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These studies look to conduct efficient pilot testing of a novel intervention strategy for chronic psychotic disorders - Pharmacologic Augmentation of Cognitive Therapy (PACT) - via an experimental medicine approach. Antipsychotics are the major therapeutic tool for chronic psychotic disorders, including schizophrenia, but do not significantly alter their course or real-life impact. Specific cognitive therapies achieve modest symptom reduction and improved function and cognition in psychosis patients, including "bottom-up" sensory-based targeted cognitive training (TCT). While benefits of TCT are evident at the group level, almost half of all patients demonstrate little or no cognitive gains after 30-40 hours (h) of TCT. For patients and clinicians, the costs and logistical complexities associated with these time- and resource-intensive interventions can be prohibitive. We propose and will test a novel "augmentation strategy" for using medications to specifically enhance the benefits of TCT in schizophrenia.
Subjects who meet criteria for study entry come to UCSD where consenting and a comprehensive screening and diagnostic assessment including a Mini-International Neuropsychiatric Interview are conducted. After initial screening, subjects return twice, approximately 7 days apart, for biomarker assessment after challenge with placebo (PBO) (Test 1) or amphetamine 5 mg po (AMPH) (Test 2). Subjects then enter the "treatment phase", completing up to 30 one-hour targeted cognitive training (TCT) sessions. Subjects are randomized to one of 2 groups: "AMPH Group" receive AMPH (5 mg po) 1h before each TCT session; "PBO Group" receive PBO dosed identically to AMPH. Pill identity (AMPH vs. PBO) is blind to subjects and staff.
TCT sessions are scheduled approximately 3 times each week for 10 weeks. TCT consists of 7 computerized exercises delivered on standardized laptops and headphones. Collectively, these exercises target learning mechanisms involving auditory perception and processing speed (Sound Sweeps, Fine Tuning) and auditory memory (Syllable Stacks, Memory Grid, To-Do List Training, Rhythm Recall, Hear-Hear). Training is structured into blocks that deliver stimulus sets with varying temporal and psychophysical parameters to allow continuous learning and improvement. Blocks consist of 10-35 adaptive trials where the subject's progression depends on their performance. Exercises apply an n-up/m-down algorithm to responses to estimate psychophysical thresholds while ensuring that participants remain engaged and challenged at an appropriate level (~80% accuracy) as their abilities improve.
Clinical and functional outcome measures are acquired at "baseline", and 1-2 days after completion of 10, 20 and 30 TCT sessions and 12 weeks post-training. Urine toxicology screens and Columbia Suicide Severity Rating Scales are performed at least weekly, prior to a TCT session. A treatment satisfaction scale (100 mm line) rates expectations at the start of the study and actual experience of treatment in three areas: "satisfaction", "hard work" and "worthwhile." Subjects from both groups return to UCSD 12 weeks after the TCT has ended, and outcome measures are reassessed to test the "durability" of benefits.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | Subjects complete 30 sessions of Targeted Cognitive Training (2-3 times per week), and receive placebo po 1 hour prior to each training. |
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| Active Drug | Active Comparator | Subjects complete 30 sessions of Targeted Cognitive Training (2-3 times per week), and receive amphetamine 5 mg po 1 hour prior to each training. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| d-amphetamine | Drug | Subjects complete 30 sessions of Targeted Cognitive Training (2-3 times per week), and receive amphetamine 5 mg po 1 hour prior to each training. |
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| Measure | Description | Time Frame |
|---|---|---|
