Cognitive and oculomotor performance in subjects with low and high schizotypy: implications for translational drug development studies.

I Koychev,E Barkus,C T Dourish,J F W Deakin,A Schmechtig,U Ettinger,G R Dawson,D Joyce,K J Craig

doi:10.1038/tp.2016.64

Abstract

The development of drugs to improve cognition in patients with schizophrenia is a major unmet clinical need. A number of promising compounds failed in recent clinical trials, a pattern linked to poor translation between preclinical and clinical stages of drug development. Seeking proof of efficacy in early Phase 1 studies in surrogate patient populations (for example, high schizotypy individuals where subtle cognitive impairment is present) has been suggested as a strategy to reduce attrition in the later stages of drug development. However, there is little agreement regarding the pattern of distribution of schizotypal features in the general population, creating uncertainty regarding the optimal control group that should be included in prospective trials. We aimed to address this question by comparing the performance of groups derived from the general population with low, average and high schizotypy scores over a range of cognitive and oculomotor tasks. We found that tasks dependent on frontal inhibitory mechanisms (N-Back working memory and anti-saccade oculomotor tasks), as well as a smooth-pursuit oculomotor task were sensitive to differences in the schizotypy phenotype. In these tasks the cognitive performance of ‘low schizotypes' was significantly different from ‘high schizotypes' with ‘average schizotypes' having an intermediate performance. These results indicate that for evaluating putative cognition enhancers for treating schizophrenia in early-drug development studies the maximum schizotypy effect would be achieved using a design that compares low and high schizotypes.

Highlights

Cognitive impairment is a core symptom of schizophrenia that predicts functional outcome[1,2,3] and treatment adherence.[4]it is largely unaffected by currently available medication[5] and the development of drugs to treat cognitive deficits in schizophrenia is a recognised unmet need.[6] a number of putative cognitive enhancers have been examined in trials none have been approved for treatment.[7]
To avoid difficulties with matrix calculations and data imputation involved in canonical correlation analysis (CCA), we only included participants with complete data sets on all demographic and biomarker variables, leading to the inclusion of n = 83 participants to derive the relevance network
In the smooth-pursuit eye-movement (SPEM) models, the low schizotypes (LS) group performed significantly better than the average schizotypes (AS) group and the LS vs HS comparisons were significant at trend level

Summary

Introduction

Cognitive impairment is a core symptom of schizophrenia that predicts functional outcome[1,2,3] and treatment adherence.[4]it is largely unaffected by currently available medication[5] and the development of drugs to treat cognitive deficits in schizophrenia is a recognised unmet need.[6] a number of putative cognitive enhancers have been examined in trials none have been approved for treatment.[7]. Cognitive impairment is a core symptom of schizophrenia that predicts functional outcome[1,2,3] and treatment adherence.[4]. It is largely unaffected by currently available medication[5] and the development of drugs to treat cognitive deficits in schizophrenia is a recognised unmet need.[6]. This approach can be complemented by selecting either patients who are more likely to respond (mild symptomatology or medication-free) or subclinical healthy volunteers that lack the confounds of patient groups (for example, heterogeneous symptom and medication profiles)

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