Clinical and Biomarker Assessment of Efficacy of Cognitive Remediation in Patients with Schizophrenia and Schizoaffective Disorder Stabilized on Lurasidone
The study will be conducted at 15-20 sites in the Treatment and Evaluation Network for Trials in Schizophrenia (TENETS). All sites are very experienced in clinical trial execution with schizophrenia patients, including trials that have cognitive measures as the primary outcome. Across all sites, about 400 patients will be initiated on lurasidone treatment and about 200 of those patients will be randomized. At our site, we plan to consent approximately 30 patients into this study. We estimate about 1 out of every 3 patients consented will be randomized to a study treatment.
Patients will be evaluated for eligibility during a screening period of up to four weeks during which time they will continue on their pre-switch antipsychotic medication. Patients in whom a change in antipsychotic therapy is clinically warranted, or whose preference is to switch to lurasidone, and who continue to meet entry criteria will be initiated on lurasidone treatment (flexible dosing in the range of 40-120 mg p.o./daily during the trial). Clinicians will have eight weeks to complete the switch. Patients who are already taking lurasidone may enter the study and complete the regular Screening and Baseline procedures. These patients will complete Visit 6 two weeks after their Baseline visit. Only patients who attain a minimum of two weeks of stable symptomatology at the end of the 8-week transition period (or two weeks after Baseline if they entered the study on lurasidone) will continue in the study. Patients stabilized on lurasidone will then be randomly assigned in a 1:1 ratio (stratified by site) to receive either 1) cognitive remediation or 2) a non-specific mental activity control condition two times/week for a total of 30 sessions over a 4-6 month period. The CR and control arms are described below under Study Detail. The two groups (CR vs. control) will be compared on cognitive and functional outcomes.
The co-primary outcome measures will be cognitive function as assessed by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) test battery and the Cognitive Assessment Interview (CAI). An important secondary outcome will be the change in psychosocial functioning as assessed by the Brief University of California at San Diego Performance-Based Skills Assessment (UPSA-B). Measures of cognition and psychosocial functioning will be performed by blinded raters. These measures will be administered at baseline (on previous antipsychotic treatment prior to switching to lurasidone), end of stabilization on lurasidone, midpoint of cognitive intervention (after session #15), and completion of cognitive intervention (after session #30).
Repeated measures of efficacy, safety and tolerability will be obtained throughout the trial. Efficacy will be measured by a change in the Positive and Negative Syndrome Scale (PANSS) score; and safety and tolerability will be measured by the Side Effect Checklist, the Abnormal Involuntary Movement Scale (AIMS), the Simpson-Angus Scale (SAS), the Barnes Akathisia Rating Scale (BAS), study completion rates, and the frequency of abnormal laboratory values. Two biomarkers of functional brain activation, auditory event related potentials (ERP) and functional Magnetic Resonance Imaging (fMRI), will be assessed during cognitive activation tasks in a subset of patients at baseline and study completion.
1. Male or female between 18-55 years of age who meet DSM-IV-TR criteria for schizophrenia or schizoaffective disorder confirmed by the Structured Clinical Interview for DSM-IV Clinical trial version (SCID-CT version). Duration of illness>1 year. Outpatient status.
2. Change in antipsychotic medication is clinically warranted as evidenced by 1) persistent psychosis despite adequate dose and duration of antipsychotic, or 2) inability to achieve therapeutic dose because of dose-limiting side effects, or 3) persistent side effects that either cause significant subjective distress or significantly increase medical risks, such as substantial weight gain or metabolic disturbances.
3. No behaviors suggesting potential danger to self or others over the 6 months prior to participation.
4. For the last 2 weeks of lurasidone stabilization phase, a score of 4 or less on PANSS items of conceptual disorganization, hallucinations, suspiciousness and unusual thought content items.
5. At end of lurasidone stabilization phase, Simpson-Angus Scale total score < 6.
6. At end of lurasidone stabilization phase, Calgary Depression Scale total score <10.
7. No acute medical problems; any chronic medical condition (e.g. hypertension) consistently treated and stable during the 1 month prior to participation.
8. Able to provide signed informed consent and to cooperate with all study procedures.
9. Able to attend twice weekly sessions (each lasting approximately 75 minutes) for CR or control sessions for the ~6 month duration of the cognitive intervention phase of the study.
10. Must meet the following cognitive performance criteria at baseline:
a. Able to complete the baseline MATRICS validly as assessed by neuropsychology tester.
b. Raw score of 12 or greater on the WTAR (Wechsler Test of Adult Reading).
11. Women who can become pregnant must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the study in such a manner that the risk of pregnancy is minimized. Acceptable methods include oral, injectable or implanted contraceptives, intrauterine devices or barrier methods such as condoms, diaphragm and spermicides. Women who can become pregnant must have a negative urine pregnancy test at the Screening Visit. Women who can become pregnant include anyone who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy), or is not postmenopausal (defined as amenorrhea 12 consecutive months).