Saturday, 22.02.2020

Thomas A. Ban Neuropsychopharmacology in Historical Perspective Education in the Field in the Post-Neuropsychopharmacology Era


RDoC in Historical Perspective

(Collated Bulletin 1)



Thomas Ban                 February 19, 2015                  Essay with question by Samuel Gershon

Bernard Carroll            March 5, 2015                        Reply to Gershon’s question

Thomas A. Ban             October 1, 2015                     Comment on Carroll’s reply

Samuel Gershon           March 12, 2015                      Response to Carroll’s reply

Martin Katz                  March 19, 2015                      Comment on RDoC

Antonio E. Nardi           March 26, 2015                      Comment on RDoC               

Samuel Gershon            May 21, 2015                         Reply to Katz’s and Nardi’s comments

Jose de Leon                April 30, 2015                        Comment on RDoC


Collated by Olaf Fjetland


Jose de Leon                August 17, 2017                     Final comment

Donald F. Klein            January 4, 2018                      Final reply


Thomas A. Ban RDoC in Historical Perspective with a comment by Samuel Gershon


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 led to the RDoC began in the mid-1950s 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 Insel 2010a,b; Insel, Cuthbert, Garvey et al. 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.


American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders -Third Edition. Washington:  American Psychiatric Association; 1980.

Ban TA. Psychopharmacology. Baltimore: Williams & Wilkins; 1969.

Ban TA. Prolegomenon to the clinical prerequisite: Psychopharmacology and the classification of mental disorders.  Prog Neuro-Psychopharmacol & Biol Psychiat 1987; 11: 527-80.

Ban TA CODE DD Composite Diagnostic Evaluation of Depressive Disorders. Brentwood: JM Productions; 1999. 

Ban TA. From DSM-III to DSM-III-IV; Progress or standstill. In: Franzek E, Ungvari GS, Ruther E, Beckmann H, editors. Progress in Differentiated Psychopathology. Wurzburg: The International Wernicke-Kleist-Leonhard Society; 2000a, pp. 1-11. 

Ban TA. Nosology in the teaching of psychiatry. J Bras Psiquiatr 2000b; 49: 39-49.

Ban, T.A. Neuropsychopharmacology: The interface between the genes and psychiatric nosology. In: Lerer B, editor:  Pharmacogenetics of Psychotropic Drugs. Cambridge: Cambridge University Press; 2002, pp. 36-56.

Ban TA. Neuropsychopharmacology and the history of pharmacotherapy in psychiatry. A review of developments in the 20th century. In: Ban TA, Healy D, Shorter E, editors.  Reflections on Twentieth-Century Psychopharmacology. Budapest:  Animula; 2004, pp. 697-720.

Ban TA.  Academic psychiatry and the pharmaceutical industry. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2006; 30, 429-41.

Ban TA. Towards a clinical methodology for neuropsychopharmacology research. Neuropsychopharmcologia Hungarica 2007; 9: 81-90.

Ban TA. Postscript to the series. In: Ban TA, series editor. An Oral History of Neuropsychopharmacology. Volume 10 (Katz MM, volume editor: History of the ACNP). Brentwood: American College of Neuropsychopharmacology; 2011, pp. 231-7.

Ban TA. Neuropsychopharmacology and the Forgotten Language of Psychiatry. From Madness to Neuronology. Risskov: International Network for the History of Neuropsychopharmacology; 2013.

Ban TA, Ucha Udabe R. Clasificacion de las Psicosis. Buenos Aires: Editorial Salerno; 1995.

Bowman RL, Caulfield PA, Udenfriend S. Spectrophotometric assay in the visible and ultraviolet. Science 1955; 122: 32-3.

Bunney WE Jr, Davis JM.  Norepinephrine in depressive reactions. A review, Arch Gen Psychiatry 1965; 13, 483-494.

Cuthbert BN. Research domain criteria. Toward future psychiatric nosology. Asian Journal of psychiatry 2014; 7: 4-5.

Cuthbert BN. The RDoC framework. Facilitating transition from ICD/DSM to approaches that integrate neuroscience and psychopathology. World Psychiatry 2014; 13: 28-35.

Cuthbert BN, Insel T. The data of diagnosis. New approaches to psychiatric classification. Psychiatry 2010a; 73: 311-4.

Cuthbert BN, Insel T. Toward new approaches to psychotic disorders. The NIMH Research Domain Criteria project. Schizophrenia Bulletin 2010b; 36: 1061-2. 

Freyhan F. Selection of patients from the clinical point of view. In: Cole JO, Gerard RW, editors.   Psychopharmacology Problems in Evaluation. Washington:  National Academy of Sciences – National Research Council; 1959, pp. 372-89.

Griesinger W. Über psychische Reflexactionen. Archiv für Physiologische Heilkunde  1843;  2: 76-112.

