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

Thomas A. Ban: Towards a clinical methodology for neuropsychopharmacological research*

Introduction

       The therapeutic and commercial success of chlorpromazine in the mid-1950s generated interest to develop drugs for psychiatric indications (Caldwell 1970). By the end of the 1950s there were at least 22 new drugs for the treatment of different psychiatric disorders (Ban 2001a; Ban and Ucha Udabe 2006). With the introduction of drugs with demonstrable therapeutic efficacy pharmacotherapy was receiving a steadily increasing share in the treatment of mental illness, and psychopharmacology became part of the teaching curriculum in psychiatry.

       The term psychopharmacology was introduced in 1920 by David Macht, an American pharmacologist, to describe the effects of drugs on psychometric performance tests (Macht 1920). In the 1940s, with the availability of the psychotomimetic, lysergic acid diethylamide (Hofmann 1970), research in psychopharmacology was extended to the study of model psychoses; and in the 1950s, with the rapidly growing number of psychotherapeutic drugs, it also embraced efficacy studies for the demonstration of the effectiveness of new treatments (Ban 1996, 2004).

       Simultaneously with the introduction of psychotropic drugs, there was a shift in the understanding of signal transduction in the brain from a purely electrical to a chemically mediated event; and by the end of the 1950s there were six chemical neurotransmitters identified in the central nervous system (CNS) (Ban 2001a). Recognition of chemical mediation at the site of the synapse, coupled with the introduction of the spectrophotofluorometer  (Bowman, Caulfield and Udenfriend 1955) -- an instrument with a resolution power to measure the concentration of cerebral monoamines, such as norepinephrine and serotonin, involved in neuronal transmission at the synapse -- led to the development of neuropharmacology, the discipline dedicated to the study of the mode of action of psychotropic drugs (Ban 1996). Previously, research dealing with centrally acting drugs, was restricted to behavioral pharmacology, and neurophysiological measures (Simon 1998). Spectrophotofluorometry provided direct access to the detection of the biochemical changes responsible for the clinical effects (Ban 1999). 

       Developments in pharmacotherapy, psychopharmacology and neuropharmacology triggered the development of neuropsychopharmacology, a composite discipline, dedicated to the study of the pathophysiology and treatment of mental pathology with the employment of centrally acting drugs (Ban 2004). The new discipline has grown on the premise that research on the mode of action of psychotropic drugs with well-defined, selective therapeutic indications will generate the necessary knowledge about the pathophysiology of psychiatric disorders to guide the development of more effective pharmacological treatments.  

       By the late 1950s, the neurotransmitter era, the first epoch in the history of neuropsychopharmacology was in progress (Ban and Ucha Udabe 2006).

The neurotransmitter era

       In the neurotransmitter era neuropsychopharmacological research in the pathophysiology and treatment of mental illness was guided by knowledge derived from the effects of psychotropic drugs on neurotransmitter dynamics and metabolism (Pletscher 2006);  psychotropic drug development was driven by a rapidly developing technology that provided neuropharmacology with a capability to determine the regional distribution of neurotransmitters (Kety and Elkes 1961), the effect of drugs on the release and uptake of neurotransmitters (Axelrod, Whitby and Hertting 1961) and the affinity of drugs to neurotransmitter receptors (Snyder, Creese and Burt 1975).

       The variations in therapeutic responsiveness to the same drug in a diagnostic category focused attention on the pharmacological heterogeneity within the diagnostic groups (Ban 1969). Yet, no attempt was made to resolve the heterogeneity by the identification of pharmacologically homogenous populations that respond selectively to one or another psychotropic drug (Ban 1999).  The difficulties, created by the pharmacological heterogeneity within the diagnostic groups for the demonstration of therapeutic efficacy, were overcome by the adoption of a statistical methodology, the randomized clinical trial (RCT).

