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

Background to An Oral History of the First Fifty Years
Psychopharmacology (Volume Four): 1. Clinical methodology
(Bulletin 44)


            The term “psychopharmacology” was introduced in 1920 by David Macht, an American pharmacologist, for describing the effects of drugs on psychometric performance tests (Macht 1920).The scope of psychopharmacology was gradually extended and by the 1960s it embraced all research dedicated to study the effects of centrally acting drugs (Ban 2006a).  

            In this series the broad, all-embracing concept of psychopharmacology is deconstructed into its component disciplines: Volume One, Starting Up, deals with measurable changes caused by drugs on behavioral parameters (“behavioral pharmacology”); Volume Two, Neurophysiology, deals with the impact of drugs on cerebral metabolism and electrical activity; Volume Three, Neuropharmacology, focuseson molecular and sub-molecular brain structures; and Volume Four, Psychopharmacology, focuses on mental faculties and psychopathology. Thus, in this volume, interviewees reflect on their contributions to psychopharmacological research.

            The story begins in the 1950s with the serendipitous discovery of effective pharmacological treatments for schizophrenia (chlorpromazine and reserpine), depression (iproniazid and imipramine), mania (lithium) and anxiety (meprobamate) (Ban 2006b).The new drugs were received incredulously by the psychiatric establishment (Ban 2007).Yet, by the end of the 20th century drug therapy was the primary form of treatment in the majority of psychiatric disorders.

            Central to psychopharmacological research is the identification of pharmacologically homogeneous populations. Recognition that the populations within psychiatric diagnoses are pharmacologically heterogeneous led to the development of the AMP documentation system in German-speaking countries for characterizing the clinical effect of drugs. To overcome the difficulty of demonstrating therapeutic efficacy in pharmacologically heterogeneous diagnostic population, the Biometric Laboratory Information Processing System (BLIPS) was developed in the United States. Both systems were introduced in the 1960s and are defined below.


The AMP System

            Activities which led to the introduction of the AMP System began in the late 1950s by two independent teams of university-based psychiatrists, one in the Federal Republic of Germany (FRG) and the other in Switzerland, collaborating in clinical studies with psychotropic drugs (Angst, Battegay, Bente et al. 1967).

            In the early 1960s, members of the two groups, together with Peter Berner from the Department of Psychiatry, University of Vienna, Austria, and Paul Schmidlin from Geigy, a Swiss pharmaceutical company, embarked on the development of a common documentation system for studying and characterizing the clinical effects of the new drugs.

            The psychiatrists in the FRGincluded: D. Bente (Erlangen), M.P. Engelmeier (Essen), K.

            Heinrich (Dűsseldorf), H. Helmchen and H. Hippius (Berlin) and N. Schmitt (Saarbrűcken.) The psychiatrists in Switzerland included: J. Angst (Zurich,) F. Cornu   (Bern), P. Dick (Geneva), H. Heimann (Lausanne) and O. Pöldinger (Basel).

            The working relationship was formalized in 1965 by the founding of the Arbeitsgemeinschaft fűr Methodik und Documentation in der Psychiatry (Working Group for the Methodology and Documentation in Psychiatry) with a secretariat at the Psychiatric Clinic of the Free University in West Berlin. The documentation system, completed in 1967, was referred to as the AMP System, using the acronym of the Working Group.In the 1970s, the acronym was changed to AMDP (Association for Methodology and Documentation in Psychiatry) (Angst, Battegay, Bente et al.1969a).

            The AMDP System consists of five integrated forms for recording: (1) Demographic Data, (2) Life Events, (3) Psychiatric History, (4) Psychopathological Symptoms (PSF) and (5) Somatic Signs (SSF). Two of the five forms, the PSF and the SSF, are suitable for the assessment of change in the clinical state of patients. The PSF includes 100 items, organized into 13 categories; the SSF consists of a catalogue of 41 physical symptoms (signs) listed under seven headings (Angst, Battegay, Bente at al. 1969b). Programs for computer processing of the AMP (AMDP) data were developed in the 1960s and 1970s at several centers, including Berlin, Erlangen, Munich and Zurich (Bente, Feder and Siegordner 1970).

            The 13 categories of the PFS: (1) intellectual deficit, (2) disorders of consciousness, (3) disturbance of orientation, (4) disturbance of attention and memory, (5) formal disorders of thought, (6) phobias and compulsions, (7) delusions, (8) disorders of perception, (9) disorders of ego, (10) disturbances of affect, (11) disorders of drive and psycho-motility, (12) circadian disturbances and (13) other disturbances, including social withdrawal, excessive social contact, aggressiveness.

                The seven headings of the SSF catalogue: (1) disturbance of sleep and vigilance, (2) appetite disturbances, (3) gastrointestinal disturbance, (4) cardiac-respiratory disturbances, (5) other autonomic disturbances, e.g., blurred vision, (6) other somatic disturbances, e.g., headache and (7) neurological disturbances.

            Since its first edition in 1971,the AMP (AMDP) Manual has been revised several times. It’s most recent eighth edition was published in 2007 (AMDP 2007; Scharfetter 1971).

