My professional development in clinical psychopharmacology
Having trained in experimental methods at the Max Planck Institute (MPI) for Medical Research in Heidelberg since 1952, I began as a clinician in neurology in 1956 and since then have been involved in the new development of treatment with psychotropic drugs at the Psychiatric Department of the Free University of Berlin, at that time one of the few departments in Germany active in the innovative field of psychopharmacotherapy.
At the MPI I investigated the permeability of the blood-brain-barrier both in cats after brain concussions (Quadbeck and Helmchen, 1955) and in mice that developed epileptic fits after hearing clanking noise (“musicogenic epilepsy”) (Quadbeck and Helmchen, 1958). This experimental work stimulated my interest in patients with epilepsy and later on in cerebral determinants of mental disturbances in epileptic patients. I assumed that bilateral EEG-(“mirror”)-foci in the temporal lobes, which had been developed as a unilateral focus after a duration of epilepsy of six years and a further duration of roughly seven years (i.e., a total of 13 years), were an essential condition for the manifestation of psychotic episodes (Helmchen, 1975a). For this study, I developed record sheets for a systematic documentation of findings. However, I could not find the necessary number of epileptic patients with psychotic episodes for a systematic investigation of my hypothesis.
Due to this context, I learned to carry out and understand electroencephalography (EEG). Very soon it became apparent to me that the normal EEG in psychotic patients treated with psychotropic drugs changed in a way that I had learned to judge as pathological; in fact the more evidently the EEG became more “pathologic” with general dysrhythmia and foci, the more the psychotic symptoms simultaneously returned (Helmchen and Künkel, 1964). Such an antagonistic phenomenon – but in the opposite direction – had been described a few years earlier as a “forced normalization” of an epilepsy specific altered EEG in epileptic patients during a psychotic episode. In this connection, I saw the possibility to assess changes of cerebral functions underlying psychopathological phenomena, the manifestation and course of which had been modified by psychotropic drugs.
Other sources of my interest in pharmacopsychiatry were clinical observations, particularly of adverse drug reactions (ADR). To exemplify this procedure, I treated a severely delusional depressed female patient (70-years-old) with the neuroleptic drug perazin (4-Methylpiperazin-1-yl)propyl]phenothiazine, Taxilan®). She developed an uncontrollable delirium and died. I looked for reasons of this unexpected death in all documented findings and in the literature, and developed the hypothesis of an interaction between the neuroleptic drug perazin and the anticholinergic drug biperiden. To prove this hypothesis, I analyzed the case records of all 40 patients in the hospital with delirious states and could confirm that this drug-drug interaction disposed patients older than 50 for such delirious states. After that finding, we avoided the combination of these drugs (Helmchen, 1961) and no longer observed these delirious states.
Together with Hanns Hippius, I focused on the description of side-effects (Helmchen and Hippius, 1962), particularly on mental side-effects of psychopharmacotherapy (Helmchen and Hippius, 1964) and the analysis of their constellations of conditions, e.g., the “syndrome genesis” of depressive syndromes (Helmchen and Hippius, 1967), which developed after several weeks of neuroleptic drug treatment and later became well-known by the term “postremissive exhausting syndrome,” introduced by Kurt Heinrich (Heinrich, 1967).
We reported these observations and analyses at the biennial symposia on special aspects of pharmacopsychiatry, organized in the 1960s and 1970s in Bad Kreuznach by Kurt Heinrich; at that time these symposia were an important place for exchanging new results of psychopharmacological research.
