Clozapine-Induced Negative Myoclonus Leads to Recurrent Falls: A Case Report

Shiny Joy; Punith Saroja Bylappa; Divyani Garg; Ayush Agarwal; Achal Kumar Srivastava

doi:10.14802/jmd.24207

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Letter to the editor Clozapine-Induced Negative Myoclonus Leads to Recurrent Falls: A Case Report: Shiny Joy, Punith Saroja Bylappa, Divyani Garg, Ayush Agarwal, Achal Kumar Srivastava; Journal of Movement Disorders 2025;18(1):99-100.
DOI: https://doi.org/10.14802/jmd.24207
Published online: November 11, 2024

Department of Neurology, All India Institute of Medical Sciences, New Delhi, India

Corresponding author: Divyani Garg, DM Department of Neurology, All India Institute of Medical Sciences, Room 705, CN Center, New Delhi-110029, India / Tel: +91-11-2659-4317 / E-mail: divyanig@gmail.com

• Received: October 9, 2024 • Revised: October 23, 2024 • Accepted: October 30, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Dear Editor,

Myoclonus is a hyperkinetic movement disorder characterized by sudden, brief jerky movements caused by either muscle contraction (positive) or inhibition (negative) [1]. Drug-induced myoclonus is a major contributor to secondary myoclonus and is frequently reversible upon drug withdrawal. The type of myoclonus can vary between different drugs and even within the same drug, thus suggesting variation in the neuroanatomical generator [2]. In this report, we describe a patient who presented with recurrent falls and jerky limb and neck movements due to clozapine-induced negative myoclonus, with the patient improving remarkably with the discontinuation of clozapine. This case highlights the phenomenon of negative myoclonus, which can present as falls; moreover, in the case of drug-induced causes, this condition is highly reversible.

A 54-year-old female with a known history of schizophrenia was admitted to psychiatry services due to worsening psychotic symptoms for one month. Despite receiving adequate doses of two antipsychotic medications and escitalopram (10 mg per day), she did not respond well to treatment. Thereafter, she was started on clozapine, with the dose being gradually increased from 50 mg to 400 mg on a weekly basis, along with weekly monitoring of blood counts, which remained normal. Her psychotic symptoms improved. One week after the target dose of 400 mg was reached, the patient developed abnormal involuntary jerky movements of the upper limbs, lower limbs, and neck. She also experienced difficulty walking, accompanied by sudden falls. The blood count assessment was normal.

On examination, she was noted to have jerky abnormal movements involving the neck and upper and lower limbs, which predominantly occurred during activity. During gait testing, she exhibited sudden knee buckling and a tendency to fall (Supplementary Video 1 in the online-only Data Supplement). The movements were characterized by sudden interruptions in muscle contraction on electromyography (Supplementary Figure 1 in the online-only Data Supplement). Electroencephalography was normal. Given the clear temporal correlation of symptoms with clozapine, clozapine-induced negative myoclonus was considered. Her metabolic parameters and neuroimaging findings were unremarkable. She was started on 0.5 mg clonazepam twice daily. However, as myoclonus persisted, clozapine was tapered off by 100 mg weekly and eventually stopped. The same dose of escitalopram was maintained throughout the duration of the case. The patient subsequently showed marked improvement in her symptoms (Supplementary Video 2 in the online-only Data Supplement).

Drug-induced myoclonus is an important cause of myoclonus and is most commonly associated with opiates, antidepressants, antipsychotics, and antibiotics. Although the exact pathogenesis is unclear, serotonergic, dopaminergic, and gamma amino butyric acid-ergic mechanisms are involved [2].

