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Saturday, 25.03.2017

Chlorpromazine after 50 Years

Thomas A. Ban

I entered psychiatry in my native country, Hungary, in 1954 and was among the last of a generation who used “insulin coma” in the treatment of schizophrenia and “opium” in the treatment of depression. Chlorpromazine became available on our service in the first months of 1955, but in spite of the favorable reports, it was received incredulously by some of our senior staff. As far as I was concerned, CPZ was great! It worked better than the morphine-scopolamine combination we used in controlling agitation, and it could also relieve psychotic symptoms regardless of patient’s diagnosis. It was especially effective for some schizophrenics. For me, the most junior member of the staff, at the National Institute of Nervous and Mental Diseases in Hungary, CPZ was a miracle drug.

Chlorpromazine was synthesized by Paul Charpentier in the laboratories of Rhône-Poulenc in December, 1950; and released for clinical investigation as a potentiator of general anesthesia in May, 1951 (Caldwell 1970). Its importance for psychiatry  was recognized by the scientific community in 1957 with the presentation of the prestigious Albert Lasker Award to the three key players in the clinical development of the drug: Henri Laborit, for using CPZ as a therapeutic agent first and recognizing its potential for psychiatry; Pierre Deniker, for his leading role in introducing CPZ into psychiatry and demonstrating its influence on the clinical course of psychosis; and Heinz Lehmann for bringing the full practical significance of CPZ to the attention of the Western World.  In the same year Daniel Bovet was awarded the Nobel Prize in Medicine for his major contributions to the synthesis of antihistamines which, through Laborit’s observations of promethazine, an antihistaminic phenothiazine, promethazine, led to the development of CPZ (Ban 1994).

The pharmacological bridge from antihistamines to “antipsychotics” was provided by a test with a potential to detect the central effects of antihistamines by the increase in time required for trained rats to climb a vertical rope for food (Charpentier et al. 1952). But the first test procedure for the prediction of antipsychotic effects which readily translated from animal to man was introduced by Leonard Cook in the United States (Cook 2004). It was based on his findings that CPZ differs from the old sedatives by selectively blocking the conditioned avoidance response, while leaving the unconditional motor reflex unaffected. Employment of Cook’s procedure was instrumental in the development of a rapidly growing number of antipsychotic drugs.

The large number of antipsychotic drugs developed by the late 1950 was reflected in the communications at the first CINP Congress in Rome, in 1958. Frank Ayd reported on clinical findings of 25 (Ayd 1959), and in Hanns Hippius’of 12. It was in Rome where Hippius first focused attention on the lack of a relationship between the preclinical pharmacological profile and the therapeutic efficacy of these drugs  (Hippius and Selbach 1959). By emphasizing that the therapeutic usefulness of a substance must be measured in terms of the relationship between therapeutic efficacy and somatic side effects, without any theoretical preconception, he opened the path for a development which led from CPZ to clozapine (Hippius 2004).

Simultaneously with the development of CPZ there was a shift in  understanding of the nature of synaptic transmission from a purely electrical to a chemically mediated event; and by the end of the 1950s, six neurotransmitters were identified in the central nervous system. Recognition of chemical mediation at the site of the synapse, coupled with the introduction of the spectrophotofluorimeter, triggered the development of neuropharmacology. There were high expectations that CPZ combined with spectrophotofluorimetry would provide a royal road to the understanding of the pathophysiology of schizophrenia. It was also hoped that there would be feedback from the clinical psychopharmacologists to the neuropharmacologists, which would help to develop clinically more selective and thereby more effective pharmacological treatments (Ban 2001).

Early neuropharmacological studies with CPZ were conducted in the periphery. In one of the first publications Laszlo Gyermek  a Hungarian pharmacologist, reported on the potent anti-serotonin effects of the drug.(Gyermek 1955). In the early 1960s interest shifted from the anti-serotonin to the antidopamine effects of CPZ, after Carlsson and Lindqvist eported that CPZ stimulated the turnover of catecholamines in the mice by a hypothesized blockade of catecholamine receptors (Carlsson and Lindqvist 1963). Postulation of a relationship between DA receptor blockade and antipsychotic effects provided the rationale for the research which led to the demonstration that antipsychotics block DA receptors (Creese, Burt and Snyder 1975).  

However, the confounding of antipsychotic properties with therapeutic effects in schizophrenia has been counterproductive.  Introduction of CPZ focused attention on the heterogeneity of schizophrenia in terms of responsiveness to treatment and persistence on a unitary concept of schizophrenia was conflicting with clinical experience and with findings in clinical psychopharmacological research. To disentangle whether the difference in responsiveness to treatment is due to individual idiosyncrasies in responding to neuroleptics, or to differences in the biology of the different forms of the disease, Frank Fish, a British professor of psychiatry, examined, the therapeutic response profile of neuroleptics with the employment of the different forms of schizophrenia in the classification of Karl Leonhard, a German professor of psychiatry (Fish 1964; Leonhard 1957). The significant differences he found in responsiveness to neuroleptics between some of the groups could not be explained by idiosyncratic individual variations in responsiveness to the drugs.. The differences were so great that in one group, more than 4 in 5 patients responded to treatment, whereas in another, less than 1 patient responded in 4. Fish published his findings in 1964 in Encephale, a French journal, but with his untimely death, coupled with reservations towards Leonhard’s classification, his findings were summarily dismissed. Nevertheless, by the  end of the 1960s, there was sufficient evidence to believe that ignoring the heterogeneity of schizophrenia  deprived neuropharmacology from the necessary feedback for developing clinically more selective and thereby more effective treatments (Ban 1969);  and by the mid-1980s, there was sufficient evidence to conclude that resolving the heterogeneity of schizophrenia is an essential prerequisite for progress in the understanding of the biology of the different illnesses pooled together in schizophrenia (Ban 1987).

Since the first time I used CPZ in a schizophrenic patient, almost 50 years have passed and during these years pharmacotherapy has become the primary treatment in psychiatry. The success of CPZ was instrumental to the development which led to the reintegration of psychiatry with the other medical disciplines by turning psychiatrists from care givers to full-fledged physicians who can help their patients and not only listen to their problems.

Introduction of CPZ was also instrumental to the development of neuropsychopharmacology, a new discipline which has forced psychiatry to examine and change its theoretical foundation. By the end of the 20th century, Wilhelm Griesinger’s contention that mental illness is a symptom of brain disease, has become an accepted reality, and Moreau de Tours’  vision of understanding mental pathology by studying the effect of centrally acting drugs, an accepted methodology Griesinger 1845; Moreau de Tours 1845).  Yet, in spite of all the progress made in the understanding signal transduction, and designing drugs, if an agitated and aggressive psychotic patient in the emergency fails to respond to the new medications I have no hesitation in recommending good old CPZ. This is why we are celebrating 50 years CPZ!



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