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Neuroleptic malignant syndrome: evaluation of drug safety data from the AMSP program during 1993–2015

  • Michael Schneider
  • Johannes Regente
  • Timo Greiner
  • Stephanie Lensky
  • Stefan Bleich
  • Sermin Toto
  • Renate Grohmann
  • Susanne Stübner
  • Martin Heinze
Original Paper
  • 11 Downloads

Abstract

Neuroleptic malignant syndrome (NMS) is a rare, but severe adverse drug reaction of drugs with anti-dopaminergic properties. The main symptoms are fever and rigor. In addition, other symptoms such as creatine kinase elevation, alteration of consciousness and various neurological symptoms may occur. A total of 52 NMS cases have been documented in the drug safety program ‘Arzneimittelsicherheit in der Psychiatrie’ from 1993 to 2015. We calculated incidences and analyzed imputed substances and additional risk factors to study the impact of changing therapy regimes. The overall incidence was 0.16‰. High-potency first-generation antipsychotics (FGAs) had the highest incidences, e.g. flupentixol with 0.61‰. Second-generation antipsychotics (SGAs) had lower incidences. Low-potency FGAs had very low incidences, comparable to SGAs, but in contrast to SGAs, had not been imputed alone in any case of NMS. Preexisting organic pathologies of the central nervous system, lithium treatment, infection/exsiccosis and the withdrawal of medication with anticholinergic properties or alcohol were found to be additional risk factors. With the increasing use of SGAs, one should always be aware of the risk of NMS. Better suited diagnostic criteria for ‘atypical NMS’ would lead to a better understanding and, therefore, to improved treatment possibilities.

Keywords

Neuroleptic malignant syndrome Antipsychotics Medication-induced movement disorder Diagnostic criteria Incidences Risk factors 

Notes

Acknowledgements

This study was supported by the AMSP Drug Safety Programme, Hannover, Germany. The analysis of the NMSdata and this publication were made possible by a grant from Immanuel Klinik Rüdersdorf.

Compliance with ethical standards

Conflict of interest

T. Greiner, M. Schneider, S. Lensky, S. Stübner, J. Regente and M. Heinze declare no conflict of interests. The AMSP Drug Safety Program is based on non-profit associations in the German-speaking countries Germany, Austria and Switzerland. In recent years, financial support has been contributed by almost all the pharmaceutical companies involved in CNS research. Since 1993, educational and research grants have been awarded by the following pharmaceutical companies to the three national non-profit associations of the AMSP. Austrian companies: AstraZeneca Österreich GmbH, Boehringer Ingelheim Austria, Bristol–Myers Squibb GmbH, CSC Pharmaceuticals GmbH, Eli Lilly GmbH, Germania Pharma GmbH, GlaxoSmithKline Pharma GmbH, Janssen-Cilag Pharma GmbH, Lundbeck GmbH, Novartis Pharma GmbH, Pfizer Med Inform, Servier Pharma Austria, Wyeth Lederle Pharma GmbH. German companies: Abbott GmbH & Co. KG, AstraZeneca GmbH, Aventis Pharma Deutschland GmbH GE-O/R/N, Bayer Vital GmbH & Co. KG, Boehringer Mannheim GmbH, Bristol-Myers-Squibb, Ciba Geigy GmbH, Desitin Arzneimittel GmbH, Duphar Pharma GmbH & Co. KG, Eisai GmbH, esparma GmbH Arzneimittel, GlaxoSmithKline Pharma GmbH & Co. KG, Hoffmann-La Roche AG Medical Affairs, Janssen-Cilag GmbH, Janssen Research Foundation, Knoll Deutschland GmbH, Lilly Deutschland GmbH Niederlassung Bad Homburg, Lundbeck GmbH & Co. KG, Nordmark Arzneimittel GmbH, Novartis Pharma GmbH, Organon GmbH, Otsuka-Pharma Frankfurt, Pfizer GmbH, Pharmacia & Upjohn GmbH, Promonta Lundbeck Arzneimittel, Rhone-Poulenc Rohrer, Sanofi-Synthelabo GmbH, Sanofi-Aventis Deutschland, Schering AG, Servier Pharma, SmithKlineBeecham Pharma GmbH, Solvay Arzneimittel GmbH, Synthelabo Arzneimittel GmbH, Dr Wilmar Schwabe GmbH & Co., Thiemann Arzneimittel GmbH, Trommsdorff GmbH & Co. KG Arzneimittel, Troponwerke GmbH & Co. KG, Upjohn GmbH, Wander Pharma GmbH, Wyeth-Pharma GmbH. Swiss companies: AHP (Schweiz) AG, AstraZeneca AG, Bristol–Myers Squibb AG, Desitin Pharma GmbH, Eli Lilly (Suisse) S.A., Essex Chemie AG, GlaxoSmithKline AG, Janssen-Cilag AG, Lundbeck (Suisse) AG, Mepha Schweiz AG/Teva, MSD Merck Sharp & Dohme AG, Organon AG, Pfizer AG, Pharmacia, Sandoz Pharmaceuticals AG, Sanofi-Aventis (Suisse) S.A., Sanofi-Synthe´labo SA, Servier SA, SmithKlineBeecham AG, Solvay Pharma AG, Vifor SA, Wyeth AHP (Suisse) AG, Wyeth Pharmaceuticals AG. S. Bleich, R. Grohmann and S. Toto are project managers of the AMSP program. S. Toto has been a member of the advisory board for Otsouka and has received speaker’s honoria from Janssen-Cilag, Lundbeck, Otsouka and Servier.