Guy W. ECDEU Assessment Manual for Psychopharmacology – Publ. No. (ADM). (DHEW No. 76-338). Washington: United States Government Printing Office; 1976.

Insel T, Cuthbert BN. Endophenotypes: Bridging genomic complexity and disorder heterogeneity 2009; 66: 988-9.

Insel T, Cuthbert B, Garvey M, Heinssen R,  Pine DS, Qunn K, Sanislow C, Wang P. Research domain criteria (RDoC): Toward anew classification framework for research on mental disorders. Am J Psychiatry 2010; 167: 748-51.   

Jaspers K. Allgemeine Psychopathologie. Berlin; Springer; 1913.

Jaspers K. Eifersuchtswahn: Entwicklung einer Persönlichkeit oder Prozess.  Z Ges Neurol  Psychiatr 1910; 1: 567-637.

Kraepelin E. Psychiatrie. Ein Lehrbuch für Studierende und Ärzte, 8 Auflage. Leipzig; Barth; 1910.

Leonhard K.  Aufteilung der endogenen Psychosen, Berlin: Akademie-Verlag; 1957.

Moreau de Tours J.  Du Hachich et de L’Aliénation Mentale. Etudes Psychologiques. Paris:  Fortin & Mason; 1845.

Wernicke C. Lehrbuch der Gehirnkrankheiten. Breslau; Schlettersche Buchhandlung; 1881.

Wernicke C. Über die Klssifikation der Psychosen. Breslau: Schlettersche Buchhandlung; 1899.

Wernicke C. Grundrisse der Psychiatrie.  Leipzig:Thieme; 2000.

Wikler A. The Relation of Psychiatry to Pharmacology. Baltimore: American Society for Pharmacology and Experimental Therapeutics and the William and Wilkins Company; 1957.


February 19, 2015


Bernard Carroll’s reply to Samuel Gershon’s question

I thought the Luhrmann piece was just pretentious pabulum and from an anthropologist, yet! Your reference to NIMH concerns RDoC - a contrived matrix of metaphysical constructs developed by armchair bound, top-down bureaucrats with too much time on their hands - I'm talking about Insel and his lieutenant Cuthbert. Dr. Insel doesn’t seem to understand the need to advance nosology by incorporating biomarkers along with clinical symptoms in diagnostic definitions, as happened in general medicine. Consider where we would end up if, for instance, we lumped Cushing disease together with juvenile onset diabetes mellitus, Type II diabetes mellitus, severe psychological or physiological stress, metabolic syndrome, anorexia nervosa, and pregnancy on the basis of an abnormal glucose tolerance test, which these all can display. We can expect that eventually the RDoC matrix that Dr. Insel insists should be adopted in new grant proposals will go the way of the eccentrics and epicycles of 16th Century astronomy. The pressing issue is how much damage will be done before that happens?


March 5, 2015


Thomas A. Ban’s comment on Bernard Carroll’s reply to Samuel Gershon’s question


I share Dr. Carroll’s concern about the adequacy of lumping together people who share one or another biological property for deriving clinically meaningful populations in psychiatry, as done in the RDoC.  I also share his view about the desirability of having biological markers of psychiatric disease. Yet, I wonder whether it is realistic to look for such markers as he suggests, before the identification of the lithium responsive subpopulation within the bipolar disorders, the chlorpromazine responsive subpopulation within the schizophrenias or imipramine responsive subpopulation within the depressions.


October 1, 2015


Samuel Gershon’s response to Bernard Carroll’s reply


I agree with you. And if I want to write a grant on bipolar disorder, they tell me not to start with a diagnosis of bipolar disorder, but start with the basis of it: genes, microcellular biochemistry and neural circuits. Very good. But I don’t know which they are nor does anyone else. So how do I or anyone else write a grant? I know, you make up a new language! At Pittsburgh I was invited by my good friend the professor of the philosophy of science to his major and important lecture. I did not understand one word, but I presume the main audience did. Therefore, these philosophers can only talk and be understood by other philosophers. Sounds very unscientific. Let us try and keep each other sane.”


March 12, 2015


Martin M. Katz’s comment


The Research Domain Criteria (RDoC) program recalls an earlier time, the early 1970s, 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, Endicott and Robins (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 and Spitzer 1989).

The RDC provided the structure for the then developed DSM III, an empirically derived, presumably, a theoretical 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, Koslow, Davis 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, Maas, Frazer 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 1970s and ‘80s. 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, Maas, Frazer et al. 1984, 1994; Katz 2004, 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.


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, Koslow SH, Bowden CL, Berman N, Swann AC, Stokes PE. Drug-induced actions on brain neurotransmitters systems and changes in the behaviors and emotions of depressed patients. Neuropsychopharmacology 1994; 11: 889-1002.