The determinants of unwanted psychic effects of psychotropic drugs had been illustrated by the “syndrome genetic trias”: the effect of the drug will be modified by the interaction with the genetical as well as acquired individual disposition and the acuity and severity of the disease (morbus) (Helmchen, 1969). I interpreted the modifications of the effect profiles of the therapeutically prescribed psychotropic drugs as a pharmacogenic uncovering of individual cerebral dispositions (Helmchen, 1963), which I tried to assess systematically by examining the regular modifications of the EEG under neuroleptic treatment in 100 female patients with paranoid hallucinatory syndromes. My findings showed that the development of a paroxysmal dysrhythmia was correlated with a therapeutic response – and, vice versa, a not modified “hyperrigid” EEG with a lack of response – and the development of foci predominantly in the right temporoparietal brain region with the formation of a psychopathological residual state (Helmchen, 1968); these EEG-foci were later interpreted as maturation deficits (Ulrich and Bohn, 1988).
These publications opened the way to invitations to conferences such as the annual meetings of the German Working Group for Neuropsychopharmacology (AGNP) (Helmchen, 1988), founded in 1960 and organized by Dieter Bente in Nuremberg, and to the biennial Kreuznach Symposia on special aspects of psychopharmacotherapy, organized by Kurt Heinrich (Helmchen and Hippius, 1964).
Hanns Hippius and I also discussed our findings on mental side effects of psychotropic drugs at a meeting in Zagreb, organized by Nenad Bohacek in 1962. This was also the beginning of my friendly cooperation with Norman Sartorius, which has now continued for more than half a century.
In 1966 I gave a report on mental side effects of psychopharmacotherapy at the Congress of the Collegium Internationale Neuropsychopharmacologicum (CINP) in Washington (Helmchen, 1969). While participating in the CINP Congress in Washington, my wife and I visited in Baltimore the physiologist Dr. Horsley Gantt, who had been a friend of my parents when they worked together at the Kaiser-Wilhelm-Institute for Brain Research in Berlin-Buch in the early 1930s. In the Phipps Clinic I gave my first English lecture on my EEG-studies, and I became a member of the Pavlovian Society.
The 7th CINP-World Congress took place in Prague in 1970 under unusual and memorable circumstances. The attempts of Czech intellectuals to reform communism in their country culminated in 1968 in the “Prague Spring” and led to considerable instability of the country. As a result, the American member of the congress preparatory committee tried to relocate the congress into another country outside the sphere of communist control; he argued that otherwise most Americans would not attend the congress. However, the Czech member of the committee, Oldrich Vinar, asked me to support the Congress meeting in Prague in order to make the world aware of the Czech situation. Although Soviet troops of the Warsaw Pact defeated the “Prague Spring,” the congress indeed took place in Prague. Immediately before the official opening of the congress a man hurried to the lecture pulpit and welcomed the participants in many different languages. It was Zdenek Votava, Professor of Pharmacology at Prague University, who had just lost his position due to collaboration with the reformers. Knowing this, the congress participants gave him a standing ovation. Three months later I received a last open postcard from him with a photo of his family holding a banner showing the single word “liberté.”
In the 1960s documentation of findings became possible in quantifying methods and soon also in electronically processing formats. For me it became clear that Kraepelin’s idea of the systematic assessment of findings by “Zählkarten” (counting cards) produces the prerequisites for a quantitative usage of empirical data instead of losing them in the “vast ocean” of case record archives. Thus, I participated in several working groups on the development of area specific documentation sheets for epileptological findings (Helmchen, et al., 1968), EEG-findings (Penin, et al., 1972), gerontopsychiatric data (Frost M, et al., 1971), and psychopathological findings. This latter one led to the AMDP system, for the further development of which I was responsible as chairman of the AMDP Group from 1974 to 1978. These working groups met in frequent joint closed meetings for elaboration of these documentation sheets and then for training of their usage or ratings in an intensive and friendly cooperation among colleagues, which later led to useful networks. The whole project began when senior psychiatrists from five German university hospitals, the group of five ("Fünfergruppe“: Dieter Bente [Erlangen], Max-Peter Engelmeier [Münster], Kurt Heinrich [Mainz], Hanns Hippius [Berlin] and Walter Schmitt [Homburg/Saar]), who were particularly interested in psychopharmacotherapy, started to develop documentation sheets for quantitative assessment of psychopharmacologic effects and joined a group of senior physicians from the five Swiss psychiatric university hospitals (as well as the Austrian psychiatrist Peter Berner from Vienna), who during the 1960s, were searching for solutions to the same problems and founded the, Arbeitsgemeinschaft für Methodik und Dokumentation in der Psychiatrie“ (AMP, since 1979) (Angst, et al., 1969; Helmchen, 1978; Fähndrich and Helmchen, 1983; Helmchen and Ahrens, 1998).
