White, grey and dark matter in psychiatric research and practice

Psychiatric diagnostic systems (ICD-10 and DSM-5) are based on patterns of symptom clusters. This approach remains popular with clinicians: the diagnostic categories have face validity and are easy to apply, as occurs in general medical diagnostic practice; and categorical diagnoses have utility when patients are seeking certainty about the causes of their illness and remedy; and commissioners favour categories because they are convenient and easily communicated in procurement and billing processes. ^{Reference Craddock and Mynors-Wallis1} A revolution in psychiatric diagnostic systems is still awaited with recommendations that, first, the weaknesses of existing systems be better defined and addressed, in part, by a dimensional approach and prototypic matching. ^{Reference First and Westen2} Yet, prototypic matching, a part of the ICD-11 Clinical Descriptions and Diagnostic Guidelines, is insufficient to improve precision and the clinical task. ^{Reference First3}

The National Institute of Mental Health’s Research Domain Criteria (RDoC) Project seeks precision medicine for psychiatry - a diagnostic system based on a deeper understanding of the biological (including genetic) and psychosocial basis of a group of disorders and better evidence about pathophysiology and the neuroscientific basis of psychiatric disorders. ^{Reference Insel4} Although subjective experiences are not entirely dismissed in RDoC, ^{Reference Insel4} no concern is expressed about biological reductionism that risks oversimplifying experiences of altered consciousness, and epistemic errors of inference and explanation. ^{Reference Parnas5} Notwithstanding concerns about biological reductionism and reifying novel findings, rapid and exciting scientific advances that hold promise for the RDoC vision are seen in the area of genomics and epigenetics. ^{Reference Rees, Walters, Georgieva, Isles, Chambert and Richards6-Reference Darby and Sabunciyan9} Promising neuroscientific research is emerging. For example, there are innovative studies of localised white matter lesions as markers of prognosis and treatment responsiveness in depression (for example, see Reppermund et al (pp. ) and Korgaonkar et al (pp. ), this issue).

‘Dark matter’ is hypothesised in astronomy to account for gravitational influences that are not explained by measurements: the discrepant findings are explained by a mass that is not observed but must exist. Several leading researchers have called for more attention to the dark matter of psychiatry to help resolve aetiology and treatments of psychosis, intellectual disabilities, autism and syndromes such as attention-deficit hyperactivity disorder. ^{Reference Insel10,Reference Lesch11} The evidence of high genetic heritability is not consistent with a failure to replicate gene-disorder associations, and much future risk (50-60%) is influenced by the shared environment and non-genetic factors in general. ^{Reference Insel10,Reference Lesch11} The same can be said of non-genetic domains of research such as social cognition ^{Reference Cummins12} and studies of intelligence. ^{Reference Ackerman13} As discrepant findings and failures of replication are not restricted to genetic research, the same ‘dark matter’ concept should be applied to all psychiatric research, whether investigating psychosis, social processes, environment, suicide, or resilience. For example, the neural processes underpinning social interaction and the social processes influencing or even biasing neuroscience methods warrant greater attention. ^{Reference Schilbach, Timmermans, Reddy, Costall, Bente and Schlicht14} A twin study of resilience in this issue (Amstadter et al, pp. ; invited commentary by Wertz & Pariante, pp. ) suggests that both genetic and social influences, changing with time and context, are better ways of conceptualising resilience as a dynamic and time-dependent construct. And there is a review by Cuijpers et al (pp. ) of psychotherapy for subclinical depression, showing some promise - modest or small effects - perhaps due to non-specific factors.

It is no coincidence that the papers most cited in the BJPsych in the past year, contributing to a 10% increase in its Impact Factor, seek to address discrepant findings - dark matter. Among the highly cited papers is a study of copy number variants (CNVs) suggesting that routine screening for CNVs may now be appropriate and helpful; ^{Reference Rees, Walters, Georgieva, Isles, Chambert and Richards6} there were meta-analyses of agomelatine as an antidepressant (finding little effect), ^{Reference Koesters, Guaiana, Cipriani, Becker and Barbui15} of cognitive-behavioural therapy for schizophrenia (a small effect), ^{Reference Jauhar, McKenna, Radua, Fung, Salvador and Laws16} and the risk of suicide by occupation (lower-skilled workers being at greater risk). ^{Reference Milner, Spittal, Pirkis and LaMontagne17} And a contentious but rigorous study showing that frequent religious attendance is a long-term protective factor against suicide. ^{Reference Kleiman and Liu18}

I welcome more explicit statement of the important ‘dark matter’ questions that authors aim to resolve, alongside studies of white, grey, mind and other brain matters.