Maas JW, Koslow S, Davis J, Katz MM, Mendels J, Robins E, Stokes PE, Bowden CL. Biological component of the NIMH clinical research branch collaborative program on the psychobiology of depression: I. Background and theoretical considerations. Psychological Medicine 1980; 10:759-776.

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


March 19, 2015                                


Antonio E. Nardi’s comment


I read with great enthusiasm your essay on RDoC in Historical Perspective, posted in Perspective on INHN’s website on the 15th of February, 2015. Some of my colleagues and I published in 2013 (Nardi, Kapczinski, Quevedo et al. 2013) discussing the difficulties of psychiatric diagnosis and the different points of view nowadays concerning RDoC and DSM-5.

I would like to highlight some ideas presented in that Editorial. For instance, we pointed out that diagnosis in psychiatry has never been an easy task. Every psychiatrist or researcher struggles with diagnostic limitations on a daily basis. The mixture of symptoms, behavior, culture, prejudice and science has always been the subject of the most enthusiastic debate, but with very few results. The release of the Research Diagnostic Criteria (Feighner, Robins, Guze et al. 1972), soon followed by the DSM-III and their diagnostic criteria, brought greater reliability to psychiatric diagnosis, but yielded almost no gains in validity. Many changes for better and for worse were implemented in the subsequent editions of the DSMs. In 2013, the latest edition – DSM-5 – was published. Even though we may criticize some of its aspects and support others, the great development observed in clinical research after the third and fourth editions of the DSM cannot be denied. The main principle of all versions of the DSM is that they are important tools for research and legal work. For clinicians, they serve as guidelines only, and should be no more than that. Clinical practice is an art in which we have to mix science and different levels of philosophy.

Thomas Insel (2013), director of the National Institute for Mental Health (NIMH), published an editorial stating that the greatest provider of funds for mental health research will not accept the DSM-5 as a valid tool for research. This statement creates an uncomfortable situation for the American Psychiatric Association, when the DSM-5 is being presented to the world as the basis for the most modern and reliable diagnoses.

We have the firm point of view that the DSM-5 categories are not supposed to be a perpetual “gold standard.” First, they represent a set of contemporary criteria for an accurate diagnosis that can and will change in the next edition of the manual. Second, the use of DSM-5 does not weaken the Research Domain Criteria (RDoC) project. In fact, the two publications could work together and mutually support each other. Any diagnostic system should be based on emerging research data, but symptom-based categories are what we currently have. We certainly agree with Insel in that research needs to gather genetic, imaging, physiologic, and cognitive evidence in order to improve our understanding of how all biological data - rather than symptoms alone - cluster and how these clusters relate to treatment response. We can already identify some of these issues in the DSM-5. Some new categories may not be sufficiently sound from the scientific point of view. For example, mild neurocognitive disorder, binge eating disorder, and disruptive mood dysregulation disorder are all very close to normal behavior, and we still lack clear cut-off points to improve diagnostic reliability. Some other categories had their formerly strict criteria changed to more open possibilities, and that should be taken very carefully by clinical and research colleagues. No diagnostic classification will address all human needs in this regard, and it must be borne in mind that not all problems in life are caused by mental disorders.

NIMH might orient its research away from DSM categories. According to Insel, patients with mental disorders deserve better. But what could be better than DSM-5 at present? Insel's editorial informs that the NIMH has released the RDoC “to transform diagnosis by incorporating genetics, imaging, cognitive science, and other levels of information to lay the foundation for a new classification system.” The NIMH tried to create a new nosology based on five major systems: 1) negative valence systems; 2) positive valence systems; 3) cognitive systems; 4) systems for social processes; and 5) arousal/modulatory systems. Even though Insel declared that at present we cannot design a system that is based on biomarkers or cognitive performance because we lack the data, symptoms and long-term follow-up is what physicians have available in practice today to support diagnosis. The data required for a precise diagnosis - one that we can really trust - will come in the future, but the patient is suffering now.

The RDoC project is a research framework, not a clinical tool. It is a decade-long project leading perhaps to a better psychiatry, with better diagnosis validity. Working with psychiatric diagnosis means dealing with and searching for all the possibilities to improve future classifications. The RDoC and the DSM are not opposing each each other; they are different pathways by which psychiatry can move to improve diagnosis. Research should be our priority in obtaining data, as research data ultimately, will be the basis to helping people with mental disorders. Physicians should be aware of the limitations of our classifications, but also that they are the best we have at the moment. As for the future, we need robust research data and less fear of challenging psychiatric diagnosis.


Feighner JP, Robins E, Guze SB, Woodruff RA, Winokur G, Munoz R. Diagnostic criteria for use in psychiatric research. Arch Gen Psychiatry1972; 26: 57-63.

Insel T. National Institute of Mental Health: Director's Blog [Internet]. Transforming diagnosis. 2013 Apr 29.

