Behavioral and qEEG effects of the PDE10A inhibitor THPP-1 in a novel rhesus model of antipsychotic activity.
Much preclinical data, almost exclusively using rodent, supports the notion that phosphodiesterase 10A (PDE10A) inhibition may offer an alternative to the current standard of care in schizophrenia. However, concerns persist regarding the clinical translatability of these models for newer drug classes like PDE10A inhibitors.



We therefore sought to characterize the clinical standard risperidone and the PDE10A inhibitor THPP-1 in nonhuman primate, both alone and when used as a combination therapy.



THPP-1 and risperidone were tested in a novel rhesus model of stimulant-induced motor activity (SIMA) and in rhesus electroencephalography (EEG).



Consistent with rodent data, both THPP-1 and risperidone significantly attenuated the stimulant effects in SIMA when administered alone, though some differences were noted. Combination therapy with a low dose of risperidone produced significantly more robust effects. THPP-1 and risperidone also produced a marked reduction of wake cycle time and gamma frequency power in EEG. However, THPP-1 differed from risperidone by reducing spectral power of lower frequencies (delta).



SIMA results suggest that PDE10A inhibition produces antipsychotic-like effects in higher species, and that combination therapy with PDE10A inhibitors may produce more robust efficacy compared to monotherapies. EEG and qEEG results confirm that PDE10A inhibition does share some central signaling effects with clinically effective antipsychotics. The present combination therapy results may carry implications for the manner in which clinical testing of PDE10A inhibitors is conducted.
Merck & Co., Inc., WP45-1114, 770 Sumneytown Pike, West Point, PA, 19486, USA.
Joshua D
JD
Vardigan
Merck & Co., Inc., WP45-1114, 770 Sumneytown Pike, West Point, PA, 19486, USA.
Henry S
HS
Lange
Merck & Co., Inc., WP45-1114, 770 Sumneytown Pike, West Point, PA, 19486, USA.
Spencer J
SJ
Tye
Merck & Co., Inc., WP45-1114, 770 Sumneytown Pike, West Point, PA, 19486, USA.
Steven V
SV
Fox
Merck & Co., Inc., WP45-1114, 770 Sumneytown Pike, West Point, PA, 19486, USA.
Sean M
SM
Smith
Merck & Co., Inc., WP45-1114, 770 Sumneytown Pike, West Point, PA, 19486, USA. jason_uslaner@merck.com.
Jason M
JM
Uslaner
D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004569:Electroencephalography / Q000187:drug effects*; D008253:Macaca mulatta; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000494:pharmacology*; D018967:Risperidone / Q000494:pharmacology*; D012559:Schizophrenia / Q000188:drug therapy*
D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D018967:Risperidone
Amphetamine; Antipsychotic; Behavior; EEG; Nonhuman primate; PDE10A; Rhesus; Schizophrenia