Neurodevelopmental liability to schizophrenia: the complex mediating role of age at onset and premorbid adjustment.

Large individual variation in the clinical presentation of schizophrenia-spectrum disorders raises key questions regarding their aetiological underpinnings. In this respect, age at onset of the disorder is a particularly interesting marker of liability, as it has been reported to be associated with other signs of developmental compromise, such as male gender, increased presence of familial history of psychosis and poor premorbid adjustment, as well as a more severe clinical outcome in terms of cognition and symptomatology. The association between these variables has encouraged a neurodevelopmental perspective of the aetiological mechanisms involved in the pathophysiology of schizophrenia. However, the complex relationships within neurobiological liability markers, and between these markers and clinical outcome, remain to be understood. In the present study, we used a path-analytic approach to explore: i) the fit of the model to observed data; and both ii) direct and iii) indirect associations between the variables. In a sample of 106 patients with schizophrenia-spectrum disorders, we found a good fit of the model to the observed data, providing further evidence that supports a neurodevelopmental pathway to the disease in a subgroup of patients. However, the most parsimonious model showed complex relationships, where age at onset and premorbid functioning acted as mediators between gender, familial history of psychosis and clinical outcome. These findings refine earlier explanations of the neurobiological basis of schizophrenia, with potential applications in genetic studies based on more homogeneous forms of the disease. We further discuss the putative implications of our results in clinical practice and prevention policies.