期刊
CNS SPECTRUMS
卷 18, 期 5, 页码 231-241出版社
CAMBRIDGE UNIV PRESS
DOI: 10.1017/S1092852913000059
关键词
depression; major depressive disorder; signal transduction; second messenger; intracellular cascades; antidepressants
资金
- National Institute of Mental Health, National Institutes of Health (IRP-NIMH/NIH, Bethesda, MD, USA)
- 7SE Inpatient Mood and Anxiety Disorders Research Unit of the NIMH/NIH
The etiopathogenesis and treatment of major mood disorders have historically focused on modulation of monoaminergic (serotonin, norepinephrine, dopamine) and amino acid [gamma-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/GSK3b, and NF kappa B/Delta FosB. 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.
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