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Clozapine: first-line treatment for schizophrenia?

24 Jul, 09 | by Steven Reid, Evidence-Based Mental Health

Long considered the Heineken of antipsychotic drugs (refreshing the parts of the brain other drugs cannot reach…sorry), clozapine also comes with more restrictions and health warnings than a pack of cigarettes in California. That might change following this study from the Lancet showing that people with schizophrenia prescribed clozapine had a lower mortality rate than those taking any other antipsychotic or on no treatment at all.

Clozapine has been around since the 1960s and when it was introduced offered the distinct advantage of an extremely low incidence of the motor side effects – stiffness, abnormal movements – that beset other antipsychotics at the time. That was until 1975 when it was withdrawn after a case series was reported of 16 patients on clozapine developing agranulocytosis (a severe deficiency of white blood cells), half of them going on to die.

The drug disappeared for 10 years or so until in 1988 it was rehabilitated following a classic study that demonstrated its superior efficacy in treatment-resistant schizophrenia, where other drugs had little or no effect. It was invited back into the formulary but this time with compulsory blood count monitoring and the proviso that at least two other antipsychotics should be tried first

For this new study Jari Tiihonen and colleagues were looking at the gap in mortality between people with schizophrenia and the general population in Finland over 11 years. They had access to data on 67000 individuals with schizophrenia – that’s right 67000. You can do research like that when you have ‘socialized’ medicine. First, they found that over the duration of the study the 25 year gap in life expectancy remained unchanged, despite the introduction of newer treatments. In what may come as a surprise to some, given the notoriety of antipsychotics and their side effects, those taking antipsychotics over the course of the study had a lower mortality rate than those who were drug-free. But by far the drug with the lowest risk of death (due to any cause) was clozapine. Quetiapine, haloperidol and risperidone increased that risk by 41 per cent, 37 per cent and 34 per cent respectively when compared to an older drug, perphenazine. In contrast use of clozapine was associated with a 26 per cent reduction in mortality. Clozapine was also associated with a lower risk of suicide than any other drug.

The NICE guidance for schizophrenia (in England and Wales) updated in March this year had this to say about clozapine: Offer clozapine to people with schizophrenia whose illness has not responded adequately to treatment despite the sequential use of adequate doses of at least two different antipsychotic drugs. At least one of the drugs should be a non-clozapine second-generation antipsychotic.

Time for a rethink perhaps as not only is clozapine the most effective antipsychotic we have; it may also be the safest.

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