Efficacy of Cognitive Remediation in Patients With Schizophrenia or Schizoaffective Disorder Stabilized on Lurasidone

Phase 3

Completed

Conditions: Schizophrenia

Interventions: Drug: Cognitive Remediation

Registration Number: NCT01173874

Lead Sponsor: New York State Psychiatric Institute

Brief Summary: The investigators hypothesize that cognitive remediation will be superior to the active control group on the change from baseline to study end point of cognitive remediation phase on both co-primary outcome measures (standardized composite MATRICS score and Cognitive Assessment Interview).

Detailed Description: OVERVIEW \& SPECIFIC AIMS Marked cognitive impairment underlies much of the social \& occupational dysfunction associated with schizophrenia. Currently available antipsychotic medications are primarily effective in treating psychotic symptoms \& have demonstrated only limited potential in ameliorating cognitive deficits in schizophrenia patients.

Lurasidone is a novel compound synthesized by SEPRACOR, Inc.for the treatment of patients with schizophrenia \& bipolar disorder. It possesses high affinity for dopamine D2, serotonin 5-HT2A, 5-HT7, 5-HT1A \& noradrenaline α2C receptors. Compared with other atypical antipsychotics, lurasidone demonstrates similar binding affinities for the D2 \& 5-HT2A receptors, but greater affinity for serotonin 5-HT1A receptors. Lurasidone displays no affinity for histamine H1 or acetylcholine M1 receptors. In animal studies, lurasidone significantly reversed memory impairment induced by MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, in a rat step-through type passive avoidance task. The maximum inhibitory effects of lurasidone were greater than those observed with risperidone, quetiapine, \& olanzapine, while aripiprazole was not effective in reversing the impairment induced by MK-801. Additionally, lurasidone significantly reversed memory impairment induced by the anticholinergic drug scopolamine in the passive avoidance task. The reversal of pharmacologically induced cognitive deficits in rats by lurasidone is promising \& warrants specific investigation in subjects with schizophrenia, given the prominence of cognitive deficits in this disorder.

From a different therapeutic perspective, the utility of cognitive remediation in ameliorating cognitive deficits \& improving functional outcomes in schizophrenia has recently been evaluated in several studies. A meta-analysis of these trials found effect sizes for improvement in cognitive \& psychosocial functioning in the low to moderate range (McGurck 2007). The best outcomes in psychosocial functioning were evident when cognitive remediation was combined with teaching of psychosocial skills.

Given the recalcitrant nature of cognitive deficits in schizophrenia \& their impact on functional capacity we felt that in designing a study to test the effectiveness of cognitive remediation we should maximize the likelihood of therapeutic benefit by administering cognitive remediation in the context of pharmacotherapy that may have potential for precognitive effects. By so doing we could possibly boost the effect sizes seen with cognitive remediation alone. In this study we will transition patients with schizophrenia (in whom a change in antipsychotic therapy is clinically warranted) from their current antipsychotic to lurasidone - clinicians will have eight weeks to complete the switch. Subjects who are successfully switched to lurasidone will then be randomized to receive either cognitive remediation or a non-specific mental activity control condition two times/week for a total of 30 sessions over a 4-6 month period. Our goal is to have 140 patients complete the cognitive remediation phase.

A subset of the sample will participate in 2 biomarker studies. Event related potentials \& fMRI will be done in these subjects at baseline \& study completion.

This study will be done as an Investigator initiated trial (J. Lieberman, M.D. - PI) under a separate IND.

Primary Aim: We hypothesize that cognitive remediation will be superior to the active control group on the change from baseline to study end point of cognitive remediation phase on both co-primary outcome measures (standardized composite MATRICS score \& Cognitive Assessment Interview).

Additional aims

1. To compare cognitive remediation to active control on functional outcome as assessed by the change in UCSD Performance-Based Skills Assessment (UPSA-Brief) from baseline to end point of cognitive remediation phase.

2. To compare cognitive remediation to active control on changes from lurasidone stabilized baseline to end point in indices of functional brain activation (ERP \& fMRI) during cognitive activation tasks.

