In 1965, Schildkraut postulated that noradrenaline may play a pivotal role in the aetiology of depression

In favour of this hypothesis was the observation that the antihypertensive drug reserpine, which depletes central and peripheral vesicular stores of catecholamines such as noradrenaline, can precipitate depression in patients in remission. The experimental drug {alpha}-methyl-paratyrosine that blocks the synthesis of noradrenaline and dopamine by inhibiting the rate-limiting enzyme tyrosine hydroxylase also precipitates depression in patients during remission. Such findings are only indirect indicators that noradrenaline plays an important role in human behaviour, and may be defective in depression – more direct evidence is needed to substantiate the hypothesis. In depression, it should be emphasised that the reduced growth hormone response to clonidine cannot be accounted for by the drug treatment, age or gender of the patient, which supports the view that the noradrenergic system is dysregulated. Lastly, determination of the urine or plasma concentrations of MHPG (an indicator of central noradrenergic activity), suggests that central noradrenergic function is sub-optimal in depression. Taken together, these results suggest that central noradrenergic function is decreased in depression, an event leading to an increase in the density of the post-synaptic ß-adrenoceptors (Leonard, 1986; Dinan, 1994). The role of serotonin (5-hydroxytryptamine, 5-HT) has also been extensively studied in patients with depression. Whereas the overall psychophysiological effects of noradrenaline in the central nervous system appear to be linked to drive and motivation, 5-HT is primarily involved in the expression of mood (see Charney et al, 1991). The main 5-HT metabolite, 5-hydroxyindole acetic acid (5-HIAA), is reduced in the cerebrospinal fluid (CSF) of patients with severe depression, as are 5-HT and 5-HIAA in the limbic regions of the brain of suicide victims (Agren, 1980). Serotonin receptor function is also abnormal in depression with an increase in the density of cortical 5-HT2a receptors in the brains of suicide victims and also on the platelet membrane of patients with depression. Dopaminergic function Studies on platelets, lymphocytes, changes in cerebrospinal fluid metabolites of brain monoamines and post-mortem studies suggest that a major abnormality in both noradrenergic and serotonergic function occurs in depression, and that such changes could be causally related to the disease process. Less attention has been paid to the possible involvement of dopamine in this disorder. However, anhedonia is a characteristic feature of major depression, and a defect in dopaminergic function is thought to be causally involved in this symptom (Willner, 1983). The concentration of the main dopamine metabolite, homovanillic acid (HVA), is decreased in the CSF of patients with depression, particularly those with psychomotor retardation.

Advances in Psychiatric Treatment (2000) 6: 178-186 © 2000 The Royal College of Psychiatrists  Clinical implications of mechanisms of action of antidepressants  Brian Leonard