BACKGROUND: Depression is a large and expanding worldwide unmet clinical need that has proven difficult to treat. Thyroid hormone has been used clinically for decades as an augmentation therapy to first-line antidepressants, although the mechanism of action (MOA) behind the beneficial effect of thyroid hormone augmentation is not clear. Here we present a narrative review of the literature to provide an understanding of the known pathophysiology that occurs in depression and the different actions that thyroid hormone promotes in the brain to develop new insight into the mechanism behind the antidepressant activity of thyroid hormone. SUMMARY: We believe this review of published literature illustrates the complex picture of depression pathophysiology and provides new insight into the MOA of thyroid hormones used as augmentation therapy to antidepressants. Impaired monoaminergic neurotransmission is an established pathophysiological hallmark of depression. However, there are other pathways that are impacted, including inflammatory and endocrine responses. Brain bioenergetics is affected, with depressed patients having lower brain ATP levels than healthy subjects. In addition, and perhaps related, depression patients display a loss in brain volume, particularly in the mood control regions of the brain. This is brought about by a dampening in neuroplasticity, the process by which new dendrites and synapses are formed. Here the connection to thyroid hormone augmentation becomes intriguing because thyroid hormone is known to play a role in stimulating neuroplasticity. At the target gene level, brain-derived neurotrophic factor, an initiator and biomarker of neuroplastic changes, is positively regulated by thyroid hormone, as are some of the immediate-early genes implicated in driving neuroplasticity. Thyroid hormone induces neuroplasticity and brain remodeling in a mouse model of behavior associated with increased decision-making and exploration, as well as mouse models of traumatic brain injury and stroke. CONCLUSIONS: We propose that thyroid hormone augmentation of antidepressant therapy works by stimulating the processes of neuroplasticity in the regions of the brain that are affected by depression, restoring synaptic connections lost from depression. Since neuroplasticity is an energy-demanding process, the cellular increase in brain bioenergetics stimulated by thyroid hormone action likely drives the initiation and maintenance of plasticity.
McIntyre et al. (Fri,) studied this question.