Nardi AE, Kapczinski F, Quevedo J, Hallak JE, Freire R, Romano-Silva MA. The quest for better diagnosis: DSM-5 or RDoC? Rev Bras Psiquiatr. 2013;35: 109-10.


March 26, 2015


Samuel Gershon’s reply to Martin M. Katz’s and Antonio E. Nardi’s comments


I agree with Marty Katz and Antonio Nardi that the etiology of mental disorders is not understood or adequately explained scientifically by any system discussed. Further, we do not have a range of pharmacotherapeutic agents that specifically and effectively treat any of our psychiatric disorders and the introduction of very many psychiatric medications has not contributed meaningfully to any of these questions. The situation of psychodynamic explanations and therapies has led us no further. Also, non- dynamic psychotherapies have a weak basis for efficacy in major psychiatric disorders. Yet oddly, the oldest therapeutic pharmacotherapeutic agent, Lithium, has been with us since its reintroduction for 65 years. During this period, we have defined its therapeutic profile and recently, Duffy and Grof have helped further in this definition by defining a group of manic-depressive patients that are responders vs. a group of non-responders and describing a genetic linkage in the responders. Thus, all possible techniques of looking and learning can contribute to the answer.


Duffy A, Horrocks J, Doucette S, Keown-Stoneman Ch, McCloskey S, Grof  P. The developmental trajectory of bipolar disorder. The British Journal of Psychiatry 2014; 204: 122-8.  


May 21, 2015


Jose de Leon’s comment


Thomas A. Ban started his commentary on the RDoC by referring to an article published by T.M. Luhrmann, an anthropologist, on January 17, 2015, in the New York Times (NYT) that did not reflect favorably on contemporary psychiatric nosology. This time, the NYT comment was published without any reply from a psychiatrist. Jeffrey Lieberman, past president of the American Psychiatric Association (APA) and chairman of an academic department in New York, had to ventilate his frustration in Medscape. The attentive reader will observe that I used the words “this time.” I personally believe the NYT has been presenting a progressively worse view of psychiatric nosology since the spring of 2013 when the DSM-5 was published. I suspect that any objective observer would agree that psychiatry’s prestige as a scientific enterprise has coursed downhill for the past two years.

In my view the anthropologist’s article in the NYT was the third step in this downhill process. This course started with a comment on April 29, 2013, by Thomas Insel, Director of the National Institute of Mental Health (NIMH), who explained just before the DSM-5’s official publication in May 2013 that it lacked “validity.” Not surprisingly, May 7, 2013, brought a comment in the NYT titled “Psychiatry’s guide is out of touch with science, experts say. To try to address that marketing catastrophe, Insel and Lieberman published an online article together.

The second step was the NYT column entitled “Heroes of Uncertainty” by David Brooks, a political columnist, which appeared on May 29, 2013. I am surely biased as I earn my salary by treating the most difficult psychiatric patients in the public system of a state with 4 million people, but I thought the description in “Heroes of Uncertainty” fairly accurately describes1 what I do for a living and is a pretty good depiction of what many excellent psychiatrists do every day in my state’s public system. I consult with these psychiatrists, who work with limited time, resources and access to medical records, but are able to treat very difficult patients. This time Lieberman was given the opportunity for a brief rebuttal to Brooks by the NYT. Moreover, he expanded his view in the APA newspaper Psychiatric News on July 1, 2013, with an article titled “Psychiatry: Nothing to Be Defensive About.” One of Liebermann’s major concerns was that Brooks questioned the scientific status of psychiatry. Brooks stated, “The recent editions of this manual exude an impressive aura of scientific authority…The problem is that the behavioral sciences like psychiatry are not really sciences; they are semi-sciences.” Since Brooks is not an expert in scientific methodology, his definition of psychiatry as a “semi-science” does not appear “scandalous” to me; my view on the application of scientific methodology to medicine and science has previously been described in detail. Following Paul McHugh, I believe that psychiatry is 150 years behind medicine and, following Karl Jaspers, I think that psychiatry is a hybrid discipline combining the methodology of the natural sciences (explaining) and of the social sciences (understanding). In my opinion, psychiatry is not only neurology and not only abnormal psychology since it includes disorders that can be called “neurological” and follow the medical model (e.g., Alzheimer disease) and also the psychological abnormalities that McHugh describes in three of his four perspectives in psychiatry, namely “behaviors,” “dimensions” and  “self and life story.” His fourth perspective is “disease,” which applies to Alzheimer disease. Supported by the wisdom of Jaspers and McHugh, I feel comfortable disagreeing with Lieberman about the “scientific” status of contemporary US psychiatry. Moreover, from the practical point of view, I believe that US psychiatry has to be “defensive” about many things. I titled an editorial in a psychopharmacological journal “Paradoxes of US Psychopharmacology Practice in 2013: Undertreatment of Severe Mental Illness and Overtreatment of Minor Psychiatric Problems.”

