1 Boring Old Man

Words Matter
NIMH Director’s Blog
By Thomas Insel
October 02, 2012

^{Those who constructed the DSM were looking for a common language to describe symptoms, not a common biology or a common treatment. As someone who entered psychiatry pre-DSM-3, I can attest to the value of a common language. But there have been costs as well. In DSM-4, for instance, the diagnostic criteria for depression require 5 of 9 features, so it would be possible for two people with 1 of 9 criteria in common to have this same diagnosis. Not exactly “precision medicine,” but this approach has delivered diagnostic reliability. What is missing is validity. DSM never presumed to confer validity or explanatory value, but the field has imbued these symptom clusters with biological meaning, perhaps understandable in the absence of biomarkers or diagnostic tests. Ironically, this linguistic oversight has precluded the development of biomarkers that might confer validity. One reason we do not have biomarkers for mental disorders is our presumption that the biomarker is only valid if it maps on to a “fictive category,” rather than developing diagnostic categories based on the experimental data, as proposed by RDoC, our version of “precision medicine”…}

Research Domain Criteria [RDoC]

^{Strategy 1.4 of the NIMH Strategic Plan calls for the development, for research purposes, of new ways of classifying psychopathology based on dimensions of observable behavior and neurobiological measures. The Research Domain Criteria project [RDoC] has been launched by NIMH to implement this strategy. In brief, the effort is to define basic dimensions of functioning [such as fear circuitry or working memory] to be studied across multiple units of analysis, from genes to neural circuits to behaviors, cutting across disorders as traditionally defined. The intent is to translate rapid progress in basic neurobiological and behavioral research to an improved integrative understanding of psychopathology and the development of new and/or optimally matched treatments for mental disorders…}

Why has it taken so long for biological psychiatry to develop clinical tests and what to do about it?
^{by Kapur S, Phillips AG, and Insel TR.}
Molecular Psychiatry. 2012 Aug 7. doi: 10.1038/mp.2012.105. [Epub]

^{Patients with mental disorders show many biological abnormalities which distinguish them from normal volunteers; however, few of these have led to tests with clinical utility. Several reasons contribute to this delay: lack of a biological ‘gold standard’ definition of psychiatric illnesses; a profusion of statistically significant, but minimally differentiating, biological findings; ‘approximate replications’ of these findings in a way that neither confirms nor refutes them; and a focus on comparing prototypical patients to healthy controls which generates differentiations with limited clinical applicability. Overcoming these hurdles will require a new approach. Rather than seek biomedical tests that can ‘diagnose’ DSM-defined disorders, the field should focus on identifying biologically homogenous subtypes that cut across phenotypic diagnosis-thereby sidestepping the issue of a gold standard. To ensure clinical relevance and applicability, the field needs to focus on clinically meaningful differences between relevant clinical populations, rather than hypothesis-rejection versus normal controls. Validating these new biomarker-defined subtypes will require longitudinal studies with standardized measures which can be shared and compared across studies-thereby overcoming the problem of significance chasing and approximate replications. Such biological tests, and the subtypes they define, will provide a natural basis for a ‘stratified psychiatry’ that will improve clinical outcomes across conventional diagnostic boundaries…}

CONCLUSION
Biological psychiatry and the related neurosciences have changed mankind’s view of itself and of mental illness, but have yet to provide biomedical tests for routine clinical practice. The delay is understandable given the later start than the rest of medicine, the complexity of the brain, the nascence of neuroscientific techniques and the evolving nature of psychiatric nosology. On the other hand, the opportunity afforded by the progress in genomics and imaging combined with the computational abilities is unprecedented and could deliver useful clinical tests. These tests will identify homogenous populations for whom one could develop targeted new therapeutics thus realising a vision of a new stratified psychiatry that cuts across the traditional diagnostic boundaries while simultaneously transforming them.

So we had the original RDC [Research Diagnostic Criteria] developed by Dr. Robert Spitzer from the Feighner Criteria that ultimately became the DSM-III Disorders in 1980. In Words Matter above, Dr. Insel proposes that we have come to view these diagnostic categories as biological entities, and searched for biomarkers to define them in vain. He proposes that, "[t]hose who constructed the DSM were looking for a common language to describe symptoms, not a common biology or a common treatment." They sure fooled me. All the Clinical Trials have been by Disorder. FDA Drug Approvals have been by Disorder. Studies in neurochemistry, neuroimaging, genetics, etc. have been by Disorder. Third Party Payers are obsessed with Disorder. Perhaps Dr. Insel might have more accurately said that the Symptomatic Classification that improved inter-rater reliability among psychiatrists has not lead to our wished-for identification of any biological underpinnings in mental illness. I think "[t]hose who constructed the DSM" would’ve just been tickled pink if someone found a biomarker or two that fit some Disorders. It just didn’t happen. That’s all. Whatever the case, our once precious formerly new Disorders have been demoted to “fictive categories” to be replaced by "diagnostic categories based on the experimental data, as proposed by RDoC, our version of ‘precision medicine’."

Having failed at finding biomarkers for our current diagnostic categories, he essentially proposes that we reverse the process and classify people by biologic parameters harvested from neuroimaging, genetics, and other things scientific, then try to create a diagnostic system from the groups thus defined. Here’s how the NIMH says it, "Develop new ways of classifying disorders based on dimensions of observable behaviors and brain functions." The goals would be to "deliver useful clinical tests" and to "develop targeted new therapeutics." I suppose the benchmark here would be Google – build a giant database collecting all things brain and all things behavior from some large cohort [or maybe everybody], then searching around using modern "computational abilities" for associations and relationships. It’s a variant of Australian Evian Gordon’s BraiNet and a raft of other personalized medicine fantasies – "targeted new therapeutics."