Elevated antisaccade error rate as an intermediate phenotype for psychosis across diagnostic categories

Abstract

Background: Elevated antisaccade error rate, reflecting problems with inhibitory behavioral control, is a promising intermediate phenotype for schizophrenia. Here, we consider whether it marks liability across psychotic disorders via common or different neurophysiological mechanisms and whether it represents a neurocognitive risk indicator apart from the generalized cognitive deficit.

Methods: Schizophrenia (n = 267), schizoaffective (n = 150), and psychotic bipolar (n = 202) probands, their first-degree relatives (ns = 304, 193, 242, respectively), and healthy controls (n = 244), participating in the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium, performed antisaccade and prosaccade tasks and completed a neuropsychological battery.

Results: Antisaccade error rate was elevated in proband groups with greatest deficit observed in schizophrenia and was unrelated to symptoms and antipsychotic treatment. Increased error rate was also observed among relatives, even those without history of psychosis or psychosis spectrum personality traits. Relatives' deficits were similar across proband diagnoses. Error rate was familial and remained elevated in proband and relative groups after accounting for generalized cognitive impairment. Speed of attentional shifting, indexed by prosaccade latency, was similarly influenced in all groups by manipulations that freed vs increasingly engaged attention systems and was inversely associated with antisaccade error rate in all but schizophrenia probands.

Conclusions: These findings indicate that elevated antisaccade error rate represents an intermediate phenotype for psychosis across diagnostic categories, and that it tracks risk beyond that attributable to the generalized cognitive deficit. The greater severity of antisaccade impairment in schizophrenia and its independence from attention shifting processes suggest more severe and specific prefrontal inhibitory control deficits in this disorder.

Keywords: bipolar disorder; endophenotype; family study; schizoaffective disorder; schizophrenia.

Fig. 1.

Mean (SE) antisaccade error rate for control, proband, and relative groups. Values reflect estimated marginal means from a mixed effect model after accounting for variance associated with target displacement, site, and race. Significance levels reflect post hoc comparisons after correction. Scz, schizophrenia; SczA, schizoaffective; BP, psychotic bipolar.

Fig. 2.

(a) Mean (SE) antisaccade error rate for controls and relatives with a history of psychosis, elevated psychosis spectrum personality traits, or neither of these characteristics (ie, unaffected). Values reflect estimated marginal means from mixed effects model after accounting for variance associated with target displacement, site, and race. (b) Percentage of relatives without a lifetime history of psychosis or elevated psychosis spectrum personality traits with antisaccade error rate 1–2 SD above control performance level.

Fig. 3.

Effect size deficit of antisaccade error rate in proband and relative groups compared to controls before (light bars) and after (dark bars) adjustment for generalized impairment as indexed by the BACS composite scores. Scz, schizophrenia; SczA, schizoaffective; BP, psychotic bipolar; BACS, Brief Assessment of Cognition in Schizophrenia.