W. Edwin Fann: A History of the Tennessee Neuropsychiatric Institute.
Thomas A. Ban’s comment
Central theme of clinical research at the TNI from the mid-1970s to the 1980s
Neuropsychopharmacology received its wings in the 1960s from Arvid Carlsson’s report on selective changes on brain monoamines with psychotropic drugs (Carlsson 1965). His findings set the stage for a development that led to the formulation of the catecholamine hypothesis of affective disorders by Joseph Schildkraut and independently William Bunney and John Davis, in 1965, and the dopamine hypothesis of schizophrenia by Jacques Van Rossum in 1967 (Bunney and Davis 1965; Schildkraut 1965; Van Rossum 1967).
Yet, there were warning signals already in those early years that something was wrong. It was apparent to all those working with patients from the beginning that one of the essential prerequisites of neuropsychopharmacological research, a clearly identified treatment responsive population, was not fulfilled. The heterogeneity in pharmacological responsiveness to the new drugs was so great within the diagnostic groups that it took eight years (1952-60) to demonstrate the therapeutic efficacy of chlorpromazine in schizophrenia and seven years (1957-65) to demonstrate the therapeutic efficacy of imipramine in depression (Casey, Lasky, Klett et al. 1960; Delay and Deniker 1962; Klerman and Cole 1965; Kuhn 1957).
During the 1960s there was still hope that the pharmacological heterogeneity within the diagnostic group would be resolved by the replacement of old psychopathology-based diagnoses with diagnoses built from new building blocks based on biological measures. By the time of my arrival to the Tennessee Neuropsychiatric Institute (TNI) in 1976, however, it was evident that this would not be the case until the pharmacological heterogeneity within psychiatric diagnoses was resolved (Ban 1969, 1987).
Impressed by the findings of Christian Astrup, a Norwegian professor of psychiatry in the late 1950s, and Frank Fish, a British professor of psychiatry in the early 1960s, I decided to develop a program along their line of research (Astrup 1957; Fish 1964a,b). Both Astrup and Fish had shown that with the employment of Karl Leonhard’s classification of “endogenous psychoses” (1957) the pharmacological heterogeneity in patients with the diagnosis of schizophrenia could be considerably reduced (Leonhard 1936, 1957, 1999). Fish’s findings were especially convincing. By re-classifying 474 schizophrenic patents with the employment of Leonhard’s diagnostic criteria, he found moderate to marked response to neuroleptics in as many as 79% of his 123 patients with the diagnosis of “non-systematic (unsystematic) schizophrenia” and only in 23% of his 351 patients with the diagnosis of “systematic schizophrenia.” In addition to the more than three-fold difference in responsiveness to neuroleptics between the two groups, Fish also revealed that from his 51 patients with “affect-laden paraphrenia,” a form of “non-systematic (unsystematic) schizophrenia” characterized by delusions with intense emotional participation (delusional dynamics), more than 4 in 5 patients (43 or 84.4%) had a moderate to marked response to treatment, whereas from his 100 patients “with systematic hebephrenia,” less than 1 in 4 (23 or 23%) had a similar response (Fish 1964b).