References

  1. 1.
    Addonizio G, Susman VL, Roth SD (1987) Neuroleptic malignant syndrome: review and analysis of 115 cases. Biol Psychiatry 22(8):1004–1020CrossRefGoogle Scholar
  2. 2.
    American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders DSM-IV-TR. Jaypee Medical Ltd, LondonGoogle Scholar
  3. 3.
    American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders DSM 5, 5 edn. American Psychiatric Association, LondonCrossRefGoogle Scholar
  4. 4.
    Belvederi Murri M, Guaglianone A, Bugliani M, Calcagno P, Respino M, Serafini G et al (2015) Second-generation antipsychotics and neuroleptic malignant syndrome: systematic review and case report analysis. Drugs RD 15:45–62.  https://doi.org/10.1007/s40268-014-0078-0 CrossRefGoogle Scholar
  5. 5.
    Bschor T, Bauer M (1998) Thyroid gland function in lithium treatment. Nervenarzt 69:189–195CrossRefGoogle Scholar
  6. 6.
    Buzan B (1996) Risperidone-induced tardive dyskinesia. Am J Psychiatry 153(5):734–735PubMedGoogle Scholar
  7. 7.
    Byrd C (1993) Neuroleptic malignat syndrome: a dangerous complication of neuroleptic therapy. J Neurosci Nurs 25(1):62–65CrossRefGoogle Scholar
  8. 8.
    Caroff SN, Mann SC, Campbell EC, Sullivan KA (2002) Movement disorders associated with atypical antipsychotic drugs. J Clin Psychiatry 63(Suppl 4):12–19PubMedGoogle Scholar
  9. 9.
    Chen Y, Guo JJ, Steinbuch M, Buckley PF, Patel NC (2009) Risk of neuroleptic malignant syndrome in patients with bipolar disorder: a retrospective, population-based case-control study. Int J Psychiatry Med 39:439–450CrossRefGoogle Scholar
  10. 10.
    Fallgatter AJ, Strik WK (1997) Reversible neuropsychiatric side effects of lithium with normal serum levels. A case report. Nervenarzt 68:586–590CrossRefGoogle Scholar
  11. 11.
    Friedrich ME, Akimova E, Huf W, Konstantinidis A, Papageorgiou K, Winkler D, Toto S, Greil W, Grohmann R, Kasper S (2016) Drug-induced liver injury during antidepressant treatment: results of AMSP, a drug surveillance program. Int J Neuropsychopharmacol 19(4):1–9.  https://doi.org/10.1093/ijnp/pyv126 CrossRefGoogle Scholar
  12. 12.
    Grohmann R, Engel RR, Möller H-J, Rüther E, van der Velden JW, Stübner S (2013) Flupentixol use and adverse reactions in comparison with other common first- and second-generation antipsychotics: data from the AMSP study. Eur Arch Psychiatry Clin Neurosci 264(2):131–141.  https://doi.org/10.1007/s00406-013-0419-y CrossRefPubMedGoogle Scholar
  13. 13.
    Grohmann R, Engel RR, Ruther E, Hippius H (2004) The AMSP drug safety program: methods and global results. Pharmacopsychiatry 37(Suppl 1):S4–S11.  https://doi.org/10.1055/s-2004-815505 CrossRefPubMedGoogle Scholar
  14. 14.
    Gurrera RJ (2017) A systematic review of sex and age factors in neuroleptic malignant syndrome diagnosis frequency. Acta Psychiatr Scand May 135(5):398–408CrossRefGoogle Scholar
  15. 15.
    Kato D, Kawanishi C, Kishida I, Furuno T, Suzuki K, Onishi H, Hirayasu Y (2007) Effects of CYP2D6 polymorphisms on neuroleptic malignant syndrome. Eur J Clin Pharmacol 63(11):991–996CrossRefGoogle Scholar
  16. 16.
