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 o f major depression more reliably than i.v. administration. Although cl inically 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 sho ck (ECS) in rats induces synthesis of TRH in multiple subcortical limb ic and frontal cortical regions, which are known in humans to be invol ved in both depression and in sleep. The increases in TRH and related peptides are regionally specific. The quantitative TRH increases in in dividual 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 anti depressants. This article provides a heuristic framework for interdisc iplinary neuroscientific study of the interrelated fields of depressio n and sleep, with a focus on TRH. preclinical data suggest that glutam atergic, subcortical limbic circuits contain TRH and related peptides as inhibitory cotransmitters that may normally restrain glutamatergic hyperactivity. It is suggested that, in depression, pathologically ove rdriven glutamatergic circuits escape inhibitory regulation by TRH. Th is escape is especially pronounced during rapid eye movement (REM) sle ep, and these phenomena may explain the prolonged latency of antidepre ssant treatment.