The Chlorpromazine Enigma

Abstract

Two revolutionary drugs were introduced into psychiatry in the early 1950s for the treatment of agitated mental patients — reserpine and chlorpromazine. These drugs initiated the modern era of drug treatment for schizophrenia and other psychoses. Early research revealed that, although the pharmacological profiles of the two drugs overlapped considerably, they had different mechanisms of action. The mechanism of action of reserpine was determined first: it depletes monoamines from the brain and other tissues. By contrast, chlorpromazine has little or no effect on brain monoamine concentrations. The mystery created by two drugs that have similar pharmacological profiles but different mechanisms of action is the chlorpromazine enigma. For about eight years after the mechanism of action of reserpine was determined, researchers followed several false leads about the mechanism of action of chlorpromazine. Then, in 1963, Arvid Carlsson and Margit Lindqvist proposed that chlorpromazine (and haloperidol) work by blocking “monoaminergic” receptors. It was quickly determined that dopamine receptor blockade was the most important action. Although the idea of chemical communication between central neurons had yet to gain wide acceptance, this idea was central to resolving the chlorpromazine enigma.

Keywords:

• Chlorpromazine
• reserpine
• pharmacodynamics
• Arvid Carlsson
• War of the Soups and Sparks

Acknowledgments

The author is grateful to Professor Arvid Carlsson for providing gracious and thoughtful responses to questions about the conceptual underpinnings of early psychopharmacologic research.

Notes

¹This appears to be an exaggeration. The total number of persons in US mental hospitals at the time was about 500,000, and, by 1956, the drug had been in use in the United States for only two years. A survey done by the California State Senate for the years 1955/1956 indicated that, in 30 of 48 states responding, about 110,000 patients had been treated with “drugs” (based on tabulation of the data by Swazey, 1974, pp. 210–213).

²Drug doses are given when they may be desired for comparing studies.

³Neurotransmitter precursors were used because the neurotransmitters do not readily cross the blood-brain barrier. After entering the brain, the precursor is converted to the neurotransmitter.

⁴Some exceptions to the many studies that reported that chlorpromazine has no effect on brain monoamine content were found. Bartlet (1960) reported that chlorpromazine slightly increases serotonin in mouse brain, whereas West (1958) reported that chlorpromazine decreases serotonin in rat brain.

⁵DOPAC is a dopamine breakdown product of MAO; HVA is a dopamine breakdown product resulting from the combined actions of MAO and COMT (Cooper, Bloom, & Roth, 2003).

⁶The IC₅₀ is the concentration required to displace 50% of the stereospecific component of the radioligand. The lower the IC₅₀ then the greater the affinity between the drug and the receptor.

⁷Amphetamine is thought today to work by stimulating catecholamine release and blocking catecholamine re-uptake (see Baumeister, 2002).