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:

 

Ackenheil, M., Hippius H. Clozapine. In: Usdin E, Forrest I, Ed., Psychotherapeutic Drugs. Applications. Volume 2. New York: Marcel Dekker; 1977, pp. 923-56.

 

Angst J, Bente D, Berner P, Heimann H, Helmchen H, Hippiusm H. The clinical efficacy of clozapine. (Investigation with the AMP System), Neuropsychopharmacol 1971; 4:  201-11.

 

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,  Eds. Reflections on Twentieth-Century Psychopharmacology. Budapest; Animula; 2004, pp. 697-720.

 

Ban TA. Academic psychiatry and the pharmaceutical industry. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2006; 30: 429-41.

 

Burt, D.R., Creese, I., Snyder, S.,H., 1976. Properties of [3H]haloperidol and [3H]dopamine binding associated with dopamine receptors in calf brain membranes. Mol. Pharmacol. 12, 800-812.

 

Carlsson, A., Lindqvist, M., 1963. Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine on mouse brain. Acta Pharmacol. Toxicol. 20, 140-144.

 

Freyhan F. The influence of specific and non-specific factors on the clinical effects of psychotropic drugs. In: Rothlin E, Ed. Neuropsychopharmacology 2. Amsterdam; Elsevier; 1961, pp. 189-203.

 

Gardener DM, Baldessarini RJ, Waraich P.  Modern antipsychotic drugs: a critical overview. CMAJ  2005; 172, 1703-11.

 

Gyermek L, Lázár GT, Csák Zs. The antiserotonin action of chlorpromazine and some other phenothiazine derivatives, Arch. Int. Pharmacodyn. 1956; 107, 62-74.

 

Idanpaan-Hikkila J, Alhava E, Olkimora M,  Palva, J. 1975. Clozapine in agranulocytosis, Lancet 1975; 2: 611.

 

Kane, J., Honigfeld, ,G., Singer, J., Meltzer, H.Y., 1988. Clozapine for the treatamnet resistant schizophrenic: a double-blind comparison  with chlorpromazine. Arch. Gen Psychiatry 45, 789-796.

 

Kelly, M.R., Fay, J.E., Laverty, S.G., 1963. Thioridazine hydrochloride (Mellaril): Its effect on the electrocardiogram and a report on two fatalities with electrocardiographic abnormalities. J. Can. Med. Assoc. J. 89, 546-554.

 

Lehmann HE, Ban TA, Eds. Toxicity and Adverse Reaction Studies with Neuroleptics and Antidepressants. Skin-eye Syndrome and Electrocardiographic Changes. Montreal: Quebec Psychopharmacological Research Association; 1965.

 

Lehmann HE, Ban TA. The history of the psychopharmacology of schizophrenia, Can. J. Psychiatry 1997; 42: 152-62.

 

Seeman P, Chau-Wong M, Tedesco J, Wong K. Brain receptors for antipsychotic drugs and dopamine: Direct binding assays. Proc Nat Acad Sci (USA) 1975;  261, 717-9.

 

Seeman P, Lee T, Chau-Wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 1976; 261; 717-19.

 

Snyder S. The dopamine hypothesis of schizophrenia. Focus on the dopamine receptor. Am J Psychiatry 1976; 133: 140-44.

 

Snyder SH, Creese I, Burt DR. 1975.  The brain’s dopamine receptor: labeling with [3H] dopamine and [3H] haloperidol, Psychopharmacol. Commun. 1975; 1, 663-73.

 

Steck H. Le syndrome extrapyramidal et diencephalique au course d.es traitements au Largactil et au Serpasil. Ann Med Psychol 1954; 112: 737-43.

 

Van Rossum JM. The significance of dopamine-receptor blockade for the action of neuroleptic drugs. In: Brill H, Cole JO, Deniker P,  Hippius H,  Bradley PB, Eds. Neuropsychopharmacology. Proceedings of the Fifth International Congress of the Collegium Internationale Neuro-Psychopharmacologicum. (March 1966).Amsterdam:  Excerpta Medica Foundation; 1967, pp. 321-29.

 

Weber. Ein Rauwolfia alkaloid in der Psychiatrie; Seine Wirkungsaehnigkleit mit Chlorpromazin.Schweiz Med Wochenschrift 1954; 44: 968-70. 

 August 3, 2017

Edward Shorter, The Rise and Fall of the Age of Psychopharmacology

New York: Oxford University Press; 431 pages

Reviewed by Edward Shorter

 

Content:

        The book covers major developments in psychopharmacology since the field was born in the 1950s.  Chapters include laying a scientific basis for psychopharmacology, the rise of interest in industry, scientific developments, the DSM, several chapters on marketing, several more chapters on clinical trials,  a chapter on academics who have aided in marketing (sometimes referred to as “KOLs,” or Key Opinion Leaders), the involvement of the FDA and the failure of the field in the last 40 years to come up with molecules having novel mechanisms of action.  Among the sources are: testimony and documents produced in legal discovery proceedings, emails and such blogs as Mickey Nardo’s “One Boring Old Man,” and private communications with the author.

 

Author’s statement

        Many psychiatrists are extraordinarily effective clinicians,  but they act in a way that has little scientific underpinning.  Psychiatry has largely lost its scientific basis.  So, for psychiatry as a medical discipline, there is a crisis.  The field lacks the kind of science that the rest of medicine has:

  1. Doubts about the diagnoses, which do not correspond to real disease entities as found in Nature (e.g., “major depression,” “schizophrenia,” bipolar disorder,” etc.).
  2. Doubts about the treatments, which are either largely inert (SSRIs) or toxic in the wrong populations (SGAs in paediatric use or in the elderly).  A number of clinicians believe thar the SSRIs and TCAs are equipotent and prescribe Prozac because it is thought to have fewer side effects.  But the literature suggests otherwise:  there has never been a trial in serious depression where the SSRIs and TCAs have come out even. 

        The most powerful treatment in psychiatry is convulsive therapy, which, ironically, many psychiatrists shy away from.

  1. Doubts about the proposed mechanisms of action, namely, neurotransmitter theory.  This theory constitutes the intellectual platform of the field – the idea that the metabolism of the amine neurotransmitters determines behavior.  This idea turns out to be bankrupt.

        Of course, discovering the reuptake mechanism was a major scientific advance.  But it was not a clinical advance.  Knowledge of neurotransmitters has contributed very little to clinical psychiatry over the past half century.

        The result of all three of these circumstances:   there have been no drugs with novel mechanisms discovered for the last 40 years.

Future:

  1. Much more interest in identifying the real phenotypes is needed.  This will help get drug discovery going again.  As they say, “You can’t discover drugs for diseases that don’t exist.”
  2. There is a need to downplay interest in the amine neurotransmitters (serotonin, dopamine, etc.).  By contrast, interest should be revived in such physiological measures of brain activity as pharmaco-EEG.
  3. Take DSM away from the APA, which is a trade guild.   A scientific organization such as NIMH or the Karolinska Institut would start from scratch and do a much better job.

 

December 9, 2021