Neuroleptic Malignant Syndrome due to Atypical Neuroleptics: Three Episodes in One Patient

• Introduction
• Case report
• Discussion
• References

Neuroleptic malignant syndrome (NMS) is a rare, but potentially lethal complication of antipsychotic medication. The risk of developing NMS under atypical neuroleptics seems lower than under typical neuroleptics. However, the use of atypical neuroleptics in modern psychopharmacotherapy is increasing, so the incidence of NMS under these drugs may also increase. Here, we will describe three episodes of NMS that fulfilled the DSM-IV criteria for NMS (APA, 1994). The epivodes of NMS occured under treatment with clozapine, risperidone, and amisulpride. These episodes had some atypical features that will be discussed with regard to the pathophysiological mechanisms leading to NMS.

Introduction

Neuroleptic malignant syndrome (NMS) is a rare, but serious adverse effect of psychotropic drug therapy. It is characterized by muscular rigidity, hyperthermia, autonomic dysfunction, altered consciousness, and elevation of serum creatine phosphokinase (CPK) levels. The majority of cases begin within two weeks after the initiation of drug treatment [1]. The risk of NMS apparently increases with the use of multiple psychotropic medications. Although most cases of NMS are associated with treatment of typical neuroleptics [21], recent case reports have emphasized that treatment with atypical neuroleptics may also cause this complication [3] [7] [18]. Diagnosis of NMS during treatment with atypical neuroleptics should be carefully distinguished from other adverse effects of these drugs, such as autonomic dysregulation and benign hyperthermia, which are likely to be misattributed to NMS. In the following, we will report on three consecutive episodes of NMS in one patient. All three episodes were associated with atypical neuroleptics (clozapine, risperidone and amisulpride) and fulfilled the DSM-IV criteria for NMS (APA, 1994).

Case report

The 59-year-old female patient diagnosed with residual schizophrenia (DSM-IV: 295.6) first developed NMS in July 1995, after clozapine had been administered and tolerated well for over eight years (100 mg/d average). Due to the onset of a depressive syndrome, it was then decided to reduce and discontinue clozapine therapy and start with amitriptyline (final dosage: 100 mg/d). Seven days after clozapine discontinuation and amitriptyline initiation, the patient developed symptoms which fulfilled the DSM-IV criteria for NMS (for more detailed information, see Table [1]). After NMS remission, amitriptyline (100 mg/d) was reinitiated in combination with risperidone (4 mg/d). About five months later, the patient herself decided to discontinue the risperidone due to a subjective feeling of weakness in the right arm. After another two weeks, she took a single dose of risperidone (4 mg/d) and developed vomiting and muscle pain within one day. Consequently, the patient had to be admitted to a hospital where NMS was diagnosed (see Table [1]). After this second bout of NMS, the decision to avoid any further neuroleptic treatment in this patient was made. As an alternative, treatment with trimipramine was initiated. Apart from its antidepressive effects, trimipramine has also been shown to have antipsychotic properties, especially in higher dosages [8]. With this medication, the patient did not experience any further psychotic symptoms for over a year. In March 1999, the patient was readmitted to our hospital due to exacerbated paranoid ideation accompanied by depressive symptoms. Treatment with amitriptyline (100 mg/d) and melperone (up to 400 mg/d) did not lead to a remission in her paranoid-depressive syndrome, so the patient was treated with amisulpride, which was later combined with fluvoxamine. During a four-month hospital stay, the patient reached a good clinical response and developed no signs of NMS. A further four months later, a third bout of NMS developed while the patient was being treated with amisulpride (dosage was increased from 600 mg/d to 800 mg/d two weeks before NMS), fluvoxamine (75 mg/d) and prothipendyl (80 mg/d) (see Table [1]). Medical workup excluded concomitant medical illness in all three episodes of NMS (normal CT scan of the head (1^st case), normal ECG (all cases), normal chest X-ray (1^st, 2^nd and 3^rd case), no laboratory or clinical signs for viral or bacterial infections (1^st, 2^nd and 3^rd case)).