| Primary Clinical Outcome PANSS Total Score (PANSSt) | Positive & Negative Symptom Scale total (PANSSt) PANSS Total Score is the primary clinical outcome measured at baseline vs. post-TCT session 10, 20 and 30 (approximately 10 weeks). The PANSS total score has a range 30-210, with higher scores indicating worse outcome. | approximately 10 weeks |
| Primary Functional Outcome WHODAS | Primary World Health Organization Disability Schedule (WHODAS 2.0) Function will be assessed via the World Health Organization Disability Schedule 2.0 (WHODAS 2.0) at baseline vs. post-TCT session 10, 20 and 30 (approximately 10 weeks). The WHODAS 2.0 has a range 12-60, with higher scores indicating worse outcome. | approximately 10 weeks |
| Primary Neurocognitive Outcome MCCB-C | MATRICS Consensus Cognitive Battery Global Composite T-score (MCCB-C) The MCCB Global Composite T-score (MCCB-C) is the primary neurocognitive outcome measured at baseline vs. post-TCT session 10, 20 and 30 (approximately 10 weeks). The MATRICS Consensus Cognitive Battery (MCCB) composite T-score has no minimum or maximum score because it uses T-scores, which are standardized based on a community sample. A normal range MCCB composite T-score is between 40 and 60 and higher scores indicate better neurocognitive outcome. | approximately 10 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Secondary Clinical Outcome Measure PANSSp | Positive & Negative Symptom Scale positive symptom subscale (PANSSp) measured at baseline vs. post-TCT session 10, 20 and 30 (approximately 10 weeks). The PANSSp is rated with 1 to 7 points ranging from absent to extreme. The range is 7-49 and higher scores indicate worse outcome. | approximately 10 weeks |
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Inclusion criteria include:
Exclusion criteria include:
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| Name | Affiliation | Role |
|---|---|---|
| Neal R Serdlow, M.D., Ph.D. | UC San Diego | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Clinical Teaching Facility (CTF-B102) at UCSD Medical Center | San Diego | California | 92103 | United States |
A total of 68 participants were enrolled but 35 were excluded for not meeting inclusion criteria and 5 withdrew from the study. Therefore 28 participants were randomized.
Antipsychotic-medicated outpatients with a primary diagnosis of SZ or schizoaffective disorder (depressed type) ages 18-55 were recruited from the San Diego community between 11/9/2020 and 3/13/2024. Of the 68 consented/enrolled participants, 28 met inclusion criteria and were randomized to treatment.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo | Subjects complete 30 sessions of Targeted Cognitive Training (2-3 times per week), and receive placebo po 1 hour prior to each training. Placebo: Subjects complete 30 sessions of Targeted Cognitive Training (2-3 times per week), and receive placebo po 1 hour prior to each training. |
| FG001 | Amphetamine | Subjects complete 30 sessions of Targeted Cognitive Training (2-3 times per week), and receive amphetamine 5 mg po 1 hour prior to each training. d-amphetamine: Subjects complete 30 sessions of Targeted Cognitive Training (2-3 times per week), and receive amphetamine 5 mg po 1 hour prior to each training. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | Subjects complete 30 sessions of Targeted Cognitive Training (2-3 times per week), and receive placebo po 1 hour prior to each training. Placebo: Subjects complete 30 sessions of Targeted Cognitive Training (2-3 times per week), and receive placebo po 1 hour prior to each training. |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Primary Clinical Outcome PANSS Total Score (PANSSt) | Positive & Negative Symptom Scale total (PANSSt) PANSS Total Score is the primary clinical outcome measured at baseline vs. post-TCT session 10, 20 and 30 (approximately 10 weeks). The PANSS total score has a range 30-210, with higher scores indicating worse outcome. | Posted | Mean | Standard Error | score on a scale | approximately 10 weeks |
|
Data was collected over the course of the study participation, about 10 weeks
Gastrointestinal symptoms (e.g. bloating, diarrhea, cramps) were all assessed/monitored under the general description "gastrointestinal symptoms".
