Modelling Negative Symptom Domains Neurobiology: Protocol for an Observational Transdiagnostic, Translational Study (Preprint)

BACKGROUND Negative symptoms (NS) such as anhedonia, avolition, asociality, blunted affect and alogia are associated with poor functional outcomes in psychiatric and neurological disorders and are an unmet treatment need. OBJECTIVE This protocol describes the design of an observational, single-center study aimed at characterizing negative symptoms across a transdiagnostic sample of individuals with mental disorders and related conditions, with a particular focus on avolition, its biological correlates, and associated neurocognitive and electrophysiological profiles. METHODS An observational study (involving no invasive procedures or drug administration other than a routine blood draw) has been designed to examine negative symptoms across psychiatric disorders. A total of 300 participants with a primary diagnosis of schizophrenia, bipolar disorder, unipolar depressive disorder, autism, or dementia will be recruited, with a target of at least 50 individuals in each diagnostic group. Consenting inpatients and outpatients will complete a battery of non-invasive behavioral and cognitive assessments, undergo electroencephalogram (EEG) recording, and provide blood samples for the assessment of polygenic risk scores. RESULTS The initial version of the study protocol was developed in February 2024. The finalized protocol was completed on August 5, 2024, and subsequently updated on January 11, 2025, to incorporate minor methodological clarifications. Participant recruitment and data collection commenced on July 1, 2024, and are ongoing at the time of manuscript submission. Data quality control and preliminary analyses are performed concurrently with data collection, while final statistical analyses and dissemination of results are planned following completion of the recruitment phase. CONCLUSIONS This study will provide critical insights into the characterization and underlying mechanisms of negative symptoms across psychiatric disorders. By focusing on avolition, reward processing, and their interaction with neurocognitive and social cognitive deficits, it will help identify potential biological and electrophysiological markers of negative symptoms. The findings may guide the development of more precise assessment tools and inform novel therapeutic strategies, with broad translational impact for improving outcomes in individuals with serious mental illness and related conditions.