            The Manual was translated into several languages because it seemed a more suitable instrument for the delineation of the therapeutic profile of psychotropic drugs than the conventional rating scales used in clinical trials (Ban, Lehmann, Galvan et al. 1974).

            The manual was translated into Croatian, Dutch, English, Estonian, French, Greek, Italian, Japanese, Portuguese, Russian and Spanish.

            The initial English translation was completed in 1974 from the second edition of the Manual by Jűri Saarma, in collaboration with Thomas Ban and Heinz Lehmann (Ban 1978; Scharfetter 1972).Saarma, chairman of the Department of Psychiatry at the University of Tartu, Dorpat, Estonia, where Emil Kraepelin began his career, was at the time Visiting Professor with the WHO Training Program in Biological Psychiatry in Montreal. 

            In 1977 the third German edition of the system, AMDP-III, was published (AMDP 1977).The changes in AMDP-III were significant enough to warrant a new English translation. This was prepared by William Guy and Thomas A. Ban,in collaboration with D. Bobon, J. Hoenig, R. Jamieson, Y. Lapierre, A. Leeds, H. Lehmann, J. Libiger and J. Saarma, and consultation with J. Angst, P. Berner, P. Grof, M. Hamilton, H. Helmchen, M. Hollender, E. Koranyi and N. Sartorius, and published in 1982 (Guy and Ban 1982). The advent of AMDP-III created a similar situation for other translations (Bobon 1978; Bobon and Saarma 1978).To coordinate activities among the groups involved with AMDP outside of German-speaking countries, an International AMDP Secretariat was established at The University of Liege, Belgium, under the leadership of Daniel Bobon (Bobon, Baumann, Angst et al. 1963).

            To render studies conducted with the AMDP accessible for data processing and analyses by BLIPS, William Guy prepared a series of input matrices for the five forms of the system with the employment of universal op-scan data sheets (Guy and Ban 1983).



            The development which led to the BLIPS began in 1956 with the establishment of the Psychopharmacology Service Center (PSC) by the National Institute of Mental Health (NIMH) and the appointment of Jonathan O. Cole as its director. The Center was mandated to facilitate the clinical development and adoption into clinical practice of the rapidly growing number of new drugs with psychotropic potential. To accomplish this task, Cole launched the NIMH Collaborative Studies with Phenothiazines in the Treatment of Schizophrenia; embarked on the development of the Early Clinical Drug Evaluation Unit (ECDEU) network (program); and established a Biometric Laboratory at George Washington University for developing a data collection, processing and reporting system with a data bank for clinical trials. The systemdeveloped by the staff of the Laboratory, in collaboration with the ECDEU investigators, was to be referred as BLIPS.

            By January 1962, the ECDEU network included 15 centers investigating a total of 48 new drugs; by the mid-1960s, BLIPS was ready to analyze clinical trials conducted by ECDEU investigators. The computer-generated “output package” consisted of a standardized report that included a brief description of the clinical study, the findings of statistical analyses and tabulations of recorded data on the various assessment instruments employed(McGlashan 1973).

            Jonathan Cole left NIMH in 1967 and was succeeded by Jerome Levine. In 1968 the PSC was converted into the Psychopharmacology Branch of NIMH with Levine as its first chief.

            In 1968, the Laboratory offered to analyze any clinical study (not just studies done within the network) in which the ECDEU assessment battery was employed.

            The first ECDEU Assessment Manual was prepared by William Guy and Roland Bonato in 1970 (Guy and Bonato 1970). A revised, enlarged manual, with the inclusion of 43 scales was published in 1976 by Guy (Guy 1976).Notably, the revised Manual serves as a guide for selecting the appropriate data collection forms for the three successive phases of clinical investigations: thePlanning Phase, the Data Collection Phase and the Analytic Phase.


            Obligatory forms to be used in all clinical investigations:

Analytic Planning Phase:      

            Research Plan Report 

            ECDEU Assessment Instrument Order Form

Data Collection Phase:

            Dosage Record and Treatment Emergent Symptom Scale

            Clinical Global Impressions

            Patient Termination Record

Analytic Phase:

            Research Completion Report

            Data Shipment Form

                        Scales recommended to beused in the assessment of change:

Studies with neuroleptics:

            Brief Psychiatric Rating Scale (BPRS)

            Nurses Observation Scale for Inpatient Evaluation (NOSIE)        

Studies with antidepressants:

            Hamilton Psychiatric  Rating Scale for Depression (HAMD)

            Depression State Inventory (DSI)

            Self-rating Scale for Depression (SRSD)

Studies with anxiolytics:

            Hamilton Anxiety Scale (HAMA)

            Anxiety Status Inventory (ASI)

            Self-rating Anxiety Scale (SRAS)

            Self Report System Inventory (SRSI). 


