Clozapine death

The seeds of this transformation were sown some years ago. The first so-called atypical antipsychotic, clozapine (Clozaril), was devised in the 1960s. Clozapine was used widely in Europe until a series of deaths from a toxic hematological (blood) side effect called agranulocytosis occurred in the mid-1970s. Clozapine resurfaced in the 1980s and was approved for use (under strict guidelines) in the United States in 1990. Since that time, several other atypical antipsychotics have been approved, and others loom on the horizon. 

Clozapine is considered to be the gold standard of treatment of schizophrenia with patients usually moving onto it after treatment failure with two other antipsychotics. Yet the history of it is quite chequered. When it was first introduced onto the European market in 1975 it was used freely with no restrictions on use. Following the death of eight patients in Finland from agranulocytosis, a very rare (< 1 %) but often fatal condition occur-ing normally within the first few months of use, it was voluntarily taken off the market. 

Klimke A, Kleiser E. Sudden death after intravenous application of lorazepam in a patient treated with clozapine. Am J Psychiatry 1994 151 780. 

In the development of new antipsychotics, cQT intervals are routinely evaluated but it is currently unclear how predictive these are of clinically significant cardiotoxicity or sudden death. For this reason, the heart rate variability (HRV) index has been developed. It has been shown that the HRV decreases after TCAs and clozapine. In a comparison of the acute effects of olanzapine, risperidone and thioridazine in healthy male volunteers, olanzapine was shown to increase, thioridazine to decrease while risperidone was without effect on the HRV. A decrease in the HRV is an established predictor of poor cardiac outcome. The cardiac changes were unrelated to the degree of sedation caused by the drugs. 

Jarskog et al. (2007) studied the effects of haloperidol, clozapine, and quetiapine on numerous so-called apoptotic markers to study the impact of these drugs on apoptosis. Essentially, they examined the neurotoxicity of neuroleptics, specifically their capacity to induce cell deterioration typical of the process of cell death. They found that the neuroleptics, both the older ones and the atypicals, caused activation of caspase-3, a marker for apoptosis. They tried to reassure their readers that this activity was probably non-lethal. ... 

The reports of sudden death associated with clozapine and the possibility that it may have direct prodysrhythmic properties have been reviewed (37). 

Taking into account the results from an epidemiological study of deaths in users and former users of clozapine... 

As of 31 December 1993, there were 18 cases of fatal pulmonary embolism in association with clozapine therapy in users aged 10-54 years. Based on the extent of use recorded in the Clozapine National Registry, the mortality rate associated with pulmonary embolism was 1 death per 3450 person years of use. This rate was about 28 times higher than that in the general population of a similar age and sex (95% Cl = 17,42). Whether pulmonary embolism can be attributed to clozapine or some characteristic(s) of its users is not clear (53). 

Over 10 000 patients have been treated with clozapine in Australia since its introduction in 1993, and the Clozaril monitoring system has ensured that since that time there have been no deaths from agranulocytosis in patients taking clozapine (155). 

The causes of sudden unexpected death in psychiatric patients are often unknown however, sudden cardiac death has been associated with clozapine (SEDA-26, 59). On the other hand, suicide is a common cause of death among patients with schizophrenia. In a recent report, the authors claimed that in cases of sudden unexpected death, toxic post-mortem drug concentrations can... 

Levin TT, Barrett J, Mendelowitz A. Death from clozapine-induced constipation case report and literature review. Psychosomatics 2002 43(l) 71-3. 

A thorough study of the risk of myocarditis or cardiomyopathy in Australia detected 23 cases (mean age 36 years 20 men) out of 8000 patients treated with clozapine from January 1993 to March 1999 (absolute risk 0.29% relative risk about 1000-2000) (17). AH the accumulated data on previous reports of sudden death, myocarditis, or cardiac disease noted in connection with clozapine treatment were requested from the Adverse Drug Reactions... 

