Targeting Neurotrophic Signal Transduction Pathways in the Treatment of Mood Disorders

Todd   D.   Gould; Husseini   K.   Manji

Abstract

Mood disorders such as bipolar disorder and unipolar depression are pervasive diseases associated with high rates of morbidity and mortality. There exists an urgent need for novel medications. Current compounds often do not bring about full remission, and if they do, it is only after a minimum of many weeks, if not months of treatment. Alterations in signaling pathways represent a likely source of pathogenesis. Dynamic regulation of complex signaling pathways plays a critical role in higher order brain functions, which include the regulation of mood, cognition, and sense of self and reality; thus implicating their involvement in mood disorder pathophysiology and pathogenesis. Impairments in neuroplasticity in the brains of patients suffering from mood disorders suggest that novel medications designed to attenuate impairments in these processes may have efficacy in their treatment. Further, since the onset of the vast majority of psychotrophic medications takes an extended period of treatment, it is a widely held belief that these drugs may act by modulation of critical neuronal signaling pathways and the resultant changes in gene expression and protein function. Preclinical, and some clinical, evidence implicates the action of specific neurotrophic signaling pathways in the downstream mechanism of action of medications useful for the treatment of mood disorders. We discuss specific signaling pathway and molecular treatment targets that are being considered for the development of novel treatments for mood disorders

Keywords: Bipolar disorder, manic-depressive illness, depression, lithium, valproate, antidepressant, glycogen synthase kinase-3, treatment