Experimental analysis of the onset mechanism of TdP reported in an LQT3 patient during pharmacological treatment with serotonin–dopamine antagonists against insomnia and nocturnal delirium

  • Ryuichi Kambayashi
  • Mihoko Hagiwara-Nagasawa
  • Ai Goto
  • Koki Chiba
  • Hiroko Izumi-Nakaseko
  • Atsuhiko T. Naito
  • Akio Matsumoto
  • Atsushi SugiyamaEmail author
Original Article


Torsade de pointes (TdP) occurred in a long QT syndrome type 3 (LQT3) patient after switching perospirone to blonanserin. We studied how their electropharmacological effects had induced TdP in the LQT3 patient. Perospirone hydrochloride (n = 4) or blonanserin (n = 4) of 0.01, 0.1, and 1 mg/kg, i.v. was cumulatively administered to the halothane-anesthetized dogs over 10 min. The low dose of perospirone decreased total peripheral vascular resistance, but increased heart rate and cardiac output, facilitated atrioventricular conduction, and prolonged JTpeakc. The middle dose decreased mean blood pressure and prolonged repolarization period, in addition to those observed after the low dose. The high dose further decreased mean blood pressure with the reduction of total peripheral vascular resistance; however, it did not increase heart rate or cardiac output. It tended to delay atrioventricular conduction and further delayed repolarization with the prolongation of TpeakTend, whereas JTpeakc returned to its baseline level. Meanwhile, each dose of blonanserin decreased total peripheral vascular resistance, but increased heart rate, cardiac output and cardiac contractility in a dose-related manner. JTpeakc was prolonged by each dose, but TpeakTend was shortened by the middle and high doses. These results indicate that perospirone and blonanserin may cause the hypotension-induced, reflex-mediated increase of sympathetic tone, leading to the increase of inward Ca2+ current in the heart except that the high dose of perospirone reversed them. Thus, blonanserin may have more potential to produce intracellular Ca2+ overload triggering early afterdepolarization than perospirone, which might explain the onset of TdP in the LQT3 patient.


Perospirone Blonanserin LQT3 JTpeakCa2+ overload 



This study was supported in part by research grants from Japan Society for the Promotion of Science, Japan (JSPS KAKENHI grant number JP16K08559); Daiichi Sankyo Research Contribution Program 2018, Japan; Okinaka Memorial Institute for Medical Research, Japan; and Japan Agency for Medical Research and Development, Japan (AMED grant number JP17am0101122 and JP18mk0104117j0001). The authors thank Dr. Yuji Nakamura, Dr. Kentaro Ando, Mrs. Yuri Ichikawa, and Mr. Shota Tsuda for their technical assistances.

Compliance with ethical standards

Conflicts of interest

The authors declare no conflicts of interest.


