Medical experts clash over use of 'danger' schizophrenia drug

Excessive caution by drug regulators in Britain and abroad has contributed to the deaths of thousands of patients with severe mental illness, say doctors.

Patients with schizophrenia have been condemned to second-rate treatments, often for years, which are less effective at controlling the illness and preventing suicide because of misplaced anxiety about the safety of the most effective drug, clozapine. The pharmaceutical industry also bears a share of the responsibility for restricting the use of clozapine because it promotes more expensive but less effective drugs which bring it more profit, the doctors say today in The Lancet.

A new study shows that clozapine, always thought to be a dangerous drug, actually cut the death rate among patients with schizophrenia by 26 per cent, compared with the standard treatment. But the finding was challenged by British experts who said the serious side effects linked with clozapine meant patients needed close monitoring and it would always be a drug of last resort.

Worldwide, millions of patients with severe mental illness are treated with antipsychotic drugs to control their delusions and hallucinations. Evidence shows that, on average, they die 25 years earlier than those in the general population, partly because of increased smoking and obesity, but also by suicide.

Professor Jari Tiihonen, of the University of Kuopio, Finland, and colleagues say that the introduction of newer antipsychotics, including clozapine, in the 1990s is widely thought to have increased deaths among patients with schizophrenia. But an analysis of the data shows that, while some drugs were associated with an increased risk, clozapine lowered the risk of dying the most, despite being the drug most closely restricted by the authorities because of safety concerns.

Clozapine can cause agranulocytoisis, which destroys the white blood cells and causes falls in blood pressure, convulsions, diabetes and weight gain. Patients must have regular blood tests while taking it. Professor Tiihonen said: "In all western countries, clozapine is recommended for use only as a second-line drug, after at least two other anti-psychotics have been tried and failed. I would like to see it considered for first line use. Doctors and the [drug regulatory] authorities are too cautious.

"Patients with schizophrenia may suffer delusions and hallucinations for years while doctors try different anti-psychotics before they get to clozapine. They are not active enough in getting patients into remission. They should try clozapine earlier." In a study two years ago in the British Medical Journal, Professor Tiihonen showed that patients were less likely to stop taking taking clozapine than other anti-psychotics, despite its side effects. "Patients are more willing to use it, probably because it is effective," he said.

But Professor Tim Kendall, deputy director of the Royal College of Psychiatrist's research unit, said a major study of clozapine in China showed it was no more effective than the older antipsychotic chlorpromazine. "The evidence for first-line use is not there. Clozapine is associated with a much broader range of side-effects. It seems to have a different effect and works better in people who have tried other drugs which have failed. These findings should be interpreted with real caution."

Les Iversen, professor of pharmacology at the University of Oxford, said: "I cannot agree that clozapine should be the drug of first choice for treating schizophrenia. This is because the adverse side effect of agranulocytosis is serious and can be life-threatening. It occurs in about 2 per cent of patients, and all patients require tedious and costly monitoring, initially weekly, later monthly to detect this side-effect. For this reason, clozapine has become a drug of last resort, and will probably remain so."

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