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

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.

Combining two model systems of psychosis: The effects of schizotypy and sleep deprivation on oculomotor control and psychotomimetic states

“…SPEM impairments in schizophrenia are well replicated (Levy, Sereno, Gooding, & O'Driscoll, ; O'Driscoll & Callahan, ). Similar deficits have been reported in overall high schizotypes (Koychev et al, ; Meyhöfer et al, ), in high positive, negative, and disorganized subgroups (Gooding, Miller, & Kwapil, ; Holahan & O'Driscoll, ; Lenzenweger & O'Driscoll, ; O'Driscoll, Lenzenweger, & Holzman, ; Smyrnis et al, ), and following sleep deprivation (Meyhöfer, Kumari, Hill, Petrovsky, & Ettinger, ).…”

“…Unexpectedly (Ettinger et al, ; Koychev et al, ), there were no schizotypy related differences in antisaccade performance. Possible reasons include less strict schizotypy inclusion criteria (Gooding, ; Holahan & O'Driscoll, ) and generally lower error rates in this study compared to prior research (Koychev et al, ).…”

“…However, due to known relationships between saccade amplitude and other measures—for example, peak velocity (Bahill, Clark, & Stark, )—further studies should analyze eccentricities separately. A third limitation refers to different methodological approaches in schizotypy research such as extreme groups using mean deviation criteria (Gooding et al, ) or absolute questionnaire scores (Koychev et al, ), median splits (Klein, Brügner, Foerster, Müller, & Schweickhardt, ), and correlative designs (Ettinger et al, ). Our inclusion criterion for high schizotypes was stricter than some (van Kampen & Deijen, ) but less strict than other studies (Holahan & O'Driscoll, ) and thus may even underestimate existing effects.…”

“…Model systems are of most use when combined with well-validated biomarkers such as oculomotor measures. Oculomotor tasks are short, parameters can be manipulated systematically (Barnes, 2008;Hutton, 2008), measurement is highly reliable (Meyh€ ofer, Bertsch, Esser, & Ettinger, 2016), their neural mechanisms are well understood (Hutton & Ettinger, 2006;Lencer & Trillenberg, 2008), performance is impacted by antipsychotic drugs (Reilly, Lencer, Bishop, Keedy, & Sweeney, 2008), and deficits in the schizophrenia spectrum have been widely replicated (Calkins, Iacono, & Ones, 2008;Koychev et al, 2016).…”

Association of schizotypy with striatocortical functional connectivity and its asymmetry in healthy adults

“…Support for the importance and validity of studying correlates of schizotypy across the entire spectrum, including low scores, comes from the detection of the neural correlates of schizotypy in previous studies of low‐to‐medium scoring participants [Aichert et al, ]. Additionally, a recent study explicitly compared medium and low schizotypes to high schizotypes and demonstrated that low schizotypes can be differentiated from medium schizotypes, who in turn perform worse than high schizotypes, on smooth pursuit eye movements [Koychev et al, ], a key endophenotype and biomarker of schizophrenia [Calkins et al, ; Levy et al, ]. Thus, we feel that the observed relationships between rsFC and schizotypy scores in the low‐to‐moderate range may be indicative of associations that may emerge across the entire spectrum of schizotypy.…”