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Background Neuropsychological investigations can help untangle the aetiological and phenomenological heterogeneity of schizophrenia but have scarcely been employed in the context of treatment-resistant (TR) schizophrenia. No population-based study has examined neuropsychological function in the first-episode of TR psychosis.Methods We report baseline neuropsychological findings from a longitudinal, population-based study of first-episode psychosis, which followed up cases from index admission to 10 years. At the 10-year follow up patients were classified as treatment responsive or TR after reconstructing their entire case histories. Of 145 cases with neuropsychological data at baseline, 113 were classified as treatment responsive, and 32 as TR at the 10-year follow-up.Results Compared with 257 community controls, both case groups showed baseline deficits in three composite neuropsychological scores, derived from principal component analysis: verbal intelligence and fluency, visuospatial ability and executive function, and verbal memory and learning (p valuesâ 0.001). Compared with treatment responders, TR cases showed deficits in verbal intelligence and fluency, both in the extended psychosis sample (t =-2.32; p = 0.022) and in the schizophrenia diagnostic subgroup (t =-2.49; p = 0.017). Similar relative deficits in the TR cases emerged in sub-/sensitivity analyses excluding patients with delayed-onset treatment resistance (p values<0.01-0.001) and those born outside the UK (p values<0.05).Conclusions Verbal intelligence and fluency are impaired in patients with TR psychosis compared with those who respond to treatment. This differential is already detectable-At a group level-At the first illness episode, supporting the conceptualisation of TR psychosis as a severe, pathogenically distinct variant, embedded in aberrant neurodevelopmental processes.

Aim: A preponderance of females develop autoimmune disease, including juvenile idiopathic arthritis (JIA), yet the reason for this female bias remains elusive. Evidence suggests that genetic risk of disease may be influenced by sex. The JIA genetic risk variant, PTPN22 rs2476601, has been reported to show female-specific association in type 1 diabetes. We sought to determine whether rs2476601 exhibits a female-specific association in JIA. Method(s): The discovery sample was drawn from the Australian CLARITY JIA biobank. Rs2476601 was genotyped in 413 cases (67% female, mean age at recruitment 9.1 years) and 690 healthy controls (42% female, mean age at recruitment 7.1 years). We used logistic regression to assess the association of rs2476601 with JIA in the total sample (males and females). We then explored the role of sex in this association: we adjusted the regression analysis for sex, stratified by sex, and performed a genotype-bysex interaction analysis. We sought to replicate the sex-specific associations in an independent JIA case-control sample collected from the USA and Norway and held at the Children's Hospital of Philadelphia (1008 JIA cases and 9287 controls). Analyses were performed using Stata or PLINK. Result(s): PTPN22 rs2476601 was associated with JIA in both datasets (Discovery OR = 1.71,95% CI 1.26-2.33,p = 0.00066; Replication OR = 1.30, 95% CI 1.09-1.55, p = 0.0068). The association remained when adjusted for sex (Discovery OR = 1.63, 95% CI 1.18-2.24, p = 0.0028; Replication OR = 1.30, 95% CI 1.08-1.56, p = 0.0051). Discovery sample sex stratified analyses demonstrated association in females (OR = 2.35, 95% CI 1.52-3.63, p = 0.00011) but not males (OR = 0.91, 95% CI 0.52-1.60, p = 0.75).This was also observed in the replication sample (Female OR = 1.38, 95% CI 1.09-1.73, p = 0.0068; MaleOR = 1.19,95% CI 0.88-1.63, p = 0.26). There was evidence for genotype-by-sex interaction (p interaction = 0.0087). Conclusion(s): We have demonstrated that the