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 2^nd 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 21^st 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 50^th 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.

REFERENCES 

Ban TA. Neuropsychopharmacology and the history of pharmacotherapy in psychiatry. A review of developments in the 20^th 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

“Specific” Drug Antagonists to Barbiturates, Morphine and Hallucinogens 

Samuel Gershon

The next opening was provided by a series of compounds synthesized by Prof. Adrian Albert at the Australian National University (ANU) in Canberra. He was synthesizing a series of acridine compounds in collaboration with the Chairman of Microbiology as antibacterial agents and possible use against tuberculosis. As the Department of Microbiology, in the next building to ours, was doing elaborate in vitro work, we planned to evaluate the pharmacologic properties of one compound in the series: THA, or 1,2,3,4 - tetrahydro - 5 - aminoacridine.

We started with little pharmacological knowledge of the compound, but had a very good dog model of morphine’s effects. So we studied it as an analeptic. Given IV to a sleeping morphinized dog, THA produced an immediate arousal and return to clear consciousness.

Our interest in this compound expanded when we were contacted by the US Army to discuss our work with anti-hallucinogens. We arranged to have a detailed discussion with them together with colleagues at the University of Melbourne, who had developed different potential compounds. They were interested in our whole program, but particularly THA, because their main hallucinogenic compounds (referred to as incapacitating agents) were related to the pharmacology of Ditran (JB-329), a mixture of two structurally related isomers of an anti-cholinergic drug (Gershon and Olaria  1960). The following day, the colonel in charge turned up with a research grant for us to sign. After we published a number of papers on THA, I received a letter from a psychiatrist at the University of Pittsburgh asking permission to access my FDA submitted IND on THA (Bell and Gershon 1964; Bell, Gershon, Carroll and Holan 1964; Brinkman and Gershon 1983; Gershon 1960; Gershon 1965; Gershon, Naubauer and Sundland 1965; Gershon and Shaw 1958; Neubauer, Sundland and Gershon 1966 a,b).  He wished to administer THA to cases of imipramine overdose or poisoning, with or without other sedatives. I granted permission and he published papers on the success of the clinical observations. Apparently he also obtained patents for this use of THA, about which I was not fully informed (Soares and Gershon 1995).

Meanwhile, other investigators tried THA administration in Alzheimer’s patients and also patented their findings. THA was then marketed as a treatment for the condition. Their observations amounted to replication of what we had shown previously; THA clearly produced arousal in many different drug-induced and clinical conditions. THA had a new life for several years as a highly touted treatment for Alzheimer’s and it had a significant effect on the established idea that Alzheimer’s was untreatable. This gave rise to the introduction of other potential therapeutic agents and the field regained some therapeutic hope. My belief is that cholinergic antagonists have considerable therapeutic value and deserve further study. Still, great caution must be adopted because the disease has often been present for many years before treatment is attempted.

I must end this section with my belief that all these antagonists have considerable therapeutic value and deserve further study.

References:

Bell C, Gershon S. Experimental anticholinergic psychotomimetics. Antagonism of Yohimbine and Tacrine {THA]. S Med Exp 1964; 10: 15-21..

Bell C, Gershon S, Carroll B, Holan G.  Behavioral antagonism  to a new psychotomimetic—JB 329. Arch IntPharmacodyv 1964; 147: 3-25

Brinkman S, Gershon S. Measurement of cholinergic drug effects on memory in Alzheimers Disease. Neurobiology of Aging 1983; 4: 139-145.                                       

Gershon S. Blocking effect of tetrahydroaminacrin on a new psychotomimetic agent. Nature 1960; 186: 1072-3,1960.

Gershon S. Behavioral effects of anticholinergic psychotomimetics  and their antagonists in man and animals. Recent Adv Biol Psychiatry 1965; 8: 141-9.

Gershon S, Neubauer H, Sundland  DM. Interaction between some anticholinergic agents and phenothiazines. Potentiation of the phenothiazine sedation and its antagonism. Clin Pharmacol Ther 1965; 6: 749- 56

Gershon S, Olaria J. JB-329, a new psychotomimetic, its antagonism to tetrahydroamino-acridane, and its comparison with LSD, mescaline and Sernyl. J Neuropsychiatry 1960; 1:283-9.

Gershon S, Shaw FH. Tetrahydroaminacrin as a decurarising agent. J Pharm 1958; 10: 22-9.

Neubauer,H, Sundland, D, M and Gershon S,     Ditran antagonists in a mixed psychiatric population. J Nerv Ment Dis 1966a; 142: 265-77

Neubauer H, Sundland DM, Gershon S. Sernyl, Ditran and their antagonists: Succinate and THA. Int J Neuropsychiatry 1966b; 2: 216-22.

Soares JC, Gershon S. THA – historical aspects, review of pharmacological properties and therapeutic effects. Dementia 1995; 6:225-34.  

Samuel Gershon
August 6, 2015