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~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.~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.~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.~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.~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.
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).