Objective: Recent evidence suggests that signalling cascades located downstream of monoamine receptors are altered following antidepressant treatment. Our objective was to investigate whether genetic polymorphisms in genes involved in these signalling cascades influenced antidepressant efficacy. Methods: Polymorphisms in the G-protein [beta] subunit GNB3, the cAMP response element binding protein 1 gene (CREB1), the brain derived neurotrophic factor (BDNF) and CREB binding protein (CREBBP) were studied in well characterised unipolar (n=166) and early onset (n=102) depressive populations and correlated with treatment response. Results: The GNB3 C825T polymorphism, which results in a 41 amino acid deletion, was significantly associated with lack of remission (OR=0.18, P=0.02) and lack of response (OR=0.26, P=0.03) following 2nd switch treatment. A cytosine deletion 16 base pairs from the start of exon 8 in CREB1 was found more frequently in remitters and responders to 2nd switch antidepressant drug therapy, although these differences failed to reach significance. Polymorphisms detected BDNF (G196A) and CREBBP (T651 C) did not appear to influence antidepressant response. Conclusions: These results suggest that inheritance of the GNB3C825T allele may significantly influence antidepressant response and emphasises the potential importance of polymorphisms in genes in signalling cascades activated by commonly prescribed antidepressants.