Abstract
Substance use disorders (SUDs) are common among individuals with schizophrenia and negatively affect the clinical course of the illness. Despite the high prevalence and significant impact on outcomes, the etiology of SUDs in individuals with schizophrenia remains poorly understood. A better understanding of the etiology, shared mechanisms, temporal evolution, and complex interplay between pathophysiologies will provide the foundation for rational development of targeted therapeutics. We review the literature on the prevalence, etiology, biomarkers, and treatment for individuals with comorbid SUDs and schizophrenia. Substance use is associated with increased risk of subsequent development of schizophrenia. However, the directionality of the relationship between substance use and schizophrenia remains unclear. While several SUDs are associated with increased psychotic symptoms, others are correlated with less severe psychopathology. Individuals with schizophrenia who have more severe symptoms are more likely to have a SUD. There is evidence for shared genetic risk for SUDs and schizophrenia. Comorbid SUDs and schizophrenia share abnormalities in the mesolimbic dopamine system, affecting drug reward, sensitization, and craving. Neuroimaging studies have identified molecular, structural, and functional pathophysiology in co-occurring schizophrenia and SUDs. Neuroinflammation may also represent a shared pathophysiology between SUDs and schizophrenia. While treatments for SUDs exist, they are generally less effective and underutilized for individuals with schizophrenia. Future research is essential to understand the underlying etiology of SUDs in schizophrenia. We propose that neuromodulatory experiments can establish this etiology and identify therapeutic targets. Longitudinal studies across multiple modalities (i.e. neuroimaging, serum, genetics) may help to identify risk factors and biomarkers.