Domain-Based Approaches to Pathology in the Development of Novel Psychiatric Therapies: Enhancing Tractability in Discovery and Trial Methodology

Chairs: Richard Keefe, PhD; George Garibaldi, MD

Clinical Trials in CNS have traditionally included patients based upon criteria from the Diagnostic and Statistical Manual (DSM) and International Classification of Diseases (ICD).  These diagnostic entities include heterogeneous populations that, most likely, do not share a common biology.  Findings from various scientific disciplines – including genetics, neurobiology, neural circuitry, neuroanatomy, neuroscience, and neuropsychology have repeatedly demonstrated that the underlying pathology of major psychiatric disorders does not abide by the discrete entities of our classification systems. Instead, pathological neurobiology and behavior are more parsimoniously explained by symptom clusters that traverse diagnostic entities.  These findings and these approaches raise the question of the relative value of symptom domains as treatment targets as opposed to traditional DSM and ICD diagnoses in CNS clinical trials.  In order to develop treatments that will more likely address the underlying neurobiology of psychiatric disorders, a more sensitive and efficient approach will be to design methods and outcomes that align with the structure of CNS pathology as it exists in the population.

This session will address a series of questions that arise in the consideration of the use of domain-based approaches to pathology in the development of novel psychiatry therapies. 

Q1: What are the domain-based approaches? Why do we believe this approach would enhance tractability in therapy development? What are the short and long-term implications on neuroscience R&D

Q2: What is the biological plausibility of the different symptom domains? What are the possible neural substrates underlying these symptom domains? Are these substrates consistent across disease states and diagnoses? Do these substrates translate from animals to healthy individuals to patients?

Q3: What is the dimensional expression of the different symptom domains across clinical diagnoses? Are these domains measurable? What are the different psychometric properties needed to evaluate the severity of symptom domains in patients with different psychiatric or neurologic conditions?

Q4: What are the pathways for drug development using the symptom-based approach? What are the regulatory approaches? Will payers adopt their value models to integrate the symptom-based approach?

Conclusions: Paving the road from a concept to implementation.

Four speakers will address these questions from various perspectives, including leaders from industry and academia who are implementing trials with a domain-based focus.  Cognition and motivation will be used as models due to advances in understanding the biology, psychometrics, and functional relevance of impairment across different diagnostic entities, and the potential applicability of animal models.  Following the four presentations, representatives from US and European regulatory agencies and representatives from public and private payer institutions will be asked to comment on the potential implications of domain-based approaches on policy. The goal will be to understand the value of these approaches for patients and how to integrate them in regulatory guidelines.