  1. 1.
    Wu CS, Tsai YT, Tsai HJ (2015) Antipsychotic drugs and the risk of ventricular arrhythmia and/or sudden cardiac death: a nation-wide case-crossover study. J Am Heart Assoc 4:e001568PubMedPubMedCentralGoogle Scholar
  2. 2.
    Onrust SV, McClellan K (2001) Perospirone. CNS Drugs 15:329–337CrossRefGoogle Scholar
  3. 3.
    Deeks ED, Keating GM (2010) Blonanserin: a review of its use in the management of schizophrenia. CNS Drugs 24:65–84CrossRefGoogle Scholar
  4. 4.
    Sumitomo Dainippon Pharma Co., Ltd. Blonanserin: Lonasen tablets 2 mg/Lonasen tablets 4 mg/Lonasen powder 2% common technical document 2.6.2 [In japanese] Available at: Accessed on March 5th, 2019
  5. 5.
    Suzuki K, Kanaji Y, Kida N, Takagi T, Inamura Y, Suzuki A, Kurihara K, Ono Y, Shimizu S, Otomo K, Isobe M (2011) A case of myotonic dystrophy who developed QT prolongation and torsade de pointes. Shinzo 43:65–72 (in Japanese) Google Scholar
  6. 6.
    Van de Water A, Verheyen J, Xhonneux R, Reneman RS (1989) An improved method to correct the QT interval of the electrocardiogram for changes in heart rate. J Pharmacol Methods 22:207–217CrossRefGoogle Scholar
  7. 7.
    Sugiyama A (2008) Sensitive and reliable proarrhythmia in vivo animal models for predicting drug-induced torsades de pointes in patients with remodelled hearts. Br J Pharmacol 154:1528–1537CrossRefGoogle Scholar
  8. 8.
    Cao X, Nakamura Y, Wada T, Izumi-Nakaseko H, Ando K, Sugiyama A (2016) Electropharmacological effects of amantadine on cardiovascular system assessed with J-Tpeak and Tpeak-Tend analysis in the halothane-anesthetizes beagle dogs. J Toxicol Sci 41:439–447CrossRefGoogle Scholar
  9. 9.
    Johannesen L, Vicente J, Mason JW, Sanabria C, Waite-Labott K, Hong M, Guo P, Lin J, Sørensen JS, Galeotti L, Florian J, Ugander M, Stockbridge N, Strauss DG (2014) Differentiating drug-induced multichannel block on the electrocardiogram: randomized study of dofetilide, quinidine, ranolazine, and verapamil. Clin Pharmacol Ther 96:549–558CrossRefGoogle Scholar
  10. 10.
    Satoh E, Sugimoto S, Tsujimoto S, Nakahara H, Miyagishi A, Katoh T (1997) General pharmacological studies of perospirone hydrochloride (SM-9018) a novel antipsychotic agent. Kiso to Rinsho 31:903–929 (in Japanese) Google Scholar
  11. 11.
    Kato T, Hirose A, Ohno Y, Shimizu H, Tanaka H, Nakamura M (1990) Binding profile of SM-9018, a novel antipsychotic candidate. Jpn J Pharmacol 54:478–481CrossRefGoogle Scholar
  12. 12.
    Une T, Kurumiya S (2007) Pharmacological profile of blonanserin. Jpn J Clin Psychopharmacol 10:1263–1272 (in Japanese) Google Scholar
  13. 13.
    Thomas G, Gurung IS, Killeen MJ, Hakim P, Goddard CA, Mahaut-Smith MP, Colledge WH, Grace AA, Huang CL (2007) Effects of L-type Ca2+ channel antagonism on ventricular arrhythmogenesis in murine hearts containing a modification in the Scn5a gene modelling human long QT syndrome 3. J Physiol 578:85–97CrossRefGoogle Scholar
  14. 14.
    Philips MH, Harper PS (1997) Cardiac disease in myotonic dystrophy. Cardiovasc Res 33:13–22CrossRefGoogle Scholar
  15. 15.
    Nguyen HH, Wolfe HT, Holmes DR, Edwards WD (1988) Pathology of the cardiac conduction system in myotonic dystrophy: a study of 12 cases. J Am Coll Cardiol 11:662–671CrossRefGoogle Scholar
  16. 16.
    Motta J, Guilleminault C, Billinghem M, Barrow W, Mason J (1979) Cardiac abnormalities in myotonic dystrophy, electrophysiologic and histopathologic studies. Am J Med 67:467–473CrossRefGoogle Scholar
  17. 17.
    Park KM, Shin KJ, Kim SE, Park J, Ha SY, Kim BJ (2013) Prolonged Corrected QT interval in patients with myotonic dystrophy type 1. J Clin Neurol 9:186–191CrossRefGoogle Scholar
  18. 18.
    Russo V, Papa AA, Rago A, Ambrosio PD, Cimmino G, Palladino A, Politano L, Nigro G (2016) Increased heterogeneity of ventricular repolarization in myotonic dystrophy type 1 population. Acta Myol 35:100–106PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Japan KK, part of Springer Nature 2019

Authors and Affiliations

  • Ryuichi Kambayashi
    • 1
  • Mihoko Hagiwara-Nagasawa
    • 1
  • Ai Goto
    • 1
  • Koki Chiba
    • 1
  • Hiroko Izumi-Nakaseko
    • 1
  • Atsuhiko T. Naito
    • 2
  • Akio Matsumoto
    • 3
  • Atsushi Sugiyama
    • 1
    • 3
    Email author
  1. 1.Department of Pharmacology, Faculty of MedicineToho UniversityTokyoJapan
  2. 2.Division of Cellular Physiology, Department of Physiology, Faculty of MedicineToho UniversityTokyoJapan
  3. 3.Department of Aging Pharmacology, Faculty of MedicineToho UniversityTokyoJapan

Personalised recommendations