       RCTs made it possible to detect the therapeutic effects of psychotropic drugs in pharmacologically heterogeneous diagnostic populations. By providing a means for the demonstration of statistically significant superior efficacy of a psychotropic drug to an inactive placebo in a diagnostic group without the identification of the characteristics of the treatment responsive subpopulation within the diagnostic group (Ban 2006), RCTs led to semi-finished products in the treatment of mental illness. They also deprived neuropsychopharmacological research from the necessary feedback to develop clinically more selective and thereby more effective psychotropic drugs.

       RCTs had a major impact on drug regulation and on the clinical use of psychotropic drugs. By accepting that a drug is effective in a particular population if statistically significantly superior to an inactive placebo with a 0.05 or greater level of probability in two pivotal studies, authorities in the US, Canada and some other countries approve the use of a psychotropic drug in a diagnostic group in which only 2 of 8 patients show a favorable response to its pharmacological effects.   Such a narrow difference between the active drug and placebo marginalizes the importance of pharmacological treatment and blurs the difference between pharmacological and other treatments. In the absence of the identification of the treatment responsive form of illness, the potential benefits of drugs may be compromised by their indiscriminate use (Ban 2006; Ban and Ucha Udabe 2006).

       In neuropsychopharmacological research the effect of a psychotropic drug on mental illness is linked with the effect of the substance on brain structures involved in its mode of action (Ban 2002). By linking the mode of action of a drug with a pharmacologically heterogeneous diagnostic population, psychopharmacologic research does not provide the necessary feedback for progress in treatment.

       As we are moving forward from the neurotransmitter era to a genetic era in neuropsychopharmacology, the gap between a neuropharmacology, with the capability to tailor drugs to receptor affinities by the employment of a rapidly growing genetic technology, and a psychopharmacology, with a methodology that is capable only to demonstrate therapeutic efficacy, has become so wide that it interferes with progress in the pharmacotherapy of mental illness. 

       The inconsistent and conflicting findings in molecular genetic research led to a steadily growing dissatisfaction (Hyman 1999) with consensus-based diagnoses and classifications, such as the DSM-IV^TM of the American Psychiatric Association (1994) and the ICD-10 of the World Health Organization (1992).  Since all the primary targets of psychotropic drugs in the brain, e.g., G-protein coupled receptors, nuclear hormonal receptors, ion channels, enzymes, etc., are encoded by genes that have been identified, any nosologic entity that corresponds with a treatment responsive population is suitable for the generation of genetic hypotheses relevant to mental illness (Ban 2002).

Towards a genetic era

       By the late 20^th century the dissatisfaction with the clinical end points given in consensus-based classifications was so severe that it was proposed to re-conceptualize mental illness in terms of genetically meaningful “discrete neurobiological deficits,” also referred to as “alternative phenotypes,” such as the “abnormality of smooth pursuit eye movement” (Holzman, Kringlen, Mathysse et al. 1988) linked to a locus on the short arm of chromosome 6 (Arolt, Lencer, Nolte et al. 1996), and the “P-50 evoked response deficit” (Freedman, Adler and Leonard 1999) linked to the α₁-nicotinic acid receptor on the long arm of chromosome 15 (Freedman, Coon, Myles-Worsley et al. 1997). Nevertheless, the usefulness of these “alternative phenotypes” in biological research in schizophrenia is questionable because both “phenotypes” are encountered several times more frequently in the general population than schizophrenic disorders (Faraone, Tsuang and Tsuang 1999).

       It has also been suggested to replace traditional psychiatric nosology by a “genetic psychiatric nosology” which would classify patients into categories that “correspond with the genes.” While such a nosology could focus attention on overlaps between certain traits, e.g., depression and anxiety, it would group together individuals who fully qualify for a particular disease and individuals who, despite carrying the genes for the disease, are symptom free (Faraone, Tsuang and Tsuang 1999).

