<p>Previous studies have shown that the heterotrimeric G protein, Gsalpha (Gsα), is ensconced predominantly in lipid rafts in acutely depressed subjects with major depressive disorder (MDD) in contrast to healthy controls, and that effective antidepressant treatment (ADT) facilitates translocation of Gsα from lipid rafts. The measurement of Gsα via prostaglandin E1 stimulation of adenylyl cyclase (PGE1 stimulation) has been proposed as a peripheral biomarker for assessing clinical status in MDD. We examined the Gsα biomarker in a new study. PGE1 stimulation was used to assess the coupling of Gsα with platelet adenylyl cyclase in depressed subjects in active treatment and healthy controls. The Quick Inventory of Depressive Symptomatology (QIDS-C₁₆) measured thresholds of symptom severity at two study visits spaced 2 weeks apart. QIDS-C₁₆ scores and PGE1 stimulated responses were stable between the two study visits. The QIDS-C₁₆ was inversely correlated with PGE1 stimulated responses at each visit (r_s = −0.33, r_s = −0.60, respectively). MDD subjects with mild-moderate depressive symptoms (defined by QIDS-C₁₆ ≥ 6) had significantly lower PGE1 stimulated responses than asymptomatic MDD subjects (QIDS-C₁₆ &lt; 6) or healthy controls (<i>p</i> = 0.001 and 0.002 respectively). MDD subjects with moderate depressive symptoms (QIDS-C₁₆ ≥ 10) had the lowest PGE1 responses of all subjects (Fisher’s exact = 0.012). These results support our earlier findings that a simple, high-throughput-capable platelet assay may be a useful biomarker to assess the clinical status of depressed subjects. Larger studies are needed to evaluate the utility of this biomarker for diagnosis and treatment response.</p>