S-Hydroxytryptamine and depression; studies using a neuroendocrine strategy I M Anderson BA MB.BS MA MRCP(UK) MRCPsych The syndrome of depression is a common psychiatric disorder with considerable morbidity and mortality. Brain pathways involving 5-hydroxytryptamine (5-HT) are likely to form part of the biological substrate for mood and there is now considerable evidence that depressed patients have abnormalities in measures of 5-HT function. However the nature of the 5-HT abnormality and its relationship to clinical features and to potentially confounding factors such as weight loss remain unknown. The present studies use a neuroendocrine challenge strategy to investigate aspects of 5-HT function related to depression. First, I study the effect of weight loss in normal volunteers and demonstrate that moderate weight loss through dieting lowers the plasma availability of the 5-HT precursor, L-tryptophan (TRP) in both sexes and that in women, but not men, brain 5-HT function, as measured by the prolactin (PRL) response to TRP, is altered. Second, I demonstrate that whereas the PRL response to infusion of the 5-HT uptake inhibitor, clomipramine, may provide an index of brain 5-HT function, its propensity to cause stressful side-effects warrants caution in interpretation of results. Using this challenge I show that depressed patients have blunted PRL responses compared to controls, particularly if they have features of melancholia, have attempted suicide or lost weight. This finding is not simply a reflection of impaired PRL secretion as I demonstrate that the PRL response to the dopamine antagonist, metoclopramide, is not altered in depression. Third, I investigate the hormone and temperature effects of a 5-HT1A agonist, gepirone, in normal volunteers and show that it may prove a useful tool in assessing the function of this 5-HT receptor subtype in humans. The implications of these studies are discussed. Weight loss is a potential confound for investigations of 5-HT function in depressed patients and may itself alter brain 5-HT function. This has implications for findings in depressed patients and for understanding the effects of dieting and the aetiology of eating disorders. The patient studies are consistent with, and add weight to, a substantial body of research showing decreased 5-HT function in depression although at present the site of the abnormality is not known. Use of specific 5-HT agonists, such as gepirone, will allow the investigation of 5-HT receptor subtype function in humans and will help to identify the nature of the 5-HT abnormality in depression