       Recognition that to-date there is no alternative methodology to psychopathology-based psychiatric nosology for classifying mental pathology in a clinically relevant manner (Ban 2002), stimulated interest in linear regression equations for the identification of the treatment responsive form(s) of illness within the currently used diagnoses. However, findings with linear regression analyses of rating scale scores -- generated in clinical drug trials designed for the demonstration of therapeutic efficacy -- were inconsistent (Ban 1987; Roth and Barnes 1981). Rating scales constructed for the assessment of change in the severity of psychopathology are sensitized by the omission of psychopathological symptoms that are not influenced by treatment, or by the retention of only those symptoms that show the largest changes (Ban 1999). While sensitized scales are eminently suited for the demonstration of the efficacy of a drug in the shortest possible time in the smallest number of patients, they preclude the possibility of findings any relevant information for the identification of treatment-responsive forms of illness by metanalyses in the data of RCTs with psychotropic drugs (Ban 2006).

The CODE System

       There are two diagnostic instruments in development to provide pharmacologically more homogenous populations for research than the diagnostic categories of consensus-based classifications: the Composite Diagnostic Evaluation (CODE) System, and Nosologic Homotyping. The CODE System is a methodology for the identification of the treatment responsive form of illness if covered up by consensus-based, or other broadly defined diagnoses. An important impetus for the development of the CODE-System was the finding of Frank Fish that the traditional diagnostic concept of schizophrenia covered up the powerful effectiveness of phenothiazine neuroleptics in a subpopulation of schizophrenia (Fish 1964). With the employment of Karl Leonhard’s classification of “endogenous psychoses,” he revealed that 3 of 4 patients with unsystematic schizophrenia, one of the two classes of disease subsumed under the diagnosis of schizophrenia, responded favorably to neuroleptic phenothiazines, whereas only about 1 of 4 patients with systematic schizophrenia showed a similar favorable response. Response rate in affect-laden paraphrenia, one of the three forms of unsystematic schizophrenia was about 85%, whereas in the different forms of systematic schizophrenia, response rates were below 25% (Fish 1964; Leonhard 1957)

       The CODE System consists of a set of diagnostic instruments (“CODES”) that can provide for polydiagnostic evaluation in distinct categories of mental illness by the employment of an integrated criteria list and standardized data collection. Each CODE consists of a vocabulary, or set of variables (“codes”), that includes all the elementary units (variables) of the diagnoses in the component classifications; a structured interview, that provides algorithms for the determination of the presence or absence of each variable; and diagnostic decision trees that provide diagnoses in all the component diagnostic systems (Ban 1991). In addition, each CODE includes a rating scale, based on a subset of variables from the vocabulary, for the determination of the severity of the clinical state across diagnoses. A unique characteristic of the CODE System is that it provides readily accessible information relevant to the diagnostic process from the lowest to the highest level of decision-making. The first set of provisional CODEs included polydiagnostic algorithms for anxiety disorders (CODE-AD), depressive disorders (CODE-DD), hyperthymic disorders (CODE-HD) and schizophrenic disorders (CODE-SD) (Ban 2001b; Gaszner and Ban 1998).

CODE-DD

       The prototype of the CODE System is CODE-DD, the CODE for unipolar depressive disorders (Ban 1989).  One of the contributing factors to its development was the recognition that the diagnosis of “vital depression” was covered up with consensus-based classifications, such as the DSM-III (American Psychiatric Association 1980). Vital depression, characterized by “corporization,” “disturbance of vital balance,” and the “feeling of loss of vitality” (Schneider 1920, 1950, 1959), is the form of depression that provided Roland Kuhn, the necessary diagnostic endpoint to recognize the antidepressant effect of imipramine (Kuhn 1957). In currently used consensus-based classifications, the diagnosis of “vital depression” is covered up to the extent that even in a severely ill patient who displays all the possible symptoms and signs considered for the DSM-III, DSM-III-R and DSM-IV (American Psychiatric Association 1980, 1987, 1994) diagnoses of “major depression” and the ICD-10 (World Psychiatric Association 1992) diagnosis of “depressive episode,” one still would not know whether the patient qualifies for vital depression.