Like Ban, I am a European psychiatrist transplanted to North America; therefore, my views on the interaction between psychiatry and psychopharmacology are very similar to his, and I consider his approach of using clinical symptoms to be one of the main ways that psychiatry can move forward with the “fantasy” of personalizing psychiatric treatments. To criticize the RDoC, Ban uses a historical approach going back 150 years to Griesinger, while my historical approach looks back only 100 years by proposing that Jaspers’s words for Wernicke’s approach, “brain mythology,” apply to the RDoC, as well. The RDoC appear to forget that some of the so-called disorders of the DSM-5 have no clear boundaries with normal human behavior, and can simply be defined as “abnormal psychology”; these disorders do not follow the medical model which was the “ideal” of Kraepelin and the US neo-Kraepelinians. In summary, I do not have Ban’s wisdom, but I cannot find any statement in his comment with which I can disagree.

I started to admire Carroll and Gershon 30 years ago, during my psychiatric training; therefore, I am not sure I can do a good job of critiquing them. Moreover, I totally agree with them that the RDoC are an absolute catastrophe for research in severe mental illness, including schizophrenia, bipolar disorder and severe depression. To conclude, Kraepelin, 100 years ago, tried to save psychiatric nosology by developing a Research Institute using the neurosciences of his time; he failed but at least he had a thorough understanding of clinical and historical issues in psychiatry during his time, while the NIMH leaders do not appear to have mastered clinical issues and have no historical knowledge. They combine Kraepelin’s marketing of curing mental illness with Wernicke’s “brain mythology.” It appears that they have not read the Harvard philosopher George Santayana, “Those who cannot remember the past are condemned to repeat it.”


Ban TA. Prolegomenon to the clinical prerequisite: psychopharmacology and the classification of mental disorders. Prog Neuropsychopharmacol Biol Psychiatry 1987; 11: 527-80.

Ban TA. Towards a clinical methodology for neuropsychopharmacological research. Neuropsychopharmacol Hung 2007; 9: 81-90.

Ban TA. Neuropsychopharmacology and the forgotten language of psychiatry.  International Network for the History of Neuropsychopharmacology. November 14, 2013.

de Leon J. Is psychiatry scientific?  A letter to a 21st century psychiatry resident. Psychiatry Invest 2013; 10: 2015; 22: 63 – 81. -17.

de Leon J. Is Psychiatry only neurology? Or only abnormal psychology? Déjà vu after 100 years.  Acta Neuropsychiatrica 2015;  22:: 63 – 81.

de Leon J.  Paradoxes of US psychopharmacology practice in 2013: Between undertreatment of the severe mentally ill and overtreatment of minor psychiatric problems (editorial). J Clin Psychopharmacol 2014; 34: 545 -8.        

de Leon J.  Focusing on drug versus disease mechanisms and on clinical subgrouping to advance personal medicine in psychiatry.  Acta Neuropsychiatrica 2014; 26: 327-33.

de Leon J.  DSM-5 and Research Domain Criteria: One hundred years after Jaspers’ General Psychopathology. Am J Psychiatry 2014; 171: 492- 4.

Insel TR, Scolnick EM. Cure therapeutics and strategic prevention: raising the bar for mental health research. Mol Psychiatry 2006; 11: 11-7.

Jaspers K. General Psychopathology. Translated from the German 7th edition by Hoenig J and Hamilton MH. Manchester: Manchester University Press;1963.

Kraepelin E.  The manifestations of insanity. Hist Psychiatry 1992; 4: 509-29.

Kraepelin E. The German institute of psychiatric research. J Nerv Ment Dis 1920; 51: 505-13.

Kraepelin E. One hundred years of psychiatry. New York: Philosophical Library;1962.

McHugh PR. Striving for coherence: psychiatry's efforts over classification. JAMA 2005; 293: 2526-8.

McHugh P, Slavney PR.  The Perspectives of Psychiatry.  2nd edition.  Baltimore:  The Johns Hopkins University Press;1998.

Robins E, Guze SB. Establishment of diagnostic validity in psychiatric illness: its application to schizophrenia. Am J Psychiatry 1970; 126: 983-7.

Santayana G. The Life of Reason: Or, The Phases of Human Progress, 5 vols. Project Gutenberg. New York: Dover Publications; 1998-2005.


April 30, 2015


Jose de Leon’s Final Comment


I would like to follow up on this Perspective started by Tom Ban in his essay “The RDoC in historical perspective.”

