MADNESS from Psychiatry to Neuronology via Neuropsychopharmacology
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Fifty years in progress
Thomas A. Ban
The dream of Jacques Moreau de Tours (1804-84), a French psychiatrist, to use drugs in the dissection of mental illness, and of Claude Bernard(1813-78), a French physiologist, in the study of the physiology of the nervous system, has become a realistic goal in the mid-1950s with the introduction of effective pharmacological treatments in psychiatry, and the spectrophotofluorimeter. The capability to measure changes in the concentration of neurotransmitter monoamines in the brain led to the birth of neuropsychopharmacology, and opened a perspective for the development of rational pharmacological treatments of mental disorders The notion that studying the mode of action of psychotropic drugs could lead to information about the neurochemical underpinning of mental pathology, a pre-requisite for the development of rational treatment, was encouraged by findings of Bernard Brodie and his associates, and especially of Alfred Pletscher (at the National Heart Institute of the United States), that drugs, like reserpine and iproniazid, reserpine, which were reported to cause depression and euphoria respectively in some patients, have the opposite effects on serotonin levels in the brain (Ban 2004).
Successful research in neuropsychopharmacology depends on communication between pharmacologists and psychiatrists, as pointed out in 1957 by Abraham Wikler, (an American pioneer of neuropsychoharmacology), in his classic text on The Relationship of Psychiatry and Pharmacology. To facilitate interaction Wolfgang de Boor, a German psychiatrist, and Corneille Radouco-Thomas, a Rumanian born pharmacologist (working in Switzerland at the time), proposed at the First International Symposium on Psychotropic Drugs in Milan, Italy, the founding of an international association that was to become the CINP. The CINP was inaugurated about four months later, on the 2nd of September in 1957, at a dinner meeting in the buffet of the Zurich railway station. Ernst Rothlin, a former director of Sandoz, (a major Swiss pharmaceutical company at the time), was elected president, and the 32 participants of the dinner became the founders of the Collegium.. Today, 50 years later, seven of the founders are alive, and two, Hanns Hippius, and Cornelis Van Rhyn, are participating in this congress.
The founders agreed that the members of the organization should meet at least once every two years to discuss matters related to neuropsychopharmacology, but differed in opinion about CINP’s role in education, and consequently about membership and the format of the biennial meetings. For Emilio Trabucchi, the professor of pharmacology at the University of Milan, (who was to become the organizer of CINP’s first congress), the purpose of the CINP was education, the spreading of information on developments in the new field, whereas for Rothlin, it was research; the bringing together experts from all around the world to scrutinize and debate their findings in order to generate information that would guide psychotropic drug development. A compromise was reached; and it was decided that membership should be restricted to experts, but congresses should alternate between open and closed meetings (Ban 2006).
The CINP was launched in September 1958 with an open meeting in Rome. At this first congress, as well as at the three subsequent congresses, (in Basel, Munich, and Birmingham, in 1960, ’62 and ’64) organized by (five of the founders): Rothlin, Dieter Bente, Hanns Hippius and Fritz Flugel, and Philip Bradley, during the presidencies of Rothlin, Paul Hoch, and Hans Hoff, issues at the heart of neuropsychopharmacology, such as drug-induced psychoses, the mode of action of drugs with known therapeutic effects, the translation of findings from animal to man, the relationship between “model psychoses” to naturally occurring psychoses, and the relevance of mode of action of psychotherapeutic drugs to the pathophysiology of psychiatric disorders, were addressed and discussed.. It was at the Basel congress that Arvid Carlsson, a Swedish professor of pharmacology, presented his findings on selective changes on brain monoamines with psychotropic drugs that were to influence psychotropic drug development for decades. Neuropharmacological research focused on monoamines was instrumental to the formulation of the catecholamine hypothesis of affective disorders by Joseph Schildkraut, (an American psychiatrist), and the dopamine hypothesis of schizophrenia by Jacques Van Rossum, (a Dutsch pharmacologist). Yet, by the time of the Tarragona congresses in 1968, organized by Francisco Valdecasas during his own presidency, it was recognized that the pharmacological heterogeneity in responsiveness to the same drug within a psychiatric diagnosis has precluded the possibility of deriving meaningful information about the biochemical underpinning of mental disorders by studying the mode of action of psychotropic drugs.
