Severity of Autism-Related Symptoms in Treatment-Resistant Schizophrenia: Associations with Cognitive Performance, Psychosocial Functioning, and Neurological Soft Signs — Clinical Evidence and ROC Analysis

Treatment-resistant schizophrenia (TRS) occurs when symptoms persist despite adequate antipsychotic treatment in terms of both timing and dosage. This severe condition is often overlooked, despite the existence of guidelines, with an average delay of 4-9 years before the introduction of clozapine, the gold standard treatment. We hypothesized that schizophrenia patients with severe autistic symptoms are more prone to develop TRS. To test this, we administered the Positive and Negative Syndrome Scale for Schizophrenia Autism Severity Scale (PAUSS) to 117 patients diagnosed with schizophrenia. Our results revealed that both TRS and clozapine nonresponder (CLZ-nR) groups had higher rates of autistic symptoms than non-TRS patients. A machine learning model was developed to examine the relationship between PAUSS scores and TRS, obtaining an accuracy of 0.65 and an AUC of 0.67. Specifically, PAUSS items N6 (“lack of spontaneity and flow of conversation”) and N7 (“stereotypical thinking”) emerged as the most significant factors in the model. In addition, PAUSS was correlated with cognitive and social functions, as well as soft neurological signs, in TRS patients. Autism-related symptoms were found to predict significant variance in motor coordination, verbal fluency, functional ability and soft neurological signs. These results suggest that autism-related symptoms in schizophrenia may define a distinct subgroup with unique neurobiological characteristics.