Objective: The determinants of response to antidepressant treatment in major depression are unknown at present. The aim of the present study was to establish whether response is predicted by Hypothalamus-Pituitary-Thyroid (HPT) axis parameters or by a recently discovered polymorphism in the enzyme type II deiodinase (DII), which catalyzes the production of T 3 in the brain. Design: We analyzed prediction of response to paroxetine treatment by calculating response rates per tertile of HPT-axis parameters and per DII genotype. Methods: Ninety-eight outpatients with major depression (DSM-IV) were included. Serum concentrations of TSH, FT 4 and delta TSH in a DEX/CRH-TRH test were measured. In addition, the presence of a polymorphism in the DII sequence (Thr92Ala) was determined. Results: The overall treatment response was 48 of 98 patients (49%). After exclusion of patients with subclinical hypothyroidism and/or TPO antibodies (nZ16), higher serum TSH significantly predicted response (response rate per tertile from low to high TSH: 36%, 42%, and 67%). Heterozygous patients for the DII polymorphism (44%) had slightly lower serum TSH (PZ0.03) as compared to patients with the wild-type DII (47%). The polymorphism was unrelated to treatment response. Conclusion: Higher serum TSH was associated with response to paroxetine in patients with major depression.European Journal of Endocrinology 154 819-825