Pharmacologically-augmented Cognitive Therapies (PACTs) for Schizophrenia.
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      MH59803 demonstrated that AMPH (20 mg p.o.) significantly increased PPI and neurocognitive
      performance (MATRICS Consensus Cognitive Battery; MCCB) in HS characterized by specific
      performance-based or genetic biomarkers, including the val/val genotype for the rs4680
      polymorphism of catechol-O-methyltransferase (COMT). Mechanistically-informative results were
      detected in studies of AMPH effects on PPI in rats with high vs. low brain regional Comt
      expression. Together with several reports of improved neurocognition and no adverse effects
      of acute or sustained AMPH administration to antipsychotic (AP)-medicated SZ/SZA patients,
      MH59803 findings provide a strong rationale for the next goal of this application: to test
      the potential utility of AMPH in a paradigm of biomarker-informed "PACTs". This "next step"
      is highly innovative - never previously reported, or perhaps even attempted - and consistent
      with National Institute of Mental Health (NIMH) objectives, directly challenges existing
      models for SZ/SZA therapeutics. Investigators will determine whether a test dose of 10 mg
      AMPH p.o. administered to biomarker-identified, AP-medicated SZ/SZA patients generates
      predicted increases in PPI, MCCB performance, and sensory discrimination learning in a
      Targeted Cognitive Training (TCT) module. In total, Investigators will leverage knowledge
      generated through converging cross-species studies in MH59803, to directly advance scientific
      and clinical domains, by testing the effects of a pro-cognitive drug on neurophysiological
      and neurocognitive performance, and Targeted Cognitive Training, in biomarker-stratified
      subgroups of SZ/SZA patients.

      Aim: To assess acute effects of AMPH (0 vs 10 mg po) on PPI, neurocognition and computerized
      TCT in AP-medicated SZ/SZA patients. Hypothesis: PPI- and MCCB-enhancing effects of AMPH seen
      previously in HS will also be detected in SZ/SZA patients, as will TCT-enhancing effects of
      AMPH. Prediction: In a within-subject, placebo-controlled, randomized design, AMPH (10 mg po)
      will increase PPI and enhance MCCB and TCT performance in medicated SZ/SZA patients,
      particularly among those characterized by low basal performance levels and/or the val/val
      rs4680 COMT polymorphism. Concurrent HS testing will confirm and extend findings of AMPH
      effects on PPI and neurocognition, and help interpret findings in SZ/SZA patients.

      In all participants, the aim to assess acute effects of 0 vs. 10 mg po dextroamphetamine
      (AMPH) on Prepulse Inhibition (PPI), neurocognition MATRICS: Consensus Cognitive Battery;
      MCCB, and computerized Targeted Cognitive Training (TCT).

      Hypothesis: AMPH will enhance:

        1. PPI

        2. neurocognition (MCCB performance)

        3. computerized TCT performance in biomarker-identified SZ/SZA patients.

        4. The PPI and MCCB-enhancing effects of AMPH seen previously in HS will also be detected
           in SZ/SZA patients, as will TCT-enhancing effects of AMPH.

      Prediction: In a within-subject, placebo-controlled, randomized design, AMPH (10 mg po) will
      increase PPI and enhance MCCB and TCT performance in medicated SZ/SZA patients, particularly
      among those characterized by low basal performance levels and/or the val/val rs4680 COMT
      polymorphism. Concurrent HS testing will confirm and extend findings of AMPH effects on PPI
      and neurocognition, and help interpret findings in SZ/SZA patients.
    

Intervention name(s): Dextroamphetamine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Each participant receives a single pill of placebo or active drug (dextroamphetamine 10 mg) and completes approximately 6 hours of testing in the laboratory. One week later, that participant receives a single pill of the alternate comparator and is again tested in the laboratory. Thus, in total, each participant receives one placebo pill and one active pill, separated by one week.; Each participant receives a single pill of placebo or active drug (dextroamphetamine 10 mg) and completes approximately 6 hours of testing in the laboratory. One week later, that participant receives a single pill of the alternate comparator and is again tested in the laboratory. Thus, in total, each participant receives one placebo pill and one active pill, separated by one week.
Other intervention name(s): d-amphetamine; Dexedrine
Intervention MeSH terms: Amphetamine; Dextroamphetamine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Schizophrenia; Schizoaffective Disorder; Mental Disorders; Anti-Dyskinesia Agents; Antiparkinson Agents; Central Nervous System Agents; Dopamine Agents; Excitatory Amino Acid Agents; Excitatory Amino Acid Antagonists; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Pharmacologic Actions; Physiological Effects of Drugs; Therapeutic Uses; Prepulse inhibition; Neurocognition; Working memory; Dextroamphetamine; MATRICS Consensus Cognitive Battery; Pharmacologic Augmentation of Cognitive Therapies; Sensory discrimination learning; Targeted Cognitive Training; rs4680 polymorphism of catechol-O-methyltransferase (COMT)