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

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.

The effects of ketamine and risperidone on eye movement control in healthy volunteers.

The non-competitive N-methyl-D-aspartate receptor antagonist ketamine leads to transient psychosis-like symptoms and impairments in oculomotor performance in healthy volunteers. This study examined whether the adverse effects of ketamine on oculomotor performance can be reversed by the atypical antipsychotic risperidone. In this randomized double-blind, placebo-controlled study, 72 healthy participants performed smooth pursuit eye movements (SPEM), prosaccades (PS) and antisaccades (AS) while being randomly assigned to one of four drug groups (intravenous 100 ng ml(-1) ketamine, 2 mg oral risperidone, 100 ng ml(-1) ketamine plus 2 mg oral risperidone, placebo). Drug administration did not lead to harmful adverse events. Ketamine increased saccadic frequency and decreased velocity gain of SPEM (all P < 0.01) but had no significant effects on PS or AS (all P > or = 0.07). An effect of risperidone was observed for amplitude gain and peak velocity of PS and AS, indicating hypometric gain and slower velocities compared with placebo (both P < or = 0.04). No ketamine by risperidone interactions were found (all P > or = 0.26). The results confirm that the administration of ketamine produces oculomotor performance deficits similar in part to those seen in schizophrenia. The atypical antipsychotic risperidone did not reverse ketamine-induced deteriorations. These findings do not support the cognitive enhancing potential of risperidone on oculomotor biomarkers in this model system of schizophrenia and point towards the importance of developing alternative performance-enhancing compounds to optimise pharmacological treatment of schizophrenia.

Advancing the defensive explanation for anxiety disorders: lorazepam effects on human defense are systematically modulated by personality and threat-type.

Clinically effective drugs against human anxiety and fear systematically alter the innate defensive behavior of rodents, suggesting that in humans these emotions reflect defensive adaptations. Compelling experimental human evidence for this theory is yet to be obtained. We report the clearest test to date by investigating the effects of 1 and 2 mg of the anti-anxiety drug lorazepam on the intensity of threat-avoidance behavior in 40 healthy adult volunteers (20 females). We found lorazepam modulated the intensity of participants' threat-avoidance behavior in a dose-dependent manner. However, the pattern of effects depended upon two factors: type of threat-avoidance behavior and theoretically relevant measures of personality. In the case of flight behavior (one-way active avoidance), lorazepam increased intensity in low scorers on the Fear Survey Schedule tissue-damage fear but reduced it in high scorers. Conversely, in the case of risk-assessment behavior (two-way active avoidance), lorazepam reduced intensity in low scorers on the Spielberger trait anxiety but increased it in high scorers. Anti-anxiety drugs do not systematically affect rodent flight behavior; therefore, we interpret this new finding as suggesting that lorazepam has a broader effect on defense in humans than in rodents, perhaps by modulating general perceptions of threat intensity. The different patterning of lorazepam effects on the two behaviors implies that human perceptions of threat intensity are nevertheless distributed across two different neural streams, which influence effects observed on one-way or two-way active avoidance demanded by the situation.

The perception of real and illusory motion in schizophrenia.

An illusion of rapid movement is normally perceived when an attentional cue (such as a peripheral flash) preceeds the onset of a line. The movement is perceived as receding away from the cue. This study investigated how this illusion was perceived by people with schizophrenia. Nineteen participants with schizophrenia and 26 healthy matched controls were presented with a series of real, illusory, no motion or combined real and illusory motion stimuli at various target speeds. Detection thresholds were measured to determine the reliability of motion perception. The participants with schizophrenia were not distinguished from the control group in the perception of real motion. However, the motion detection curves for the schizophrenia group revealed a reduction in the perceptual effect of illusory motion in comparison to controls. The findings revealed that people with schizophrenia may be less easily deceived by illusory motion in comparison to healthy participants.

Association of Neuregulin 1 rs3924999 genotype with antisaccades and smooth pursuit eye movements.

Neuregulin 1 (NRG1) has been identified as one of the leading candidate genes for schizophrenia. However, its functional mechanisms and its effects on neurocognition remain unclear. In this study, we used two well-established oculomotor endophenotypes, the antisaccade (AS) and smooth pursuit eye movement (SPEM) tasks, to investigate the functional mechanisms of a single nucleotide polymorphism (SNP) in NRG1 (rs3924999) at the neurocognitive level in a healthy volunteer sample. A total of 114 healthy Caucasian volunteers completed genotyping for NRG1 rs3924999 and infrared oculographic assessment of AS and SPEM (at target velocities of 12 degrees , 24 degrees and 36 degrees per second). Additionally, self-report questionnaires of schizotypy, neuroticism, attention deficit hyperactivity and obsessive-compulsive traits were included. A significant effect of rs3924999 genotype, with gender as a covariate, was found for AS amplitude gain (P < 0.01), with an increasing number of A alleles being associated with increasingly hypermetric performance. No statistically significant associations were found for other AS and SPEM variables or questionnaire scores. These findings indicate that NRG1 rs3924999 affects spatial accuracy on the AS task, suggesting an influence of the gene on the neural mechanisms underlying visuospatial sensorimotor transformations, a mechanism that has been previously found to be impaired in patients with schizophrenia and their relatives.