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | Subjects complete 30 sessions of Targeted Cognitive Training (2-3 times per week), and receive placebo po 1 hour prior to each training. Placebo: Subjects complete 30 sessions of Targeted Cognitive Training (2-3 times per week), and receive placebo po 1 hour prior to each training. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| increase in psychiatric symptoms | Psychiatric disorders | Non-systematic Assessment | Increased psychiatric symptoms including increased auditory hallucinations and worse mood |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Neal R. Swerdlow, M.D., Ph.D. | UCSD | 6194719455 | nswerdlow@health.ucsd.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Oct 11, 2019 | Sep 17, 2025 | Prot_001.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Oct 11, 2019 | Sep 17, 2025 | SAP_002.pdf |
| ICF | No | No | Yes | Informed Consent Form | May 2, 2022 | Nov 1, 2024 | ICF_000.pdf |
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| ID | Term |
|---|---|
| D012559 | Schizophrenia |
| D011618 | Psychotic Disorders |
| ID | Term |
|---|---|
| D019967 | Schizophrenia Spectrum and Other Psychotic Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D003913 | Dextroamphetamine |
| ID | Term |
|---|---|
| D000661 | Amphetamine |
| D000662 | Amphetamines |
| D010627 | Phenethylamines |
| D005021 | Ethylamines |
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| Placebo | Drug | Subjects complete 30 sessions of Targeted Cognitive Training (2-3 times per week), and receive placebo po 1 hour prior to each training. |
|
| Secondary Clinical Outcome Measure PANSSn | Positive & Negative Symptom Scale negative symptom subscale (PANSSn)measured at baseline vs. post-TCT session 10, 20 and 30 (approximately 10 weeks). The PANSSn is rated with 1 to 7 points ranging from absent to extreme. The range is 7-49 and higher scores indicate worse outcome. | approximately 10 weeks |
| Psychotic Symptoms PSYRATS Hallucinations | Psychotic Symptom Rating Scales (PSYRATS hallucination subscale) assesses auditory hallucinations measured at baseline vs. post-TCT session 10, 20 and 30 (approximately 10 weeks). The PSYRATS auditory hallucinations subscale (AHS) consisting of 11 items, with each item being rated from 0 (absent) to 4 (severe), range 0-44, with higher scores indicating more severe auditory hallucinations or worse outcome. | approximately 10 weeks |
| Manic Symptoms YMRS | Young Mania Rating Scale total score measured at baseline vs. post-TCT session 10, 20 and 30 (approximately 10 weeks). The range for the YMRS total score is 0-60, with higher scores indicating more severe manic symptoms or worse outcome. | approximately 10 weeks |
| Current Depressive Symptoms PHQ | Patient Health Questionnaire-9 (PHQ-9) total score measured at baseline vs. post-TCT session 10, 20 and 30 (approximately 10 weeks). The PHQ-9 has a range from 0 to 27 with higher scores indicating more severe depression or worse outcome. | approximately 10 weeks |
| Active Drug |
Subjects complete 30 sessions of Targeted Cognitive Training (2-3 times per week), and receive amphetamine 5 mg po 1 hour prior to each training. d-amphetamine: Subjects complete 30 sessions of Targeted Cognitive Training (2-3 times per week), and receive amphetamine 5 mg po 1 hour prior to each training. |
| BG002 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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Subjects complete 30 sessions of Targeted Cognitive Training (2-3 times per week), and receive amphetamine 5 mg po 1 hour prior to each training.
d-amphetamine: Subjects complete 30 sessions of Targeted Cognitive Training (2-3 times per week), and receive amphetamine 5 mg po 1 hour prior to each training.
