Pharmacologically-augmented Cognitive Therapies (PACTs) for Schizophrenia.
Status:
Completed
Trial end date:
2020-08-01
Target enrollment:
Participant gender:
Summary
This application seeks renewed support for MH59803, "Dopaminergic substrates of startle
gating across species," to extend a clear path of "bench-to-bedside" progress towards a
critical paradigm shift in therapeutic models for schizophrenia (SZ) and schizoaffective
disorder, depressed type (SZA): the use of Pharmacologic Augmentation of Cognitive Therapies
(PACTs). This novel therapeutic strategy for SZ/SZA directly addresses the need for more
effective treatments for this devastating disorder. MH59803 has investigated the neural
regulation of laboratory-based measures of deficient information processing in SZ/SZA
patients, using rodents and healthy human subjects (HS) to explicate the biology of these
deficits, and to establish a rational basis for developing novel therapies for SZ/SZA. In its
first 9 years, MH59803 studies of the neural regulation of prepulse inhibition (PPI) of
startle in rats focused on basic neurobiological and molecular mechanisms. Over the past 2
years of support, MH59803 studies moved "from bench-to-bedside," focusing on dopamine (DA)
agonist effects on PPI and neurocognition in HS, and their regulation by genes identified in
cross-species studies. These studies detected biological markers that predict PPI-enhancing
and pro-cognitive effects of the DA releaser, amphetamine (AMPH) in humans, leading to
specific predictions of AMPH effects on PPI, neurocognition and Targeted Cognitive Training
in SZ/SZA patients. If confirmed in the present application, these predictions could help
transform therapeutic approaches to SZ/SZA. This renewal application of MH59803 thus reflects
a logical progression of studies at systems and molecular levels, translated first to HS, and
now to potentially transformative therapeutic models in SZ/SZA patients.