Second messenger/signal transduction pathways in major mood disorders: Moving from membrane to mechanism of action, part I: Major depressive disorder

Mark J. Niciu, Dawn F. Ionescu, Daniel C. Mathews, Erica M. Richards, Carlos A. Zarate

Research output: Contribution to journalReview articlepeer-review

Abstract

The etiopathogenesis and treatment of major mood disorders have historically focused on modulation of monoaminergic (serotonin, norepinephrine, dopamine) and amino acid [γ-aminobutyric acid (GABA), glutamate] receptors at the plasma membrane. Although the activation and inhibition of these receptors acutely alter local neurotransmitter levels, their neuropsychiatric effects are not immediately observed. This time lag implicates intracellular neuroplasticity as primary in the mechanism of action of antidepressants and mood stabilizers. The modulation of intracellular second messenger/signal transduction cascades affects neurotrophic pathways that are both necessary and sufficient for monoaminergic and amino acid-based treatments. In this review, we will discuss the evidence in support of intracellular mediators in the pathophysiology and treatment of preclinical models of despair and major depressive disorder (MDD). More specifically, we will focus on the following pathways: cAMP/PKA/CREB, neurotrophin-mediated (MAPK and others), p11, Wnt/Fz/Dvl/GSK3β, and NFκB/ΔFosB. We will also discuss recent discoveries with rapidly acting antidepressants, which activate the mammalian target of rapamycin (mTOR) and release of inhibition on local translation via elongation factor stimulation. Throughout this discourse, we will highlight potential intracellular targets for therapeutic intervention. Finally, future clinical implications are discussed.

Original languageEnglish (US)
Pages (from-to)231-241
Number of pages11
JournalCNS spectrums
Volume18
Issue number5
DOIs
StatePublished - Oct 2013
Externally publishedYes

Keywords

  • antidepressants
  • depression
  • intracellular cascades
  • major depressive disorder
  • secondmessenger
  • signal transduction

ASJC Scopus subject areas

  • Clinical Neurology
  • Psychiatry and Mental health

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