We studied circadian thyrotropin (TSH) and prolactin (PRL) response to synthetic thyrotropin-releasing-hormone (protirelin) infusion (200μg IV) at 8 am and 11 pm in 35 drug-free inpatients with DSM III-R Major Depressive Episode and in 22 hospitalized controls. In each group, maximum TSH and PRL responses were lower at 8 am than at 11 pm. The difference between 11 pm-ΔTSH and 8 am-ΔJTSH (ΔΔTSH) was significantly lower in depressed patients compared to controls. No such blunting was observed in PRL responses to protirelin in depressed patients. In the overall population, TSH response to protirelin (ie8 am-ΔTSH, 11 pm-ΔTSH, ΔΔTSH) correlated significantly with TSH circadian parameters (ie mesor and amplitude). These correlations were also observed with PRL (except for ΔΔPRL). TSH mesor and amplitude were lower in depressives than in controls. In contrast, PRL mesor and amplitude were not significantly different between diagnostic groups. ΔΔTSH is thus a chronobiological refinement to the measure of thyroid axis dysfunction in major depression. The blunted TSH response to protirelin suggests that the TRH receptors of the pituitary thyrotrophs are hyposensitive in major depression.