GUIDE to Leonhard’s Classification
Stimulated by these findings, in the late 1970s we developed a guide to Leonhard’s classification of chronic schizophrenias (GUIDE) which was published in 1982 in Comprehensive Psychiatry (Ban 1982). Findings with the GUIDE (and other instruments used is assigning patients a diagnosis in Leonhard’s classification) revealed that the significantly different response to neuroleptics in the two classes of schizophrenias is not restricted to therapeutic effects but extend to adverse reactions. Analyses of data of an international survey conducted with 768 chronic schizophrenic patients showed that tardive dyskinesia (TD) occurred three times more frequently in patients diagnosed with “systematic schizophrenia” (13.3%) than in patients diagnosed with “non-systematic (unsystematic) schizophrenia” (4.3%) (Ban 1990a; Guy, Ban and Wilson 1985). Since in Fish’s study moderate to marked response to neuroleptics was more than three times as frequent in the “non-systematic schizophrenias” (79%) than in the “systematic schizophrenias” (23%), the inverse relationship between therapeutic effects and TD (i.e., less TD if the drug works and more TD if it does not) indicates that the functional state of the structures involved in the mode of action of neuroleptics is different in the “systematic schizophrenias” than the “non-systematic schizophrenias” (Ban 1987, 1990a)
The functional state of the structures involved in the mode of action of lithium is also different in the “systematic schizophrenias” than in the “non-systematic schizophrenias.” In a survey conducted in 24 schizophrenic patients whose neuroleptic medication was supplemented with lithium to potentiate therapeutic effects, it was found that 9 of the 10 patients from the population with “non-systematic schizophrenia” responded favorably to the lithium supplementation, whereas 9 of the 14 of patients diagnosed with “systematic schizophrenia” responded unfavorably. It was also noted that 5 of the 14 patients diagnosed with “systematic schizophrenia” developed neurotoxicity to lithium supplementation, whereas in the population with “non-systematic schizophrenia” neurotoxicity was not encountered at all (Ban 1990a; Prakash, Kelwala and Ban 1982).
DCR Budapest - Nashville
In the early 1980s, I became involved with a Hungarian team, led by Bertalan Pethö, who were developing research diagnostic criteria based primarily on Leonhard’s work. The “KDK Budapest. Kutatasi diagnosztikus kriteriumok functionalis psychosisok korismezesehez. (Research diagnostic criteria for diagnosing functional psychoses)” was published in Hungarian in 1984 (Pethö, Ban, Kelemen, et al. 1984). In the mid-1980s the KDK Budapest was adopted, with some modifications, from Hungarian into English at the TNI and titled “DCR Budapest-Nashville in the Diagnosis and Classification of Functional Psychoses”; in 1988 it was published in Psychopathology by Pethö and Ban in collaboration with András Kelemen, Gabor Ungvari, István Karczag, István Bittér and Judith Tolna from Budapest; Marek Jarema (from Poland); François Ferrero (from Switzerland); Eugenio Aguglia and Giovanni Luca Zurria (from Italy); and Olaf Fjetland (from the United states) at the time working with me at the TNI (Pethö and Ban 1988).
Neither the “KDK Budapest” nor the “DCR Budapest-Nashville” is restricted to Leonhard’s (1957) diagnostic concepts of “endogenous psychoses” (Leonhard 1957). Both include also August Wimmer’s (1916) diagnostic concept of “psychogenic (reactive) psychoses” and the German diagnostic concept of “delusional development” formulated by Robert Gaupp (1914) and Ernst Kretschmer (1927), at the University of Tübingen (Faergeman 1945; Gaupp 1914; Kretschmer 1927; Perris 1974; Retterstol 1978, Strömgren 1974).
At the core of the “DCR” is a diagnostic decision tree that consists of 524 variables organized into 179 diagnostic decision clusters that yield 21 tentative, 33 provisional, 45 working and 55 final diagnoses. The variables of the DCR are almost exclusively psychopathological symptoms, as in the course of its development it was found that adding variables of social adjustment lowered predictive validity of the diagnoses (Pethö 1984, 1990; Pethö, Tolna and Tusnády 1979; Strauss and Carpenter 1974).
Composite Diagnostic Evaluation (CODE)
While the DCR was still in development the DSM-III of the American Psychiatric Association, introduced in 1980, became an unprecedented success. By combining both major traditions of medicine, the tradition of Galen (131-201 AD), focused on disease (Axis 1 and Axis III), and the tradition of Hippocrates (460-370 BC), focused on patient (Axis IV and Axis V), the DSM-III with its multi-axial diagnoses was received with open arms by practicing psychiatrists (Ban 2000). Yet, the adoption of DSM-III was counterproductive for neuropsychopharmacological research. Progress in neuropsychopharmacology is dependent on pharmacologically homogeneous populations, as indicated above, and the DSM-III reified pharmacologically heterogeneous diagnostic concepts which, for psychopathologists, were only “ideas” and not “carved-in-stone” realities. It also blocked nosological research in psychiatry that, “guided by the idea of disease entity,” gave preference to certain particular elements of the clinical picture to “isolate for diagnostic purposes relative disease-entities” that best fit the needs of a particular research (Jaspers 1910, 1913, 1963).
