There is evidence that in affective disorders there are biochemical disturbances in three main areas: in amine metabolism, in electrolyte distribution and in adrenal cortical activity. There is growing evidence of a causal association between brain monoamines and affective disturbances; if brain monoamines are depleted by reserpine a significant proportion of mentally normal subjects suffer from a depression not distinguishable from severe endogenous depression. There is good evidence that drugs such as imipramine and the monoamine oxidase inhibitors, which increase the effective activity of brain monoamines, alleviate depression. Although 3, 4-dihydroxyphenylalanine (the precursor of the catecholamines) has apparently no antidepressive effect, whether given with or without a monoamine oxidase inhibitor, it has been shown that when tryptophan, the precursor of 5HT and tryptarmine, is fed to depressed patients it will potentiate the antidepressive action of a monoamine oxidase inhibitor. There is also direct evidence that there are disturbances in amine metabolism in depression, as shown by the very significantly decreased excretion of tryptamine, decreased levels of 5-hydrOxyin doles in cerebrospinal fluid, and changes in the metabolism of noradrenaline. There is therefore a reasonable case of supposing that these monoamines are involved in the aetiology of depressive illness, but monoamine deficiency is not the sole cause of the disorder, and although patients do respond to monoamine oxidase inhibitors and tryptophan they do not do so as quickly or effectively as with E.C.T.
Turning now to the changes in electrolyte distribution, are these causal or are they secondary phenomena? We cannot say yet, but the therapeutic effect of lithium salts in affective disorders suggests that electrolyte changes may play a part, although the matter will not be settled until we determine the underlying causes of the change in electrolytes and learn how to restore them to normal. It might be envisaged that alterations in the electrolyte distribution could produce two changes in the brain: (1) a direct change in excitability of neurones and (2) a change in the production of monoamines, such as 5-hydroxytryptamine, which are presumably used to "modulate" synaptic transmission. This would be of especial importance when cerebral function is already impaired by changes in electrolytes.
If the underlying abnormalities in electrolyte distribution are endocrinological, it must be confessed that so far only small changes in adrenal cortical activity have been demonstrated and that these seem unlikely to be of much aetiological importance. Apart from cortisol and thyroid hormone, few other endocrine functions have been adequately examined. As well as extending the scope of endocrinological investigations, it seems that it would be fruitful to make the investigations more specific and to measure the effects of various hormones, in vivo, on the distribution of electrolytes and on amine metabolism. Very little is known about these questions, which are now of importance in the study of affective disorders.
Finally, we must face the very real possibility that we are far from the primary disturbance in depression. The changes may all be secondary to other abnormalities which have not been taken into account at all, and we may be in the position of investigators of pernicious anaemia before anything was known about vitamin B12. In spite of all the numerous investigations and very exciting leads that are now opening up, we are perhaps only in a slightly better position than Sanctorius of Padua, who can be regarded as the father of metabolic studies in man. He summarized the position some 300 years ago in words which are still relevant today when he said: "Where the bond of union is between the mind and the animal fluids God Almighty alone knows, but there is no one theory better confirmed by experience than that they mutually influence one another."