Clinical Research in Depression

Abstract

reflect changes in the body as a whole and not just in the brain. Moreover, urinary levels of noradrenaline and normetanephrine, the product formed from noradrenaline by catechol-0-methyltransferase, are in very small part derived from brain metabolism as the blood-brain barrier is not permeable to hydroxylated amines. Schildkraut? and his associates found that urinary levels of normetanephrine were increased in patients with mania or cyclic manicdepressive psychosis and were also increased in patients in whom imipramine was an effective antidepressant whereas urinary levels of vanillylmandelic acid ( V M A ) were decreased. Normetanephrine is regarded as the breakdown product of noradrenaline which is thought to reflect chiefly extracellular metabolism whereas V M A levels reflect intracellular deamination. The fact that imipramine blocks the reuptake of noradrenaline is in accord with these findings. However the source of the noradrenaline could be from autonomic adrenergic neurones rather than from the central nervous system. In this case, the observations would have more relevance to sideeffects than to the desired effect of imipramine.The metabolism of indoleamines in depression has been studied by Coppen and his associates6. They found that urinary excretion of tryptamine and its metabolic product indoleacetic acid was decreased during depression and increased upon recovery with treatment. Here, as in studies with catecholamine metabolites, interpretation is difficult for similar reasons, namely that urinary changes may not reflect brain changes especially as indoleamines and their metabolites are not freely transported across the blood-brain barrier.While much of this evidence for the role of biogenic amines seems to fit into a satisfactory pattern, Dewhurst has criticized the methodology of the clinical and laboratory studies*. He put forward an alternative theory of cerebral amine action based on studies of the behavioural effects of sixty amines and related compounds in various species and proposed that amines can be divided according to their cerebral actions into two distinct and opposing categories: type A (excitant) and type C (depressant). The determinant of type of action is lipid solubility, type A amines (substituted ethylamines) being both lipophilic and hydrophilic, and type C amines (substituted ethanolamines) being hydrophilic only. Other variations in the chemical structure affect potency and duration of action but not type of action. Naturally occurring amines of type A are tryptamine and B-phenylethylamine. The excitant action of type A amines is specifically antagonized by methysergide, and this drug is reported to be of use in the treatment of manian. Naturally occurring type C amines are noradrenaline and adrenaline. S-hydroxytryptamine has a biphasic (excitant then depressant) action and is classed as type B. Dewhurst's conclusions have obvious points of difference from the catecholamine theory, but he is examining the role of monoarnines in cerebral function from a different standpo...