Depression and treatment response: dynamic interplay of signaling pathways and altered neural processes

Abstract

Since the 1960s, when the first tricyclic and monoamine oxidase inhibitor antidepressant drugs were introduced, most of the ensuing agents were designed to target similar brain pathways that elevate serotonin and/or norepinephrine signaling. Fifty years later, the main goal of the current depression research is to develop faster-acting, more effective therapeutic agents with fewer side effects, as currently available antidepressants are plagued by delayed therapeutic onset and low response rates. Clinical and basic science research studies have made significant progress towards deciphering the pathophysiological events within the brain involved in development, maintenance, and treatment of major depressive disorder. Imaging and postmortem brain studies in depressed human subjects, in combination with animal behavioral models of depression, have identified a number of different cellular events, intracellular signaling pathways, proteins, and target genes that are modulated by stress and are potentially vital mediators of antidepressant action. In this review, we focus on several neural mechanisms, primarily within the hippocampus and prefrontal cortex, which have recently been implicated in depression and treatment response.

Fig. 1

Initial molecular and cellular effects of stress can progress to severe structural modifications of neurons and limbic brain regions implicated in MDD. Consistent alterations at the molecular level (green), such as changes in levels of neurotransmitters, expression of key neurotrophic factors and signaling molecules can result in cellular destabilization and remodeling (blue). Long-term consequences of stress-induced molecular and cellular adjustments lead to morphological changes characterized by deficiencies in neuronal function and neural network connectivity (red). Therapeutic effects of typical antidepressant treatment (agents targeting monoamine system) coincides with the time course required to reverse the negative effects of stress at all three levels (molecular-cellular-morphological/tissue)

Fig. 2

Interactions of neurotrophic factor and Wnt intracellular signaling cascades that mediate the negative cellular responses to stress/MDD and/or the therapeutic actions of antidepressant treatment. Wnt/Frizzled-mediated blockade of GSK-3 signaling or neurotrophic factor-mediated activation of PI3K–Akt, MEK–ERK, and mTOR pathways lead to increased synaptogenesis, neuronal survival, growth and neuroplasticity, and resilience to stress, which contribute to antidepressant behavioral responses. BAD Bcl2-antagonists of cell death; Bcl-xL B cell lymphoma-extra large; FRS fibroblast growth factor receptor substrate; GRB2 growth factor receptor-bound protein 2; IRES insulin receptor substrate; MEK MAPK kinase; PDK1 3-phosphoinositide dependent protein kinase-1; RAF v-raf-1 murine leukemia viral oncogene homolog 1; RAS RAt sarcoma; RSK ribosomal S6 kinase; Shc Src homology/collagen; SOS son of sevenless; TCF/LEF T cell-specific transcription factor, lymphoid enhancer factor