From The Quarterly, Winter 2015

For the first time, researchers have shown in a clinical trial that a chemical called a D1 agonist can reduce “working memory” impairments found in schizotypal personality disorder. Working memory is the ability to retain various pieces of information over short periods of time so that other parts of the brain can work with them. The scientists found that the D1 agonist increases activity at D1 receptors, which is important for memory. These receptors connect with dopamine, a neurotransmitter known to be involved in working memory disorders.

The research was conducted by a team that included seven past NARSAD Grantees and members of the Foundation’s Scientific Council.* They reported their findings in a paper that appeared online August 27, 2014 in Neuropsychopharmacology.

Targeting the D1 receptor represents a step forward in possible strategies for managing schizophrenia and other disorders. Antipsychotic medications are the common drug treatment for such disorders, but they do not improve symptoms for everyone who needs treatment. Because the antipsychotic drugs block D2 receptors, they work better at controlling psychosis, which is associated with excess D2 activity.

Because memory disorders are linked to reduced D1 activity, successfully targeting the D1 receptor to enhance its activity may expand possible treatment options for schizophrenia and other disorders and perhaps avoid some of the more serious side effects caused by antipsychotics.

The team tested the effects of a compound called DAR-0100A, a type of a known dopamine agonist called DHX (dihydrexidine). The researchers found that compared to placebo,** DAR-0100A significantly improved the ability of patients with schizotypal personality disorder to add pairs of numbers, a task that requires working memory to keep track of the numbers as new pairs are continuously supplied.

Results were mixed for a second task that required sustained attention as well as visual memory and working memory. More research is needed to repeat the finding in a larger study and across a larger set of tasks, in order to demonstrate its robustness and its clinical significance, one of the study authors, Anissa Abi-Dargham, M.D., notes. And although no significant side effects were observed in this study immediately after the tasks or during follow-up testing, more research is needed to test for possible side effects of D1 agonists.

To build on this work, the team says they are conducting a larger clinical trial to assess the effects of DAR-0100A on other cognitive functions besides working memory. They also suggest that better drugs need to be aimed at the D1 receptor in order to more fully test this target; the compound used in the research reported here, DAR-0100A, did not build up very well in the brain.