- Biochemical research in mood disorders has focused, along the cascade of events involved in signal transduction, from studies at the level monoamine neurotransmitters and their receptors to mechanisms beyond receptors. Growing evidence suggests that G proteins may be involved in the pathophysiology and treatment of mood disorders: (1) lithium, other antibipolar and antidepressant treatments affect G protein levels, function, and mRNA levels; (2) differential alterations exist in G proteins measures in peripheral blood elements of patients with mood disorders; (3) alterations in G proteins levels exist in postmortem tissues of patients with mood disorders; and (4) candidate G protein–encoding genes as susceptibility loci for bipolar mood disorder and depression were detected. G protein signal transduction is regulated at a proximal point: following phosphorylation by G protein–coupled receptor kinases, receptors bind to arrestins, uncoupling the receptors from G proteins; at a distal regulatory point, regulators of G protein signaling proteins act primarily as GTPase-activating proteins. Both regulatory points have been recently found to be involved in the pathophysiology and treatment of mental disorders. It is to be hoped that an admixture of genomics, proteomics, multi-marker, large-scale automated measures, together with the “old” biochemical approaches, will enable the development of an objective biological differential diagnostic system for major mental disorders that will also enable monitoring and predicting response to treatments. Drug Dev. Res. 65:147–155, 2005. © 2005 Wiley-Liss, Inc.