Since Dr. Samuel Gershon made the last comment on this perspective on June 4, 2015, I have become aware of Dr. Donald Klein’s articles on the RDoC. I am going, first, to describe Dr. Klein’s first published article; second, to redefine the RDoC as a marketing issue more than a scientific issue; third, to describe Dr. Klein’s second published article; fourth, to describe the answer to Dr. Klein’s second article by Dr. Bruce Cuthbert; fifth, to describe other opinions on the RDoC; and sixth, to give Dr. Klein, who helped convince New York psychiatrists to move from psychoanalysis to psychopharmacology, the much easier job of convincing the current NIMH director to drop the RDoC, for the good of psychiatry, as a specialty. 

1) Dr. Klein’s first published article on the RDoC.  In December of 2015, Dr. Klein and his collaborators (Weinberger, Glick and Klein 2015) wrote as their viewpoint of the RDoC: “It is not based on the science it proclaims and it ignores the key clinical reality of sickness vs wellness.”

2) My view that the RDoC are mainly based on marketing, not on science. My view of the importance of marketing to explain the RDoC can best be understood by looking at history as described by Dr. Ban. I want to remind the reader that 100 years ago Kraepelin (1920) was trying to use the neurosciences of the time to improve psychiatric nosology and wanted to build a research institute so he decided to use marketing, saying, “The foremost task for such a research institute would be to make clear the nature and the sources of mental disturbances, and then to discover ways of preventing them, healing them or making them easier to bear.”  If one presents Kraepelin's words to any of the NIMH neuroscientists who defend the RDoC, they are likely to agree that: 1) Kraepelin was not successful in his research program, and 2) Kraepelin’s proposal was not about science, since science in Kraepelin’s day was primitive; rather, it was about marketing.

Then, if one looks at articles by Dr. Thomas Insel, the prior NIMH director who promoted the RDoC, one starts seeing a similar marketing pattern. In 2006, Insel appeared to be competing for funding with other NIH institutes that manage other illnesses and using the same type of marketing that Kraepelin used 100 years ago: “In contrast to researchers in cancer and heart disease who have sought cures and preventions, biological psychiatrists in both academia and industry have set their sights on incremental and marketable advances, such as drugs with fewer adverse effects. This essay argues for approaches that can lead to cures and strategies for prevention of schizophrenia and mood disorders.” The best proof that these words were pure marketing is that five years later it was clear that pharmaceutical companies, who had to respond to their shareholders, decided to abandon psychiatric research (Klein, Glick and Shader 2011).  Insel insisted on pressing forward by further focusing on marketing and presenting the RDoC as an alternative to the DSM-5, which he considers lacking in “validity”  (Insel 2013). In summary, I propose that in 100 years Insel’s statements about curing mental illness and his implementation of the RDoC will seem as laughable as those of Kraepelin may appear to 21st century neuroscientists.

3) Dr. Klein’s second article on the RDoC.  In November of 2016, Dr. Klein wrote a letter titled “RDoC is adverse to scientific creativity” for the Debate section of Acta Psychiatrica Scandinavica. The conclusion of his commentary “emphasizes that RDoC strictures will firmly mold psychiatric research into a particular, at least questionable, model rather than support the necessary creativity for approaching the mysteries of psychiatric illness and treatment.”

In order to compare Dr. Klein with his adversary in the debate (Dr. Cuthbert), any objective observer would have to acknowledge that Dr. Klein is a senior psychiatrist who made very important contributions in the areas of psychopharmacology and psychiatric nosology. On 04/29/17 a PubMed search using the term “klein df” provided 479 articles. The more accurate ResearchGate search using his name “Donald Franklin Klein” provided 641 articles, 24,738 citations and an h-index of 85. More importantly, anybody who knows the history of psychopharmacology knows that in the 1960s Klein was one of the pioneers who fought to introduce the scientific approach in pharmacological trials in a very difficult environment, US academic departments, particularly in his city of New York, which was dominated by psychoanalysts. Fifty years later, due to Klein’s disciples and his disciples’ disciples, there are many top psychopharmacological researchers in New York.  It looks worrisome when a senior psychiatrist like Dr. Klein, who is beyond the self-interest of competing for funding or academic honors and who, throughout his career, has demonstrated a major commitment to the best interest of the future of psychiatric research, proposes that “RDoC is adverse to scientific creativity.”

4) Dr. Cuthbert’s answer to Dr. Klein’s second article on RDoC. Dr. Cuthbert is a psychologist working in the NIMH (which anybody objective would acknowledge is a bureaucracy). A PubMed search provided 63 articles when using the term “cuthbert bn” and 91 articles for the term “cuthbert b” (Dr. Cuthbert does not appear to have included his articles in ResearchGate). 

