reating schizophrenia involves not only addressing the primary positive and negative symptoms but also the frequent cognitive dysfunction that accompanies the disorder, known as cognitive impairment associated with schizophrenia (CIAS). These deficits in attention, working memory and executive function have a detrimental impact on a patient’s quality of life and their functional capacity to manage daily tasks.
In new research published in Molecular Psychiatry, researchers simulated CIAS in healthy volunteers by triggering hypofunction of N-methyl-D-aspartate receptors (NMDARs), which significantly lowers learning and memory functions when the NMDAR antagonist, ketamine, is administered. They did this to test the strategy of stimulating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) to correct NMDAR hypofunction in humans, an approach which has been previously demonstrated in laboratory rats
“Most AMPAR-focused drug discovery has targeted AMPAR activation via positive allosteric modulators (‘potentiators’) to better match the degree and/or duration of AMPAR opening to synaptic activity,” wrote the researchers. “AMPAR potentiators bind to the allosteric site on AMPAR to slow their deactivation and/or desensitization and thereby enhance receptor signaling.”
One of these AMPAR potentiators, PF-04958242, has been shown to improve memory effects from NMDAR hypofunction in rats. In the current study, researchers extended this testing to human subjects by administering the treatment to an experimental group while the control group received a placebo.
After inducing CIAS-like cognitive deficits through a ketamine dose, the volunteers’ cognitive abilities were tested with the Hopkins Verbal Learning Test, the Positive and Negative Syndrome Scale and Clinician-Administered Dissociative Symptoms Scale, and components of the Cogstate schizophrenia test battery. Specifically, this battery included the one-back and two-back working memory tests, a spatial working memory test and a visual learning test.
Following an 8-hour fast, healthy men between the ages of 21 and 45 (n=29), received an oral 0.35 mg loading dose of PF-04958242 on the first day, followed by daily oral administration of 0.25 mg on days 2 through 5 to provide total plasma concentrations at or slightly above the projected clinically efficacious exposure at the time of ketamine administration.
On day 5, the volunteers received a ketamine dose that has been shown to safely produce CIAS-like symptoms, including verbal learning and memory deficits. As expected, this ketamine dose significantly impaired verbal learning and working memory in the volunteers, creating an opportunity to test the efficacy of PF-04958242 versus the placebo.
Comparing the two groups, the researchers reported, “PF-04958242 significantly reduced ketamine-induced impairments in immediate recall and the 2-Back and spatial working memory tasks (Cogstate Battery), without significantly attenuating ketamine-induced psychotomimetic effects. Interestingly, PF-04958242 completely reduced the ketamine-induced impairments in spatial working memory.”
This research suggests that AMPAR potentiators may have a role in the treatment of the cognitive symptoms associated with schizophrenia, and the strong congruity between the animal studies, human studies, and in silico modeling are exciting results for early translational research.
