Neuroimaging has also helped in the further investigation of the neurochemical deficits in depression. PET and SPET imaging can use radiolabelled ligands to measure receptor binding (a product of receptor density and receptor sensitivity) for specific neurochemical targets in the different brain regions.
The status of brain 5-HT2 receptors in depression and the effect of antidepressant treatment remain unclear, and vary depending on the method used to assess them: studies have found receptor binding to be increased, normal or decreased. While the largest study to date using PET found a marked global reduction in receptor binding (22-27% in various regions), there remains difficulty in reconciling the accumulating finding of reduced binding with the fact that effective antidepressant treatments lead to further downregulation of 5-HT2 receptors (Sheline & Minyun, 2002).
Using a recently introduced radioligand, Sargent and colleagues (Sargent et al., 2000) found a generalised reduction in 5HT1A receptor binding throughout the cortex. However, this was not altered by treatment with an SSRI. The authors note that receptor numbers may not represent receptor function, but they hypothesise a trait reduction in 5HT1A receptors that is unaffected by treatment. Reduced 5-HT1A binding has been replicated elsewhere (Fu et al., 2003).
One of the pieces of evidence making up the serotonin hypothesis of depression is the impaired endocrine response to challenge with serotonergic drugs such as fenfluramine (see above). This same approach has now been transferred to neuroimaging: challenge with the serotonin releaser fenfluramine leads to marked changes in neural activity. These serotonergically mediated changes were found to be markedly attenuated in depression, suggesting impaired central 5-HT neurotransmission. However, a study using the more specific d-isomer of fenfluramine could not replicate this finding (Fu et al., 2003).
As described earlier, a proportion of subjects show a depressive relapse after tryptophan depletion. When undertaken in the PET scanner, this depressive relapse was correlated with reduced activity in the orbito-frontal cortex, anterior cingulate, left caudate nucleus, and superior parietal cortex, like those seen in unmedicated depressed subjects (Smith et al., 1999). Furthermore, while a verbal fluency task was performed, there was a significant attenuation of usual task-induced activation in the anterior cingulate. These results help link changes in serotonin function with changes in activity in specific brain areas during depressive relapse. Furthermore, they also provide a possible neurobiological link between 5-HT changes and the cognitive effects of depression.
Finally, support for dysfunction in other neurochemical systems is also emerging. For example, the use of the challenge drug clonidine reveals evidence of noradrenergic dysfunction in depression, postulated to arise from functionally impaired pre-synaptic alpha2-adrenoceptors as well as regionally supersensitive post-synaptic cortical alpha2-adrenoceptors (Fu et al., 2001).
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