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Arch Hellen Med, 25(4), July-August 2008, 456-462


The biological basis of depression: Neuropeptides and new therapeutic perspectives

Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, Alexandroupoli, Greece

Depression is a mood disorder with rapidly increasing incidence in the Western world. It has multiple coexisting symptoms deriving from the central nervous system and the periphery. Pharmacological observations have led to the monoamine hypothesis for a biological explanation of depression, according to which diminished neurotransmission of dopamine, serotonin and norepinephrine is the critical pathophysiological factor. All the modern antidepressant drugs, including the selective monoamine reuptake inhibitors, tricyclic compounds and monoaminoxidase inhibitors, aim at elevating the levels of monoamine neurotransmitters in the synapsis. However there are significant drawbacks in their use, such as the marked delay in onset of the therapeutic action, significant adverse effects and a high percentage of non-response. Recent neuroendocrinological data demonstrate a close association of depression with anxiety disorder and point to a crucial involvement of the hypothalamus-pituitary-adrenal (HPA) axis, which regulates the stress response. Based on these findings, the diathesis-stress model has been proposed, which attempts to correlate the genetic with the environmental input as risk factors for the development of depression. The activation of the HPA axis is under the control of the amygdala and the hippocampus in a push-pull manner, with contributing effects of a plethora of neuropeptides and other regulatory factors. Modulation of these molecular pathways is suggested as an alternative therapeutic strategy for depression, a prospect that is supported by preclinical pharmacological and genetic manipulations of the action of neuropeptides such as corticotropin releasing factor, substance P, galanin, vasopressin and neuropeptide Y. The recent availability of non-peptide micromolecular components with high specificity for neuropeptide receptors and bioavailability through the blood-brain barrier has allowed the planning of clinical trials to study the safety, side effects and antidepressant potential of these molecules. Further studies are expected, to evaluate these new therapeutic perspectives for the treatment of depression.

Key words: Depression, Hypothalamus, Neuropeptide, Neurotransmitter, Stress.

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