Antipsychotic drugs used to treat schizophrenia can have serious side effects called extrapyramidal symptoms. These include tremor, slurred speech, anxiety, and distress. Now a team of Toronto-based researchers led by three-time NARSAD grantee Fang Liu, M.D., Ph.D, has tested a new pharmaceutical approach that may generate antipsychotic effects—helping to regulate thought, mood and perception—without causing those damaging side effects. The research was published in Neuron on December 17th.

The team’s key achievement was figuring out a way to more selectively target the D2 receptor, one of several receptors for dopamine, a neurotransmitter that helps to control movement, emotional responses, and the reward system in the brain. Most antipsychotic medicines have had some success treating symptoms of schizophrenia by blocking activity at the D2 receptor. (These drugs sometimes also block receptors for serotonin, another neurotransmitter.)  But dopamine has many different roles in the brain, and directly interfering with its receptors can disrupt normal brain function—hence the extrapyramidal symptoms.

The researchers included four other past NARSAD grant recipients, among them 2006 NARSAD Distinguished Investigator John C. Roder, Ph.D. The team discovered that the D2 dopamine receptor forms a complex with a protein called Disrupted in Schizophrenia 1 (DISC1). A gene, also called DISC1, instructs cells to manufacture DISC1 protein. It is a well-known “risk” gene for schizophrenia. The researchers found that when the DISC1 protein “docks” with the D2 receptor, it sets off a cascade of signals inside brain cells. In postmortem brain tissue of people who had been diagnosed with schizophrenia, as well as in mice with mutated versions of the DISC1 gene, abnormally high amounts of the DISC1–D2 receptor complex were found. This abnormality is perhaps part of the pathology that gives rise to schizophrenia symptoms, which notably include psychosis.

The intriguing achievement of Dr. Liu’s team was their success in reversing schizophrenia-like symptoms in the DISC1-mutant mice. They did this by giving the mice doses of a synthetic peptide, or protein fragment, designed to disrupt the complex formed by the D2 receptor and DISC1 protein. Most encouraging of all, this success in interfering with the complex did not generate the extrapyramidal side effects associated with current antipsychotic drugs.

The investigators say their findings point toward a general approach for making antipsychotic medicines more effective: reducing side effects by more narrowly targeting receptors in the brain. However, the work is preliminary. The synthetic peptide that interfered with the DISC1–D2 receptor complex in mice is experimental. More research is needed to determine whether it causes side effects unnoticed in the just-reported experiments.

Read the abstract.