Genetic Vulnerability to Neurodevelopmental Disorders Influences Antipsychotic Response in Schizophrenia

Overview

This study explored how genetic risks for ADHD and ASD affect antipsychotic treatment efficacy in schizophrenia (SCZ). Using postmortem brain samples, the authors found suggestive correlations between polygenic risk scores for these neurodevelopmental disorders and responsiveness to antipsychotics, alongside gene expression differences in the prefrontal cortex.

Background

Schizophrenia is a highly heritable psychiatric disorder with overlapping genetic architecture with neurodevelopmental disorders such as ADHD and ASD. Despite multiple antipsychotic treatments, about 30% of patients exhibit treatment-resistant schizophrenia. ADHD and ASD traits are often observed in SCZ, and genetic risks for these disorders may influence symptomatology and treatment response. Understanding these relationships could elucidate mechanisms underlying antipsychotic responsiveness.

Data Highlights

Postmortem brain samples from 24 SCZ patients and 48 controls were analyzed. Polygenic risk scores (PRSs) for ADHD and ASD were calculated. In 19 SCZ patients with clinical data, antipsychotic responsiveness scores (ARS) were correlated with PRSs. Gene expression analysis identified 1,773 differentially expressed genes (DEGs) between high and low ADHD-PRS groups, enriched in neuronal and mitochondrial pathways.

Key Findings

• ARS for positive symptoms showed a suggestive negative correlation with ADHD-PRS and a positive correlation with ASD-PRS, though not statistically significant after correction.
• No correlations were found between ARS for general psychopathology or negative symptoms and either ADHD-PRS or ASD-PRS.
• Gene expression analysis revealed 1,773 DEGs between high and low ADHD-PRS SCZ subgroups, including neuropsychiatric disorder-related genes such as CHRNB2.
• DEGs were enriched in pathways related to neuronal systems and mitochondrial function, implicating these in antipsychotic responsiveness.
• The study highlights potential molecular markers linked to neurodevelopmental genetic risk influencing treatment response in SCZ.

Clinical Implications

Genetic vulnerability to neurodevelopmental disorders like ADHD and ASD may modulate antipsychotic treatment efficacy in schizophrenia, particularly affecting positive symptom responsiveness. Assessing polygenic risk profiles could eventually aid in stratifying patients for personalized therapeutic approaches. Further large-scale studies are needed to validate these preliminary findings and translate them into clinical practice.

Conclusion

This exploratory study suggests that genetic risks for neurodevelopmental disorders influence antipsychotic responsiveness in schizophrenia and are associated with distinct gene expression profiles in the brain. These insights provide a foundation for future research into personalized treatment strategies.

References

1. Kuramitsu et al. 2024 -- Exploring the Influence of Genetic Vulnerability to Neurodevelopmental Disorders on Antipsychotic Efficacy in Schizophrenia