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Report for Clinical Trial NCT02634684

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

Pharmacologic Augmentation of Neurocognition and Cognitive Training in Psychosis

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.

NCT02634684 Schizophrenia
MeSH: Schizophrenia
HPO: Schizophrenia

2 Interventions

Name: Dextroamphetamine

Description: 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.

Type: Drug

Placebo dextroamphetamine

Name: Placebo

Description: 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.

Type: Drug

Placebo dextroamphetamine


Primary Outcomes

Description: 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.

Measure: Prepulse inhibition (PPI)

Time: 5 years

Secondary Outcomes

Description: 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.

Measure: MATRICS Consensus Cognitive Battery Performance (MCCB)

Time: 5 years

Description: 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.

Measure: Targeted Cognitive Training (TCT): PositScience, Inc.

Time: 5 years

Purpose: Treatment

Allocation: Randomized

Crossover Assignment


There is one SNP

SNPs


1 rs4680

Analytic software yields the dependent measures: subjects' across-session improvement score, processing speed percentile and total number of levels completed.. 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) 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) Schizophrenia Schizophrenia 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).

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.

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.



HPO Nodes


HPO:
Schizophrenia
Genes 71
USH1C RTN4R USH1G HIRA UPF3B GJA5 DNAJC13 DNMT3A KRT86 HTR2A APOL4 CLRN1 DRD3 CEP78 ARSG MSTO1 TRNE PRODH RREB1 GIGYF2 PDZD7 MTHFR RBM12 ADGRV1 NKX2-1 TRNS2 KRT83 SNCA MYO7A COMT CIB2 PCDH15 WHRN TBX1 GP1BB DSG4 ZDHHC9 ARSA ARVCF WFS1 PRODH PSAP APOL2 SEC24C KRT81 LRRK2 CHI3L1 MYO7A ATP2A2 SHANK3 SYN2 EIF4G1 CHRNA7 GBA FLI1 MED12 VPS35 JMJD1C MSTO1 USH2A AKT1 GJA8 TBX1 COMT UFD1 PRODH DISC2 TBX1 HARS1 CDH23 DAOA