The documentation sheets of the AMDP System were applied to all patients of the Berlin Psychiatric University Hospital (FUB) after 1968 when Hanns Hippius became the head of the department, and also after 1971 at the Munich Psychiatric University Hospital, where Hippius took the Kraepelin Chair of Psychiatry at the Ludwig Maximilian University. At this time I became his successor in Berlin. Resting upon the broadly based data of several thousand patients, the system was evaluated and further elaborated (Baumann, et al., 1976; Bobon, et al., 1983; Pietzcker and Gebhardt, 1983; Haug and Stieglitz, 1997). The documentation at all sites according to same terms and rules was (and is) a necessary prerequisite of multicenter trials (Sartorius and Helmchen, 1981). The AMDP data system was also used for investigations of the diagnostic process and the psychiatric classification (Baumann, et al., 1975; Helmchen, 1975b; Helmchen and Fähndrich, 1996); to date the AMDP system continues to be widely used as a didactic tool in psychopathological training of young psychiatrists (AMDP, 2016; Fähndrich and Stieglitz, 2016; Fähndrich and Renfordt, 1985).
All of this work was closely connected with the clinical testing of psychotropic drugs, in the forefront of which the Berlin Psychiatric Department was engaged from the beginning of the psychopharmacotherapeutic era. Particularly memorable was the testing of the investigational drug Wander HF 1854 by AMP-affiliated colleagues in Berlin, Zürich and Vienna (Berzewski, et al., 1969; Angst, et al., 1971). We identified the specific effectiveness of this substance in its good antipsychotic efficacy without motoric side effects. This finding overturned the dogma that only those neuroleptic drugs have antipsychotic efficacy that produce a brain stem triad (“Hirnstamm-Trias”) with extrapyramidal effects (Stille and Hippius, 1971). After its clinical introduction as Leponex (clozapine), this substance soon enjoyed greater acceptance by patients than the previously known neuroleptic drugs with motoric side effects. However, in the early 1970s an epidemic of 30 cases (half of them fatal) of agranulocytosis in Finland, Switzerland and Germany (Helmchen, et. al., 1975) caused the producer of clozapine to withdraw it from the market in order not to spoil the company’s reputation. But Hippius was able to convince Dr. Bühlmann, the CEO of Sandoz Pharmaceutical Company/Germany (the parent company of the Wander Company), that a withdrawal of this successful drug would eliminate an important treatment chance for severely ill patients. By negotiations with the German licensing authority, Hippius and I achieved an agreement stating that clozapine could stay in the market under strong restraints, not only as a drug, but also as a “therapeutic system.” Fifteen years later clozapine was rediscovered in the USA and acclaimed as a breakthrough in the treatment of schizophrenia; it then acted as a starting point for the development of the so-called “atypical” neuroleptic drugs or, more correctly, “antipsychotic drugs” (Helmchen, 1989).