3. Evaluate the effect of 8 weeks of lurasidone treatment on cognitive \& functional outcomes as assessed by changes from baseline in the MATRICS composite score, CAI, \& UPSA-Brief.

4. Evaluate the effect of cognitive remediation compared to nonspecific mental activity on cognitive \& functional outcomes as assessed by changes from lurasidone stabilized baseline to end of cognitive remediation phase in the MATRICS composite score, CAI, \& UPSA-Brief.

5. Evaluate the efficacy, safety, \& tolerability of lurasidone in patients with schizophrenia as assessed by the change from baseline to week 8 \& to end of cognitive remediation phase in the PANSS total score, Side Effect Checklist, AIMS, SAS, BAS, \& frequency of abnormal laboratory values.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 120

Inclusion Criteria

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.
Change in antipsychotic medication is clinically warranted as evidenced by
- persistent psychosis despite adequate dose and duration of antipsychotic, or * inability to achieve therapeutic dose because of dose-limiting side effects,
- persistent side effects that either cause significant subjective distress or significantly increase medical risks, such as substantial weight gain or metabolic disturbances, or
- patient preference to switch and treating psychiatrist is in agreement.
No behaviors suggesting potential danger to self or others over the 6 months prior to participation.
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.
At end of lurasidone stabilization phase, Simpson-Angus Scale total score <
At end of lurasidone stabilization phase, Calgary Depression Scale total score <10.
No acute medical problems; any chronic medical condition (e.g. hypertension) consistently treated and stable during the 1 month prior to participation.
Able to provide signed informed consent and to cooperate with all study procedures.
Able to attend twice weekly sessions (each lasting approximately 75 minutes) for cognitive remediation or active control sessions for the ~6 month duration of the cognitive remediation phase of the study.
Must meet the following cognitive performance criteria:
- Able to complete the baseline MATRICS validly at baseline as assessed by NP tester.
- Raw score of 12 or greater on the WTAR (Wechsler Test of Adult Reading) at screening.
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).

Exclusion Criteria

Documented history of learning disability.
Hearing or visual impairment; not fluent in English.
Current treatment with clozapine or history of treatment resistance as evidenced by failure to improve (in the judgment of the investigator) with 2 or more adequate dose antipsychotic trials of at least 6 weeks duration in preceding 1 year.
Concomitant or anticipated treatment with potent CYP 3A4 inhibitor such a cimetidine, cyclosporine, erythromycin or erythromycin-like drugs (e.g., azithromycin, clarithromycin except short term acute treatment for 1 week or less), diltiazem, itraconazole, ketoconazole or other systemic antifungal agents in the azole class, nefazodone; or potent CYP3A4 inducer including: carbamazepine, modafinil, Phenobarbital, phenytoin, rifampin, St. Johns Wort, and troglitazone.
Current treatment with psychotropic agents known to affect cognition such as amphetamines, topiramate.
History of treatment with electroconvulsive therapy within the 6 months prior to participation or expectation that patient may require ECT during the study.
History of neurological or neuropsychiatric conditions (e.g. stroke, traumatic brain injury, epilepsy, etc).
Subjects with a history of clinically significant neurological, metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, and/or urological disorders (e.g. unstable angina, decompensate congestive heart failure, CNS infection or history of HIV seropositivity), which would pose a risk to the patient if they were to participate in the study or that might confound the results of the study. Active medical conditions that are minor or well controlled are not exclusionary if they do not affect risk to the patient of the study results. For example, the following are not exclusionary: a) stable and well-controlled hypertension; b) asthma (no serious attacks in the past year); c) hypothyroidism (TSH within normal limits).
A positive test for Hepatitis C antibody with concurrent evidence of impaired hepatic function (increased AST or ALT greater than 2 times the upper limit of normal) or positive tests for Hepatitis A antibody IgM fraction or Hepatitis B surface antigen, irrespective of the AST or ALT values.
History of alcohol or substance abuse or dependence during the 6 months prior to participation.
Participation in a clinical trial involving an investigational medication within 3 months prior to participation or 2 or more investigational drug trials in the preceding 12 months.
Pregnant women or women of child-bearing potential who are not using adequate birth control.
Woman who are breast feeding.
Individuals who: a) received any cognitive remediation in the 6 months prior to study entry or b)received more than 6 hours of cognitive remediation in the 12 months prior to study entry or c) received more than 15 hours in the 24 months prior to study entry. Cognitive remediation is defined as any behavioral intervention consisting of training activities that aim to target impairments in cognitive domains of sensory processing, attention, memory, processing speed, working memory, and executive functioning.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cognitive Remediation	Cognitive Remediation	Cognitive remediation intervention will be administered in small group settings twice weekly for 30 sessions and will utilize computerized and verbal group training exercises to address basic skills such as auditory processing, attention, processing speed, and verbal working memory and learning, as well as intermediate and complex skills such as deductive reasoning, planning and sequencing, set shifting, and complex problem solving.