    Keck PE, Pope HG, McElroy SL (1991) Declining frequency of neuroleptic malignant syndrome in a hospital population. Am J Psychiatry 148:880–882.  https://doi.org/10.1176/ajp.148.7.880 CrossRefPubMedGoogle Scholar
  17. 17.
    Keck PE, Pope HG, McElroy SL (1987) Frequency and presentation of neuroleptic malignant syndrome: a prospective study. Am J Psychiatry 144:1344–1346.  https://doi.org/10.1176/ajp.144.10.1344 CrossRefPubMedGoogle Scholar
  18. 18.
    Keck PE, Sebastianelli J, Pope HG, McElroy SL (1989) Frequency and presentation of neuroleptic malignant syndrome in a state psychiatric hospital. J Clin Psychiatry 50:352–355PubMedGoogle Scholar
  19. 19.
    Lannas PA, Pachar JV (1993) A fatal case of neuroleptic malignant syndrome. Med Sci Law 33(1):86–88CrossRefGoogle Scholar
  20. 20.
    Letmaier M, Grohmann R, Kren C, Toto S, Bleich S, Engel R, Gary T, Papageorgiou K, Konstantinidis A, Holl KA, Painold A, Kasper S (2018) Venous thromboembolism during treatment with antipsychotics—results of a drug surveillance program. World J Biol Psychiatry 19(3):175–186.  https://doi.org/10.1080/15622975.2017.1285048 CrossRefPubMedGoogle Scholar
  21. 21.
    Masi G, Milone A, Viglione V, Mancini A, Pisano S (2014) Massive asymptomatic creatine kinase elevation in youth during antipsychotic drug treatment: case reports and critical review of the literature. J Child Adolesc Psychopharmacol 24:536–542.  https://doi.org/10.1089/cap.2014.0047 CrossRefPubMedGoogle Scholar
  22. 22.
    Meisenzahl EM, Schmitt G, Gründer G, Dresel S, Frodl T, la Fougère C et al (2008) Striatal D2/D3 receptor occupancy, clinical response and side effects with amisulpride: an iodine-123-iodobenzamide SPET study. Pharmacopsychiatry 41:169–175.  https://doi.org/10.1055/s-2008-1076727 CrossRefPubMedGoogle Scholar
  23. 23.
    Moore AP, Macfarlane IA, Blumhardt LD (1990) Neuroleptic malignant syndrome and hypothyroidism. J Neurol Neurosurg Psychiatry 53:517–518CrossRefGoogle Scholar
  24. 24.
    Nagel M, Freisberg S, Junghanns K, Moll CKE, Willenborg B (2015) The neuroleptic malignant syndrome]. Fortschr Neurol Psychiatr 83:373–380.  https://doi.org/10.1055/s-0035-1553246 CrossRefPubMedGoogle Scholar
  25. 25.
    Nielsen RE, Wallenstein Jensen SO, Nielsen J (2012) Neuroleptic malignant syndrome-an 11-year longitudinal case-control study. Can J Psychiatry 57:512–518.  https://doi.org/10.1177/070674371205700810 CrossRefPubMedGoogle Scholar
  26. 26.
    Oruch R, Pryme IF, Engelsen BA, Lund A (2017) Neuroleptic malignant syndrome: an easily overlooked neurologic emergency. Neuropsychiatr Dis Treat 13:161–175CrossRefGoogle Scholar
  27. 27.
    Picard LS, Lindsay S, Strawn JR, Kaneria RM, Patel NC, Keck PE (2008) Atypical neuroleptic malignant syndrome: diagnostic controversies and considerations. Pharmacotherapy 28:530–535.  https://doi.org/10.1592/phco.28.4.530 CrossRefPubMedGoogle Scholar
  28. 28.
    Perrault G, Depoortere R, Morel E, Sanger DJ, Scatton B (1997) Psychopharmacological profile of amisulpride: an antipsychotic drug with presynaptic D2/D3 dopamine receptor antagonist activity and limbic selectivity. J Pharmacol Exp Ther 280:73–82PubMedGoogle Scholar
  29. 29.
