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Olanzapine-associated neuroleptic malignant syndrome: Is there an overlap with the serotonin syndrome?

Abstract

Background

The neuroleptic malignant syndrome is a rare but serious condition mainly associated with antipsychotic medication. There are controversies as to whether "classical" forms of neuroleptic malignant syndrome can occur in patients given atypical antipsychotics. The serotonin syndrome is caused by drug-induced excess of intrasynaptic 5-hydroxytryptamine. The possible relationship between neuroleptic malignant syndrome and serotonin syndrome is at present in the focus of scientific interest.

Methods

This retrospective phenomenological study aims to examine the seventeen reported olanzapine – induced neuroleptic malignant syndrome cases under the light of possible overlap between neuroleptic malignant syndrome and serotonin syndrome clinical features.

Results

The serotonin syndrome clinical features most often reported in cases initially diagnosed as neuroleptic malignant syndrome are: fever (82%), mental status changes (82%) and diaphoresis (47%). Three out of the ten classical serotonin syndrome clinical features were concurrently observed in eleven (65%) patients and four clinical features were observed in seven (41%) patients.

Conclusion

The results of this study show that the clinical symptoms of olanzapine-induced neuroleptic malignant syndrome and serotonin syndrome are overlapping suggesting similarities in underlying pathophysiological mechanisms.

Background

The neuroleptic malignant syndrome (NMS) is a rare but potentially fatal condition associated with antipsychotic medication. It is mainly characterized by fever, extrapyramidal symptoms, autonomic instability and an altered state of consciousness. It is primarily caused by dopamine (D2) receptors blockage in the nigrostriatal tract, mesocortical pathway and hypothalamic nuclei [1]. Recently, many authors have expressed the view that NMS is not caused by dopamine block alone. Other aminergic systems have also been implicated such as serotonin, norepinephrine, GABA e.t.c. [1, 2]. There are controversies as to whether atypical antipsychotics can cause "classical" forms of NMS [35].

During the last years, a condition of serotoninergic hyperstimulation called "serotonin syndrome" (SS) has been described. It is mainly associated with administration of antidepressive medication. The most frequent clinical features of this syndrome are changes in mental status, restlessness, myoclonus and hyperreflexia [6].

The difficulty of differentiating between NMS and SS has been well recognized [7, 8].

Olanzapine is an atypical antipsychotic, which exhibits greater affinity to serotonin (5-HT2) receptors than to dopamin (D2) receptors [9].

The aim of this study was to examine the recently reported NMS cases induced by olanzapine regarding SS clinical features and to elucidate phenomenological similarities between the two syndromes.

Methods

A MEDLINE search related to olanzapine-induced NMS cases reported in the international literature from January 1996 to March 2001 was conducted. On the basis of the titles and information included in the abstracts, seventeen case reports were found [1026]. Olanzapine-induced NMS cases have been presented and critically reviewed elswhere [27]. All cases were re-analyzed against SS clinical features according to Sternbach diagnostic criteria [6].

Results

NMS associated with olanzapine has been reported in twelve males (mean age 44.5 ± 20.9 years) and in five females (mean age 54.2 ± 22.4 years). Schizophrenia was the primary diagnosis in nine of the patients (53%). The mean olanzapine dosage was 10.7 ± 4.3 mg/day.

As shown in table 1, the SS clinical features presented in cases initially diagnosed as NMS were the following: fever (82%), mental status changes (82%), diaphoresis (47%), tremor (35%), agitation (23%), hyperreflexia (18%), incoordination (12%), myoclonus (6%), diarrhea (6%). There was no report on shivering.

Table 1 Serotonin syndrome clinical features presented in NMS cases induced by olanzapine

Three out of the ten SS clinical features set by Sternbach [6] were concurrently observed in eleven (65%) patients. Four clinical features were observed in seven (41%) patients and five clinical features in two (12%) patients.

Discussion

According to Sternbach [6], for the establishment of the diagnosis of SS, the following three criteria should be fulfilled: a. presence of at least three of the ten proposed clinical features, b. addition to the therapeutic regiment or increase of a known serotonergic agent, and c. a neuroleptic had not been started or increased in dosage. If the last two criteria of drug use were excluded, the SS diagnosis in olanzapine-associated NMS cases could be made in eleven patients (65%). This means that there is a phenomenological overlap between NMS and SS symptoms in patients on olanzapine treatment. According to several authors NMS and SS can be differentiated with difficulty in many cases induced by antipsychotics or selective serotonin-receptor inhibitors (SSRI's) [7, 8].

