The role of TRH and related peptides in the mechanism of action of ECT.

Thyrotropin-releasing hormone (TRH) has been known anecdotally to produce antidepressant (AD) effects since the 1970s. Recent clinical reports have shown that intrathecal administration of TRH can more reliably induce remissions of major depression that last for 2-3 days. Although clinically impractical, it is important to note that these remissions are rapid within hours, and they survive at least 1 night's sleep. This review summarizes and integrates clinical and preclinical research on TRH and related peptides, which 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 (forced-swim test of AD effects). Intraperitoneal TRH also gives a positive response in this test, as do all effective AD medications. By considering neurobiological phenomena in depression and sleep, it is possible to outline a role for TRH and related peptides that may assist in the understanding both of depression and of the depressogenic effect of sleep in depressively vulnerable people. It is concluded that TRH and related peptides are likely to play a significant role in the inhibition of glutamatergic subcortical limbic neurons, which may be hyperactive in depression. Electroconvulsive therapy is believed to act, in part, by augmenting this inhibition. AD medications are believed to act indirectly, by activation of a subset of GABAergic interneurons, which then inhibit the pathologically hyperactive glutamatergic limbic neurons. Continued exploration of TRH and related peptides will be essential for further progress toward the control of these debilitating and often lethal diseases.