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Letter to the Editor

Pleurothotonus (Pisa syndrome) Induced by an Association of Clozapine and Mirabegron

Teresa Prior Filipe, MD, and João Gama Marques, MD

Published: March 15, 2018

Pleurothotonus (Pisa syndrome) Induced by an Association of Clozapine and Mirabegron

To the Editor: Pleurothotonus or Pisa syndrome is a postural deformity occurring most commonly in the coronal plane defined by an abnormal lateral trunk flexion of more than 15°.1,2 Pisa syndrome can be classified by the angle of lateral trunk flexion as mild (< 20°) or severe (≥ 20°) and can present in a chronic or subacute form.3,4

Case report. A 56-year-old woman with bipolar disorder (DSM-5 criteria), borderline personality disorder (DSM-5 criteria), hypercholesterolemia, and hypothyroidism presented to our clinic in February 2017 reporting left trunk flexion present for the past 2 days. Neurologic examination showed no other abnormalities. The patient’s medications included levothyroxine, bupropion, topiramate, clonazepam, lithium, clozapine, atenolol, and atorvastatin, with no reported adverse effects over the last few months. There had been no adjustment to these medications, with the exception of mirabegron, which was started 5 days ago for urinary incontinence. The patient scored 5 on the Naranjo scale,5 indicating a probable correlation between mirabegron and her symptoms.

The dose of clonazepam was increased (from 1 to 2 mg/d), mirabegron was discontinued, and the patient was sent to the emergency department. During the hospital admission, clozapine was discontinued while maintaining the other medications. No neurologic lesions were identified on brain magnetic resonance imaging, and there was spontaneous symptomatic remission of Pisa syndrome. One month later, the patient presented for follow-up in complete remission despite the reintroduction of mirabegron and clozapine.

Mirabegron is a selective β3-adrenoceptor agonist that acts as a moderate time-dependent inhibitor of cytochrome P450 2D6 (CYP2D6) and a weak inhibitor of CYP3A.6 Clozapine is an atypical antipsychotic recommended for treatment-resistant schizophrenia7 and has been associated with Pisa syndrome.8 Clozapine is almost completely metabolized before excretion by CYP1A2 and CYP3A4 and to some extent by CYP2C19 and CYP2D6. Concomitant administration of medications known to inhibit the activity of some CYP isozymes may increase the levels of clozapine, with eventual need for dose reduction due to undesirable events.9

This case report suggests that the association of mirabegron and clozapine may have led to an increase in clozapine levels, which may have caused Pisa syndrome. Clonazepam dose adjustment may have induced symptomatic remission. Psychiatric patients are frequently polymedicated. These patients are at high risk for adverse reactions triggered by an interaction between psychiatric drugs and medications for treatment of nonpsychiatric disorders.


1. Ekbom K, Lindholm H, Ljungberg L. New dystonic syndrome associated with butyrophenone therapy. Z Neurol. 1972;202:94-103. PubMed

2. Doherty KM, van de Warrenburg BP, Peralta MC, et al. Postural deformities in Parkinson’s disease. Lancet Neurol. 2011;10(6):538-549. PubMed CrossRef

3. Tinazzi M, Geroin C, Gandolfi M, et al. Pisa syndrome in Parkinson’s disease: an integrated approach from pathophysiology to management. Mov Disord. 2016;31(12):1785-1795. PubMed CrossRef

4. Tinazzi M, Juergenson I, Squintani G, et al. Pisa syndrome in Parkinson’s disease: an electrophysiological and imaging study. J Neurol. 2013;260(8):2138-2148. PubMed CrossRef

5. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239-245. PubMed CrossRef

6. Betmiga. The European Agency for the Evaluation of Medicinal Products website.
. Accessed February 19, 2018.

7. Kane JM, Honigfeld G, Singer J. Clozapine for the treatment resistant schizophrenic: a double-blind comparison versus chlorpromazine/benztropine. Arch Gen Psychiatry. 1988;45(9):789-796. PubMed CrossRef

8. Faridhosseini F, Omidi-Kashani F, Baradaran A. Pisa syndrome associated with clozapine: a rare case report and literature review. Spine Deform. 2015;3(4):386-389. PubMed CrossRef

9. Leponex and associated names. The European Agency for the Evaluation of Medicinal Products website.
. Accessed February 19, 2018.

Teresa Prior Filipe, MDa

João Gama Marques, MDa,b

aClí­nica de Psicoses Esquizofrénicas, Hospital Júlio de Matos, Centro Hospitalar Psiquiátrico de Lisboa, Lisboa, Portugal

bClí­nica Universitária de Psiquiatria e Psicologia Médica, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal

Potential conflicts of interest: None.

Funding/support: None.

Patient consent: Permission was obtained from the patient to publish this case report, and information was de-identified to protect anonymity.

Published online: March 15, 2018.

Prim Care Companion CNS Disord 2018;20(2):17l02161

To cite: Filipe TP, Marques JG. Pleurothotonus (Pisa syndrome) induced by an association of clozapine and mirabegron. Prim Care Companion CNS Disord. 2018;20(2):17l02161.

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© Copyright 2018 Physicians Postgraduate Press, Inc.

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