Study may prompt rethink on schizophrenia drugs

Schizophrenia patients given a cheap older drug are less likely to die prematurely than people on newer treatments, despite the older product’s well-known adverse side effects, Finnish researchers said on Monday.

The finding may lead to wider use of clozapine—sold by Novartis as Clozaril, but also available as a generic—instead of newer drugs like AstraZeneca’s Seroquel, the current market leader.

Clozapine was the first of a new generation of schizophrenia drugs, known as atypical antipsychotics, but its use has been restricted by health authorities because of safety concerns, and patients taking it require regular blood tests.

Despite this, an analysis of 10 years’ records for 67,000 patients in Finland found that, compared with treatment with the first-generation drug perphenazine, the risk of early death for patients on clozapine was reduced by 26 percent.

By contrast, mortality risk was 41 percent higher for those on Seroquel, known chemically as quetiapine; 34 percent higher with Johnson & Johnson’s Risperdal, or resperidone; and 13 percent higher with Eli Lilly’s Zyprexa, or olanzapine.

“We know that clozapine has the highest efficacy of all the antipsychotics and it is now clear, after all, that it is not that risky or dangerous a treatment,” study leader Jari Tiihonen of the University of Kuopio said in a telephone interview.

“We should consider whether clozapine should be used as a first-line treatment option.”

THOUSANDS OF PREMATURE DEATHS

Tiihonen estimates clozapine is given to around one fifth of Finnish schizophrenia patients, but less than 5 percent in the United States.

Clozapine’s side effects include agranulocytosis, a potentially fatal decline in white blood cells, and current rules stipulate the drug can only be used after two unsuccessful trials with other antipsychotics.

Tiihonen and colleagues wrote in the Lancet medical journal that these restrictions should be reassessed in the light of their findings, since not using the drug may have caused thousands of premature deaths worldwide.

But Les Iversen, a professor of pharmacology at the University of Oxford in Britain, who wasn’t involved in the study, said the risk of agranulocytosis was serious and should not be under estimated.

“For this reason, clozapine has become a drug of last resort—and will probably remain so,” he said.

Seroquel, Zyprexa and Risperdal are among the world’s top-selling drugs, with combined sales of $12.5 billion in 2008, though Risperdal now faces generic competition.

Worries about the safety profile of all the atypical antipsychotics have loomed large since 2002, however, following evidence of increased rates of diabetes and cardiovascular disease.

The Finnish study found no pronounced differences in heart deaths between the different atypicals, but patients on clozapine had a substantially lower risk of suicide, while those on Seroquel were more likely to kill themselves.

An AstraZeneca spokeswoman said the Anglo-Swedish company was comfortable that Seroquel was safe, effective and an important treatment for mental illness.

Schizophrenia is a severe psychiatric disorder in which patients experience distorted thinking, hallucinations and abnormal emotions.

SOURCE: The Lancet, online first July 13, 2009.