East Asian Arch Psychiatry 2024;34:18-9 | https://doi.org/10.12809/eaap2338

CASE REPORT

Santanu Nath, Susanta Kumar Padhy, Shalini Kumari

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Key words: China; Suicide; Urbanization

Santanu Nath, Department of Psychiatry, All India Institute of Medical Sciences, Deoghar, Jharkhand, India
Susanta Kumar Padhy, Department of Psychiatry, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
Shalini Kumari, Department of Psychiatry, All India Institute of Medical Sciences, Deoghar, Jharkhand, India

Submitted: 24 July 2023; Accepted: 11 January 2024

Clozapine is an effective antipsychotic for treatment-resistant schizophrenia. Its dopamine receptor–binding profile differentiates it from other antipsychotics in terms of efficacy and adverse effects. Sinus tachycardia is a common, dose-dependent, early cardiovascular adverse effect of clozapine. If untreated, it can lead to further negative cardiovascular outcomes.¹ Beta blockers such as atenolol are typically used for this adverse effect, although ivabradine is also effective and well-tolerated.² We report on a case of rapid-onset ivabradine-induced delirium in a patient who developed sinus tachycardia after having taken clozapine for treatment-resistant schizophrenia.

In January 2021, a 42-year-old man presented to the psychiatry department with a 6-year history of paranoia characterised by suspecting neighbours and family members, muttering to self, wandering out of the house aimlessly, violent behaviour, occasional disrobing, and remaining aloof for hours. On mental state examination, he was found to have an unkempt appearance, third-person auditory hallucinations, delusions of reference, poor personal judgement, and poor insight. He was provisionally diagnosed with undifferentiated schizophrenia (ICD-10 code F20.3)³ and was commenced on trials of oral olanzapine and oral risperidone, but there was no adequate response.

Owing to treatment resistance, he was prescribed clozapine 25 mg nocte, which was titrated up to 150 mg/day over a few weeks, after having been checked for baseline haematological and biochemical parameters. The patient’s symptoms gradually responded to this regimen. Daily evaluation for adverse effects revealed persistent tachycardia (120 beats/minute). His weekly haematological test results were normal. At the suggestion of a cardiologist, electrocardiography was performed, and the results were unremarkable except for sinus tachycardia. The patient was prescribed ivabradine 2.5 mg twice a day. His heart rate returned to the normal acceptable range within 3 days.

After 5 days, he started to exhibit irritable behaviour, increased psychomotor activity, and had difficulty recognising family and friends; these symptoms were worse during the late evening hours. He was disorientated to time, place, and person and had a fluctuating attention span with prominent sundowning; all these were suggestive of delirium. Results of blood tests for serum electrolytes and renal, liver, and thyroid functions were normal, as were outcomes of computed tomography of the brain. Therefore, possible infective, metabolic, and vascular causes were excluded. In the absence of fever and Brudzinski and Kernig signs for meningeal irritation, a lumbar puncture was not performed.

Ivabradine was discontinued, and the delirium symptoms improved over the following 2 days. The patient was then maintained on clozapine monotherapy. He was prescribed atenolol 25 mg/day for his persisting tachycardia, which was well-tolerated. A rechallenge with ivabradine was not performed. The patient was discharged on clozapine 200 mg/day and atenolol 25 mg/day, with improvement in psychiatric symptoms.

Ivabradine was likely responsible for the worsening sensorium in our patient; the causality was ‘probable’, based on a score of 6 on the Naranjo Adverse Drug Reaction Probability Scale.⁴ However, clozapine can also cause delirium. A 44-year-old man developed delirium after 6 days of clozapine monotherapy (125 mg/day); delirium resolved after discontinuation of clozapine.⁵ A 56-year-old man with schizophrenia developed dysarthria and delirium after 16 days of taking clozapine (100 mg/day); he was also taking paliperidone 9 mg/day, but it was not found to be contributory, as stopping the clozapine improved the clinical picture.⁶ A 44-year-old man with schizophrenia developed delirium while taking clozapine; delirium recurred after he was rechallenged with clozapine.⁷ A 32-year-old man with paranoid schizophrenia developed delirium after 22 days of taking clozapine (250 mg/day); delirium resolved after 18 © 2024 Hong Kong College of Psychiatrists. CC BY-NC-ND 4.0

Ivabradine-induced delirium discontinuation of clozapine.⁸ In all these reports, clozapine was found to be causative for delirium. In a retrospective chart review, 10% of inpatients who had taken clozapine (mean dose, 282 ± 203 mg) exhibited delirium during admission; the risk factors identified included old age, unfavourable clinical outcome, co-prescriptions of centrally antimuscarinic agents, and longer hospitalisation.⁹

Ivabradine regulates heart rate through selective inhibition of the If current across the cardiac pacemaker, thereby inhibiting spontaneous depolarisation in the sinus node. It is a heart rate–controlling agent for stable angina, cardiac failure, and inappropriate sinus tachycardia.¹⁰ Clozapine can cause sinus tachycardia by vagal inhibition through blockade of cardiac muscarinic M2 receptors and sympathomimetic action by blocking presynaptic α2 adrenoceptors, although these effects are usually transient and dose-related.¹¹ Cardio-selective beta blockers such as atenolol, bisoprolol, and metoprolol are usually the preferred treatment for tachycardia caused by clozapine. However, these drugs are contraindicated in the presence of comorbidities such as hypotension, bradycardia, and bronchial asthma.¹² Ivabradine is increasingly used and well-tolerated in patients treated with clozapine who develop sinus tachycardia; the only documented interaction between ivabradine and clozapine involves a rare risk of arrhythmia.¹³ A study examining interactions between antipsychotics and cardiovascular drugs identified a case of potential interaction between ivabradine and clozapine, which was possibly mediated by the CYP3A4 isoenzyme.¹⁴ A case series reported two patients on clozapine who developed sinus tachycardia and were treated effectively with ivabradine.²

Ivabradine is generally well-tolerated, with occasional adverse effects of bradycardia and atrial fibrillation. There have been no reports of ivabradine-induced delirium. Rarely, it can cause visual symptoms characterised by enhanced brightness in a limited area of the visual field, kaleidoscopic effects, or multiple images typically associated with sudden variations in light intensity; such symptoms are known as luminous phenomena owing to its effect on the retina.¹⁵ Our patient did not report any such visual symptoms during the onset of delirium.

The occurrence and resolution of delirium after commencement and discontinuation of ivabradine, respectively, while clozapine is used indicates that ivabradine may have caused the delirium. Cardio-selective beta blockers can be used as an alternative to ivabradine for sinus tachycardia.

All authors designed the study, acquired the data, analysed the data, drafted the manuscript, and critically revised the manuscript for important intellectual content. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

All data generated or analysed during the present study are available from the corresponding author on reasonable request.

The patient was treated in accordance with the tenets of the Declaration of Helsinki. The patient provided written informed consent for all treatments and procedures and for publication.

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