            Following the publication of the revised manual there was an expansion in the use of the BLIPS from a limited number of ECDEU investigators to a rapidly growing number in Canada and the United States. The ECDEU network was dismantled and replaced by the New Clinical Drug Evaluation Units (NCDEU) network, which included clinical investigators using the BLIPS regardless of NIMH support. Having fulfilled its purpose by developing a data processing system for clinical investigations with psychotropic drugs, in the late 1970s the Biometric Laboratory at George Washington University was closed. Since interest in the BLIPS continued, in the early 1980s a Center for Clinical Psychopharmacology Documentation was set up by Jerome Levine, Cole’s successor, with NIMH support at the Psychiatric Clinic II of the University of Pisa in Italy for clinical investigators in Europe.      

                Introduction of the BLIPS had a major impact on the development of a clinical methodology. During the 1970s testimonials about clinical effects were replaced by findings in properly designed clinical experiments and by the early 1980s the double-blind, placebo-controlled clinical trial with random assignment of patients to parallel treatment groups (RCT) had become standard for efficacy studies with psychotropic drugs. As multi-center clinical investigations were replacing single center clinical trials, in the 1980s power statistics entered the design in order to prevent a type-II beta error -- the overlooking of a statistically significant difference between placebo and aninvestigational drug because of insufficient sample size(Ban and Wilson 1981).

            Simultaneously with the changes in methodology, descriptive statistics were complemented with non-parametric statistical techniques (chi square test, Mood’s median test, the Mann-Whitney U-test and the Wilcoxon matched-pairs signed rank test) in the analyses of data. As the sample size of studies grew, non-parametric statistical techniques were replaced by parametric statistical techniques (Student’s t-test, analyses of variance and covariance) assuming that in larger samples rating scores have a Gaussian normal distribution (Wilson and Ban 1982).


Diagnostic End Points

            The clinical end-points of efficacy studies are psychiatric diagnoses. The first consensus-based diagnostic classification with a glossary of definitions was the Diagnostic and Statistical Manual (DSM)-I of the American Psychiatric Association (American Psychiatric Association 1952).A variant of the WHO’s International Classification of Disease (ICD)-6, DSM-I was introduced in 1952, just about the time chlorpromazine was launched for clinical use in France. Both classifications were replaced by the end of the 1960s: ICD-6, first by ICD-7 in 1955, then by ICD-8 in 1965,and DSM-I by DSM-II in 1968 (American Psychiatric Association 1968; World Health Organization 1949, 1955, 1965).

            There were conflicts between diagnoses in the consensus-based classifications and the classification of psychotropic drugs. West and Dally found iproniazid, a monoamine oxidase inhibitor (MAOI) classified as an antidepressant, effective in a group of patients who showed opposite features, such as hypersomnia and hyperphagia, to those encountered in patients who would qualify for a depressive diagnosis in the ICD-7 or DSM-I; Sargant and Dally reported on the effectiveness of MAOIs in “anxiety states,”and several clinicians noted that some MAOIs, e.g., phenelzine, could control phobic-anxiety-depersonalization, a syndrome with spontaneously recurring anxiety (panic) attacks, described  by Martin Roth in 1959 (Hollander and Ban 1979;  Roth 1958; Sargant and Dally1962; West and Dally 1959).

            In order to facilitate the development of a classification of psychiatric disorders which corresponds more closely than consensus-based diagnoses with the therapeutic profile of psychotropic drugs, the first multi-axial classifications were proposed by Wing and his associates in the UK; Ottoson and Perris in Sweden; Helmchen in Germany; and Strauss in the United States (Helmchen1975, 1980; Ottoson and Perris 1973; Strauss 1975; Wing, Bramley, Hailey and Perris 1968).The development of multi-axial classifications culminated in 1980 with the publication of DSM-III (American Psychiatric Association 1980).

            DSM-III was the first consensus-based classification with a multi-axial evaluation and operationalized diagnostic criteria. Its development was linked to research focused on the verification of psychiatric diagnoses by “external validators,” in the Department of Psychiatry of Washington University in St. Louis, Missouri,and on the measurement of concordance in diagnosis (reliability) among clinicians by kappa statistics developed in the Biometric Research Department of the New York State Psychiatric Institute (Fleiss, Spitzer and Endicott1972; Robins and Guze 1970).The diagnostic formulations of DSM-III combine both traditions of medicine, the tradition of Galen (131-201 AD) focused on disease and the tradition of Hippocrates (460-370 BC) focused on the patient (Garrison 1960).Thus, they contain categorical judgments regarding the disease, recorded on Axis I (clinical psychiatric syndromes) and Axis III (non-psychiatric medical illness) and dimensional ratings regarding the patient, recorded on Axis IV (severity of psychosocial stressor) and Axis V (level of adaptive functioning) (Mezzich1980).In the DSM-III, personality disorders were separated from the clinical syndromes on Axis II. In spite of severe criticisms, DSM-III and its successors, the DSM-III-R, published in 1987,and the DSM-IV, published in 1994, have become an unprecedented success(American Psychiatric Association1987, 1994).  The operationalized criteria for diagnostic decisions provided reliable clinical end-points for single-center and multi-center clinical investigations with psychotropic drugs (Ban 2000).




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November 15, 2018