Clozapine is often considered as the gold standard of care for patients with treatment refractory schizophrenia but it has a concerning side effect profile, including death1. Clozapine can cause death by way of deliberate overdose; accidental overdose caused by over prescription; accidental overdose caused by a change in the deceased’s metabolism of Clozapine; and / or direct cardio-toxic effects on the heart or bone marrow leading to fatal secondary conditions.
In any response to a request for information by a Coroner in the context of a Coronial inquest where post-mortem toxicology indicates Clozapine blood concentration levels as falling within the toxic / fatal range, it will be important to consider that there is a wide recommended dosage range for Clozapine – between 100 and 900 milligrams per day, with the most common range between 300 to 600 milligrams2. For any given dose of Clozapine, different people will end up with quite different blood concentration levels. There are many things that can influence how much of the drug ends up in a person’s blood stream including individual liver function, ingestion of other drugs and levels of cigarette smoking. There may be some debate as to the blood concentration levels of Clozapine needed to get a therapeutic response and what those levels were ante mortem.
Careful scrutiny must be given to the validity of the label given to the range of post mortem concentration as “toxic / fatal”. Many toxicology reports will contain a notation that the apparent effect described in that label may not be appropriate for all individuals, particularly those with significant pharmacological tolerance, and, in addition, the clinical effect for many drugs do not correlate well with blood concentration.
Furthermore the labelling of the ranges are based on a compilation of data, mostly coming from scientific case reports. That primary material may not be current and may not take into consideration more recent studies in relation to post mortem drug redistribution. This is a phenomenon where drugs which are bound to muscle, fat and other tissues are released after death and this is reflected in a rise of the concentration of the drug in the blood. There are a number of competing factors in the case of Clozapine which change the blood serum concentrations of those drugs, including clinical treatment prior to death; storage of the body post mortem; site of blood sample (ie peripheral or central); length of time from death to sampling; consistency of and length of time of refrigeration of sample.
Studies3 suggest that the process of post-mortem drug redistribution can result in 3.00 to 4.89 times increases in clozapine levels in central blood vessels and 1.5 fold increases in peripheral vessels compared to ante-mortem levels. One study recorded a 6.66 times increase in post mortem clozapine levels in peripheral vessels.
The general conclusion must be that the use of post-mortem clozapine levels to determine clozapine toxicity as a cause of death is unreliable. Consequently the question to be asked is “was the cause of death poisoning or an overdose”, rather than “was there a fatal level of the drug post mortem”.4
In the event that the evidence establishes that overdose, either accidental or otherwise was unlikely, it should be noted Clozapine can prolong the QT interval5 which increases the chance of heart arrhythmias and death. Cardiac disorders such as cardiomyopathy and myocarditis are difficult to predict in patients taking Clozapine. All that can be done is to use best efforts to pick it up if there are clinical indicators of it. Death from cardiac arrhythmia will often leave no physical damage that can be identified upon autopsy.
This article was written by Alexandra Darcey, Partner.
1 Stark, A and Scott J, Australian & New Zealand Journal of Psychiatry 46(9) 816 – 825.
2 Nielsen J, Damkier P, Lublin H, Taylor D. Optimising Clozapine Treatment Act Psychiatr Scand 2011: 123 : 411-422, at p 412.
3 Stark, A and Scott J, Australian & New Zealand Journal of Psychiatry 46(9) 816 – 825 and as discussed in S Bleakley and D Taylor, Clozapine Handbook, First Edition, Lloyd-Reinjold Communications.
4 R. J. Flanagan Trans Med Soc Lond 2012-2013; 129: 40-61 (see abstract).
5 Handbook of Forensic Toxicology for Medical Examiners by D. K. Molina, M.D. published by CRC Press, Taylor & Francis Group, 2009, notations to the table at page 74.