Covert clozapine overdose: Clozapine toxicity in a naïve patient

To the Editor

We present a case of clozapine overdose in a patient naïve to the medication. His levels are the highest reported in a patient not routinely prescribed clozapine who survived the overdose.

A 68-year-old male was found collapsed and unresponsive at his front door. On arrival at the emergency department his Glasgow Coma Scale score was 5/15 (E1, V1, M3). The rest of his clinical examination was unremarkable. He had no documented psychiatric history. Computerised tomography showed no acute brain injury. Toxicology indicated recent cannabis use. A chest radiograph showed consolidation of the right lung consistent with an aspiration pneumonia.

His course was notable for haemodynamic instability, mydriasis, multifocal myoclonus, ileus and fluctuating encephalopathy, and this was complicated by an aspiration pneumonia and acute kidney injury. A review of the notes showed that Emergency Medical Services personnel reported finding empty sachets of clozapine dating from 1999 in the vicinity of the patient. After 3 days, the patient’s admission clozapine level came back as > 5000 nmol/L, which peaked on day 3 at 10,800 nmol/L. It later transpired that his late wife had schizophrenia and had been prescribed clozapine.

The patient was treated with amoxicillin and chest physiotherapy for his aspiration pneumonia and with fluid resuscitation for his hypotension and acute kidney injury. Inotropic support was not required in this case. The patient survived this admission. He was reviewed by the Liaison Psychiatry service and adamantly denied intentional overdose, symptoms consistent with a mood disorder or other mental illness. He was advised to return the old clozapine packets to his local pharmacist for disposal.

Clozapine overdose was first reviewed by Le Blaye et al. (1992) when they outlined post-marketing surveillance data in 1992. Kramer et al. (2011) quantified presenting features after their 13-year retrospective study of 73 cases. Common signs and symptoms seen during overdose are: central nervous system (CNS) depression (63.1%), tachycardia (39.7%), agitation (16.4%), confusion (15.1%), dysarthria (15.1%), hypertension (10.9%), bradykinesia (9.6%), respiratory depression (9.6%) and QTc prolongation (8.2%). The overall mortality was approximately 12%. Most deaths occurred after a single oral dose exceeding 2 g (Le Blaye et al., 1992).

There is no reversing agent, but supportive care can reduce mortality by addressing complications. As CNS depression is a common feature, airway protection is a priority. Infective episodes may increase clozapine levels and therefore development of aspiration pneumonia may prolong the symptomatic period (Darling and Hurthwaite, 2011).

Electrocardiographic monitoring is required. Electrolytes should be monitored and corrected. Fluid-refractory haemodynamic instability has been reported and paradoxically worsens with the administration of β-agonists (Trenton et al., 2003). Therefore, α-adrenergic agonists should be used.

Seizures can be difficult to diagnose as myotonic movements associated with confusion can occur in a clozapine-induced anticholinergic syndrome. Often seizures are difficult to manage and can present as status epilepticus. Standard treatment algorithms should be followed starting with benzodiazepines (Trenton et al., 2003).

Reports of anticholinesterase inhibitors reversing CNS symptoms do exist, but there are no randomised data and it is not routinely recommended because their safety with antipsychotics are not established (Broich et al., 1998). However, anticholinergics have been used if movement disorder symptoms predominate (Kramer et al., 2011).

The clinical course with clozapine overdose is unpredictable even with known oral doses or levels. In the authors’ experience, patients who have been prescribed regular clozapine seem to tolerate higher doses with fewer symptoms than naïve patients.

With increasing use of clozapine there will be more presentations to acute services with toxicities. Our case highlights the clinical features of clozapine toxicity, as recognition and aggressive supportive care can be life-saving. The best practices from the available literature suggest that these patients will present significant clinical challenges, but that good outcomes are possible, even with significant overdoses in naïve patients.