       CODE-DD consists of a 90-item vocabulary, a structured interview, a 40-item severity subscale and 25 diagnostic decision trees. Of the diagnostic systems included in CODE-DD, three are based on the conceptual development of the classifications of depressive disorders in Europe (Kraepelin 1896, 1921; Leonhard 1957; Schneider 1959); and three on the conceptual development of classifications in North America (Feighner, Robins, Guze et al. 1972; Robins and Guze 1972; Spitzer, Endicott and Robins 1978); two are consensus-based classifications, one based primarily on the consensus of experts in the USA (American Psychiatric Association 1987) and one on the consensus of experts in Europe (World Health Organization 1988); 10 are empirically derived  classifications, the result of factor or  cluster analyses of psychiatric rating scales (Foulds  1973, 1976; Hamilton and White 1959; Lewis 1934; Kiloh and Garside 1963; Mendels and Cochrane 1968; Overall, Hollister, Johnson and Pennigton 1966; Paykel 1971; Pilowsky, Levine and Boulton 1969; Raskin and Crook  1976; Wing, Cooper and Sartorius 1974); six are miscellaneous classifications (Berner, Gabriel, Katschnig et al. 1983; Kielholz 1972; , Klein 1973, 1974; Pollitt 1965; Taylor 1986; Winokur, 1974, 1979); and one is a composite diagnostic classification, based on the different classifications included in CODE-DD.

       One would expect low inter-rater agreement in such a complex system like CODE-DD. However, in the first reliability study that included 239 patients there was an 87.8% inter-rater agreement on the presence or absence of the 90 items of the vocabulary (Morey 1991). In the second, inter-rater agreement increased to 100% (Ban, Fjetland, Kutscher et al. 1993). In a validation study that included 230 of patients with a clinical diagnosis of major depression, there was a 99.6% correspondence between the clinical DSM-III-R and CODE-DD diagnosis of major depression. In another validation study, which included 322 patients, the correspondence was 97.2% (Ban, Fjetland, Kutscher et al. 1993). CODE-DD was translated and adopted from the English original (Ban 1987) into Estonian (Mehilane 1992), French (Ferrero, Crocq, and Dreyfus 1992), Italian (Aguglia and Forti 1989), Polish (Pużyński, Jarema and Wdowiak 1989) and Portuguese (Nardi and Versiani 1990). It was used in a series of clinical studies in the early development of reboxetine, a selective NE re-uptake blocker (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. If depressive illness were characterized by unmotivated depressed mood, depressive evaluations, and lack of reactive mood changes, from the 322 patients with the clinical diagnosis of major depression -- included in the second validation study -- only 119 patients, i.e., 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. From the 322 patients only 95 patents, i.e., 29.5%, fulfilled definite criteria of Kraepelin’s depressive states, characterized by motor retardation, retardation of thought and difficulties of concentration (Kraepelin 1896), and even less, 45 patients, i.e., 14%, fulfilled criteria of Schneider’s vital depression (Schneider 1920). The overlap between the two forms of depressive illness was negligible (Ban 2001b)

CODE-UD

       To extend the scope of CODE-DD for uncovering depressive diagnoses, the instrument was revised. In the revised instrument (CODE-DD-R), also referred to as CODE-UD, the vocabulary was increased from 90 to 220 variables, and the number of diagnostic algorithms from 25 to 84. CODE-UD includes all major diagnostic concepts and classifications of melancholia/depression from Hippocrates (460-377 BC) to the DSM-IV(American Psychiatric Association 1994).

       The term “melancholia” was first used in the 5^th century BC, in reference to all chronic mental syndromes that did not qualify for epilepsy, hysteria or Scythian disease (transvestism), in the Works of Hippocrates (Adams 1929). Until the late 18^th century the concept of melancholia had virtually no relationship with our current concept of depression; Boissier de Sauvages classified the melancholias as disorders of intellect (Sauvages 1769) and Willam Cullen as disorders of judgment (Cullen 1772).

