Tryptophan Pyrrolase—A Biochemical Factor in Depressive Illness?

Abstract

Reserpine, which depletes brain amines, not infrequently causes depression (Bunney and Davis, 1965), whereas monoamine oxidase inhibitors (MAOI) which raise brain amine levels (Macleanet al.,1965) may alleviate depressive symptoms. The alleviation has been reported to be enhanced by tryptophan (Coppenet al.,1967), which is a precursor of the amines 5-hydroxytryptamine (5HT) and tryptamine. The apparent prophylaxis by tryptophan of an annual episode of depression has also been reported (Hertz and Sulman, 1968). These findings suggest that elevation of one or both of the above amines is responsible for the therapeutic effect of MAOI, and that their insufficiency may be responsible for symptoms of the disease. Defective 5HT synthesis in depressive illness is indicated by a number of findings. (1) Depressed patients responding to the MAOI drug iproniazid were found in two studies (Pare and Sandier, 1959; Praag and Leijnse, 1963), though not in a third (Burgermeisteret al.,1963), to have a lower initial urinary excretion of the 5HT metabolite 5-hydroxyindole acetic acid (5HIAA) than those who did not respond. (2) Depressed patients have a low content of 5HIAA in the lumbar cerebrospinal fluid (Ashcroftet al.,1966), which rises on recovery. Although work using animals (Guldberg and Yates, 1968; Ecclestonet al.,1968) shows that changes in brain 5HT are paralleled by changes of 5HIAA in the CSF, the significance of this result is not altogether clear, as lumbar 5HIAA depends not only on brain 5HT metabolism but also on 5HIAA transport within the CSF (Ashcroftet al.,1966). Furthermore, a small group of acute schizophrenics on phenothiazines also had low 5HIAA. (3) There is some direct evidence of low 5HT (Shawet al.,1967) or 5HIAA (Bourneet al.,1968) in the hindbrains of depressive suicides. (4) While single doses of 5-hydroxytryptophan, the immediate precursor of 5HT, do not alleviate depression, the remission of a prolonged episode of severe depression by administration of 5-hydroxytryptophan for five days has been reported (Persson and Roos, 1967).