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Thursday, 25.05.2017

Comment by Martin M. Katz

Martin M. Katz’s comment on Thomas A. Ban’s RDoC in Historical Perspective Samuel Gershon’s question

 

The Research Domain Criteria (RDoC) program recalls an earlier time, the early 1970’s, when the NIMH sought to launch an ambitious collaborative program on the psychobiology of depression, designed primarily to test the then new hypotheses identifying the role of dysfunction in central neurotransmitter systems. In view of the variations in the diagnostic systems applied at that time, and the resultant ambiguities in language, a diagnostic system applicable for research was required that would be more reliable and generalizable across studies. To render the then controversial and unreliable diagnostic system suitable for research, a group led by Eli Robins, Robert Spitzer and Jean Endicott, was convened by the NIMH’s Clinical Research Branch to refine the definitions so that reliable operational criteria could be articulated for each of the categorical diagnostic types. This contracted effort resulted in the “research diagnostic criteria”, the RDC, published by Spitzer et al (1979). In addition, a data collection instrument was constructed that would ensure that all domains and criteria of psychopathology would be covered in the diagnostic interview, the “schedule for affective disorders and schizophrenia”, the SADS (Endicott, Spitzer 1989).

The RDC provided the structure for the then developed DSM III, an empirically derived, presumably, atheoretical system, designed to be more reliable than previous systems applied in psychiatry. Spitzer, a developer of the RDC was selected to serve as Chairman of the Classification Committee that then created the DSM III. In today’s view the RDC could be construed as a more elementary version of the currently proposed RDoC, and thus, a precursor of the RDoC  It relied on traditionally accepted symptoms, then articulated them more explicitly, thus, increasing their reliability as elements to be utilized in the  structure of the system.

The field was not yet ready to define the underlying mechanisms of the disorder or drug actions in terms of dysfunction in neurochemistry or associated neural circuits or genetic bases. Applying the RDC to research on the psychobiology of depression as conducted in the collaborative (Maas et al 1980) and other programs during this period, permitted significant advances in the science and in psychopharmacology, assisting in identifying relationships between the neurochemistry underlying the diagnoses and the behavioral elements that contributed to the symptomatology of the categorical disorders.

Nevertheless, as Maas and I pointed out (1994), the diagnostic system fell short of advancing the science beyond a certain point, and could in fact, be an obstacle in attempting to uncover the neurobehavioral mechanisms underlying the disorders and the bases for the efficacy of the established antidepressant agents. We contended then, that the components or dimensions that structured the disorder, along with the effects on central neurotransmitter systems, should be the starting points for these types of investigation and not the more complex, still partially understood diagnostic types. We demonstrated how that substitution worked in Katz et al 1994, a study that linked drug-induced changes in metabolites of serotonin and norepinephrine with different changes in components of behavior and mood, e.g., 5-HIAA with changes in anxiety, MHPG with motor activity. Again, I see these earlier findings now as further evidence that relying on diagnosis as we knew it then, as central to uncovering basic information about the disorders or their reactivity to chemical agents that impact central neurotransmitter systems, was the “wrong” path, incapable of resolving problems in this realm of research. We proposed at the time to set diagnosis aside, to adopt in its place a componential or dimensional approach to defining psychopathology, in order to advance science in this area. In that case, based on an intensive analysis of a large multisite patient sample, we identified as major dimensions for depression, depressed mood-retardation, anxiety –agitation-somatization, and hostility, with additional components from disturbances in motor activity and cognitive impairment. Today the Insel-Cuthbert RDoC  approach leads to a somewhat similar structure on the behavioral side, but looks much beyond the neurochemical framework we applied in the 1970’s and ‘80’s. They have included more recent work on neural circuitry and genetics and provided space for expected further advances in these areas.

Their proposal and the target they are working towards in the matrix is a bold attempt to provide a set of long term goals, a structure to guide future research, while releasing the field from its decades-long reliance on an inapplicable diagnostic network.  I admire the effort and with them, believe that it is the proper direction and further, that theirs is a well thought out plan to achieve its aims.

Achieving their goal of completing the matrix is, however, a work in progress and the long term goals still well beyond their grasp. The pressing question we face today relates to investigations in the here and now. How do investigators deal with the traditional centrality of diagnosis in clinical research, generally, and in clinical trials, specifically, in the interim, i.e., in the meantime, while we await the long term goals of the RDoC to be achieved?

My recommendation is straightforward. It is that the RDoC program continue as it has, to integrate current advances in neurochemistry, molecular biology, neural circuitry, genetics into the matrix columns. To effect associations with clinical phenomena, with psychopathology the program needs, however, to take another path. Why not adopt the dimensions, the componential approach that have already been developed as the central clinical phenomena, those facets that are currently capable, as evidenced in psychometric research, of being measured validly. As one example, I refer to the system that my colleagues and I developed and is now well represented in several publications (Katz et al 1984, 1994, 2004, Katz 2013). These studies identifying well-established reliable, quantitative dimensions, have already been applied in several areas of clinical research, specifically, in the creation of a new, componential model for the clinical trial of putative antidepressants. This system based on these earlier studies can be productively applied to a range of new work in these areas and serve well in this field while we await further progress of the RDoC program.

 

References

Endicott J, Spitzer RL. A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiatry 1978; 35:837-44.

Katz MM. Depression and Drugs: The Neurobehavioral Structure of a Psychological Storm. New York: Springer; 2013.

Katz MM, Houston JP, Brannan S, et al. A multivantaged method for measuring onset and sequence of the clinical actions of antidepressants. Int’l J Neuropsychopharmacology 2004; 7:471-79. 

Katz MM, Koslow S, Berman N et al. Multivantaged approach in the measurement of behavioral and affect states for clinical and psychobiological research. Psychological Reports 1984; 55:619-91. 

Katz MM, Maas JW Psychopharmacology and the etiology of psychopathological states: Are we looking in the right way? Neuropsychopharmaocology 1984; 10: 139-144. 

Katz MM, Maas JW, Frazer A et al . Drug-induced actions on brain neurotransmitters systems and change in the behaviors and emotions of depressed patients. Neuropsychopharmacology 1994; 11: 889-1002.

Maas JW, Koslow S, Davis J et al. Biological component of the NIMH-Clinical Research Branch Collaborative Program on the Psychobiology of Depression. Psychological Medicine 1980; 10:759-776.

Spitzer RL, Endicott J, Robins E.  Research diagnostic criteria: rationale and reliability. Arch gen Psychiatry1979; 35,773-782.

 

Martin M. Katz

March 19, 2015