The impact of genetics on future drug discovery in schizophrenia

ABSTRACT

Introduction: Failures of investigational new drugs (INDs) for schizophrenia have left huge unmet medical needs for patients. Given the recent lackluster results, it is imperative that new drug discovery approaches (and resultant drug candidates) target pathophysiological alterations that are shared in specific, stratified patient populations that are selected based on pre-identified biological signatures. One path to implementing this paradigm is achievable by leveraging recent advances in genetic information and technologies. Genome-wide exome sequencing and meta-analysis of single nucleotide polymorphism (SNP)-based association studies have already revealed rare deleterious variants and SNPs in patient populations.

Areas covered: Herein, the authors review the impact that genetics have on the future of schizophrenia drug discovery. The high polygenicity of schizophrenia strongly indicates that this disease is biologically heterogeneous so the identification of unique subgroups (by patient stratification) is becoming increasingly necessary for future investigational new drugs.

Expert opinion: The authors propose a pathophysiology-based stratification of genetically-defined subgroups that share deficits in particular biological pathways. Existing tools, including lower-cost genomic sequencing and advanced gene-editing technology render this strategy ever more feasible. Genetically complex psychiatric disorders such as schizophrenia may also benefit from synergistic research with simpler monogenic disorders that share perturbations in similar biological pathways.

KEYWORDS:

• Genetics
• schizophrenia
• pathophysiology
• patient stratification
• precision medicine
• biomarker

Article highlights

• Improper trial design may mask or reduce the effect of otherwise-efficacious investigational new drugs.

• Patient stratification is likely essential, given the complex, biologically heterogeneous nature of schizophrenia.

• It is imperative to take advantage of advances in lower-cost genomic sequencing, transgenic model creation and new gene-editing strategies to establish better understanding of pathophysiological underpinnings of the disease.

• To accelerate discovery and link gene function to pathophysiology, it may be possible to apply insights from monogenic disorders to more complex psychiatric disorders.

• The confluence of technological advances in patient-specific medicine, genomics and biomarker detection will likely be essential in the formation of next-gen drugs for psychiatric disorders.

This box summarizes key points contained in the article.

Declaration of interest

M Matsumoto and Y Kondo are employees of Astellas Pharma Inc while G Marek is an employee of Astellas Pharma Global Development. N Walton, H Yamada and K Tajinda are all employees of Astellas Research Institute of America LLC. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The authors are supported and funded by Astellas Pharma Inc.