From Case Reports to Drug Surveillance

The era of psychopharmacology in psychiatry commenced with clinical investigations of a few cases in France in 1952: the discovery of the antipsychotic (”neuroleptic”) efficacy of chlorpromazine. Confirmatory results were subsequently published in Switzerland, Austria, and Germany, and later in Canada, the USA, and Great Britain. During this pioneering period of pharmacopsychiatric research, interest was focused almost exclusively on the various therapeutic qualities of antipsychotic effects. The somatic effects of antipsychotic drugs, in contrast, were mentioned only as a matter of secondary importance. This view changed in the middle of the 1950 s after cases of various undesired adverse reactions had been observed, e. g., cholestatic jaundice, skin reactions, and blood dyscrasia. Clinical pictures and the frequency of these ”side effects” were described in numerous publications, recommendations were made for their early diagnosis, and steps were elaborated to prevent severe complications.

It was, however, striking that only one particular group of side effects was judged differently: extrapyramidal symptoms, first observed during therapy with phenothiazines and reserpine as Parkinsonism. Some clinicians suspected quite early that extrapyramidal side effects were intimately connected with antipsychotic efficacy. The hypothesis that extrapyramidal effects are the prerequisite for therapeutic efficacy strongly influenced the development of pharmacopsychiatry. After the introduction of butyrophenone derivatives (haloperidol type antipsychotics), the so-called ”neuroleptic dogma” became the foundation for basic and clinical research (”no therapeutic effects without extrapyramidal efficacy”).

This ” dogma” could be refuted only after the antipsychotic agent clozapine was found to lack such extrapyramidal side effects [13]. Only then did antipsychotic agents without extrapyramidal side effects appear to be possible (especially without posing a risk of tardive dyskinesia). Clozapine, however, posed another serious problem. Compared with other antipsychotic drugs, clozapine induces an increased frequency of blood dyscrasia. If this side effect is not diagnosed in time, there is a risk of developing agranulocytosis, possibly with a fatal outcome.

In the middle of the 1970 s, therefore, it seemed imminent that the therapeutic use of clozapine would be halted or even forbidden completely. This threat was successfully circumvented by demonstrating that regular monitoring of the blood would permit the diagnosis of blood dyscrasia early enough to terminate drug therapy before serious complications arose.

The ”rescue” of clozapine therapy was the starting point of two important developments in psychopharmacology:

Although clozapine had been considered after its discovery to be a unique outsider, labeled an ”atypical neuroleptic,” it was in reality an important breakthrough. However, almost two decades passed before the error of the ”neuroleptic dogma” could be corrected. Now 15 years later the group of modern (”atypical”) antipsychotic agents with no or very few extrapyramidal side effects (e. g., amisulpride, olanzapine, quetiapine, risperidone, ziprasidone) has increasingly replaced the older conventional antipsychotics. Once clozapine was approved for therapeutic use, the demand for reliable monitoring of side effects became more and more accepted.

My own experience with the side effects of drugs began in the early 1950 s when I observed a case of agranulocytosis induced by mepazine [8], a phenothiazine derivative closely related chemically to chlorpromazine. This was followed by

a systematic search for other cases of agranulocytosis induced by phenothiazines in the early literature, culminating in a review with the first calculation of the incidence of agranulocytosis in phenothiazine therapy (0,1 %) 11; and discussions on the role of the somatic effects of antipsychotic drugs, i. e., concomitant effects, undesired side effects, and risks 9 10.

At the same time the first programs for ”drug surveillance” or ”drug monitoring” were being established in hospitals for internal medicine in the USA, Canada, Switzerland, and Germany [USA: 1963: Johns Hopkins Hospital; 1966: Boston Collaborative drug surveillance program”; Germany: Medizinische Universitätsklinik Heidelberg [2] [3] [14]. Several years later analogue programs were initiated in psychiatric hospitals in Canada and the USA [1] [12]. In Germany a task force ”Arzneimittelüberwachung in der Psychiatrie (AMÜP)” was launched in 1978 under the aegis of the ”Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP)” [7]. After setting up standardized definitions of all kinds of undesired drug effects (”Unerwünschte Arzneimittelwirkungen - UAW”), the instruments for recording and evaluating them were developed. Then from 1979 until 1986 the data on circa 15,000 patients treated with psychoactive drugs were recorded and evaluated. Two Psychiatric University Hospitals (Munich and Berlin) took part in the AMÜP study [4] [6].

