Soon after the discovery of extrahypothalamic TRH, several studies revealed central pharmacological effects of TRH that were independent of HPT axis control in laboratory animals, including increased locomotion, arousal, improvement of depression-like behaviors, reduction of epileptic seizures, and neuroprotection (Horita, 1998; Gary et al., 2003; Daimon et al., 2013; Fröhlich and Wahl, 2019). This evidence concerns the gene TRH and major depressive disorder.