Pharmacologic Augmentation of Targeted Cognitive Training in Schizophrenia

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.

Study Overview

• Status: Completed
• Conditions: Schizophrenia; Schizoaffective Disorder
• Intervention / Treatment: Drug: Placebo; Drug: d-amphetamine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92103
      • Clinical Teaching Facility (CTF-B102) at UCSD Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria include:

• DSM-IV diagnosis of schizophrenia or schizoaffective disorder, depressed type
• Written informed consent to participate in the study
• Age 18 - 55
• Absence of dementia or mental retardation
• Urine toxicology negative for recreational drugs
• Fluent and literate in English (needed for completion of WIN and QuickSIN)

Exclusion criteria include:

• Meets DSM-IV criteria for current substance abuse or dependence and has been substance abstinent for less than 30 days
• A history of traumatic brain injury
• Auditory or visual impairments severe enough to prevent study participation
• Under conservatorship (determined by Anasazi)
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Subjects complete 30 sessions of Targeted Cognitive Training (2-3 times per week), and receive placebo po 1 hour prior to each training.	Drug: Placebo; Subjects complete 30 sessions of Targeted Cognitive Training (2-3 times per week), and receive placebo po 1 hour prior to each training.
Active Comparator: 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.	Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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
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

Collaborators and Investigators

• Sponsor: University of California, San Diego
• Investigators: Principal Investigator: Neal R Serdlow, M.D., Ph.D., UC San Diego

Study record dates

Study Major Dates

• Study Start (Actual): November 9, 2020
• Primary Completion (Actual): December 30, 2024
• Study Completion (Actual): December 30, 2024

Study Registration Dates

• First Submitted: May 22, 2020
• First Submitted That Met QC Criteria: May 29, 2020
• First Posted (Actual): June 4, 2020

Study Record Updates

• Last Update Posted (Estimated): December 17, 2025
• Last Update Submitted That Met QC Criteria: November 20, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Schizophrenia; Psychotic Disorders; Organic Chemicals; Amines; Phenethylamines; Ethylamines; Amphetamines; Amphetamine; Dextroamphetamine
• Other Study ID Numbers: R33MH123603-01 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No