A Biochemical and Pharmacological Suggestion about Certain Mental Disorders.

Recent findings in this laboratory1' 2 and elsewhere3 , 4have permitted an understanding of some aspects of mental diseases in relation to the hormone-like compound, serotonin. Furthermore, these findings lead directly to a suggestion for a logical treatment of diseases known as "schizophrenia." The experimental observations have been made solely on laboratory animals, but they have reached a point where clinical trials in human psychiatric patients are required to test the validity of the conclusions. Being only biochemists, we are unable to do these experiments on patients and can only hope that this paper will stimulate those who are professionally qualified to undertake in man what we cannot pursue further in laboratory animals. This discussion is going to revolve about serotonsin,5 or enteramine, if Erspamer's terminology is followed.6 Serotonin is one of the latest hormone-like substances to be discovered. Chemically it has been shown to have the structure given in Figure 1.7 Being a simple molecule, it has been synthetically produced without great difficulty8' 9 and is thus readily available. It was discovered because it is the vasoconstrictor long known to form in the serum when blood clots. Erspamer's works with it, done independently of that of Rapport, et al.,5 on the vasoconstrictor material, was based on the abundant occurrence of this new compound in the enterochromaffinic cells of the gastric and intestinal mucosa. Serotonin has now been isolated from several different organs, including the brain, of a wide variety of animal forms.'0-'2 There can be no doubt of its wide-spread occurrence in living things. Furthermore, a variety of pharmacological properties in isolated organs and tissues has been demonstrated, in addition to the vasoconstrictor effect. 13 The pharmacological properties which have been described thus far are attributable in large part to the ability of serotonin to cause various smooth muscles to contract; but there are indications that it has other effects which may become more clearly defined as time for study of them goes by. Aside from the occurrence and importance of serotonin, a second general idea is prerequisite to this discussion. It is now well known that several classes of drugs are related. chemically to individual hormones and other essential metabolites.14' 15 In fact, a major part of the pharmacological effects of these drugs is attributed to a specific interference with the biological functioning of these metabolites to which the drugs are related structurally. That is, the drugs are antimetabolites. Our thinking and experimentation about certain mental disorders has been in the following vein. Several synthetic compounds have been produced which are very closely related in structure to serotonin. These were shown to antagonize, in a competitive fashion, the contractions of artery walls caused by serotonin.16' 17 Also, the fact that the ergot alkaloids are structurally related to serotonin Was appreciated, and it was demonstrated that several of these actually did antagonize