|
|
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| Primary | Primary Functional Outcome WHODAS | Primary World Health Organization Disability Schedule (WHODAS 2.0) Function will be assessed via the World Health Organization Disability Schedule 2.0 (WHODAS 2.0) at baseline vs. post-TCT session 10, 20 and 30 (approximately 10 weeks). The WHODAS 2.0 has a range 12-60, with higher scores indicating worse outcome. | Posted | Mean | Standard Error | score on a scale | approximately 10 weeks |
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| Primary | Primary Neurocognitive Outcome MCCB-C | MATRICS Consensus Cognitive Battery Global Composite T-score (MCCB-C) The MCCB Global Composite T-score (MCCB-C) is the primary neurocognitive outcome measured at baseline vs. post-TCT session 10, 20 and 30 (approximately 10 weeks). The MATRICS Consensus Cognitive Battery (MCCB) composite T-score has no minimum or maximum score because it uses T-scores, which are standardized based on a community sample. A normal range MCCB composite T-score is between 40 and 60 and higher scores indicate better neurocognitive outcome. | Posted | Mean | Standard Error | score on a scale | approximately 10 weeks |
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| Secondary | Secondary Clinical Outcome Measure PANSSp | Positive & Negative Symptom Scale positive symptom subscale (PANSSp) measured at baseline vs. post-TCT session 10, 20 and 30 (approximately 10 weeks). The PANSSp is rated with 1 to 7 points ranging from absent to extreme. The range is 7-49 and higher scores indicate worse outcome. | Posted | Mean | Standard Error | score on a scale | approximately 10 weeks |
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| Secondary | Secondary Clinical Outcome Measure PANSSn | Positive & Negative Symptom Scale negative symptom subscale (PANSSn)measured at baseline vs. post-TCT session 10, 20 and 30 (approximately 10 weeks). The PANSSn is rated with 1 to 7 points ranging from absent to extreme. The range is 7-49 and higher scores indicate worse outcome. | Posted | Mean | Standard Error | score on a scale | approximately 10 weeks |
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| Secondary | Psychotic Symptoms PSYRATS Hallucinations | Psychotic Symptom Rating Scales (PSYRATS hallucination subscale) assesses auditory hallucinations measured at baseline vs. post-TCT session 10, 20 and 30 (approximately 10 weeks). The PSYRATS auditory hallucinations subscale (AHS) consisting of 11 items, with each item being rated from 0 (absent) to 4 (severe), range 0-44, with higher scores indicating more severe auditory hallucinations or worse outcome. | Posted | Mean | Standard Error | score on a scale | approximately 10 weeks |
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| Secondary | Manic Symptoms YMRS | Young Mania Rating Scale total score measured at baseline vs. post-TCT session 10, 20 and 30 (approximately 10 weeks). The range for the YMRS total score is 0-60, with higher scores indicating more severe manic symptoms or worse outcome. | Posted | Mean | Standard Error | score on a scale | approximately 10 weeks |
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| Secondary | Current Depressive Symptoms PHQ | Patient Health Questionnaire-9 (PHQ-9) total score measured at baseline vs. post-TCT session 10, 20 and 30 (approximately 10 weeks). The PHQ-9 has a range from 0 to 27 with higher scores indicating more severe depression or worse outcome. | Posted | Mean | Standard Error | score on a scale | approximately 10 weeks |
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| 0 |
| 10 |
| 0 |
| 10 |
| 7 |
| 10 |
| EG001 | Amphetamine | Subjects complete 30 sessions of Targeted Cognitive Training (2-3 times per week), and receive amphetamine 5 mg po 1 hour prior to each training. d-amphetamine: Subjects complete 30 sessions of Targeted Cognitive Training (2-3 times per week), and receive amphetamine 5 mg po 1 hour prior to each training. | 0 | 18 | 0 | 18 | 10 | 18 |
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| Gastrointestinal | Gastrointestinal disorders | Non-systematic Assessment | Gastrointestinal symptoms (e.g. bloating, diarrhea, cramps) |
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| Restless night | Psychiatric disorders | Non-systematic Assessment | Restless Night (1 night) |
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| Worsening TD-related tremor | Nervous system disorders | Non-systematic Assessment | Worsening Tardive Dyskinesia-related tremor |
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| Minor Accident (e.g. trip, fall) | General disorders | Non-systematic Assessment | Minor Accident (e.g. trip, fall) |
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| Elevated blood pressure and/or heart rate | Cardiac disorders | Non-systematic Assessment | Elevated blood pressure and/or heart rate as measured at study visit |
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| ear ache | Ear and labyrinth disorders | Non-systematic Assessment | ear ache |
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| D000588 |
| Amines |
| D009930 | Organic Chemicals |
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