New Strategies in the Development of Antidepressants: Towards the Modulation of Neuroplasticity Pathways

Author(s): Rebeca Vidal, Fuencisla Pilar-Cuellar, Severiano dos Anjos, Raquel Linge, Begona Treceno, Veronica Ines Vargas, Antonio Rodriguez-Gaztelumendi, Ricardo Mostany, Elena Castro, Alvaro Diaz, Elsa M. Valdizan, Angel Pazos.

Journal Name: Current Pharmaceutical Design

Volume 17 , Issue 5 , 2011

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Abstract:

Over the past five decades, the pharmacological treatment of depression has been based on the pathophysiological hypothesis of a deficiency in monoamines, mainly serotonin and noradrenaline. Antidepressants prescribed today, all of them designed to enhance central monoaminergic tone, present several important limitations, including a 2-5 weeks response lag and also a limited clinical efficacy. As it is increasingly evident that the abnormalities associated to depression go beyond monoamines, the development of better antidepressants will depend on the identification and understanding of new cellular targets. In this regard, much evidence supports a role for cellular and molecular mechanisms of neuroplasticity, including neurotrophic inputs, in mood disorders, in parallel with the biological features associated to stress conditions. In order to illustrate the possible relevance of neuroplasticity-related pathways for the therapy of depressive states, we here review the biological evidence supporting some therapeutic strategies in a very initial phase of development (modulation of the Wnt/GSK-3β/β-catenin pathway, potentiation of endocannabinoid activity, agonism of 5-HT4 receptors), which involve modulation of downstream mechanisms and neuroplasticity circuits. These strategies also show the existence of mixed mechanisms of action, constituting a nexus between the “classic” aminergic theory and the “new” neuroplasticity hypothesis.

Keywords: Antidepressant, stress, neuroplasticity, endocannabinoid, 5-HT4 receptors

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Article Details

VOLUME: 17
ISSUE: 5
Year: 2011
Page: [521 - 533]
Pages: 13
DOI: 10.2174/138161211795164086
Price: $58

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