As 16 of Dr. Cuthbert’s articles are on the RDoC, it cannot be defended that Dr. Cuthbert is unbiased in his defense of the RDoC since he is one the main developers. In his answer to Dr. Klein (Cuthbert 2016), he quotes the details of a grant to insist that the RDoC is only one of the main priorities of the NIMH. Dr. Cuthbert finished with a comment, “In sum, the author’s letter misrepresents the role of RDoC in the NIMH’s overall strategic plan and mischaracterizes the particular RFA that is quoted at some length. If anything, the author’s points only serve to point out the extent to which NIMH is attempting to foster scientific creativity with the "RDoC concept.”  I recommend that the reader read both comments, but any objective observer would acknowledge that it is worrisome when an unbiased senior psychiatric researcher believes that the RDoC is adverse to scientific creativity. On the other hand, I do not feel particularly comforted by the answer of Dr. Cuthbert that we should believe that the RDoC fosters creativity, when Dr. Cuthbert is a psychologist working in the NIMH bureaucracy who was heavily involved in the development of the RDoC.

5) Other opinions regarding the RDoC. Since 2013, as I have lectured in many countries all over the world from Australia to Argentina, I have heard research psychiatrists express bewilderment because the RDoC approach does not fit with their research in severe mental illness: schizophrenia, bipolar disorder and severe depression. They are concerned that the NIMH, as the leading research center in the US and in the world, is setting an awful example for the future of psychiatric researchers and jeopardizing research in severe mental illness. I always told these troubled psychiatrists that it appears that the RDoC was approved by Insel, but the best sign of how problematic that decision was is that it was not supported by the directors of other closely related institutes, such as NIDA.

If my argument is correct that the RDoC is mainly a marketing strategy and Insel has left the NIMH, one can only wish that the new director of the NIMH, Joshua A. Gordon, M.D., Ph.D., has the good sense to drop the RDoC program, which many psychiatric researchers around the world think is a serious threat to scientific creativity.


Cuthbert B. Klein critique. Acta Psychiatrica Scandinavica 2016; 134: 454-455.

Insel TR, Scolnick EM. Cure therapeutics and strategic prevention: raising the bar for mental health research. Molecular Psychiatry 2006; 11: 11–17.

Insel T. Transforming Diagnosis.

Klein D. RDoC is adverse to scientific creativity. Acta Psychiatrica Scandinavica 2016; 134: 452 454.

Klein DF, Glick ID, Shader RI. Central nervous system drug development, basic, and clinical research: thinking outside the box. Journal of Clinical Psychopharmacology 2011; 31: 553-534.

Kraepelin E. The German institute of psychiatric research. Journal of Nervous and Mental Diseases 1920; 51: 505-513.

Weinberger DR, Glick ID, Klein DF. Whither Research Domain Criteria (RDoC)?: the good, the bad, and the ugly. JAMA Psychiatry 2015; 72: 1161-1162.


August 17, 2017


Donald F. Klein’s final reply to Jose de Leon’s final comment


This note updates Dr. de Leon’s conclusion that RDoC is marketing and not science. His view is that “one can only wish that the new director of the NIMH, Joshua A. Gordon MD PhD, has the good sense to drop the RDoC program, which many psychiatric researchers around the world think is a serious threat to scientific creativity.” This hope is contradicted by Dr. Gordon’s messages (June 5 and June 22, 2017) entitled “The Future of RDoC” and “RDoC: Outcomes to Causes and Back.”  Dropping RDoC is not Dr. Gordon’s goal.  Instead, he holds up a bright marketable future: “Imagine a world where your psychiatrist runs a panel of tests—behavioral and brain function tests—in addition to her clinical assessment. She gives you a diagnosis and realistic prognosis, and helps you choose between treatments with the knowledge of your individualized chance of responding to each of them. This is the ambition of the Research Domain Criteria (RDoC) project.”

This reframes and distorts prior RDoC descriptions in which crucial distinctions between sickness and health were avoided in favor of dimensional measures that cut across obsolete categorical distinctions.  Defining the cut points for caseness was antithetical to the RDoC strategy that condemned categorical distinctions.   The idea of treatment outcome comparisons that were relevant to a particular individual was central to the theme of personalized medicine. It was not an RDoC goal.

Dr. Gordon gave an example of RDoC at work cited below. My comments are in parentheses.

“Imagine we have a dataset based on a whole bunch of people with a diagnosis of major depressive disorder. Some of these individuals get better with fluoxetine, and some with cognitive behavioral therapy (CBT).”

(Note this is naturalistic data rather than experimental.  There's no randomization and therefore treatment outcomes are open to multiple unmeasured confounds. Also starting with a group that meets a particular DSM diagnosis is antithetical to RDoC strategy.  The dimensions come from factor analyses applied to handy mixes of various patients and normal subjects. This view was important enough to modify peer review.  It declared grants using diagnoses as immediate failures without further review.)

“Furthermore, suppose we can demonstrate aberrant function specific to one or more RDoC constructs that can be measured through brain or behavioral observations.”

