A heuristic model of mental depression derived from basic and applied research on thyrotropin-releasing hormone

Recent clinical reports have shown that intrathecal administration of thyrotropin-releasing hormone (TRH) can induce 2 to 3 day remissions of major depression more reliably than i.v. administration. Although clinically impractical, these remissions are rapid, occur within hours, and they survive at least one night's sleep. TRH and related peptides have regulatory effects in the limbic forebrain. Electroconvulsive shock (ECS) in rats induces synthesis of TRH in multiple subcortical limbic and frontal cortical regions, which are known in humans to be involved in both depression and in sleep. The increases in TRH and related peptides are regionally specific. The quantitative TRH increases in individual limbic regions have been correlated with the amount of forced-swimming done by the individual animal after ECS. Intraperitoneal TRH also gives a positive response in this test, as do all effective antidepressants. This article provides a heuristic framework for interdisciplinary neuroscientific study of the interrelated fields of depression and sleep, with a focus on TRH. Preclinical data suggest that glutamatergic, subcortical limbic circuits contain TRH and related peptides as inhibitory cotransmitters that may normally restrain glutamatergic hyperactivity. It is suggested that, in depression, pathologically overdriven glutamatergic circuits escape inhibitory regulation by TRH. This escape is especially pronounced during rapid eye movement (REM) sleep, and these phenomena may explain the prolonged latency of antidepressant treatment.