Discussion

We reported three episodes of NMS under three different atypical neuroleptics. All cases fulfilled the DSM-IV criteria for NMS (APA, 1994; see Table [1]). NMS under treatment with clozapine or risperidone has also been reported by other authors [3] [4] [7] [13] [18] [20] [25] [26]. To our knowledge, this is the first time NMS has been associated with amisulpride in the literature.

The patient's first bout of NMS had developed within a one week interval after discontinuation of clozapine and initiation of amitriptyline. Since the reported symptomatology developed after the discontinuation of clozapine, a clozapine withdrawal or discontinuation syndrome, suggested to be a result of a central cholinergic rebound phenomenon [28], should be taken into account. However, the elevation of CPK levels and severe muscle rigidity do not seem to be compatible with a clozapine withdrawal syndrome, being more in line with the NMS diagnosis. Although the development of NMS after discontinuation of the neuroleptic medication is unusual, other case reports in the literature indicate that this may happen [17] [27]. An additional impact of amitriptyline on the NMS in our patient cannot be completely excluded, as NMS under amitriptyline has been reported in the literature [6] [19]. A weak argument against the impact of amitriptyline on the observed NMS could be that amitriptyline was reinitiated in combination with risperidone after remission of the NMS, and was tolerated well for more than five months. The patient's second bout of NMS also occurred in the presence of amitriptyline, but was closely related to the intake of a single dosage of risperidone. After the intake of risperidone, typical clinical symptoms of NMS with highly increased serum levels of the CPK developed rapidly within hours (see Table [1]). The patient's third adverse reaction happened during long-term amisulpride treatment in combination with fluvoxamine and prothipendyl. Since fluvoxamine can cause toxic serotonin syndrome, which has a symptomatic overlap with the NMS, this differential diagnosis also has to be considered [9]. Although extrapyramidal symptoms may occur during treatment with serotonin reuptake inhibitors [11], the presence of severe rigidity, high CPK serum levels and absence of serotoninergic adverse effects such as vomiting, headache or myocloni, which are common features of a serotonin syndrome [29], does not tally with this differential diagnosis. Furthermore, serotonin syndrome seems more likely to develop during treatment with higher dosages of serotoninergic drugs [11]. In our case, the dosage of fluvoxamine was rather low. The same applies for prothipendyl, and no cases of NMS have been reported with this drug. Thus, the diagnosis of NMS during treatment with amisulpride is probably the best explanation for the observed symptomatology. The long-term interval (about 8 months) between the initiation of amisulpride and the onset of NMS seems somewhat atypical, but comparable observations with other neuroleptics have been reported [15] [16]. The increase of amisulpride from a dosage of 600 mg/d to 800 mg/d two weeks before the patient's third NMS may have had an additional impact on the development of the NMS. An association between changes in the dosage of a neuroleptic medication and development of NMS has been emphasized in the literature [24] [27] and may be also responsible for the patient's first and second NMS, which were both closely related to changes in the neuroleptics dosage.

With this in mind, it could be suggested that apart from a central dopaminergic blockade alone, which is seen as a precipitating factor for NMS, the rate of change in dopaminergic neurotransmission (mediated by changes in neuroleptics dosage, for example) or dopaminergic dysregulation in general may trigger the development of NMS. Despite the involvement of central dopaminergic mechanisms in the development of NMS, a large body of evidence also indicates that peripheral mechanisms associated with an excess of catecholamines [10] or direct myotoxic and neurotoxic effects of neuroleptics play a role in the pathogenesis of NMS [23]. Furthermore, the three successive episodes of NMS under treatment with different neuroleptics in the same patient reported here point to the possibility of a genetically determined increased susceptibility for developing NMS. And indeed, there is some evidence that a variety of genetic alterations (for example mutations in the debrisoquine 4-hydroxylase, dopamine D2 receptor genes or mutation of the CYP2D6 gene) could increase an individuals risk to develop NMS [12] [14] [22].