(This is a major supposition. Many papers have presented various brain structural or functional variations as correlated with behavioral dimensions or diagnoses.  None have had sufficient sensitivity, specificity, effect size or replicability to qualify as a diagnostic criterion. Only the monogenic rare diseases, such as Huntington’s Disease, have proven diagnostically tractable. However, the promised therapeutic advances, that would be obvious once genomic architecture was discovered, has not succeeded in these appropriate conditions.)

“Brain scanning might, for example, reveal hyper- or hypo-activity in different areas of the brain, or disrupted connectivity between different brain areas; or behavioral measures might detect impaired working memory. We can quantitatively measure the degree of influence that dysfunction in each of these constructs has on the two different subtypes of depression.”

(This is unclear. The term” constructs” is used improperly. Where did the two diagnostic subtypes come from? They are used as valid goal posts. Why is it of interest whether the subtypes are better demarcated by one or the other measure of brain process? Dr. Gordon states his interest.)

Are the subtypes better described as each arising from dysfunction in one of these constructs, or more than one? Or are the constructs and diagnostic subtypes more likely independent observations? With enough data, you can test which of these models best explains what you see. behavioral better described as each arising from dysfunction in one of these constructs, or more than one? Or are the constructs and diagnostic subtypes more likely independent observations? With enough data, you can test which of these models best explains what you see. …Now you find that most of the fluoxetine-sensitive patients also score low on tests of motivation, but only a few of the CBT-sensitive patients do.

One can then ask whether applying other tests relevant to the same behavioral domain would improve your ability to predict which treatment the patient will respond to—again, with a quantitative evaluation of how much the addition of these measures improves that prediction.

The well-known problems with the analysis of naturalistic data that precludes making definitive contrasts and predictions without a roster of non-evaluable assumptions have no place in this rousing call for unquestioning support. 

Dr. Gordon believes that enough data enables getting experimental blood out of a naturalistic stone. He assumes statistical methods that will crack the naturalistic problem.  Making discovery from naturalistic data remains a focus for statistical development as well as generating heterodox approaches.  A Bayesian approach receives one passing reference. Machine learning takes advantage of the strange distributions that are problematic for multiple regression. Unfortunately, this leads to incomprehensible results.  Judea Pearl has developed graphic measures asserted to effectively analyze naturalistic data. However, they have not been applied to psychiatric data with discovery as a goal. Dr. Gordon says, in contradiction to RDoC formulations, that its approach combines the values of both dimensional and categorical analyses. RDoC’s value will be measured by rigorous comparisons of work using the newly, loosely defined RDoC methodology to non-RDoC approaches. This will determine its fruitfulness and continuation of its programmatic status.       

A mechanism that could achieve this complex goal is impossible with current grant review principles. It requires a roster of detailed specified contracts that require study parallelism, except for the newly defined RDoC methods. Feasibility is doubtful. Dr. Gordon does not consider the major investment necessary before the supposed RDoC specific methods can be applied. For instance, the enormous literature consists of scattered, variously based, conclusions. Detailed integrating of these efforts has proven an unsolved, even more enormous, problem for bioinformatics.  Dr. Gordon assumes the solution will be shortly available for RDoC development. There is no reference to the critical literature assailing RDoC.  Simply encouraging following up novel observations will bury the investigator in non-replications and false positives. Dr. Gordon continues with big picture sales talk that ignores scientific requirements for valid comparisons and predictions. They interfere with marketing.

Dr. Gordon states, “Finally, imagine you had this complete dataset—with hundreds of thousands of patients, each with diagnoses, clinical response, longitudinal course, and behavioral tests across the RDoC domains. One can make quantitative predictions not only of outcome—how a patient will do with a given medication, what that patient’s prognosis is, etc.—but also about the nature of the underlying structure of psychological and biological processes: Are the neural substrates (the brain processes on which treatments act) for fluoxetine-sensitive and CBT-sensitive patients separable? How many different kinds of processes are there, and which brain regions might relate to each? One can build models of the underlying processes and quantify how much they explain about the symptoms and behavioral measures, which can help refine those quantitative predictions of prognosis and outcome. Combine the features of this approach—integration of RDoC behavioral constructs and DSM observational diagnoses, quantitative comparisons of model accuracy, iterative improvements in the combined model, and integration with longitudinal data (including developmental history, illness progression, and treatment response)—and you have the makings of an evidence-based diagnostic and clinical tool that has built-in automatic updating capability. Of course, there are a lot of things that have to go right for this to work. Getting the data will be challenging, especially data inclusive of hard-to-reach people like children and individuals with serious mental illnesses. Early editions of a comprehensive diagnostic tool will likely be rudimentary. Nonetheless, with enough data, creativity, and computation, we can build the tool of the future, sooner than you might think. Let’s get busy.”

This confidence breeding sketch is cited extensively so the reader will grasp both the grandiosity of the program as well as the neglect of elementary warnings about analysis of naturalistic data—even if it is big data. Dr. de Leon’s diagnosis of marketability is amply confirmed.


January 4, 2018