    Pileggi DJ, Cook AM (2016) Neuroleptic malignant syndrome. Ann Pharmacother 50:973–981.  https://doi.org/10.1177/1060028016657553 CrossRefPubMedGoogle Scholar
  30. 30.
    Spindelegger CJ, Papageorgiou K, Grohmann R, Engel R, Greil W, Konstantinidis A et al (2014) Cardiovascular adverse reactions during antidepressant treatment: a drug surveillance report of German-speaking countries between 1993 and 2010. Int J Neuropsychopharmacol 18(4):1.  https://doi.org/10.1093/ijnp/pyu080 CrossRefGoogle Scholar
  31. 31.
    Spivak B, Gonen N, Mester R, Averbuch E, Adlersberg S, Weizman A (1996) Neuroleptic malignant syndrome associated with abrupt withdrawal of anticholinergic agents. Int Clin Psychopharmacol 11(3):207–209CrossRefGoogle Scholar
  32. 32.
    Spivak B, Maline DI, Kozyrev VN, Mester R, Neduva SA, Ravilov RS et al (2000) Frequency of neuroleptic malignant syndrome in a large psychiatric hospital in Moscow. Eur Psychiatry 15:330–333CrossRefGoogle Scholar
  33. 33.
    Stübner S, Rustenbeck E, Grohmann R, Wagner G, Engel R, Neundörfer G et al (2004) Severe and uncommon involuntary movement disorders due to psychotropic drugs. Pharmacopsychiatry 37(Suppl 1):S54–S64.  https://doi.org/10.1055/s-2004-815511 CrossRefPubMedGoogle Scholar
  34. 34.
    Susman VL, Addonizio G (1988) Recurrence of neuroleptic malignant syndrome. J Nerv Ment Dis 176:234–241CrossRefGoogle Scholar
  35. 35.
    Su Y-P, Chang C-K, Hayes RD, Harrison S, Lee W, Broadbent M et al (2014) Retrospective chart review on exposure to psychotropic medications associated with neuroleptic malignant syndrome. Acta Psychiatr Scand 130:52–60.  https://doi.org/10.1111/acps.12222 CrossRefPubMedGoogle Scholar
  36. 36.
    Tse L, Barr AM, Scarapicchia V, Vila-Rodriguez F (2015) Neuroleptic malignant syndrome: a review from a clinically oriented perspective. Curr Neuropharmacol 13:395–406CrossRefGoogle Scholar
  37. 37.
    Tseng P-T, Chang Y-C, Chang C-H, Wang H-Y, Cheng Y-S, Wu C-K et al (2015) Atypical neuroleptic malignant syndrome in patients treated with aripiprazole and clozapine: a case-series study and short review. Int J Psychiatry Med 49:35–43.  https://doi.org/10.2190/PM.49.1.c CrossRefPubMedGoogle Scholar
  38. 38.
    Woodbury MM, Woodbury MA (1992) Neuroleptic-induced catatonia as a stage in the progression toward neuroleptic malignant syndrome. J Am Acad Child Adolesc Psychiatry 31(6):1161–1164CrossRefGoogle Scholar
  39. 39.
    World Health Organisation (WHO) (2016) The international statistical classification of diseases and related health problems, ICD-10 2016 by World Health Organization (WHO) (2015-10-26)Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.University Clinic for Psychiatry and Psychotherapy, Brandenburg Medical SchoolImmanuel Klinik RüdersdorfRüdersdorf bei BerlinGermany
  2. 2.Department of Psychiatry and Psychotherapy, Campus Charité MitteCharité-Universitätsmedizin BerlinBerlinGermany
  3. 3.Department of Psychiatry, Social Psychiatry and PsychotherapyHannover Medical SchoolHannoverGermany
  4. 4.Department of PsychiatryLudwig-Maximilians-UniversityMunichGermany
  5. 5.Department of Psychiatry, Kbo-IAKAcademic Teaching Hospital of the Ludwig-Maximilians UniversityMunichGermany

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