BACKGROUND: Soft neurological signs (SNS) are subtle, nonspecific neurological abnormalities that are present in first episode psychosis (FEP) patients. SNS are associated with clinical variables such as poor long term psychosocial functioning, executive functioning, and positive and negative symptomology. However, few studies have evaluated treatment responsiveness with respect to SNS. OBJECTIVE: To investigate whether SNS show: 1.) baseline and longitudinal differences between both diagnostic groups (schizophrenia (FEP-SZ), non-schizophrenia FEP-NSZ, and healthy controls (HC)) and treatment outcome (week 26 and year 1); 2.) relationships to clinical measures; 3.) predictive characteristics of treatment response. METHODS: SNS scores (Neurological Evaluation Scale) were obtained for 312 FEP (236 FEP-SZ and 76 FEP-NSZ subjects and 169 HC subjects and for subjects classified as treatment responsive and non-responsive at week 26 (N=105, N=105) and year 1 (N=101, N=97), respectively. Diagnostic group and treatment responsiveness group comparisons were assessed with ANCOVA and logistic regression models and both were co-varied for age, sex, race, and handedness. Baseline and longitudinal SNS relationships to clinical variables were determined using Spearman correlations and repeated measures correlations, and both were corrected by False Discovery Rate. Linear mixed effects model was utilized to analyze the data longitudinally. RESULTS: Baseline cognitive perceptual SNS measures had the greatest effect size differences, were predictive of group membership, and differentiated the two proband groups with FEP-SZ having worse SNS scores. Baseline cognitive perceptual SNS did not significantly predict treatment response at week 26 or year 1, but changes in cognitive perceptual at week 26 was predictive of treatment responsiveness at week 26 and year 1. Longitudinally, SNS scores drop in both FEP groups and treatment groups. The FEP-SZ group showed greater longitudinal within subject correlations than FEP-NSZ. SNS scores were only differentiated between year 1 outcome groups at week 8. There were greater longitudinal within subject correlations for the responsive group. CONCLUSION: Our findings indicate that there are baseline group differences and that changes in cognitive perceptual SNS scores at week 26 are predictive of treatment responsiveness at week 26 and year 1. / 2019-07-03T00:00:00Z