The faster schizophrenia patients receive effective treatment, the better their prognosis. EU-funded researchers are establishing a profile of individuals unlikely to respond to the drugs used in first-line treatment, for whom the last-resort antipsychotic clozapine should be considered sooner. They are also improving the safety of this drug.
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The Crestar project looked for genetic and clinical biomarkers that indicate whether a person suffering from schizophrenia is likely to respond to standard antipsychotic drugs or whether clozapine is likely to be required. Coordinated by King’s College London, it draws on thousands of DNA samples donated by patients and healthy individuals across Europe.
This vast collection notably includes genetic material from patients who have responded to first-line treatment, from sufferers who have only responded to clozapine and from individuals who developed the blood disorder agranulocytosis as a side-effect of clozapine treatment.
The partners have studied this material to pinpoint characteristic differences between these groups. Their insights could be used to develop biomarkers, genomic tests and clinical decision-making tools that would enable doctors to see if a particular patient should be started on clozapine sooner in their illness.
Following the end of the project in October 2015, more work will be needed to validate and replicate the team’s findings and produce clinical applications, says scientific coordinator David Collier of Eli Lilly and Company Ltd. Patients could begin to benefit from these advances within approximately five years.
When first-line treatments fail
The ability to determine which patients are unlikely to benefit from antipsychotics other than clozapine could help to save precious time in their treatment. “It can take five years or more for patients with treatment-resistant schizophrenia to be offered clozapine, when in fact many could benefit a lot if they had this treatment earlier and if that treatment were safer,” notes project coordinator James MacCabe of King’s College London. “The longer you leave schizophrenia without an effective treatment, the worse the prognosis.”
Under current guidelines, doctors will try at least two other antipsychotics before commencing clozapine, MacCabe explains. Where other antipsychotics fail, clozapine may be the patient’s last hope. It is a powerful drug that works in about half the cases where earlier treatments have failed.
However, there are downsides. Clozapine can have a number of side effects, which range from the merely unpleasant to the potentially fatal. Possible life-threatening complications notably include agranulocytosis, a condition marked by the loss of white blood cells. Patients on clozapine have to have their blood checked frequently to ensure that early signs of this disorder don’t go unnoticed.
Better prediction, better prescriptions
“We have recruited thousands of patients who are on clozapine and are comparing their DNA to that of thousands of patients who respond to the usual antipsychotics quite well, to try to find genetic differences between them,” Collier explains.
“We are just in the process now of putting all the data together to identify some biomarkers,” he adds. There are many candidate markers to consider, as schizophrenia is not linked to a single gene, but to hundreds of variations in the way genes are coded, expressed or potentially altered throughout life.
However, there is already one important finding. “It seems that the more genetic risk factors you have for schizophrenia, the more likely you are to be resistant to treatment with the usual antipsychotics and to move on to clozapine,” Collier notes.
Reducing the risk of agranulocytosis for patients moving on to clozapine was another Crestar priority. The partners have found a number of promising leads for markers that might indicate if a person is at risk of develop this condition when treated with clozapine. These findings could be used to design an effective test within five years or so, according to Collier.
But there is still a lot of work to be done to translate Crestar’s findings into reliable diagnostic and decision-making tools for treatment resistance and agranulocytosis risk. A follow-on project named Strata, funded by the UK’s Medical Research Council, has begun to combine Crestar insights with neuroimaging measures in order to improve the necessary biomarkers, says MacCabe, and the cooperation among the project partners continues.