Although clozapine has a well-documented proconvulsive effect [3], myoclonus is less frequently reported, with an incidence ranging from 0.9% to 12.5% [4]. This wide range in incidence suggests that it may be potentially underrecognized. Most of the reported cases involve positive myoclonus, which may be multifocal or generalized. Despite its rarity, two phenomena associated with clozapine include isolated cataplexy (which manifests as knee buckling without emotional triggers or features of narcolepsy) and the leg folding phenomenon. Both phenomena are considered to be forms of negative myoclonus [5]. However, other phenomena reported with clozapine-induced myoclonus include drop attacks, orofacial and truncal jerking, and dysarthria. Myoclonus induced by clozapine is usually observed in the uptitration phase and can be dose-related. This may be followed by the development of seizures, thus suggesting that the origin of myoclonus may be cortical. Although it is commonly dose dependent, myoclonus with low-dose clozapine has also been reported. Myoclonus may also be precipitated by abrupt dose changes in clozapine. Among all of the neurotransmitter theories, clozapine-induced myoclonus is most likely attributed to multiple effects of clozapine on the serotonin transmission pathway. In our patient, the use of the antidepressant escitalopram along with clozapine may have contributed to the development of myoclonus, although resolution with the removal of clozapine makes this scenario unlikely.

Management of clozapine-induced seizures involves a 30%–40% dose reduction and the discontinuation of other seizure-provoking drugs. However, if a second seizure occurs, antiseizure medications are needed. For myoclonus, clonazepam or valproate is the preferred treatment, which may permit the continuation of clozapine. However, many reports suggest that the tapering of clozapine may ultimately be required while balancing this effect with the risk of worsening psychosis [4]. Negative myoclonus must be considered in any patient on clozapine who presents with jerks and/or falls.

Supplementary Materials

The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.24207.

Video 1.

Myoclonic jerks involving the neck, both upper limbs, and lower limbs, which resulted in knee buckling while standing and a near fall.

Video 2.

Improvements in myoclonic jerks and stances were observed following the discontinuation of clozapine (at 2 weeks).

Supplementary Table 1.

Surface electromyography from the arm muscle demonstrating silent periods in ongoing muscle contraction in the extensor digitorum communis while keeping the arms raised, which was suggestive of negative myoclonus. EDC, extensor digitorum communis; FCU, flexor carpi ulnaris.

jmd-24207-Supplementary-Fig-1.pdf

Notes

Ethics Statement

The authors confirm that an approval by the Institutional Review Board was not required for this work. Written informed consent was taken from the patient.

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

None

Author Contributions

Conceptualization: Divyani Garg. Data curation: Shiny Joy, Punith Saroja Bylappa. Formal analysis: Shiny Joy, Divyani Garg. Investigation: Shiny Joy, Divyani Garg. Methodology: Divyani Garg. Project administration: Divyani Garg. Resources: Divyani Garg, Ayush Agarwal, Achal Kumar Srivastava. Software: Shiny Joy, Achal Kumar Srivastava. Supervision: Divyani Garg. Validation: Divyani Garg. Visualization: Divyani Garg, Ayush Agarwal. Writing—original draft: Shiny Joy. Writing—review & editing: Punith Saroja Bylappa, Ayush Agarwal, Divyani Garg, Achal Kumar Srivastava.

Acknowledgments

We thank the patient and his family for their co-operation.

REFERENCES

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2. Janssen S, Bloem BR, van de Warrenburg BP. The clinical heterogeneity of drug-induced myoclonus: an illustrated review. J Neurol 2017;264:1559–1566.Article PubMed PDF
3. Pisani F, Oteri G, Costa C, Di Raimondo G, Di Perri R. Effects of psychotropic drugs on seizure threshold. Drug Saf 2002;25:91–110.Article PubMed
4. Osborne IJ, McIvor RJ. Clozapine-induced myoclonus: a case report and review of the literature. Ther Adv Psychopharmacol 2015;5:351–356.Article PubMed PMC PDF
5. Praharaj SK, Venkatesh BGM, Sarkhel S, Zia-ul-Haq M, Sinha VK. Clozapine-induced myoclonus: a case study and brief review. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:242–243.Article PubMed

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