There is growing evidence of a connection between the metabolism of monoamines and severe depressive illness, but the exact role of these substances in affective disorders has yet to be defined. We know that reserpine depletes the brain of monoamines and that a proportion of patients treated with this compound develop a depressive illness. Conversely a number of compounds which raise the levels of amines in the brain by blocking the enzyme monoamine oxidase have been used in antidepressant therapy. The knowledge that loss of amines may be associated with depression, and that their replenishment in the brain may induce recovery, immediately leads to the question as to which of the biogenic amines is responsible for the affective changes. Pollin, Cardon and Kety (1961) observed the effect of giving various amino acids together with a monoamine oxidase inhibitor (M.A.O.I.) to patients suffering from chronic schizophrenia. They found that only tryptophan, the precursor of the monoamine 5-hydroxytryptamine (5HT), produced an elevation of mood. On the basis of their results, Coppen, Shaw and Farrell (1963) treated a number of patients suffering from severe depressive illness with M.A.O.I. and half of this group also received an oral dose of a suspension of D L-tryptophan (214 mg./kg. body weight) for one week. The patients taking tryptophan and M.A.O.I. recovered more rapidly than those receiving M.A.O.I. alone both while they were on tryptophan and also subsequently. One explanation for these findings was that the combination of M.A.O.I. and tryptophan increased the amount of amines derived from tryptophan in the brain, and that it was this which was responsible for the therapeutic effect. If this were so, then there were several possibilities. The first was that the level of 5HT in the brain was low in depression and the combination of amine precursor and enzyme inhibitor brought it back to normal. Alternatively it may be that recovery occurred as a result of the presence of abnormally large quantities of 5HT in the central nervous system or even following the production of tryptamine, another amine derived from tryptophan.
Development of new antidepressants