Enhancing treatment options for schizophrenia

Expanding the options for treating central nervous system disorders such as schizophrenia has emerged with a new approach and a potential new class of drug.

The research, conducted by Dr Rob Lane and colleagues from the Monash Institute for Pharmaceutical Sciences (MIPS) at Monash University, involves selective molecules with particular binding abilities that can act as a ‘dimmer switch’ to control schizophrenia, without causing some of the common side effects associated with current anti-psychotic medicines.

Affecting 1% of the world’s population, schizophrenia is a major health condition. It affects a person’s ability to think, feel and act, and is associated with distressing symptoms including hallucinations and delusions.

Current anti-psychotic medicines block the action of dopamine in the brain via the dopamine D2 receptor and can cause serious side effects.

“These medications frequently result in serious side effects because this protein is also important for the control of movement. The side effects can sometimes persist even after the patient has stopped taking the medication,” Lane said.

Co-lead researcher Professor Arthur Christopoulos said gaining a better understanding of the biology of schizophrenia will lead to more effective drugs.

“The idea behind our research is to develop a drug that doesn’t completely block dopamine. We found a molecule that, rather than blocking the effect of dopamine at the D2 receptor, acts to subtly dial down dopamine’s effect, a bit like a dimmer switch,” Christopoulos said.

The drug does this by concomitantly binding two sites on the receptor - the active site and a regulatory site. The drug has a high affinity for the receptor’s active site allowing lower doses of drug to be used, and binds a site other than the active site by which it reduces or dims the effectiveness of the activated receptor.

“This means that if we can get just the right amount of dial-down, we could treat the symptoms of the disease and avoid some of these side effects,” said Christopoulos.

“We’re a long way yet from developing a drug, but our dimmer switch approach to controlling schizophrenia means it’s conceivable we could have a whole new class of anti-psychotics in the future.”

The research team also found a unique twist with the molecule, its mechanism of action changed depending on the arrangement of the D2 receptor in the brain.

Lane said not only does this represent a new approach to develop anti-psychotics, it gives researchers more information about the protein involved in the disease.

“This extra information will help researchers develop new drugs that target the protein,” Lane said.

The next phase of the research will involve Lane and Christopoulos collaborating with chemists at MIPS with the aim of developing a better version of the drug.

The findings have been published in Nature Chemical Biology.