The comprehensive results of this extensive study were published in a book in 1994 [5] as well as in numerous single papers presented at congresses and in various journals. Based on the knowledge gained by the AMÜP study and the broad experience accumulated in such an investigation in two hospitals, a new research program (”Arzneimittelsicherheit in der Psychiatrie, the AMSP”) was put into operation. Since 1993, 45 hospitals have participated in this program.

The first comprehensive presentation of the results of the AMSP program, independently of the numerous single publications, took place at a symposium on the occasion of the foundation of the Institute for Drug Safety in Psychiatry (”Institut für Arzneimittelsicherheit in der Psychiatrie - AMSP e. V.”) in Munich in 2001. Most of the contributions to this symposium are now published in this issue of ”Pharmacopsychiatry”. For me personally this supplement is an additional milestone on the long road we have travelled from case reports to systematic drug monitoring.

References

• 1 Ananth J V, Ban T A, Lehmann H E, Rizvi F A. An adverse reaction unit: Results and functions.  Am J Psychiatry. 1971;  127 1339-1344
• 2 Borda I T, Slone D, Jick H. Assessment of adverse reactions within a drug surveillance program.  JAMA. 1968;  204 99-102
• 3 Cluff L E, Thornton G F, Seidl L G. Studies of the epidemiology of adverse drug reactions.  JAMA. 1964;  188 976-983
• 4 Grohmann R. The AMÜP-study - a final summary.  Pharmacopsychiatry. 1990;  23 241
• 5 Grohmann R, Rüther E, Schmidt L G. Unerwünschte Wirkungen von Psychopharmaka - Ergebnisse der AMÜP-Studie. Springer Verlag Berlin, Heidelberg, New York; 1994
• 6 Grohmann R, Hippius H, Helmchen H, Rüther E, Schmidt L G. The AMÜP study for drug surveillance in psychiatry - a summary of inpatient data.  Pharmacopsychiatry. 2004;  37 Suppl 1 S16-26
• 7 Helmchen H, Hippius H, Müller-Oerlinghausen B, Rüther E. Arzneimittelüberwachung in der Psychiatrie.  Nervenarzt. 1985;  56 12-18
• 8 Hiob J, Hippius H. Über die Behandlung von Psychosen mit dem Phenothiazinderivat ”Pacatal”. Med. Klin 1955: 1746-1748
• 9 Hiob J, Hippius H. Avoidance of physical side effects. In: Kline NS (ed) Psychopharmacology Frontiers. Little, Brown Boston/Toronto; 1959: 209-214
• 10 Hiob J, Hippius H, Kanig K. Über die Bedeutung ”körperlicher Nebenwirkungen” bei der Pharmakotherapie der Psychosen. Wien; Zschr. Nervenkr 1958 15: 135-147
• 11 Hippius H, Kanig K. Die Agranulozytose unter neuro-psychiatrischer Phenothiazin-Therapie. Ärztl. Wschr 1958: 501-507
• 12 Shader R I. Fear of side effects and denial of treatment. In: Ayd FJ (ed) Rational psychopharmacotherapy and the right to treatment. Ayd Medical Communications Maryland; 1975: 106-117
• 13 Stille G, Hippius H. Kritische Stellungnahme zum Begriff der Neuroleptika (anhand von pharmakologischen und klinischen Befunden mit Clozapin).  Pharmakopsychiat.. 1971;  4 182-191
• 14 Weber E. Arzneimittelnebenwirkungen in Abhängigkeit von dem Verordnungsmuster.  Verh Dtsch Ges Inn Med. 1977;  83 1502-1512