The monoamine hypothesis has dominated research into the pathophysiology and pharmacotherapy of depression for a long time. This has led to the development of antidepressants that are now more selective than the early tri- and tetracyclics from which they have evolved. Alternative hypotheses such as those involving adult neurogenesis or components of the hypothalamic–pituitary–adrenal (HPA) axis are either too premature or have not led to drugs with improved antidepressant activity. Recent new approaches include DNA techniques (identifying genes and gene expression)1,2 and proteomics (a complete inventory of all proteins).3,4 To date, they have not contributed to the development of new drugs. Although many exciting developments are occurring, it does not appear as easy to develop the next generation of antidepressant drugs that do not influence monoamines. In the meantime there may be no choice other than to make the best of the existing hypotheses. This is not as hopeless as it may seem, because there is still considerable potential in the concept of monoamine reuptake inhibition.
Monoamines, Neuroimaging and Sub-components of the Depressive Syndrome
The monoamine hypothesis of depression5 does not only propose the crucial involvement of monoamines in the therapeutic effects of antidepressant drugs but also suggests that depression is directly related to decreased monoaminergic transmission. In view of recent developments in molecular biology, it is relevant to consider what the actual position of this hypothesis is and whether recent findings (e.g. based on neuroimaging techniques) still support its validity.
There are new data that fit well into the monoamine hypothesis. Many of them originate from positron emission tomography (PET) studies. By using selective radioligands, evidence was found for reduced pre- and post-synaptic 5-hydroxy-tryptamine (5-HT)1A receptor binding in depression. Drevets et al.6 demonstrated that the mean 5-HT1A-receptor-binding potential (BP) was reduced in the mesiotemporal cortex and raphe area in unmedicated depressives relative to controls using PET and (11C) WAY-100635. A similar reduction was evident in the parietal cortex, striate cortex and left orbital cortex/ventrolateral pre-frontal cortex. These data are consistent with those of Sargent et al.,7 who found decreased 5-HT1A-receptor-binding potential (BP) in unmedicated depressed patients relative to healthy controls in the raphe, mesiotemporal cortex, insula, anterior cingulate, temporal polar cortex, ventrolateral pre-frontal cortex and orbital cortex. However, a subgroup of the subjects was scanned both pre- and post-paroxetine treatment and the 5-HT1A receptor BP did not significantly change in any area.