Study offers insight into schizophrenia drug success
20 December 2010
Researchers from the Institute of Psychiatry and colleagues have shed light on why a drug proven to alleviate symptoms of schizophrenia works, when others like it fail.
One in 100 people experience schizophrenia in their lifetime. The mental disorder is thought to be caused by a combination of genetic and environmental factors leading to an imbalance in the level of the neurotransmitter dopamine in the brain.
One suggested treatment, proposed in the 1970s, is the use of partial agonists – compounds that compete with dopamine for the same receptors in the body but only partially activate them. This would reduce the level of activity when dopamine levels are high but also maintain some degree of neurotransmission at the same time. However, to date, only one such compound, aripiprazole, has proven effective and been approved for clinical use.
Professor Shitij Kapur and colleagues set out to assess the relatively low clinical success of this class of agents using traditional animal models used to predict potential drugs before their use in patients. In rats, they compared aripiprazole with four other partial agonists that had failed clinical trials in a variety of tests that predict antipsychotic efficacy.
They found two effects that distinguished aripiprazole from the other compounds. Aripiprazole had the least amount of receptor activation among the comparators and had the highest ability to induce a brain protein called Fos, a marker for antipsychotic drug activity.
The results suggest that the success of ariproprazole is due to it being just effective enough - enough to maintain a low level of neurotransmitter activity but reduce the effect of dopamine where it is hyperactive.
The findings also suggest that the traditional animal models used to evaluate new compounds are insufficient for evaluating potential new partial agonists effectively. "While they certainly have the sensitivity, they do not have sufficient predictive value," the researchers write, adding that until new developments take place their results provide some guidance to those developing new partial agonists.
'Partial agonists in schizophrenia - why some work and others do not: insights from preclinical animal models' is published in the International Journal of Neuropsychopharmacology to read the paper in full, please follow the link.