       Development of our current conceptual framework relevant to depressive illness began in the early 19^th century by Johann Christian Heinroth’s recognition that melancholia is a disorder of affect. Heinroth (1818) perceived insanity as exaltation or depression of one of three faculties (emotion, intellect, volition) of the mind and classified melancholia as partial insanity that is characterized by depression of emotions (Heinroth 1818). Twenty years later, by separating lypemania (lupos=sadness), or melancholy of the ancient (Healy 1997) from the monomanias (intellectual, affective and instinctive), Jean-Etienne Dominique Esquirol set the stage for a development that led to our current diagnostic concepts and classifications of depression (and also of other mental disorders) (Esquirol 1838).      

Nosologic Homotyping

       The need for a pharmacologically valid, empirically derived nosology was first expressed in the late 1950s by Fritz Freyhan, a German born, American psychiatrist. He recognized the differential responsiveness to the same psychotropic drug in the same (Kraepelinian) diagnostic category and suggested a pharmacological re-evaluation of psychiatric nosology with the employment of target symptoms and diagnoses (Freyhan 1959; Shorter 2005).

       Nosologic homotyping is a methodology for the development of an empirically derived, pharmacologically valid, classification of mental disorders. Nosologic homotypes are identical in “elementary units” of mental illness and are assigned the same position in the “nosologic matrix” constructed with the employment of nosologic organizing principles (Ban 2002)

       The elementary units of mental illness are psychopathologic symptoms; each psychopathologic symptom has a content derived from past experience and a form, characteristic of the illness (Jaspers 1910, 1913). Each psychopathologic symptom represents a distinct pathology in the processing of mental events and each psychopathological symptom profile, is a “phenotype” of a mental disorder. The temporal organization of the psychopathologic symptoms reflects the pathological process in its “dynamic totality” and the “dynamic totality” of the pathological process, together with the “totality” and “polarity” of the clinical picture, provides a “structure” that is determined by the illness (Ban 1987). It is in terms of this “determining structure,” that each mental illness is defined and assigned a place in the “nosologic matrix” based on three nosologic organizing principles (Ban 2002).

       The first organizing principle of psychiatric nosology is “totality,” i.e., the inclusiveness of the psychopathologic process (Ban 2000). It was the organizing principle in the classification of Cullen (1772), Esquirol (1838), Kahlbaum (1863), and many others. On the basis of “totality,” insanity is divided into “universal” (“total”) and “partial”; in “partial insanity,” in contrast to “universal insanity,” personality remains preserved. The concept of “partial insanity” was extended to include “abortive” (distinct from “true”), “selective” (distinct from “universal”) and “incomplete” (distinct from “complete”) mental illness (Ban 2000).   In “abortive” mental illness patients are aware (have insight) that their thinking and/or feelings and/or actions are pathological. (Westphal 1878); in “selective” mental illness, the pathology of mental integration is restricted to one (or two) of the three field(s) of consciousness, i.e., the external world (“allopsychic”), the self (“autopsychic”) and the body (“somatopsychic”) (Wernicke 1899); and in “incomplete” mental illness the pathology is restricted to one or two of the three components of the “psychic reflex,” i.e, afferent (“perceptual-cognitive”), central (“relational-affective”) and efferent (“motor-adaptive”) (Leonhard 1957).

       The second organizing principle of psychiatric nosology is the temporal organization of the psychopathologic process, i.e., the “onset” (“sudden” vs/ “insidious”), “course” (“episodic” vs. “continuous”) and “outcome” (“recovery” vs “defect”).  It was the organizing principle of mental illness in the sixth edition of Kraepelin’s textbook (Kraepelin 1899) and has remained the organizing principle in the classifications of mental illness to-date. On the basis of the temporal organization of psychopathologic symptom “attacks,” i.e., episodes that last from minutes to hours, are distinguished from “phases,” i.e., episodes that last from days to years, and from “periods,” i.e., “phases” that recur with regularity; and “thrusts,” i.e., acute events that yield lasting changes, are distinguished from “ continuous process,” i.e., chronic events that yield highly differentiated irreversible “end-states,” and from “progressive deterioration,” i.e., chronic events that yield severe dedifferentiation terminating in irreversible dementia  (Jaspers 1913).