The pharmacological heterogeneity within psychiatric diagnoses also delayed the acceptance of psychotropic drugs by the psychiatric community. It was only in the 1970s, during the presidencies of Eric Jacobssen, Hippius, Pierre Deniker, and Leo Hollister, that pharmacotherapy became the primary form of treatment of mental disorders. Presentations, like Mogens Schou’s, a Danish pioneer of neuropsychopharmacology, at the Prague congress in 1970 during Heinz Lehmann’s presidency, on the prophylactic use of lithium in bipolar disorder, and of many others, to international audiences at other CINP congresses, facilitated this development
In the early 1980s, during the presidencies of Carlsson, Paul Janssen, and Paul Kielholz, neuropharmacological research extended from cerebral monoamines to neuropeptides, and from neurochemistry at the synaptic cleft to receptor bindings. Since the clinical methodology remained restricted to that developed for the demonstration of “efficacy” (with the objective that no substance with potential benefit in a given population should be discarded), the gap between pre-clinical and clinical findings grew so wide that it required the translation of neuropharmacological findings for clinicians that the new drugs could be used optimally. With these new developments, the emphasis at CINP congresses shifted to presentations that would guide and train a steadily growing new cadre of neuropsychopharmacologists to be involved in teaching prescribing physicians how to use of psychotropic drugs with consideration of their pharmacodynamic and phramacokinetic properties. The changes began in the mid-1980s, during the presidencies of Ole Rafaelsen and William Bunney, with the establishment of Travel Awards for Young Investigators to be able to attend CINP meetings. They continued throughout the 1990s by extending CINP activities to presidents’ workshops, during the presidencies of Alec Coppen and Julien Mendlewicz, and regional meetings, during the presidencies of Lewis Judd, and Claude de Montigny; increasing the size of the biennial meetings and implementing a “mentor-mentee - program, during the presidencies of Julien Mendlewicz and Giorgio Racagni. . Simultaneously with these developments in 1986, during Rafaelsen’s presidency, CINP’s logo was introduced; in 1999 (July 26), during Helmut Beckmann’s presidency, the Collegium was incorporated in Zurich; and, at the dawn of the 21st century, during the presidencies of Eugene Paykel and Herbert Meltzer, the corporation established its central office in Nashville with Oakley Ray as its executive secretary, and regionalized, to facilitate its educational activities.
The increasing emphasis in CINP on communication of information and education about the use of psychotropic drugs was formally recognized in 2006 during Brian Leonard’s presidency with the amendment of CINP’s constitution to include training programs as one of the three activities for the CINP to achieve its objectives. By appointing Norman Sartorius, the former director of the division of mental health of the World Health Organization, as chairman of a special task force with the mandate to review the evidence for the use of antidepressant medications, Leonard succeeded in having the report of the task force, and CINP’s recommendations about the use of antidepressants, based on the report, discussed worldwide. It was also during Leonard’s presidency that CINP’s history committee, chaired at the time by Ronaldo Ucha Udabe (an Argentine psychiatrist) published its review, on the neurotransmitter era, the first epoch in the history of neuropsychopharmacology (Ban and Ucha Udabe 2006). The history committee has evolved from a working collaboration that started in 1986 at CINP’s San Juan congress between Ole Rafaelsen, Hanns Hippius and Tom Ban with the objective to document the founding and early years of the organization. However, in the mid-1990s, with the appointment of David Healy, a psychiatrist with special interest in critically reviewing the history of neuropsychopharmacology, and Edward Shorter, a medical historian to the committee, the objective of the committee was extended to review, in autobiographical accounts, the history of neuropsychopharmacology and the CINP.
While CINP’s educational activities were extended by meetings worldwide, organized by the antidepressant task force, CINP’s administrative structure was completed in 2006 during Torgny Svensson’s presidency, after moving the central office from Nashville to Glasgow, with the appointment of Mike Mitchell, as the corporation’s first executive director. Svensson’s presidency concludes the first 50 years in the history of CINP with this Congress, the third CINP Congress in Munch, organized by Hans-Jurgen Moller.
