MULTITRANSMITTER MECHANISMS AND TREATMENT OF AFFECTIVE DISEASE

Abstract Substantial advances in the last 20 years in the use of psychotropic drugs in the treatment of mental disease has directly stimulated biological investigations intended to elucidate the mechanism of action of these drugs as well as to find biological and biochemical bases for various mental and neurological diseases. While considerable attention has been devoted to research in electrolytes, hormones, energy metabolism, most investigators have worked on the biogenic amines. Initially, it was thought that a simplistic single amine–single disease notion could explain so-called aberrations in mental states. But just as psychotropic drugs have received considerably more credit for clinical efficacy and for specificity of action than they deserve, similarly single transmitter theories such as the “catecholamine hypothesis” have received considerably more attention than they deserve. Recent investigations have suggested not only that the single transmitter-single disease theory is outmoded, but that indeed a balance of different transmitters is probably involved in the hypothalamic control of pituitary releasing factors which in turn have interrelationships with hormonal and electrolyte balances. Concomitantly, biochemical advances related to the synaptic function have suggested that neurotransmitters must be understood as a set of interrelationships among various biogenic amines. Moreover, since multiple neurotransmitter relationships exist for motor behavior, appetite, thermal regulation, sleep, we expect that in the next decade we will begin to understand a number of mental abnormalities as correlates of multitransmitter mechanism abnormalities, whether these abnormalities be related to the genetic programming which induces multitransmitter development or whether they be induced due to particular environmental events. Our report will review current models of multiple neurotransmitter mechanisms and suggest several strategies for research in man intended to delineate the interrelationships among the various amines. Several phases of sleep and the underlying multitransmitter mechanisms are described with regard to the effects of certain psychotropic agents on the sleep on the one hand and on neurotransmitters on the other. This model is discussed in terms of its potential for elucidating the mechanism of, particularly, depressions as well as of the action of tricyclic antidepressants and for the development of new drugs. Recent technological advances in methods of biochemical analysis could profitably be applied to these problems, allowing a variety of biogenic amines and their metabolites to be simultaneously determined in single patient samples. Several other amines which occur in the brain in addition to the catecholamines, serotonin and acetylcholine, but which have not been systematically studied in relationship to psychiatric diseases will be discussed. Pertinent studies may then lead to a biochemical profile that could be used to assess possible mechanisms by which multiple transmitters are involved in mental disease and to elucidate the effects of drug therapy upon these neurochemical systems. Ultimately these strategies could be applied in the development of newer drugs for application in mental states.