       The third organizing principle of psychiatric nosology is the spatial organization of the psychopathologic process, i.e., “polarity” of the psychopathological process. The origin of the concept of “polarity,” is in Edda Neele’s evalution of phasic sicknesses diagnosed between 1938 and 1942 in Karl Kleist’s “clinic” in Frankfurt (Neele 1949; Teichmann 1990). Polarity was to become the dominant organizing principle in Karl Leonhard’s classification of endogenous psychoses in which “monopolar” (“simple”) psychoses, such as the phasic psychoses and systematic schizophrenias, were separated from the “bipolar” (“multiform”) psychoses, such as manic-depressive disease, the cycloid psychoses, and the unsystematic schizophrenias (Leonhard 1957). Within Leonhard’s frame of reference, bipolar illness swings between two poles of mood and/or emotions and/or motility and displays a continuously changing, variable clinical picture, whereas “unipolar” illness is restricted to one pole of mood and/or of emotions and/or of motility and displays the same symptomatology within and across episodes. Each form of “unipolar” illness is distinct and characterized by a syndrome associated with no other forms and not even transitionally related to any other form.

       Nosologic homotypes are more homogenous populations in terms of psychopathology than populations identified by any of the available diagnostic instruments. If nosologic homotyping would identify pharmacologically or genetically homogenous populations, it would indicate that phenomenological psychopathology and psychiatric nosology could provide the key for the delineation of biologically meaningful disease categories in psychiatry. By linking the mode of action of psychotropic drugs to pharmacologically homogeneous populations, nosologic homotyping could break the impasse in progress of neuropsychopharmacological research, pharmacotherapy and molecular genetic research in mental illness (Ban 2002).

       Furthermore, considering that “nosological homotypes” are defined in terms of their effect on processing of mental events, and psychotropic drugs are defined in terms of their effects on “signal transduction” in the brain, the empirically derived diagnostic categories could provide clinical entities which are suitable for testing hypotheses relevant to the relationship between processing of mental events and “signal transduction” in the central nervous system. Thus, “nosologic homotyping” could open the path for the development of a psychiatry, in which mental pathology is perceived in terms of pathology in “signal transduction” in the brain and for a rational pharmacotherapy of mental illness. 

Concluding Remarks

       Recognition of a possible relationship between drug-induced changes in psychopathology, and in the concentration of monoamine neurotransmitters and their metabolites in the brain led to the formulation of the hypothesis that the psychotropic effects of drugs are related to their action on the transmission (processing) of impulses at the synaptic cleft (Ban 2000, 2002, 2006; Brodie, Shore and Pletscher 1956; Brodie, Pletscher and Shore 1956; Pletscher, Shore and Brodie 1955, 1956; Shore, Silver and Brodie 1955a,b). The notion that drugs exert their psychotropic effects through the modification of transmission of impulses from one neuron to another has far reaching heuristic implications for psychiatry. The cerebral cortex of the human brain contains about 10 billion neurons, with about one million billion connections, of which the majority communicates only with each other (Edelman 1992). The lack of consistent biological manifestations in mental illness has raised the possibility that the site of mental pathology is the major compartment of the cerebral cortex that has no direct contact with either sensory input or behavioral output (Ban 2004). If this is the case, the primary manifestations of the psychiatric disease process are psychopathological symptoms and nosologic entities, i.e., patterns of psychopathologic symptoms (Ban 1987), and nosologic homotyping is a suitable methodology for rendering the morphologic substrate of mental pathology accessible to scientific scrutiny.

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*Based on a paper presented in Keszthely, Hungary, and published in Neuropsychopharmacologia Hungarica  2007:9:81-90.

November 11, 2021