsive therapy for the treatment of neuroleptic malignant syndrome with psychotic symptoms: A report of five cases. J ECT. 1999;15:158-163 85 Nopoulos P, Flaum M, Miller DD. Atypical neuroleptic malignant syndrome (NMS) with an atypical neuroleptic: Clozapine-induced NMS without rigidity. Ann Clin Psychiatry. 1990;2:251-253

24

86 Otani K, Horiuchi M, Kondo T, Kaneko S, Fukushima Y. Is the predisposition to neuroleptic malignant syndrome genetically transmitted? Br J Psychiatry. 1991;158:850-853 87 Padgett R & Lipman E. Use of neuroleptics after an episode of neuroleptic malignant syndrome. Can J Psychiatry. 1989;34:323-325 88 Pelonero AL, Levenson JL, Silverman JJ. Neuroleptic therapy following neuroleptic malignant syndrome. Psychosomatics. 1985;26:946-948 89 Reddig S, Minnema AM, Tandon R. Neuroleptic malignant syndrome and clozapine. Ann Clin Psychiatry. 1993;5:25-27 90 Reznik I, Spivak B, Melman R, Kotler M, Weizman A, Mester R. Safety and efficacy of long-term low-dose clozapine aftercare treatment in a patient with learning difficulties who suffered from neuroleptic malignant syndrome. Int J Psychiatry Clin Prac. 2002;6:121-123 91 Ries RK & Schuckit MA. Catatonia and autonomic hyperactivity. Psychosomatics. 1980; 21:349-350 92 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 93 Singh AN & Hambidge DM. Successful use of risperidone after neuroleptic malignant syndrome (NMS): A 1-year follow-up. Hum Psychopharmacol. 1997;12:65-66 94 Slack T & Stoudemire A. Reinstitution of neuroleptic treatment with molindone in a patient with a history of neuroleptic malignant syndrome. Gen Hosp Psychiatry. 1989;11:365-367 95 Solomons, K. Quetiapine and neuroleptic malignant syndrome. Can J Psychiatry. 2002;47:791-792 96 Srivastava A, Borkar H, Chandak S. Olanzapine-induced neuroleptic malignant syndrome in a patient with paranoid schizophrenia. Psychiatry Clin Neurosci. 2009;63:119-121 97 Suh H, Bronson B, Martin R. Neuroleptic malignant syndrome and low-dose olanzapine. Am J Psychiatry. 2003;160:796 98 Taylor NE & Schwartz HI. Neuroleptic malignant syndrome following amoxapine overdose. J Nerv Ment Dis. 1988;176:249-251 99 Trutia A, Bledowski J, Pandurangi A, Kahn D. Neuroleptic rechallenge with aripriprazole in a patient with previously documented neuroleptic malignant syndrome. J Clin Psychiatr Prac. 2008;14:398-402

25

100 Verdoot P, Constant E, Seghers A. Neuropsychiatric systemic lupus erythematosus associated with neuroleptic malignant syndrome. Br J Psychiatry. 2008;193:507-517 101 Weller M & Kornhuber J. Clozapine rechallenge after an episode of neuroleptic malignant syndrome. Br J Psychiatry. 1992;161:855-856 102 Yacoub A & Francis A. Neuroleptic malignant syndrome induced by atypical neuroleptics and responsive to lorazepam. Neuropsychiatr Dis Treat. 2006;2:235-240 103 Zalsman G, Lewis R, Konas S, Loebstein O, Goldberg P, Burguillo F, Nahshoni E, Munitz H. Atypical neuroleptic malignant syndrome associated with risperidone treatment in two adolescents. Int J Adolesc Med Health. 2004;16:179-182 104 Zammit GK & Sullivan TB. Thioridazine and neuroleptic malignant syndrome. Biol Psychiatry. 1987;22:1296-1297 105 Lee JWY. Catatonic variants, hyperthermic extrapyramidal reactions, and subtypes of neuroleptic malignant syndrome. Ann Clin Psychiatry. 2007;19:9-16

26

Table 1. Levenson criteria for neuroleptic malignant syndrome.

Major Criteria Minor Criteria Fever Tachycardia Rigidity Abnormal blood pressure Elevated CPK Tachypnea Altered consciousness Diaphoresis Leukocytosis

All three major criteria or two major plus four minor were considered positive for NMS in this study.

Table 2. Risk of recurrence by time to rechallenge.

N Recurrence No

Recurrence p

value ALL CASES

Before sx resolved 25 10 (40%) 15 (60%) After sx resolved 101 43 (43%) 58 (57%) 0.815 < 5 days after sx resolved 42 15 (36%) 27 (64%) > 5 days after sx resolved 59 30 (51%) 29 (49%) 0.132 < 2 wks after sx resolved 58 20 (35%) 38 (65%) > 2 wks after sx resolved 49 26 (53%) 23 (47%) 0.053

NON-CATATONIC CASES Before sx resolved 17 7 (41%) 10 (59%) After sx resolved 80 36 (45%) 44 (55%) 0.773 < 5 days after sx resolved 31 12 (39%) 19 (61%) > 5 days after sx resolved 48 23 (48%) 25 (52%) 0.42 < 2 wks after sx resolved 44 16 (36%) 28 (64%) > 2 wks after sx resolved 41 21 (51%) 20 (49%) 0.167

CATATONIC CASES Before sx resolved 8 3 (62%) 5 (38%) After sx resolved 21 7 (33%) 14 (67%) 0.833 < 5 days after sx resolved 11 3 (27%) 8 (73%) > 5 days after sx resolved 11 7 (64%) 4 (36%) 0.083 < 2 wks after sx resolved 14 4 (29%) 10 (71%) > 2 wks after sx resolved 8 5 (63%) 3 (37%) 0.119

Percentages reflect number of recurrences or non-recurrences per total number assessed in each group (N).

27

Table 3. Risk of recurrence by potency of rechallenge drug.

N Recurrence No

Recurrence p

value ALL CASES

Highest Potency 23 10 (43%) 13 (56%) Lowest Potency 75 27 (36%) 48 (64%) 0.518

NON-CATATONIC CASES Highest Potency 17 7 (41%) 10 (59%) Lowest Potency 65 23 (35%) 42 (65%) 0.659

CATATONIC CASES Highest Potency 6 3 (50%) 3 (50%) Lowest Potency 10 4 (40%) 6 (60%) 0.696

Percentages reflect number of recurrences or non-recurrences per total number assessed in each group (N).

Table 4. Risk of recurrence by dose of rechallenge drug.

Recurrence No Recurrence p

value ALL CASES Mean St Err Mean St Err

Starting Dose 115.8 28.4 156.1 25.2 0.292 Maximum Dose 174.0 52.4 388.0 45.5 0.0026

NON-CATATONIC CASES Mean St Err Mean St Err Starting Dose 124.9 33.1 169.7 31.4 0.331 Maximum Dose 173.8 63.0 412.1 55.4 0.006

CATATONIC CASES Mean St Err Mean St Err Starting Dose 56.5 31.0 112.4 20.7 0.162 Maximum Dose 172.9 81.6 307.0 67.9 0.221

All doses are given in chlorpromazine equivalents.

28