Primary Outcome Measures

Name	Time	Method
Cognitive Function Measured by MCCB Composite Score	4-6 month period	The MATRICS Consensus Cognitive Battery (MCCB) will be used to assess cognitive function. The MCCB composite score is comprised of sub-scale measures of: a) working memory; b) attention and vigilance; c) verbal learning; d) visual learning; e) speed of processing; f) reason and problem solving; and g) social cognition. The MCCB takes 90 minutes or less to complete. MCCB assessed 4 times: prestabilization (screening), randomization (after 6-8 weeks of lurasidone stabilization, prior to initial cognitive remediation), midpoint (after 20 cognitive remediation session), and study completion (final visit after 30 cognitive remediation sessions). MCCB composite scores are reported as t-scores where a t-score = 50 is the population average. Every 10 points is one standard deviation. There is no range as scores are as far from population average.
Cognitive Function as Measured by the University of California, San Diego, Performance-Based Skills Assessment-Brief (UPSA-B) Scale	4-6 month period	The UPSA-B assesses functional capacity to perform tasks similar to those in daily life. Raw scores are converted into scaled scores ranging from 0-100, with higher scores indicating better functional capacity.

Secondary Outcome Measures

Name	Time	Method
Efficacy as Measured by Positive and Negative Syndrome Scale (PANSS)	4-6 month period	Total PANSS score with 30 items. Each item is rated 1-7 so the minimum Total PANSS score =30 and the maximum is 210. Anchors for each item are as follows, the higher values represent an increase in severity of symptoms: 1. Absent 2. Minimal 3. Mild 4. Moderate 5. Moderately severe 6. Severe 7. Extremely severe
Cognition as Measured by Cognitive Assessment Interview (CAI)	4-6 month period	Cognitive Assessment Interview was used to obtain information about cognitive functioning from both subject and an informant. Composite CAI scores were reported. Scale ranges from 1-7 with the following anchors: 1. Normal, no cognitive impairment 2. Borderline impairment 3. Mildly impaired 4. Moderately impaired 5. Markedly impaired 6. Severely impaired 7. Among the most extremely impaired

Trial Locations

Locations (16): Medical College of Georgia
🇺🇸
Augusta, Georgia, United States
University of Texas Southwestern Medical Center at Dallas
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Dallas, Texas, United States
Columbia University
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New York, New York, United States
Yale University
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New Haven, Connecticut, United States
University of Miami Department of Psychiatry
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Miami, Florida, United States
San Fernando Mental Health Center
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Granada Hills, California, United States
Psychopharmacology Research Unit- Nathan KIine Institute for Psychiatric Research
🇺🇸
New York, New York, United States
Rush University Psychiatric Clinical Research Center
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Chicago, Illinois, United States
Northwestern University
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Chicago, Illinois, United States
Indiana University
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Indianapolis, Indiana, United States
Duke University Medical Center
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Butner, North Carolina, United States
University of California - Irvine
🇺🇸
Orange, California, United States
University of Missouri
🇺🇸
Columbia, Missouri, United States
University of Texas Health Science Center, San Antonio
🇺🇸
San Antonio, Texas, United States
Beth Israel Deaconess Medical Center
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Boston, Massachusetts, United States
University of Minnesota
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Minneapolis, Minnesota, United States