This application proposes the first test of a novel therapeutic model, in which a pro-cognitive agent augments the impact of a cognitive therapy for schizophrenia (SZ). "Pharmacologic Augmentation of Cognitive Therapy" (PACT) for SZ, first proposed by the PI in 2010 and first tested in this application, funda- mentally challenges existing approaches to enhancing function in SZ patients, both in theory and practice. To date, MH59803 has investigated the neural regulation of laboratory-based measures of deficient information processing in SZ patients, using preclinical rodent and healthy human models to explicate the biology of these deficits, and to establish a rational basis for developing novel therapies for SZ. MH59803 studies of the neural regulation of prepulse inhibition (PPI) of startle in rats initially probed basic anatomical, neurochemical and molecular mechanisms. These studies then moved "from bench-to-bedside," focusing on dopamine (DA) agonist effects on PPI and neurocognition in healthy human subjects (HS), and their regulation by genes identified in cross-species studies. In the process, MH59803 detected biomarkers that predict PPI- enhancing and pro-cognitive effects of the DA releaser, amphetamine (AMPH). These findings have led to specific predictions of AMPH effects on PPI and neurocognition in antipsychotic (AP)-medicated SZ patients that, if confirmed in the present application, could help transform therapeutic approaches to SZ. This renewal application reflects a logical progression of studies at systems and molecular levels, translated next to HS, and now to experimental models in SZ patients. The path of "bench-to-bedside" progress in MH59803 has helped generate a critical paradigm shift in therapeutic models for SZ, which will directly address the need for more effective treatments for this devastating disorder.
In Aim 1, the effects of AMPH (placebo (PBO) vs. 10, or PBO vs. 20 mg, p.o.) will be tested on PPI, neurocognition (assessed with the MATRICS Consensus Cognitive Battery (MCCB)) and computerized Targeted Cognitive Training (TCT) performance in 120 AP-treated SZ patients and 40 HS, in a double-blind, randomized, PBO-controlled cross-over design. Moderating roles on AMPH effects will be assessed for both behavioral (low baseline performance) and genetic (single nucleotide polymorphisms for catechol-O-methyl- transferase (COMT)) biomarkers.
In Aim 2, parallel animal model studies will inform Aim 1 results in AP- medicated SZ patients by testing the effects of systemic APs and D1 antagonism on: 1) AMPH-potentiated PPI, and 2) AMPH effects on new cross-species paradigms assessing MCCB-like measures of a 5-choice continuous performance task and a TCT-like sensory discrimination task in rats. In total, Aim 1 findings will generate strong, testable predictions about the ability of AMPH to safely enhance the benefits of cognitive therapies in biomarker-identified SZ patients;
Aim 2 will establish informative animal models to explicate the neural basis of Aim 1 findings, setting the stage for future advances in this novel approach to SZ therapeutics.

Public Health Relevance

Current therapies for schizophrenia include antipsychotic medications, which do not significantly improve function or correct cognitive deficits in this disorder, and cognitive therapies, which produce only modest benefits to most schizophrenia patients. We hypothesize that medications that specifically target neurocognitive processes like attention and vigilance will significantly augment the clinical benefits of cognitive therapies in schizophrenia. Here, we will test the effects of the attention-enhancing psychostimulant, amphetamine, on deficits in basic information processing and neurocognition in biomarker-identified, antipsychotic-medicated schizophrenia patients, and assess its impact on performance of a Targeted Cognitive Therapy;parallel animal model studies will elucidate the neural mechanisms underlying the observed amphetamine effects in schizophrenia patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH059803-14A1
Application #
8756465
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Morris, Sarah E
Project Start
1999-05-01
Project End
2019-05-31
Budget Start
2014-07-08
Budget End
2015-05-31
Support Year
14
Fiscal Year
2014
Total Cost
$387,500
Indirect Cost
$137,500
Name
University of California San Diego
Department
Psychiatry
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Swerdlow, Neal R; Gur, Raquel E; Braff, David L (2015) Consortium on the Genetics of Schizophrenia (COGS) assessment of endophenotypes for schizophrenia: an introduction to this Special Issue of Schizophrenia Research. Schizophr Res 163:16-Sep
Chou, Hsun-Hua; Talledo, Jo A; Lamb, Sarah N et al. (2013) Amphetamine effects on MATRICS Consensus Cognitive Battery performance in healthy adults. Psychopharmacology (Berl) 227:165-76
Swerdlow, Neal R; Hines, Samantha R; Herrera, Sebastian D et al. (2013) Opposite effects of tolcapone on amphetamine-disrupted startle gating in low vs. high COMT-expressing rat strains. Pharmacol Biochem Behav 106:128-31
Swerdlow, Neal R; Light, Gregory A; Trim, Ryan S et al. (2013) Forebrain gene expression predicts deficits in sensorimotor gating after isolation rearing in male rats. Behav Brain Res 257:118-28
Swerdlow, Neal R; Powell, Susan B; Breier, Michelle R et al. (2013) Coupling of gene expression in medial prefrontal cortex and nucleus accumbens after neonatal ventral hippocampal lesions accompanies deficits in sensorimotor gating and auditory processing in rats. Neuropharmacology 75:38-46
Swerdlow, Neal R (2012) Beyond antipsychotics: pharmacologically-augmented cognitive therapies (PACTs) for schizophrenia. Neuropsychopharmacology 37:310-1
Chang, Wei-Li; Weber, Martin; Breier, Michelle R et al. (2012) Stereochemical and neuroanatomical selectivity of pramipexole effects on sensorimotor gating in rats. Brain Res 1437:69-76
Chang, Wei-li; Breier, Michelle R; Yang, Alex et al. (2011) Disparate effects of pramipexole on locomotor activity and sensorimotor gating in Sprague-Dawley rats. Pharmacol Biochem Behav 99:634-8
Sutherland Owens, Ashley N; Miguel, Euripedes C; Swerdlow, Neal R (2011) Sensory gating scales and premonitory urges in Tourette syndrome. ScientificWorldJournal 11:736-41
Swerdlow, Neal R; Breier, Michelle R; Saint Marie, Richard L (2011) Probing the molecular basis for an inherited sensitivity to the startle-gating disruptive effects of apomorphine in rats. Psychopharmacology (Berl) 216:401-10

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