- Objective : Heterotrimeric G proteins play a pivotal role in postreceptor information transduction. These proteins were previously implicated in the biochemical mechanism underlying lithium action and in the pathophysiology of mood disorders. The present study sought to quantitatively and functionally evaluate G proteins in patients with major depression. Method: G proteins were measured in mononuclear leukocytes of 37 untreated patients with major depression and 31 comparison subjects. Receptor-coupled G proteins sanction was evaluated through β-adrenergic and muscarinic-agonist-induced increases in guanine nucleotide binding capacity, which were substained by quantitative measures of G proteins through immunoblot analyses that used polyclonal antibodies against stimulatory (G 5 α) and inhibitory (G,α) G proteins. Results: Mmononuclear leukocytes of depressed patients showed significantly reduced immunoreactive quantities of G s α and G i α together with markedly bypofunctional G s and G i . The reductions in both function and quantity of G s and G i were significantly correlated with the severity of depressive symptoms. Morever, simultaneous quantitative and functional measurements in a large number of patients showed significant correlations between the function and the quantity of nononuclear leukocyte G s and G i proteins. Conclusions: These findings lend further support to the implication of G proteins in the pathophysiology of mood disorders. G protein functional and quantitative measurements in mononuclear leukocytes of patients with mood disorders may potentially serve as a biochemical marker for the affective state of these patients.