Pathophysiology Of Depression

The first coherent biological theory of depression was the catecholamine hypothesis31 which suggested that when too little NE and/or 5HT are present in brains, this may lead to a depressive reaction. This theory was based the observation that reserpine which depletes catecholamines can cause depression and that anti-tubercular drugs which had monoamine oxidase (MAO) properties led to a manic-like state. With a better understanding of receptors this theory has been modified and still forms the basis of all currently approved medications for depression. Problems with this theory can be recognized by looking at the effectiveness of current antidepressants, all of which lay around 60-65% with a placebo response rate at over 40% on average. This suggests amine systems play a role in initiating depression but cannot be the sole explanation.

Subsequently it was found that the majority of people had a disturbance of HPA axis function during a depressive episode32. Since the HPA axis is a major pathway in mediating stress it was logical to consider that alteration in HPA axis function might be the underlying mechanism giving rise to depression. Here again a problem is that there are people with totally typical depressive illness who do not have alterations in HPA axis function, and some people with increased HPA axis function do not develop depression. Thus, it appears that HPA axis dysfunction cannot provide us with a necessary and sufficient explanation of depression. However, it is clear that the HPA axis does play a role in depression and considering this together with the catecholamine theory, it was postulated that there might be multiple routes which could lead to a depressive illness and there might be a general common final pathway leading to the expression of a depression.

With increasing knowledge of signal transduction pathways it was soon speculated that depression was the result of changes in gene expression mediated by transcription factors such as CREB. Nestler and Duman developed this idea and suggested that the activated genes might be neurotrophins33-35. They subsequently focused on the role of BDNF as a final common mediator of depression. It was found that a variety of factors such as stress could suppress BDNF and lead to a depressive state, antidepressants would activate BDNF transcription and elicit plastic changes which returned the organism to a balanced state relieving the depression36-38. The antidepressant effect of BDNF infusions into the dorsal raphe nucleus and the differentially regulated expression of BDNF mRNA after a stress challenge in the learned helplessness model support the importance of BDNF in depression39,40. This theory has the advantage that it suggests there are inputs from the catecholamine systems, HPA axis, and other peptide systems such as substance P and NPY which are integrated in a final common pathway. Importantly, there is some evidence for an association of MDD and polymorphisms in the BDNF

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