However, despite these findings and evidence, it is not yet possible to provide a conclusive pathophysiological model or concept for NMS. Thus, it is still unclear whether NMS represents a distinct medical condition, a subtype of catatonia [5] [9] or just an idiosyncratic reaction associated with the use of neuroleptic drugs.

References

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Ronald Bottlender, MD 

Psychiatrische Klinik der Ludwig-Maximilians-Universität

Nussbaumstr. 7


80336 München

Germany

Phone: +49-89-5160-5751

Fax: +49-89-5160-4749

Email: bottlend@psy.med.uni-muenchen.de

References

• 1 Addonizio G, Susman V L, Roth S D. Symptoms of neuroleptic malignant syndrome in 82 consecutive inpatients.  Am J Psychiatry. 1986;  143 1587-1590
  PubMedSearch in Google Scholar
• 2 American Psychiatric Association .Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition. Washington D.C. 1994
  Search in Google Scholar
• 3 Anderson E S, Powers P S. Neuroleptic malignant Syndrome Associated With Clozapine Use.  J Clin Psychiatry. 1991;  52 102-104
  PubMedSearch in Google Scholar
• 4 Bajjoka I, Patel T, O'Sullivan T. Risperidone-induced neuroleptic malignant syndrome.  Ann Emerg Med,. 1997;  30 698-700
  PubMedSearch in Google Scholar
• 5 Blumer D. Catatonia and the neuroleptics: psychobiologic significance of remote and recent findings.  Compr Psychiatry. 1997;  38 (4) 193-201
  CrossrefPubMedSearch in Google Scholar
• 6 Corrigan F M, Coulter F. Neuroleptic malignant syndrome, amitriptyline and thioridazine.  Biol Psychiatry. 1988;  23 320-321
  CrossrefPubMedSearch in Google Scholar
• 7 DasGupta K, Young A. Clozapine-Induced Neuroleptic Malignant Syndrome.  J Clin Psychiatry. 1991;  52 105-107
  PubMedSearch in Google Scholar
• 8 Eikmeier G, Muszynski K, Berger M, Gastpar M. High-dose trimipramine in acute schizophrenia. Preliminary results of an open trial.  Pharmacopsychiatry. 1990;  23 (5) 212-214
  PubMedSearch in Google Scholar
• 9 Fink M. Toxic Serotonin Syndrome or Neuroleptic Malignant Syndrome.  Pharmacopsychiat. 1996;  29 159-161
  PubMedSearch in Google Scholar
• 10 Gurrera R J. Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome.  Am J Psychiatry. 1999;  156 169-180
  PubMedSearch in Google Scholar
• 11 Hegerl U, Bottlender R, Gallinat J. et al . The serotonin syndrome scale: first results on validity.  Eur Arch Psychiatry Clin Neurosci. 1998;  248 96-103
  CrossrefPubMedSearch in Google Scholar
• 12 Iwahashi K. CYP2D6 genotype and possible susceptibility to the neuroleptic malignant syndrome.  Biol Psychiatry. 1994;  36 781-782
  CrossrefPubMedSearch in Google Scholar
• 13 Karagianis J L, Phillips L C, Hogan K P. et al . Clozapine-associated neuroleptic malignant syndrome: two new cases and a review of the literature.  Ann-Pharmacother. 1999;  33 623-630
  PubMedSearch in Google Scholar
• 14 Kawanishi C, Shimoda Y, Fujimaki J, Onishi H, Suzuki K, Hanihara T, Sugiyama N, Kosaka K. Mutation involving cytochrome P450IID6 in two Japanese patients with neuroleptic malignant syndrome.  J Neurol Sci. 1998;  160 (1) 102-104