Taking into account the results from an epidemiological study of deaths in users and former users of clozapine (32), the cardiovascular mortality risk related to clozapine may be outweighed by the overall lower mortality risk associated with its beneficial effects, since the death rate was lower among current users (322 per 100 000 person years) than among past users (696 per 100 000 person years). The reduction in death rate during current use was largely accounted for by a reduction in the suicide rate compared with past use (RR = 0.25 Cl = 0.10, 0.30). 

Tie H, Walker BD, Singleton CB, Bursill JA, Wyse KR, Campbell TJ, Valenzuela SM, Breit SN. Clozapine and sudden death. J Clin Psychopharmacol 2001 21(6) 630-2. 

Of 524 inquiries received by the National Poisons Information Service concerning new neuroleptic drugs over 9 months, only 45 cases involved overdose with a single agent (olanzapine, n — 10 clozapine, n — 8 risperidone, n — 10 sulpiride, n = 16) (503). There were no deaths or cases of convulsions. Cardiac dysrhythmias occurred only with sulpiride. Symptoms were most marked with clozapine most patients had agitation, dystonia, central nervous system depression, and tachycardia. Most of the patients who had taken risperidone were asymptomatic. 

Clozapine has a very low incidence of extrapyramidal side effects and very few cases of tardive dyskinesia. It is very sedating and has some anticholinergic and an-tiadrenergic side effects (see Fig. 17-B). Sedation is the most troublesome side effect. Clozapine lowers the seizure threshold and can cause hepatitis. The most serious side effect, however, is a severe blood disorder, aplastic anemia, which has caused several deaths in the United States. These deaths have occurred despite the mandatory weekly monitoring of white blood cell count. Clozapine can cost as much as 10,000 per year because of the need for weekly blood tests, although this cost is offset by reduced hospitalizations. Also, there have been a few sudden deaths associated with clozapine, presumably cardiac in nature. 

I Databases can be linked by computer, e.g. people exposed to a particular product, and people admitted to hospital with a particular problem. Linking a national registry of clozapine recipients to national death records found that clozapine increased the risk of fatal pulmonary embolism and respiratory disorders but reduced the risk of stticide. 

Although we include clozapine as a newer atypical antipsychotic medication, it does have a long history and in some texts may be listed as a traditional antipsychotic. Known by the brand name Clozaril, clozapine was originally synthesized in 1957 and in 1960 was one of the first antipsychotics released on the European market (Hippius, 1989). It was believed to be more successful than the typical antipsychotics because it did not seem to have the same negative side-effect profiles. Years later, eight documented cases of death were attributed to infections secondary to clozapine-induced agranulocytosis, and the product was withdrawn from unrestricted use (Davis Casper, 1977). Based on later studies that supported the success of clozapine with strict monitoring for treatment-resistant schizophrenia, the FDA approved it in 1990 (Barnes McEv-edy, 1996). 

The mechanism of clozapine-induced agranulocytosis has been under intensive investigation but has yet to be conclusively identified. It appears likely that activation of clozapine, to norclozapine and/or a further metabolite, clozapine N-oxide, to electrophilic nitrenium ions is the initial step in the events leading to neutropenia/ agranulocytosis. Oxidation of clozapine by neutrophilgenerated hypochlorous acid (HOCl) via the NADPH oxidase/myeloperoxidase system has been demonstrated, which could then lead to granulocyte death. 

The authors of the first of these reports say that the relative risk of the car-diovascular/respiratory reaction is only 2.1%. Another report says that the death cited above is the only life-threatening event among 162 patients given clozapine and benzodiazepines between 1986 and 1991 so that the incidence of serious problems is quite low. Even so, concurrent use should be very well monitored because of the severity of the reaction, even if it is rare. 

Klimke A, Klieser E. Sudden death after intravenous plication of lomzepam in a patient treated wiA clozapine. AmJPsyddaby (1994) 151,780. 

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