It is widely accepted that changes underlying depression and antidepressant-like effects involve not only alterations in the levels of neurotransmitters as monoamines and their receptors in the brain, but also structural and functional changes far beyond. During the last two decades, emerging theories are providing new explanations about the neurobiology of depression and the mechanism of action of antidepressant strategies based on cellular changes at the CNS level. The neurotrophic/plasticity hypothesis of depression, proposed more than a decade ago, is now supported by multiple basic and clinical studies focused on the role of intracellular-signalling cascades that govern neural proliferation and plasticity. Herein, we review the state-of-the-art of the changes in these signalling pathways which appear to underlie both depressive disorders and antidepressant actions. We will especially focus on the hippocampal cellularity and plasticity modulation by serotonin, trophic factors as brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) through intracellular signalling pathways—cAMP, Wnt/β-catenin, and mTOR. Connecting the classic monoaminergic hypothesis with proliferation/neuroplasticity-related evidence is an appealing and comprehensive attempt for improving our knowledge about the neurobiological events leading to depression and associated to antidepressant therapies. 1. Introduction Major depressive disorder (MDD) constitutes the first leading cause of years lived with disability [1], and its incidence is on the rise globally. Yet, until recently, little was known about its pathogenesis, as these conditions are not associated with relevant brain alterations or clear animal models for spontaneous recurrent mood episodes. The clinical phenomenology of major depression implicates brain neurotransmitter systems involved in the regulation of mood, anxiety, fear, reward processing, attention, motivation, stress responses, social interaction, and neurovegetative function [2]. MDD is associated with blunted reactivity to both positively and negatively stimuli [3]; thus, the decline in hedonic responses may be related to generalized affective insensitivity, instead of deficits in the capacity to feel pleasure at the level of basic sensory experience [4]. From the middle of the last century, a great effort has been made to elucidate the brain areas involved in emotion control and in the pathophysiology of mood disorders. Animal and human studies have indicated the involvement of the limbic system—including the hippocampal
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