Pharmacologically-augmented Cognitive Therapies (PACTs) for Schizophrenia.

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.

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: PPI neurocognition (MCCB performance) computerized TCT performance in biomarker-identified SZ/SZA patients. 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.

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)

Drug: Dexedrine, dextroamphetamine, d-amphetamine. Dosage form, frequency and duration: Each participant receives a single pill of placebo or active drug (dextroamphetamine 10 mg) 30 minutes after arriving at the lab. The participant then completes approximately 6 hours of testing in the laboratory. The participant stays at the lab for 7.5 hours in order to monitor physical condition in case the participant received the active pill 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.

Drug: Dexedrine, dextroamphetamine, d-amphetamine Dosage form, frequency and duration: Each participant receives a single pill of placebo or active drug (dextroamphetamine 10 mg) 30 minutes after arriving at the lab. The participant then completes approximately 6 hours of testing in the laboratory. The participant stays at the lab for 7.5 hours in order to monitor physical condition in case the participant received the active pill 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.

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.

PPI was assessed with 42 trials of 6 types: 118 dB 40 ms pulse alone (P) & the same P preceded 10, 20, 30, 60, or 120 ms by a prepulse (pp) 16 dB over background. Startle magnitude (SM), habituation, latency & latency facilitation were measured to interpret changes in PPI. %PPI = 100 x [(SM on P trials) - (SM on pp+P trials)] / SM on P trials. Example: SM on P trials = 80 units SM on pp+P trials = 30 units %PPI = 100 x (80-30)/80 = 100 x 50/80 = 62.5% Greater %PPI mean the reflex has been inhibited to a greater extent in the presence of a pp. %PPI can't exceed 100: when SM on pp+P trials = 0, then %PPI = 100 x (SM on P trials - 0)/SM on P trials = 100 x 1 = 100%. However, %PPI can theoretically be infinitely negative since SM on pp+P trials could be infinitely large ("prepulse facilitiation" (PPF)), i.e. SM is potentiated in the presence of a pp. PPF is "normal" at very short & very long pp intervals, but not within a species-specific physiological range of intervals.

The T-score indicates the performance on a neurocognitive battery of tests. Higher score reflects better performance.

Auditory discrimination learning: Subjects identify direction (up vs. down) of 2 consecutive sound sweeps. Parameters (e.g. inter-sweep interval, sweep duration) are established for subjects to maintain 80% correct responses. On screen and test days, subjects complete 1h of TCT. Analytic software yields the key measures: auditory processing speed (APS) and APS "learning". APS is the shortest inter-stimulus interval at which a subject performs to criteria and APS learning is the difference (ms) between the first APS and the best APS of the subsequent trials. A smaller APS reflects "better" discrimination (i.e., subject correctly identified frequency "sweep" direction despite a smaller ms gap between stimuli) and a larger ms value for APS learning reflects more learning, i.e., faster APS with repeated trials. Limits for APS are capped at 0-to-1000 ms; values for APS learning are capped at (-) 1000-to-APS.

Inclusion Criteria: 18-55 years old: Drug Free (No recreational/street drugs) Diagnosis of Schizophrenia or Schizoaffective Disorder, Depressed Type Must be stable on antipsychotic medication for at least 1 month Any medications other than antipsychotic medications need to be stable for at least 1 week Exclusion Criteria: Dominant hand injury Hearing impairment at 40 dB Irregular menstrual cycle or cycle is no within in 25-35 days (menopausal is eligible) EKG, conduction abnormalities confirmed by cardiologist Reading component of Wide Range Achievement Test 4 (WRAT4) Score less than 70 Any serious illness, including: Insulin-dependent diabetes, HIV, AIDS, cancer, stroke, heart attack, uncontrolled hypothyroidism Sleep apnea A diagnosis of epilepsy or history of seizures with loss of consciousness Open/closed head injury with loss of consciousness greater than 1 minute at any time in the lifetime Blood pressure: Systolic Blood Pressure < 90 or > 160, Diastolic Blood Pressure < 45 or > 95 Heart Rate < 55 or > 110 Current use of Dexatrim or drugs containing phenylephrine (eligible if not used for at least 72 hours prior to participation) Current use of St. John's Wort, Milk Thistle (eligible if for at least 1 month) Self report of any illicit drug use within the last 30 days Positive urine toxicology Self-report of any use of ecstasy, lysergic acid diethylamide (LSD), mushrooms, gamma hydroxybutyrate (GHB), ketamine, phencyclidine (PCP), heroin or any intravenous-drugs within past year If there is a history of substance abuse/addiction, participant must be in remission for at least 6 months Within 1 month of recent psychiatric hospitalization Current mania Dementia/Alzheimer's diagnosis Mania episode meeting criteria outlined in the MINI-International Neuropsychiatric Interview Plus 6.0 (M.I.N.I. plus 6.0) anytime in the lifetime (hypomania/Bipolar II eligible)

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