Psychiatry Classics #2: Chlorpromazine for Psychosis

Classic Paper: Elkes J, Elkes C. Effect of chlorpromazine on the behavior of chronically overactive psychotic patients. Br Med J. 1954;2(4887):560-5

In 1950, a group of anesthesiologists in France were trying to find new drugs for anesthesia. They tested the newly synthesized drug chlorpromazine on animals (dogs, rodents, and mice) and found that it led to drowsiness and indifference to aversive stimuli.

Since this was the 1950’s, they were able to quickly try it on people as a booster for anesthesia. They found that people who took chlorpromazine did not lose consciousness, but it did have a profound calming effect. Quickly people thought of trying it on patients with psychosis, for which the available treatments were very limited.

This study by Joel Elkes and Charmian Elkes, who were married, was the first to report a placebo-controlled trial on the effect chlorpromazine in psychosis. It appears that the majority of the data collecting and work was done by Charmian, rather than Joel. Screen Shot 2016-04-11 at 8.19.22 PM

They used a classic crossover study design, testing each patient on both chlorpromazine and an inert placebo (although they do not use the word “random”). They used notes written by the doctors and nurses that were blind to the treatment type to decide whether or not the patient had improved.

Of the 23 patients with a type of psychosis in their study, 7 (30%) showed “definite improvement” when they were taking the drug compared to when they were not, 11 (48%) showed “slight improvement,” and 5 (22%) showed “no improvement.”

Other interesting notes from the paper:

  • They describe the effect of chlorpromazine as symptomatic, since the psychosis itself did not abate: “the essentially symptomatic nature of the response has already been stressed, and cannot be overemphasized. Although affect became more subdued, and attitude and behaviour reflected this improvement, the ingrained psychotic thought disorder seemed to be unchanged.”
  • Because of their detailed records, they noted significant weight gain in 9/23 of the patients (in all of whom the drug led to at least a slight improvement), which has been borne out in both chlorpromazine and in the drug class in general: almost all antipsychotics result in weight gain. Of this effect, they say: “For the present we are inclined to attribute this to improved eating habit as the patients became less tense, less preoccupied, or less assaultive; though more direct metabolic effects of the drug cannot be excluded.”
  • They also tried it on 3 patients with senile dementia, all of whom had “no improvement.” This is yet another example of how Alzheimer’s is where drug discovery goes to die.

Notably, the mechanism remained pretty unknown until the mid-1960s, when it was shown that dopamine metabolites correlated with the chlorpromazine dose given to animals. In 1976, Seeman et al. found a nearly perfect correlation (on the log-log scale) between the ability of antipsychotic drugs to displace haloperidol from binding to the dopamine receptor and the clinical dose required for its effect.

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Seeman et al., 1976

Interestingly, you can see in this figure that chloroprazamine actually has one of the less strong dopaminergic affinities and higher doses required for controlling schizophrenia. Despite this, it and its derivatives have on to become some of the most game-changing psychiatric drugs of all time.

References

Shen WW. A history of antipsychotic drug development. Compr Psychiatry. 1999;40(6):407-14.
Elkes J, Elkes C. Effect of chlorpromazine on the behavior of chronically overactive psychotic patients. Br Med J. 1954;2(4887):560-5.
Bak M, Fransen A, Janssen J, Van os J, Drukker M. Almost all antipsychotics result in weight gain: a meta-analysis. PLoS ONE. 2014;9(4):e94112.

Seeman P, Lee T, Chau-wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature. 1976;261(5562):717-9.