Pharmacologic Augmentation of Targeted Cognitive Training 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.

• 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.
• 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.

Primary outcomes

• Primary Clinical Outcome PANSS Total Score (PANSSt) [approximately 10 weeks]: 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.
• Primary Functional Outcome WHODAS [approximately 10 weeks]: 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.
• Primary Neurocognitive Outcome MCCB-C [approximately 10 weeks]: 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.

Secondary outcomes

• Secondary Clinical Outcome Measure PANSSp [approximately 10 weeks]: 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.
• Secondary Clinical Outcome Measure PANSSn [approximately 10 weeks]: 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.
• Psychotic Symptoms PSYRATS Hallucinations [approximately 10 weeks]: 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.
• Manic Symptoms YMRS [approximately 10 weeks]: 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.
• Current Depressive Symptoms PHQ [approximately 10 weeks]: 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.

Sex: All, ages: 18 Years to 55 Years

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

Participant flow

Outcome results

• Primary Clinical Outcome PANSS Total Score (PANSSt) (Primary), Mean, score on a scale: Placebo 65.4 +/- 5.7; Amphetamine 55.6 +/- 3.2 (p 0.28)
• Primary Functional Outcome WHODAS (Primary), Mean, score on a scale: Placebo 26.6 +/- 4.7; Amphetamine 53.1 +/- 8.0 (p 0.05)
• Primary Neurocognitive Outcome MCCB-C (Primary), Mean, score on a scale: Placebo 17.7 +/- 3.2; Amphetamine 29.8 +/- 5.0 (p 0.93)
• Secondary Clinical Outcome Measure PANSSp (Secondary), Mean, score on a scale: Placebo 16.6 +/- 2.3; Amphetamine 15.2 +/- 1.3 (p 0.43)
• Secondary Clinical Outcome Measure PANSSn (Secondary), Mean, score on a scale: Placebo 16.6 +/- 2.1; Amphetamine 12.8 +/- 1.1 (p 0.77)
• Psychotic Symptoms PSYRATS Hallucinations (Secondary), Mean, score on a scale: Placebo 2.7 +/- 1.8; Amphetamine 16.3 +/- 2.8 (p 0.50)
• Manic Symptoms YMRS (Secondary), Mean, score on a scale: Placebo 7.0 +/- 2.1; Amphetamine 5.6 +/- 1.4 (p 0.636)
• Current Depressive Symptoms PHQ (Secondary), Mean, score on a scale: Placebo 4.4 +/- 1.4; Amphetamine 6.3 +/- 1.7 (p 0.19)

Adverse events

Time frame: Data was collected over the course of the study participation, about 10 weeks

Other adverse events by term

• Study Protocol (PDF, 2019-10-11)
• Statistical Analysis Plan (PDF, 2019-10-11)
• Informed Consent Form (PDF, 2022-05-02)

• Neal R Serdlow, M.D., Ph.D., Principal investigator, UC San Diego