Due to its favorable efficacy and safety ratio, the neuroleptic drug perazin became the most used drug in our hospital; we studied it intensively and, as a result, developed a multidimensional methodology (Helmchen, et al., 1974; Helmchen, Hippius and Tölle, 1988). Perazin seemed to be qualified particularly for long-term treatment of outpatients. Therefore, shortly after the clinical introduction of perazin in 1957, a working group began to test the question whether perazin could attenuate, delay, or even prevent further episodes of schizophrenia. Since 1958 this so-called catamnestic working group (“Schizophrenie-Katamnese”) (Enss, et al., 1958; Enss, et al., 1960) – the first in Germany for long-term-monitoring of the treated course of mental disorders – has developed as a research tool for the analysis of the course of psychiatric diseases under long-term therapy with psychotropic drugs. Ten years later, after the establishment of the relapse preventing efficacy of lithium, in 1968 another working group began the long-term monitoring of patients with bipolar affective disorders treated with lithium (“Lithium-Katamnese”) (Berzewski and Kanowski, 1970; Müller-Oerlinghausen, 1977) which had been developed as an efficient research tool by the clinical pharmacologist of the Berlin Psychiatric Hospital, Bruno Mueller-Oerlinghausen (Müller-Oerlinghausen, Greil and Berghöfer, 1986).
Reviewing the data of long-term treatment of mental disorders with psychotropic drugs, I developed a framework for further research by posing open questions (Helmchen, 1978; Helmchen, 1979). Among others, the Department applied successfully for federal grants for two large studies:
Based on the “Schizophrenie-Katamnese,” a study was undertaken whether the efficacy of an Ambulant Neuroleptic Interval treatment in schizophrenic patients (“ANI”-Study) was as effective as a continuous drug treatment, but with lesser side effects: the result was negative, i.e., with regard to the frequency of relapses the study was unequivocally in favor of the continuous neuroleptic treatment (Pietzcker and Gaebel, 1987; Pietzcker, et al., 1993).
The “Lithium-Katamnese” study compared the recurrent prophylactic efficacy of lithium versus carbamazepine treatment in a Multicenter study of Affective Psychosis (“MAP”-Study, led by Waldemar Greil from Munich). The result showed a significantly superior efficacy of lithium in bipolar and unipolar courses with regard to relapses, whereas in schizoaffective disorders carbamazepine had possibly a better relapse preventing efficacy, but led to more preterm drop-outs (Greil, et al., 1994). A remarkable finding was the complete lack of suicidal actions in the lithium group, which led to further investigations of the antisuicidal efficacy of lithium (Ahrens and Muller-Oerlinghausen, 2001; Muller-Oerlinghausen, Berghofer and Ahrens, 2003).
In the broader context of our research in psychopharmacotherapy, we disseminated and discussed our empirical findings and experience in psychopharmacological long term treatment especially with practitioners and worked with them in order to investigate both the efficacy and safety under the everyday conditions of practitioners’ work (“phase IV-research”) (Helmchen, Linden and Schüssler, 1985; Linden, 1987; Helmchen and Linden, 1992; Linden, 1993; Linden, et al., 1997). Furthermore, we asked psychiatric residents to participate in at least one clinical trial of potential psychotropic drugs and trained them in psychopharmacological research (Helmchen and Müller-Oerlinghausen, 1975; Helmchen and Müller-Oerlinghausen, 1976). In this context, we dealt particularly and continuously with methodological and ethical aspects of clinical testing and therapeutic applications of psychotropic drugs. In 1975 we published a “paradox of clinical trials” by which we explained the relationship of ethical concerns of exposing patients in clinical trials to unknown risks of non-efficacy and unwanted drug-effects to the unethical introduction of new drugs into the market unproven with regard to their efficacy and safety (Helmchen and Müller-Oerlinghausen, 1975). In addition, we extended our efforts on a broader scale of ethical and legal concerns in psychiatric therapy research, i.e., not only on research of drug treatment, but also on that of psychotherapeutic and social treatment (Helmchen and Müller-Oerlinghausen, 1978; Helmchen and Lauter, 1995; Helmchen and Sartorius, 2010; Helmchen, 2010; Helmchen, 2013; Helmchen, 2014; Helmchen, et al., 2014; Helmchen, 2015). An overview of the Department’s psychopharmacological research is given in its short history, dating from 2007 (Helmchen, 2007).
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