Thomas A. Ban’s reply to Vimal Razdan’s comment
Thomas A. Ban: Chlorpromazine after 50 years
Your point that even today chlorpromazine (CPZ) is the most reliable drug to control excited and agitated “psychotic” patients cannot be sufficiently emphasized. Since the time of its introduction well over 60 years have passed and, arguably, over these years CPZ has remained not only the most reliable drug for controlling excited and agitated “psychotic” patients, but arguably also the most reliable antipsychotic (AP) drug in the treatment of schizophrenia (SCH) with an at least comparable “efficacy index” to all the numerus available antipsychotic drugs today (Ban, 2006).
How could this happen?
Subsequent to the introduction of CPZ, systematic efforts were directed to develop more effective antipsychotic (neuroleptic) drugs in the treatment of schizophrenia than CPZ. In the course of this “research” a series of structurally similar neuroleptic drugs were introduced. In the late 1950s these drugs were separated into CPZ-type of “sedative” neuroleptics and prochlorperazine-type of “incisive” neuroleptics, with incisive neuroleptics characterized by their inverse relationship between their extrapyramidal sign inducing propensity and dose requirement in treatment (Lambert et al., 1959). By that time, Gyermek and his associates (1956) had shown, with the employment of behavioral measures, that there was a linear relationship between the sedative and anti-serotonin (5-HT) effect of these drugs.
The origin of the notion that there is a linear relationship between the propensity of a drug to induce extrapyramidal signs and antipsychotic effect was in observations that both CPZ and reserpine (used at the time for controlling excitement and agitation of psychotic patients) induced extrapyramidal signs, reported by Steck and Weber independently, in 1954. By the end of the 1950s it was recognized that this was not the case; “sedative neuroleptics” (antipsychotics), e.g., CPZ, methotrimeprazine, chlorprothixene, which produce only mild EPS -- and as later shown have relatively low affinity to the dopamine-D2 receptors to produce receptor blockade -- are just as effective in the treatment of SCH as “incisive neuroleptics,” e.g., prochlorperazine, thiproperazine and haloperidol, which produce marked EPS (Freyhan, 1961). Yet, fueled by neuropharmacological theory -- implicating dopamine (DA) receptor blockade in the mode of action of APs (Carlsson and Lindqvist, 1963; Van Rossum, 1967) -- by the late-1960s “incisive neuroleptics” dominated the field in the treatment of SCH. Their extensive use led to acute EPS, in the form of akathisia, dystonia and Parkinsonism, in 50% to 90% of neuroleptic-treated patients, and to chronic EPS, in the form of tardive dyskinesia (TD), in 15% to 20% (Ban, 2004). The dominance of “incisive neuroleptics” was perpetuated by the demonstration of DA receptor blockade (Burt et al., 1976; Seeman et al., 1975; Snyder et al., 1975); the finding of an inverse relationship between DA receptor blocking potency and dose requirements to produce therapeutic effects (Seeman et al., 1976); and the formulation of the DA-hypothesis of SCH (Snyder, 1976).
There was notably one widely used neuroleptic, thioridazine, a piperidyl phenothiazine, marketed by Sandoz, a Swiss pharmaceutical company, which was promoted for its relative absence of EPS. It was a commercial success despite its potential to produce pigmentary retinopathy and potentially lethal cardiac conductance changes (Kelly, Fay and Laverty, 1963; Lehmann and Ban, 1965).
In the early 1970s, Sandoz, the same company that was involved in the marketing of thioridazine, introduced clozapine, a substance with an even lesser propensity to induce EPS than thioridazine (Ackenheil and Hippius, 1977; Angst et al., 1971). But by the mid-1970s clozapine was withdrawn from the market because of 18 cases of agranulocytosis, including eight fatal, reported with the drug from Finland alone (Idanpaan-Heikkila et al., 1975; Lehmann and Ban, 1997). Then, after well over a decade, clozapine was re-introduced (Kane et al., 1988) and became a commercial success despite the numerous side effects of the drug, These included potentially life threatening agranulocytosis in about 1% of patients, dose dependent risk of epileptic seizures in about 5%, massive weight gain, cardiac damage including early myocarditis and late cardiomyopathy, cerebral intoxication with delirium and fever, and depression of intestinal motility (Gardner et al., 2005). Yet, clozapine became the prototype of “atypical neuroleptics,” a series of neuroleptics, which, similar to “sedative neuroleptics,” have a lesser propensity to induce EPS than “incisive neuroleptics,” now referred to as “typical neuroleptics.” By the end of the 20th century, treatment with “atypical neuroleptics” became the main stream of treatment in schizophrenia and has remained the main stream of treatment to-date.
Corresponding with the difference in the frequency and severity of EPS with these drugs are findings with receptor binding assays which indicate that “atypical neuroleptics,” such as aripiprazole, clozapine, olanzapine, risperidone, quetiapine and ziprasidone, have a higher affinity to the serotonin-5-HT2A receptors than to the dopamine-DA2 receptors, whereas “typical neuroleptics” have a higher affinity to the dopamine- DA2 receptors than to the serotonin-5-HT2A receptors. Delineation of the receptor profile of neuroleptics has revealed that “atypical neuroleptics” represent a return to the “CPZ-type of neuroleptics” after about a 20-year detour, with “typical,” “haloperidol-type of neuroleptics” without offering a more effective antipsychotic than CPZ (Ban, 2006).
References:
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Weber. Ein Rauwolfia alkaloid in der Psychiatrie; Seine Wirkungsaehnigkleit mit Chlorpromazin.Schweiz Med Wochenschrift 1954; 44: 968-70.
August 3, 2017