Mood disorders

RDoc – entering the matrix

RDoC (Research Domain Criteria) is a new research framework for studying mental disorders. It integrates many levels of information (from genomics to self-report) to better understand the basic dimensions of functioning underlying the full range of human behaviour from normal to abnormal. Dr Bruce Cuthbert, the Acting Director of the National Institute of Mental Health (NIMH) and Head of the NIMH’s RDoC Unit, gave a fuller description of just how RDoC works and how it might influence 21st century psychiatric drug discovery.

RDoC was devised because current practices in clinical diagnosis (DSM, ICD) are no longer optimal for contemporary research. For example, diagnosis currently is based on signs and symptoms, behavioural data do not align well with DSM or ICD categories, disorders are heterogeneous syndromes, almost all of which are dimensional in severity.

 

Research is categorical

The main problem researchers have in adopting the RDoc approach is that diagnostic categories drive the entire research system. However, things need to change. For example, in a plea to drop the term ‘schizophrenia’ it was pointed out that only 30% of those with psychotic illness have schizophrenia. Thus, not only are 70% of those with other psychotic illnesses being ignored, but the implication is that we really don’t understand schizophrenia – if it exists as a single entity – at all.

Furthermore, with the marked advances in our understanding of the operation of the main brain circuits and the behaviours they implement, instead of continuing with symptom-based definitions, can we not understand mental disorders as deviations from the normal functioning of these brain systems, Dr Cuthbert suggested. Such is the overarching goal of the RDoC.

 

Enter the matrix – construct identification

RDoC aims to develop a research framework for studying psychopathology based on dimensions of observable behaviour and neurobiological measures. To do so, fundamental ‘constructs’ that span multiple disorders, e.g. executive function, affect regulation, must be identified*. The full range of the variation within each construct then has to be determined using as many components as are available, be they genetic, neurobiological, behavioral, environmental or experiential. Crucially, reliable and valid measures of these fundamental components must be developed for use in basic and clinical studies.

 

Homogeneity is the key

Suffice to say, RDoC is not an alternative nosology – simply because as yet it isn’t known exactly what an integrated multi-measurement diagnostic system looks like. However, it is a focused research initiative moving towards a new classification system. The idea underlying this is that by gaining a deeper understanding of the psychological and biological systems related to mental illness, it should be possible to identify new biomarkers and biosignatures for mental illness. These, in turn, should facilitate more homogeneous groupings for the underlying psychopathology and pathophysiology. The development of new, enhanced interventions and treatments should follow thereafter.

 

Always under construction

Dr Cuthbert was adamant that RDoC is a dynamic initiative. The matrix can be expanded with new research discoveries as these become available. For example, a motor construct domain and integration of new connectome data are planned for inclusion soon.

Of course, challenges exist to be overcome. Two of the key issues highlighted were granularity and biomarkers; granularity because determining the size of change to be assessed when defining normal and abnormal function is likely to be challenging, and biomarkers because it needs to be clear exactly what the biomarkers are marking – is it identification of a DSM/ICD disorder or of individual differences within a DSM/ICD disorder?

 

RDoC – a fruitful approach?

Already evidence from studies such as the Bipolar and Schizophrenia Network for Intermediate Phenotypes (BSNIP) study is mounting to show that the RDoC approach is likely to be fruitful in making homogeneous subgroups from a heterogeneous psychotic population. 

And, there may also be movement on overcoming the requirement for clinical studies to classify patients based on the DSM diagnostic categorization. This follows EMA and the FDA approval of cognition as an indication in depression and in schizophrenia clinical studies. Indeed, the FAST-MAS study was devised solely on RDoC criteria. Its aim was to recruit patients with anhedonia to examine their responses to kappa opioid antagonism and the primary outcome was to be the engagement of circuitry related to hedonic processing. Whether future studies will be undertaken using such an RDoc-inspired approach is keenly awaited.

 

*Further details of the RDoC matrix showing the constructs and units analysis and how these were derived can be obtained from the RDoC website. https://www.nimh.nih.gov/research-priorities/rdoc/index.shtml

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