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The biogenic amine hypothesis of depression, which suggests that depression is the result of a functional deficiency of noradrenaline (NA) and/or serotonin (5-hydroxytryptamine, 5-HT) at certain synapses in the brain, has had a major influence on research into the neurochemistry of depression for over fifty years, and most of the antidepressants currently available have an effect on one or both of these biogenic amines. However, it was obvious early on that other neurotransmitters or neuromodulators must also be involved, and the search continues for other targets that may give clues for the development of future antidepressant drugs that are effective in a greater number of depressed patients, are faster acting and have an improved side effect profile over those currently available. Some of those targets will be discussed in this overview.
The amino acids gamma-aminobutyric acid (GABA) and glutamate are major inhibitory and excitatory neurotransmitters, respectively in the brain, and a delicate balance between them must be maintained for normal brain function. Research on GABA at the animal model and clinical levels implies a GABAergic deficit in depression, and animal studies and the rapid antidepressant action of intravenous ketamine in human subjects suggest hyperglutamatergia in depression, although the results of some neuroimaging studies to date do not seem to support these ideas. In recent years, there has been a great deal of interest in the possible roles of neuroactive steroids (rapid acting neurosteroids which can act as positive or negative modulators of a number of neurotransmitter receptors, most notably GABA-A and NMDA glutamate receptors) in the etiology and pharmacotherapy of depression. Allopregnanolone has received particular attention in this regard. Several researchers have proposed that the hypothalamic-pituitary-adrenal (HPA) axis plays a central role in the etiology of depression and there has been considerable interest in corticotropin-releasing hormone (CRH) receptor antagonists as potential antidepressants. The peptide substance P acts on neurokinin 1 (NK1) receptors, and there is ongoing interest in NK1 receptor antagonists as potential antidepressants. The role of the immune system in depression has been the focus of considerable research and it has been proposed that excessive proinflammatory cytokines (which are released by activated microglia) may result in depressive symptoms; it is of interest that such cytokines can activate CRH release and reduce levels of 5-HT in the brain. Although there are some contradictory results, several studies suggest that antidepressants increase expression of cyclic AMP-regulated element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF). Dysfunction of melatonin secretion in depression has been suggested and this may account, at least in part, for sleep disorders experienced by many depressed subjects. Agomelatine, a melatonin receptor agonist and 5-HT2C receptor antagonist, is now marketed as an antidepressant. The potential interactions of several of the targets mentioned above will be discussed.
Acknowledgements: The authors are grateful to the Canadian Institutes of Health Research (CIHR), the Canada Research Chairs program and the University of Alberta for Funding.