  PubMedSearch in Google Scholar
• 15 Kern J L, Cernek P K. Delayed risperidone-induced neuroleptic malignant syndrome.  Ann Pharmacother. 1996;  30 (3) 300
  PubMedSearch in Google Scholar
• 16 Lee M S, Lee H J, Kim L. A case of delayed NMS induced by risperidone.  Psychiatr Serv. 2000;  51 (2) 254-255
  CrossrefPubMedSearch in Google Scholar
• 17 Merriam A E. Withdrawal NMS after drug treatment.  Biol Psychiatry. 1988;  24 (3) 368-369
  CrossrefPubMedSearch in Google Scholar
• 18 Miller D D, Sharafuddin J A, Kathol R G. A Case of Clozapine-Induced Neuroleptic Malignant Syndrome.  J Clin Psychiatry. 1991;  52 99-101
  PubMedSearch in Google Scholar
• 19 Miyaoka H, Kamijima K. Encephalopathy during amitriptyline therapy: are neuroleptic malignant syndrome and serotonin syndrome spectrum disorders?.  Int Clin Psychopharmacol. 1995;  10 265-267
  PubMedSearch in Google Scholar
• 20 Newman M, Adityanjee , Jampala C. Atypical neuroleptic malignant syndrome associated with risperidon treatment (letter).  Am J Psychiatry. 1997;  154 1475
  PubMedSearch in Google Scholar
• 21 Pope H G, Keck P E , McElroy S L. Frequency and presentation of neuroleptic malignant syndrome in a large psychiatric hospital.  Am J Psychiatry. 1986;  143 1227-1233
  PubMedSearch in Google Scholar
• 22 Ram A, Cao Q, Keck P E, Pope H G, Otani K, Addonizio G, McElroy S L, Kaneko S, Redlichova M, Gershon E S, Gejman P V. Structural change in dopamine D2 receptor gene in a patient with neuroleptic malignant syndrome.  Am J Med Genet. 1995;  60 228-230
  CrossrefPubMedSearch in Google Scholar
• 23 Reznik I, Volchek L, Mester R, Kotler M, Sarova-Pinhas I, Spivak B, Weizman A. Myotoxicity and neurotoxicity during clozapine treatment.  Clin Neuropharmacol. 2000;  23 276-280
  PubMedSearch in Google Scholar
• 24 Shaley A, Munitz H. The Neuroleptic Malignant Syndrome. Agent and host interaction.  Acta Psychiatr. Scand1986;  73 337
  PubMedSearch in Google Scholar
• 25 Sharma R, Trappler B, Ng Y K, Leeman C P. Risperidone-induced neuroleptic malignant syndrome.  Ann Pharmakother. 1996;  30 775-778
  PubMedSearch in Google Scholar
• 26 Singer S, Richards C, Boland R J. Two cases of risperidone-induced neuroleptic malignant syndrome (letter).  Am J Psychiatry. 1995;  152 1234
  PubMedSearch in Google Scholar
• 27 Spivak B, Weizman A, Wolovick L. et al . Neuroleptic malignant syndrome during abrupt reduction of neuroleptic treatment.  Acta Psychiatr Scand. 1990;  81 168-169
  PubMedSearch in Google Scholar
• 28 Stanilla J K, de Leon J, Simpson G M. Clozapine withdrawal resulting in delirium with psychosis: a report of three cases.  J Clin Psychiatry. 1997;  58 252-255
  PubMedSearch in Google Scholar
• 29 Sternbach H. The serotonin syndrome.  Am J Psychiatry. 1991;  148 705-713
  PubMedSearch in Google Scholar

Ronald Bottlender, MD 

Psychiatrische Klinik der Ludwig-Maximilians-Universität

Nussbaumstr. 7


80336 München

Germany

Phone: +49-89-5160-5751

Fax: +49-89-5160-4749

Email: bottlend@psy.med.uni-muenchen.de