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Pharmacologically-augmented Cognitive Therapies (PACTs) for Schizophrenia.

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ClinicalTrials.gov Identifier: NCT02634684
Recruitment Status : Recruiting
First Posted : December 18, 2015
Last Update Posted : April 17, 2019
Sponsor:
Information provided by (Responsible Party):
Neal R. Swerdlow, M.D., Ph.D., University of California, San Diego

Brief 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.

Condition or disease Intervention/treatment Phase
Schizophrenia Drug: Dextroamphetamine Drug: Placebo Phase 2

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 10-20 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, 10 and 20 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 and/or 20 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 (20 mg) and extend (10 mg) 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 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 and/or 20 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 (20 mg) and extend (10 mg) findings of AMPH effects on PPI and neurocognition, and help interpret findings in SZ/SZA patients.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 160 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Pharmacologic Augmentation of Neurocognition and Cognitive Training in Psychosis
Actual Study Start Date : July 1, 2014
Estimated Primary Completion Date : April 2020
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia

Arm Intervention/treatment
Active Comparator: dextroamphetamine

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: Dextroamphetamine
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 Names:
  • d-amphetamine
  • Dexedrine

Drug: Placebo
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.

Placebo Comparator: Placebo

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: Dextroamphetamine
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 Names:
  • d-amphetamine
  • Dexedrine

Drug: Placebo
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.




Primary Outcome Measures :
  1. Prepulse inhibition (PPI) [ Time Frame: 5 years ]
    Startle and PPI are assessed using 42 trials of 6 types: a 118 decibels (dB) (A) 40 ms noise alone, and the same "pulse" preceded 10, 20, 30, 60, or 120 ms by a prepulse 16 dB over a 70 dB(A) background. Startle amplitude, habituation, latency and latency facilitation are tested, and are used to interpret drug and subgroup effects on %PPI. Primary dependent measure: AMPH effects on %PPI.


Secondary Outcome Measures :
  1. MATRICS Consensus Cognitive Battery Performance (MCCB) [ Time Frame: 5 years ]
    The MCCB includes 10 tests assessing 7 cognitive domains". In "low baseline" HS, AMPH primarily increased speed of processing (SP) and attention/ vigilance (A/V), but some gains were evident in all domains except visual learning (30). Total test time is 1-1.5h. The primary dependent measures will be AMPH effects on SP and A/V T-scores; secondary and exploratory measures will include T-scores for both spatial (Wechsler Spatial Span) and verbal (Letter-Number Span) working memory, as well as T-scores for the other cognitive domains.

  2. Targeted Cognitive Training (TCT): PositScience, Inc. [ Time Frame: 5 years ]
    Sensory discrimination learning module: Sound "Sweeps" of adaptive auditory processing exercises: 1) parameters (e.g. inter-stimulus interval, stimulus duration) are established for subjects to maintain 80% correct responses in each stimulus set, and 2) task difficulty increases systematically and parametrically as performance improves. On screen and test days, subjects complete 1h of TCT. Analytic software yields the dependent measures: subjects' across-session improvement score, processing speed percentile and total number of levels completed.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02634684


Contacts
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Contact: Jo Talledo, B.A. 619-543-3093 atalledo@ucsd.edu

Locations
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United States, California
Clinical Teaching Facility (CTF-B102) at UCSD Medical Center Recruiting
San Diego, California, United States, 92103
Contact: Jo Talledo, B.A.    619-543-3093    atalledo@ucsd.edu   
Principal Investigator: Neal R. Swerdlow, M.D., Ph.D.         
Sponsors and Collaborators
University of California, San Diego
Investigators
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Principal Investigator: Neal R. Swerdlow, M.D., Ph.D. UC San Diego

Publications:
Wilkinson GS, Robertson GJ (2006) WRAT4: Wide Range Achievement Test professional manual, 4th edn Psychological Assessment Resources: Lutz, FL

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Responsible Party: Neal R. Swerdlow, M.D., Ph.D., Professor of Psychiatry and Director of the Research Residency Track at the University of California, San Diego, School of Medicine., University of California, San Diego
ClinicalTrials.gov Identifier: NCT02634684     History of Changes
Other Study ID Numbers: 5R01MH059803-15 ( U.S. NIH Grant/Contract )
Eyeblink Study ( Other Identifier: UC San Diego )
First Posted: December 18, 2015    Key Record Dates
Last Update Posted: April 17, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Neal R. Swerdlow, M.D., Ph.D., University of California, San Diego:
Dextroamphetamine
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
MATRICS Consensus Cognitive Battery
Pharmacologic Augmentation of Cognitive Therapies
Sensory discrimination learning
Targeted Cognitive Training
rs4680 polymorphism of catechol-O-methyltransferase (COMT)

Additional relevant MeSH terms:
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Amphetamine
Dextroamphetamine
Schizophrenia
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Excitatory Amino Acids
Molecular Mechanisms of Pharmacological Action
Excitatory Amino Acid Antagonists
Central Nervous System Stimulants
Physiological Effects of Drugs
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Dopamine Agents
Neurotransmitter Agents
Adrenergic Agents
Adrenergic Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Dopamine Uptake Inhibitors
Excitatory Amino Acid Agents