Far from being an aging, moribund society, the CINP is an active, energetic society at its 50th anniversary, invigorated by the debate triggered by the report of its antidepressant task force in CINP’s journal, The International Journal of Neuropsychopharmacology, launched in 1998 during de Montigny’s presidency with Bernard Lerer as editor-in chief Central to this debate is the limitation of the methodology used in clinical investigations with antidepressants, and the danger that a review of evidence-based findings without the necessary understanding the limitations of the methodology, could lead to wrong conclusions about the optimal use of antidepressants.
Today, the CINP is a prosperous organization with a membership approaching 1500 from 52 countries on six continents. But the organization is confronted with the fact that despite all advances in neuropharmacological research, rational drug development has not progressed since the birth of neuropsychopharmacology in the 1950s.
In about two days, at the business meeting Robert Belmaker will take over the baton from Torgny Svensson to lead the CINP into a new epoch. It remains to be seen whether the organization will continue only moving further in the direction set in the mid-1980s and become an even more powerful organization in the communication of information as it is, or extends its activities by spearheading a continuous pharmacological re-evaluation of psychiatric classifications and diagnoses to fulfill the vision of Ernst Rothlin, its founding president, to generate information that would guide the pharmaceutical industry in the development of rational pharmacological treatments for mental illness.
Ban TA. Neuropsychopharmacology and the history of pharmacotherapy in psychiatry. A review of developments in the 20th century. In: Ban TA, Healy D, Shorter E, editors.. Reflections on Twentieth-century Psychopharmacology. Budapest: Animula; 2004, pp. 697-720.
Ban TA. A history of the Collegium Internationale Neuro-Psychopharmacologicum. Progress in Neuro-Psychophamacology & Biological Psychiatry 2006; 30: 599-616.
Ban TA, Ucha Udabe R, editors.. The Neurotransmitter Era in Neuropsychopharmacology. Buenos Aires: Polemos; 2006.
Thomas A. Ban
September 12, 2013
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).
During the 1980s, I developed an algorithm for a stepwise adjustment of antidepressive treatment to therapy resistance and implemented this algorithm during the 1990s. I was stimulated to do so due to the observation that the treating physicians on the ward often saw a mild reduction of depressive symptoms during the course of inpatient treatment, whereas I, in contrast, saw no change when I saw the patients only every second week (Adli, Berghofer, Linden et. al., 1994; Helmchen 1990; Linden, Helmchen, Mackert and Muller-Oerlinghausen 2012).
Initiated in 1977 by Eckart Rüther and Hanns Hippius from the Munich-Psychiatric Department we (Lutz Schmidt and myself) joined them for the AMÜP (Arzneimittelüberwachung in der Psychiatrie)-project for almost 20 years; AMÜP monitored systematically all drug applications in our both departments, particularly with regard to unwanted effects of psychotropic drug (Grohman, Strobel, Ruther et al 1993; Helmchen, Hippius, Muller-Oerlinghausen and Ruther1985; Helmchen and Ruther 1985).
In 1993 the AMÜP-Project was transferred into the “AMSP – Institut für Arzneimittelsicherheit in der Psychiatrie,” has expanded to ca. 60 psychiatric hospitals in six central European countries, and is now coordinated from the Psychiatric Department of the University of Hannover (Prof. Stefan Bleich).
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-Oerlinghausen1976). 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).
Adli M, Berghöfer A, Linden M, Helmchen H, Muller-Oerlinghausen B, Mackert A, Stamm T, Bauer M. Effectiveness and feasibility of a standardized stepwise drug treatment regimen algorithm for inpatients with depressive disorders: results of a 2-year observational algorithm study. J Clin Psychiatry 2002; 63 :782-90.
Ahrens B, Muller-Oerlinghausen B Does lithium exert an independent anti suicidal effect? Pharmacopsychiat 2001; 34 :132-136.
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Grohmann R, Ströbel C, Rüther E, Dirschedl P, Helmchen H, Hippius H, Müller-Oerlinghausen B, Schmidt LG, Wolf B (1993) Adverse Psychic Reactions to Psychotropic Drugs - A Report from the AMÜP Study. Pharmacopsychiat 1993; 26: 84-93.
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