Regressing to Prior Response Preference after Set Switching Implicates Striatal Dysfunction Across Psychotic Disorders: Findings from the B-SNIP Study

Difficulty switching behavioral response sets is established in psychotic disorders. In rodent models, prefrontal lesions cause difficulty initially switching to new response sets (perseverative errors) while striatal lesions cause difficulty suppressing responses to previous choice preferences (regressive errors). Studies of psychotic disorders have not previously assessed these 2 error types. Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) participants included probands with schizophrenia (N = 212), psychotic bipolar (N = 192), and schizoaffective disorder (N = 131), their first-degree relatives (N = 267,226,165 respectively), and healthy controls (N = 258). Participants completed the Penn Conditional Exclusion Test (PCET) to assess cognitive set switching and the Brief Assessment of Cognition in Schizophrenia (BACS) to assess generalized neuropsychological dysfunction. All proband groups displayed elevated rates of perseverative and regressive errors compared to controls. After correcting for generalized cognitive deficits to identify specific deficits in set shifting and maintenance, there were no significant group differences for perseverative errors, while the increased rate of regressive errors remained significant. Level of regressive errors was similar across proband groups with minimal correlations with antipsychotic medication dose, clinical ratings, and demographic characteristics. Relatives of schizophrenia patients showed increased rates of regressive errors, but familiality of this trait was significant only in bipolar pedigrees. Regressive errors were partially independent of generalized cognitive deficits, suggesting a potentially informative and specific cognitive deficit across psychotic disorders. Preclinical data indicate that this deficit could be related to altered function in a neural system that may include the dorsal striatum or other elements of frontostriatal systems.