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Tuesday, 28.03.2017


Redefining Mental Illness by Tanya M. Luhrmann

Samuel Gershon’s question       

Thomas A. Ban

In her article, “Redefining Mental Illness”, published in the Sunday Review of New York Times on January 17, 2015  (, Tanya Luhrmann wrote that in 2013, Thomas R. Insel, the director of the National Institute of Mental Health (NIMH) of the United States “announced that psychiatric science had failed to find unique biological mechanisms associated with specific diagnoses” and “diagnoses were neither particularly useful nor accurate for understanding the brain, and would no longer be used to guide research”. She pointed out that Insel dismissed  “a decades-long tradition of diagnosis-driven research” and  introduced a program he called Research Domain Criteria  in which  “all research must begin from a matrix of neuroscientific structures (genes, cells, circuits) that cut across behavioral, cognitive and social domains (acute fear, loss, arousal)”. By doing so, Luhrmann asserts, the NIMH, similar to the “British Psychological Association, rejects the centrality of diagnosis”, albeit for quite different reasons.

On January 18, the day after Luhrmann’s article was published, Samuel Gershon sent an e-mail with the subject “help me to understand”, to Bernard Carroll and Tom Ban, copied to Roy Chengappa and Gurhjinder Mali that reads: “The NYT last Sunday, in the Sunday Review section on page 5, has an article entitled ‘Redefining Mental Illness’ by TM Luhrmann of Stanford which says that NIMH ‘jettisoned’ a decade long tradition of diagnosis driven research and mandates that all research must begin from a matrix of neuro-scientific structures, such as genes, cells, circuits that cut across behavioural, etc. domain. How can one do this as (A) the diagnostic system is in fact very defective, and (B) the data in the genetic realm is also undefined? What are the benchmarks”?

Development that lead to the RDoC began in the mid-1950’s with expectations that findings on the mode of action of therapeutically effective psychotropic drugs would provide information on the biochemistry of mental diseases to guide development towards rational pharmacological treatments (Wikler 1957). As the therapeutic effect of the same drug, in the same dose, in patients with the same diagnosis was inconsistent, Fritz Freyhan (1959), a German born American pioneer of psychopharmacology suggested a pharmacological re-evaluation of diagnostic concepts in psychiatry. This did not happen.  Instead, a statistical methodology, the randomized clinical trial (RCT), was adopted for the demonstration of therapeutic efficacy of psychotropic drugs in pharmacologically heterogeneous diagnostic populations (Ban 2004, 2011). Simultaneously with this development a newly introduced biochemical technology rendered drug  induced changes in the concentration of neurotransmitter monoamines in the brain accessible to measure (Ban 2006; Bowman, Caulfield and Udenfriend 1955) and an avant-garde intramural research program at the National Institute of Mental Health of the United States embarked on the study of the biochemistry of mental illness (Bunney and Davis 1965).

To meet the need of RCTs, rating scales (Guy 1976) sensitive to document changes and consensus based diagnoses which can reliably identified, as DSM-III diagnoses (American Psychiatric Association 1980; Ban 2000a) were introduced.  The replacement of psychopathology by psychiatric rating scale scores, and psychiatric nosology derived diagnoses (nosological entities) by consensus-based diagnostic algorithms profoundly affected psychiatry by confounding developmental anomalies (abnormal psychology) with psychopathology (Jaspers 1910) and extending the scope of psychiatry from pathologies in mental processing to behavioral anomalies with compromised social functioning. By the end of the 1980s, psychopathology (Jaspers 1913) and psychiatric nosology (Ban 2000b), the disciplines which enabled psychiatry to detect the differences in the pathologies in the processing of signals in the brain and in the organization of these pathologies in time, were forgotten languages in psychiatry (Ban 2013).

By the early 1990s, it was evident that the pharmacological heterogeneity within psychiatric diagnoses prevented the generation of valid information on the biochemistry of psychiatric diseases, blocked the development of rational pharmacological treatments and interfered with the optimal use of psychotropic drugs (Ban 1969, 1987, 2004). Yet, when the recognition that the primary targets of psychotropic drugs are encoded by genes which are identified ushered in a molecular genetic era in neuropsychopharmacology, the story of the neurotransmitter era was replicated. Since the pharmacological heterogeneity, now within the broad consensus-based diagnoses was not resolved, similar to findings in biochemical studies in mental illness, findings in molecular genetic studies, remained inconsistent, the results of one study could not be replicated in others (Ban 2002).

This was the state of affairs in 2010 when the RDoC was launched by Bruce Cuthbert and Thomas Insel, NIMH’s Director (Cuthbert and Insel2010 a, b; Insel, Cuthbert, Garvey, Heinssen, Pine, Quinn, Sanislow and Wang 2010). The objective of the RDoC is to develop end points for psychiatric research based on the biological substrate involved in the shaping of mental activity and/or altered in abnormal mental activity. To achieve this objective “fundamental domains” of “behavioral functioning” are related to their underlying neurobiology by the identification of the “sites of dysregulation” that becomes manifest as “psychosis” on “neurobiological circuit maps” (Cuthbert 2010a, b; Insel and Cuthbert 2009). Thus, in the RDoC, the three “psychic structures” of Carl Wernicke (1881, 1899, 1900),  the  afferent “psychosensory,” central “intrapsychic” and efferent “psychomotor,” based on Griesinger’s (1843) “psychic reflex”, is replaced  by five “domains” of “neurobiological circuits,” labeled as “negative affect,” “positive affect,” “cognition,” “social processes” and “arousal/regulatory system”;  psychopathological symptoms  by “circuit-based constructs,” such as “fear,” “distress,” “aggression,” etc.; and diagnostic end points (nosological hypotheses),  by positions in ”neurobiological circuit-based matrices” in which the rows consist of “circuit-based constructs” and the columns which  determine “circuit-based units” by  “genes,” “molecules,” “cells,” etc.

In a historical perspective, the RDoC is a tabula rasa, in which 200 years of development in “psychiatry” is summarily dismissed.   As presented, it is floating in the air, without any anchor in clinical reality. But would the population of “circuit-based units” defined by “nosological homotyping” (Ban 2008), using a matrix in which the rows consist of psychopathological symptoms, and the columns which determine “nosological homotypes” by    nosological organizing principles, such as form of onset, course, polarity and outcome (Ban 2000b; Kraepelin 1910; Leonhard 1957), the RDoC could provide a bridge between past and future psychiatry (Ban 1989; Ban and Ucha 1995).  “Nosological homotypes” are the most homogeneous populations in terms of psychopathology and psychiatric nosology and if Jacques Moreau de Tours (1845) contention that patients with different mental pathology respond differently to the same drug, “nosological homotypes” provide a suitable population for psychiatric and neuropsychopharmacological research.


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Thomas A. Ban
February 19, 2015