There has been considerable recent discussion in the popular press regarding DSM-5, the American Psychiatric Association‘s new version of their diagnostic manual, heavily utilized by mental health providers of all stripes, some much more reluctantly than others. NIR was asked recently how DSM-5 will affect CNS drug development, and our answer is: Very little, if at all. Beyond the bold shift away from the anachronism of Roman numerals, for the most part DSM-5 does not alter the categorization of the disorders most heavily pursued by what is left of the psychopharm industry: Schizophrenia, depression, and bipolar disorder. To the degree to which categories have been altered, the changes obscure, rather than illuminate. For example, Asperger’s Syndrome has now been incorporated into the broad umbrella category of Autism Spectrum Disorder, which means that a poorly defined and unvalidated subgroup has now been collapsed into a broad, poorly defined, and unvalidated large category. Clinically, it’s a terrible idea, and it does nothing for pharma companies who need to parse out ASD subcategories in the hope of identifying groups who are at least slightly less heterogeneous, and who might thus provide a fair test for a new therapeutic agent. The same is true of depression, where the ‘bereavement’ exclusion has been deleted, in order to affirm that the presence of a significant loss does not mean a major depression may not have been triggered or unearthed. But then again, we do not know whether the biology of depression with bereavement is the same as depression that is not preceded by a loss, and woe to antidepressant developers who do not parse the latter from the former.
Which brings us to the larger issue, the disconnect between the observational reliability sought by the producers of the DSM-5, and the biological substrates underlying these disorders. The ability to consistently categorize patients according to their surface manifestations has little, perhaps nothing, to do with defining the biological circuits that must be accessed and modified in order to achieve psychopharmacological benefit–or to put it colloquially, help patients.
Some observers of the psychiatric world have suggested that patients be parsed by symptomatic features which transcend the traditional diagnostic categories inherited from Emil Kraepelin: For example, Roche‘s George Garibaldi has emphasized the treatment of apathy as a clinical phenomenon that has a distinct cost to the patient in terms of functioning, and exists across multiple ‘disorders.’ While an intriguing concept, we do not know whether this parsing strategy will turn out to have any more correlation with underlying biologies than do the usual diagnostic categories.
The NIMH, in conjunction with numerous academic and industry groups, is devoting valiant effort to setting forth on the journey required to identify critical disease biologies; the pathways by which they interconnect and exert downstream effects on observable features and behaviors; and the biomarkers whereby they can be tracked. Over time, those academics and companies wishing to access NIMH funding will have to become conversant in whatever new biologically-rooted nomenclature emerges via the NIMH’s RDoC (Research Domain Criteria) project. But that project is in its relative infancy, and NIMH is not the audience to which the pharma industry in general is attuned. For them, ‘the Agency” does not refer to the NIMH, it refers to the FDA. And the FDA will continue to insist upon a treatment population framework that matches up with what clinicians in the field utilize, the observational paradigm of the DSM, in order to maximize the likelihood that clinicians will know which drugs are validated for which patients. As biomarkers and revised etiological categories gradually emerge, they will first be embraced iwhtin the outer circles of Hell by the NIMH and NIMH’s ‘customers’, academics and smaller companies. Eventually, when relevant biomarkers are available to clinicians in the field, these changes will percolate into the innermost circles of the Inferno–Big Pharma and the FDA. For now, the DSM-5 provides a revenue stream for the American Psychiatric Association, added ambiguity for those contending with Autism Spectrum Disorder, and an extended stay in Purgatory* for those trying to develop new drugs for psychiatric illness.
*Purgatory=CNS drug development metaphor first suggested by Roche‘s Luca Santarelli