The atypical or moderate forms of NMS attributed to novel antipsychotics (that have greater affinity to serotonin 5-HT2A receptors than to dopamine D2 receptors) and the overlapping in clinical features between SS and NMS observed in patients treated with olanzapine, reinforce the view that the two syndromes may share the same underlying pathophysiology, i.e. imbalance between aminergic systems, despite differences in the causative drugs [28].

According to Fink [29], NMS and SS are non-specific generalized neurotoxic syndromes. This author recommends the immediate withdrawal of the offending agent and the administration of benzodiazepines in the early stages in both these syndromes.

Further studies, particularly of prospective nature are warranted in patients receiving conventional or atypical antipsychotics as well as serotoninergic agents in order to elucidate the common elements between NMS and SS regarding phenomenology, pathophysiology and treatment response.

Study limits

This is a retrospective analysis of the reported NMS cases induced by olanzapine. The fact that the data were collected from published case reports by other authors, has an inherent bias. The major limitation of this study stems from the lack of detailed information provided regarding the SS clinical symptoms, since the authors were mainly focusing on the description of NMS symptomatology.

Competing intrests

None declared.

References

  1. Caroff SN, Mann SC: Neuroleptic malignant syndrome. Med Clin North Am. 1993, 77: 185-202.

    CAS  PubMed  Google Scholar 

  2. Bobolakis I: Neuroleptic malignant syndrome after antipsychotic drug administration during benzodiazepine withdrawal. J Clin Psychopharmacol. 2000, 20: 281-283. 10.1097/00004714-200004000-00033.

    Article  CAS  PubMed  Google Scholar 

  3. 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. 10.1097/00004714-199510000-00010.

    Article  CAS  PubMed  Google Scholar 

  4. Karagianis JL, Phillips LC, Hogan KP, Le Drew KL: Clozapine-associated neuroleptic malignant syndrome: two new cases and review of the literature. Ann Pharmacother. 1999, 33: 623-630.

    Article  CAS  PubMed  Google Scholar 

  5. Caroff SN, Mann SC, Campbell EC: Atypical antipsychotics and neuroleptic malignant syndrome. Psychiatr Ann. 2000, 30: 314-321.

    Article  Google Scholar 

  6. Srernbach H: The serotonin syndrome. Am J Psychiatry. 1991, 148: 705-713.

    Article  Google Scholar 

  7. Nimmagadda SR, Ryan DH, Atkin SL: Neuroleptic malignant syndrome after venlafaxine. Lancet. 2000, 365: 289-290. 10.1016/S0140-6736(99)03514-X.

    Article  Google Scholar 

  8. Martin TG: Serotonin syndrome. Ann Emerg Med. 1996, 28: 520-526.

    Article  CAS  PubMed  Google Scholar 

  9. Martin J, Gomez JC, Garcia-Bernardo E, Cuesta M, Alvarez E, Gurpegui M: Olanzapine in treatment refractory schizophrenia: results of an open-label study. J Clin Psychiatry. 1997, 58: 479-483.

    Article  CAS  PubMed  Google Scholar 

  10. Johnon V, Bruxner G: Neuroleptic malignant syndrome associated with olanzapine. Aust NZJ Psychiatry. 1998, 32: 884-886.

    Article  Google Scholar 

  11. Filice GA, Mc Dougall BC, Ercan-Fang N, Billington CJ: Neuroleptic malignant syndrome associated with olanzapine. An Pharmacother. 1998, 32: 1158-1159.

    Article  CAS  Google Scholar 

  12. Moltz DA, Coeytaux RR: Case report: possible neuroleptic malignant syndrome associated with olanzapine. J Clin Psychopharmacol. 1998, 18: 485-486. 10.1097/00004714-199812000-00014.

    Article  CAS  PubMed  Google Scholar 

  13. Hanel RA, Sandmann MC, Kranich M, De Bittencourt PRM: Neuroleptic malignant syndrome: case report of a recurrence related to olanzapine. Arq Neuropsychiatr. 1998, 56: 833-837.

