Neuropeptide and Sigma Receptors as Novel Therapeutic Targets for the Pharmacotherapy of Depression

Among the most prevalent of mental illnesses, depression is increasing in incidence in the Western world. It presents with a wide variety of symptoms that involve both the CNS and the periphery. Multiple pharmacological observations led to the development of the monoamine theory as a biological basis for depression, according to which diminished neurotransmission within the CNS, including that of the dopamine, noradrenaline (norepinephrine) and serotonin systems, is the leading cause of the disorder. Current conventional pharmacological antidepressant therapies, using selective monoamine reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors, aim to enhance monoaminergic neurotransmission. However, the use of these agents presents severe disadvantages, including a delay in the alleviation of depressive symptoms, significant adverse effects and high frequencies of non-responding patients. Neuroendocrinological data of recent decades reveal that depression and anxiety disorders may occur simultaneously due to hypothalamus-pituitary-ad renal (HPA) axis hyperactivity. As a result, the stress-diathesis model was developed, which attempts to associate genetic and environmental influences in the actiology of depression. The amygdala and the hippocampus control the activity of the HPA axis in a counter-balancing way, and a plethora of regulatory neuropeptide signalling pathways are involved. Intervention at these molecular targets may lead to alternative antidepressant therapeutic solutions that are expected to overcome the limitations of existing antidepressants. This prospect is based on preclinical evidence from pharmacological and genetic modifications of the action of neuropeptides such as corticotropin-releasing factor, substance P, galanin, vasopressin and neuropeptide Y. The recent synthesis of orally potent non-peptide micromolecules that can selectively bind to various neuropeptide receptors permits the onset of clinical trials to evaluate their efficacy against depression.