Beneficial and adverse effects of antipsychotic medication on cognitive flexibility are related to COMT genotype in first episode psychosis.

This study evaluated the ability to flexibly shift cognitive set and to consistently maintain a new response preference using the Penn Conditional Exclusion Test (PCET). The relationship of performance errors with catechol-O-methyltransferase (COMT) rs4680 (Val158Met) genotype (Met carriers vs. Val homozygotes) on test performance before and after antipsychotic treatment in 32 first episode psychosis (FEP) patients was examined. After treatment, patients demonstrated a mixture of beneficial and adverse cognitive outcomes that varied in relation to COMT genotype. Met carriers showed decreased perseverative and regressive errors, reflecting improved cognitive flexibility and enhanced stability of behavioral preferences, respectively. In contrast, Val homozygotes exhibited an increase in regressive errors after treatment. These findings suggest that Val homozygotes may be vulnerable to adverse effects of antipsychotic medication on cognitive processes that maintain consistent adaptive response preferences, an ability linked to the striatum in rodent models.

Working memory impairment in probands with schizoaffective disorder and first degree relatives of schizophrenia probands extend beyond deficits predicted by generalized neuropsychological impairment.

OBJECTIVE: Working memory impairment is well established in psychotic disorders. However, the relative magnitude, diagnostic specificity, familiality pattern, and degree of independence from generalized cognitive deficits across psychotic disorders remain unclear. METHOD: Participants from the Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study included probands with schizophrenia (N=289), psychotic bipolar disorder (N=227), schizoaffective disorder (N=165), their first-degree relatives (N=315, N=259, N=193, respectively), and healthy controls (N=289). All were administered the WMS-III Spatial Span working memory test and the Brief Assessment of Cognition in Schizophrenia (BACS) battery. RESULTS: All proband groups displayed significant deficits for both forward and backward span compared to controls. However, after covarying for generalized cognitive impairments (BACS composite), all proband groups showed a 74% or greater effect size reduction with only schizoaffective probands showing residual backward span deficits compared to controls. Significant familiality was seen in schizophrenia and bipolar pedigrees. In relatives, both forward and backward span deficits were again attenuated after covarying BACS scores and residual backward span deficits were seen in relatives of schizophrenia patients. CONCLUSIONS: Overall, both probands and relatives showed a similar pattern of robust working memory deficits that were largely attenuated when controlling for generalized cognitive deficits.