    CAS  Google Scholar 

  14. Burkhard PR, Vingerhoets FJG, Alberque C, Landis T: Olanzapine-induced neuroleptic malignant syndrome. Arch Gen Psychiatry. 1999, 56: 101-102. 10.1001/archpsyc.56.1.101.

    Article  CAS  PubMed  Google Scholar 

  15. Emborg C: Neuroleptic malignant syndrome after treatment with olanzapine. Ugeskz Laeger. 1999, 161: 1424-1425.

    CAS  Google Scholar 

  16. Apple JE, Van Hauser G: Neuroleptic malignant syndrome associated with olanzapine therapy [letter]. Psychosomatics. 1999, 40: 267-268.

    Article  CAS  PubMed  Google Scholar 

  17. Hickey C, Stewart C, Lippmann S: Olanzapine and NMS. Psychiatr Services. 1999, 50: 836-837.

    Article  CAS  Google Scholar 

  18. Margolese HC, Chouinard G: Olanzapine-induced neuroleptic malignant syndrome with mental retardation. Am J Psychiatry. 1999, 156: 1115-1116.

    CAS  PubMed  Google Scholar 

  19. Garcia Lopez MM, Cipres L, de Centra E, Vilalta Franch J: Neuroleptic malignant syndrome associated with olanzapine. Med Clin (Barcelona). 1999, 113: 239-

    CAS  Google Scholar 

  20. Levenson JL: Neuroleptic malignant syndrome after the initiation of olanzapine. J Clin Psychopharmacol. 1999, 19: 477-478. 10.1097/00004714-199910000-00016.

    Article  CAS  PubMed  Google Scholar 

  21. Georghiou S, Knobler HY, Drumer D: Recurrence of neuroleptic malignant syndrome with olanzapine treatment. Am J Psychiatry. 1999, 156: 1836-

    Google Scholar 

  22. Hagarty JM, Husni M, Peat C, Allain S: Atypical neuroleptic malignant syndrome?. Can J Psychiatry. 1999, 44: 711-712.

    Google Scholar 

  23. Nyfort-Hansen K, Alderman CP: Possible neuroleptic malignant syndrome associated with olanzapine. An Pharmacother. 2000, 34: 667-10.1345/aph.19239.

    Article  CAS  Google Scholar 

  24. Jarventausta K, Leinonen E: Neuroleptic malignant syndrome during olanzapine and levopromazine treatment. Acta Psychiatr Scand. 2000, 102: 231-233. 10.1034/j.1600-0447.2000.102003231.x.

    Article  CAS  PubMed  Google Scholar 

  25. Stanfield SC, Privette T: Neuroleptic malignant syndrome associated with olanzapine therapy: a case report. J Emerg Med. 2000, 19: 355-357. 10.1016/S0736-4679(00)00263-8.

    Article  CAS  PubMed  Google Scholar 

  26. Sierra-Biddle D, Herran A, Diez-Aja S, Gonzalez-Mata JM, Vidal E, Diez-Manrique F, Vaquez-Barquero JL: Neuroleptic malignant syndrome and olanzapine. J Clin Psychopharmacol. 2000, 20: 704-705. 10.1097/00004714-200012000-00021.

    Article  CAS  PubMed  Google Scholar 

  27. Kontaxakis VP, Havaki-Kontaxaki BJ, Christodoulou NG, Paplos KG: Olanzapine-associated neuroleptic malignant syndrome. Progr Neuropsychopharmacol Biol Psychiatry. 2002, 26: 897-902. 10.1016/S0278-5846(02)00202-6.

    Article  CAS  Google Scholar 

  28. Nisijima K: Abnormal monoamine metabolism in celebrospinal fluid in a case of serotonin syndrome. J Clin Psychopharmacol. 2000, 20: 107-108. 10.1097/00004714-200002000-00022.

    Article  CAS  PubMed  Google Scholar 

  29. Fink M: Toxic serotonin syndrome or neuroleptic malignant syndrome. Pharmacopsychiatry. 1996, 29: 159-161.

    Article  CAS  PubMed  Google Scholar 

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Kontaxakis, V.P., Havaki-kontaxaki, B.J., Christodoulou, N.G. et al. Olanzapine-associated neuroleptic malignant syndrome: Is there an overlap with the serotonin syndrome?. Ann Gen Hosp Psychiatry 2, 10 (2003). https://doi.org/10.1186/1475-2832-2-10

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