To provide a methodology for uncovering diagnostic concepts that might fit better the needs of neuropsychopharmacological research than consensus-based diagnoses, a Composite Diagnostic Evaluation (CODE) System was developed in the late 1980s and early 1990s (Ban 1989b).
The CODE System is a set of instruments that can simultaneously assign to a patient a diagnosis from several diagnostic systems. Each instrument (CODE) can provide for a poly-diagnostic evaluation in a distinct category of mental illness by the employment of an integrated criteria list and standardized data collection. Each instrument consists of a set of symptoms (“codes”) that yield diagnoses in all its component diagnostic systems; a semi-structured interview suitable for the elicitation of all the symptoms (“codes”) encountered in the system; and diagnostic decision trees that organize symptoms into distinct psychiatric disorders (Ban 1991, 1992).
CODE - DD
The prototype of the CODE System is CODE-DD, the CODE for depressive disorders that provides a depressive diagnosis in 25 different classifications (from Kraepelin’s to the DSM-III-R) of depressive disorders on the basis of the “presence” or “absence” of 90 symptoms (“codes”) determined in 30-40 minutes by a semi-structured interview administered with or without computer prompting (Ban, Fjetland, Kutcher and Morey 1993).
CODE-DD is a reliable and valid instrument. In the first reliability study, there was an 87.8% inter-rater agreement on the presence or absence of the 90-items of the vocabulary; in the second, inter-rater agreement increased to 100%; and in two validation studies the correspondence between the clinical DSM-III-R diagnosis of “major depression” and the CODE-DD diagnosis of “major depression” was 99.6% and 97.2%, respectively (Ban, Fjetland, Kutcher and Morey 1993; Morey 1991).
CODE-DD was translated and adopted from the English original into several languages: Estonian by Mehilane (1992); French by Ferrero, Crocq and Dreyfus (1992); Italian by Aguglia and Forti (1989); Polish by Pużyński, Jarema and Wdowiak (1989); and Portuguese by Nardi and Versiani (1990) (Ban 1989a,b,c, 1990b, 1992a,b). Early development of the instrument was linked to clinical studies which led to the demonstration of the therapeutic efficacy of reboxetine, a selective norepinephrine re-uptake blocker, in “major depression” (Ban, Gaszner, Aguglia et al. 1998).
Findings with CODE-DD correspond with the commonly held view that the DSM-III-R diagnosis of major depression is a broad diagnostic category (American Psychiatric Association 1987). If depressive illness were characterized by unmotivated depressed mood, depressive evaluations and lack of reactive mood changes, as in the latest version of CODE-DD, then of the 322 patients with the clinical diagnosis of major depression included in the second validation study of CODE-DD only 119 patients (37%) would have qualified for depression. Findings with CODE-DD are also in keeping with the notion that depression consists of more than one form of illness: of the 322 patients only 95 patents (29.5%) fulfilled definite criteria of Kraepelin’s (1896, 1913) depressive states, characterized by motor retardation, retardation of thought and difficulties of concentration, and even less, 45 patients (14%), fulfilled criteria of Schneider’s (1920) vital depression. The overlap between the two forms of depressive illness was negligible (Ban 2000, 2007; Kraepelin 1896, 1913; Schneider 1920).
Yet, however broad the DSM-III-R diagnosis of “major depression” is, it covers up diagnostic concepts with possible relevance to treatment. For example, the diagnosis of Schneider’s (1920) “vital depression” with the cardinal symptoms of corporization, disturbance of vital balance and feeling of loss of vitality that provided the key for Roland Kuhn’s (1957) recognition of imipramine’s antidepressant effect, is covered up to the extent that even if the patient is so severely ill that he/she displays all possible symptoms and signs for the diagnosis of “major depression” in the DSM-III-R and DSM-IV, one still would not know whether the patient qualifies for vital depression (American Psychiatric Association 1987, 1994; Ban 2000; Kuhn 1957; Schneider 1920). The same applies to Kraepelin’s depressive states (Ban 2000; Kraepelin 1913).
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