Graves' disease as a driver of depression: a mechanistic insight

Abstract

Graves' disease (GD) is characterized by diffuse enlargement and overactivity of the thyroid gland, which may be accompanied by other physical symptoms. Among them, depression can dramatically damage patients' quality of life, yet its prevalence in GD has not received adequate attention. Some studies have established a strong correlation between GD and increased risk of depression, though the data from current study remains limited. The summary of mechanistic insights regarding GD and depression has underpinned possible pathways by which GD contributes to depression. In this review, we first summarized the clinical evidence that supported the increased prevalence of depression by GD. We then concentrated on the mechanistic findings related to the acceleration of depression in the context of GD, as mounting evidence has indicated that GD promotes the development of depression through various mechanisms, including triggering autoimmune responses, inducing hormonal disorders, and influencing the thyroid-gut-microbiome-brain axis. Finally, we briefly presented potential therapeutic approaches to decreasing the risk of depression among patients with GD.

Keywords: Graves’ disease; autoimmune; depression; gut; hormone.

Figure 1

Graves’ disease as a mechanistic driver of depression. Specific pathways of autoimmune responses, hormonal disorders and microbiota dysbiosis in GD trigger neuron dysfunction in the brain and promote the development of depression. (1) Autoimmune responses in GD cause altered inflammatory cytokines levels. Continuous activation of the HPA axis induced by persistent inflammatory cytokines stimulation can damage neurons and activate continuing central inflammation, along with affecting the expression and action of hormone receptors. Inflammatory cytokines can also disrupt monoamine neurotransmitter metabolism, resulting in lower accessibility to these neurotransmitters. The increase of BBB permeability in the inflammatory state of GD allows inflammatory cytokines to enter the brain and may lead to neuroinflammation. (2) Multiple hormonal disorders can develop as a result of GD hyperthyroidism, including thyroid hormones, insulin and sex hormones. The increase of thyroid hormones can reduce the secretions of dopamine (DA) and norepinephrine (NE). Insulin resistance (IR) in GD can increase both blood and intracellular glucose level, inducing neuronal tissue damage and afterhyperpolarization (AHP). Additionally, sex hormone disorders in GD are likely to lower Synaptic efficacy, which is related to the pathogenesis of depression. (3) Gut dysbiosis in GD can result in lower accessibility to 5-HT and activate host immune responses, increasing the risk of depression. HPA axis, the hypothalamic-pituitary-adrenal axis; 5-HT, serotonin; IR, insulin resistance; DA, dopamine; NE, norepinephrine; BBB, the blood-brain barrier; SCFA, short-chain fatty acids; AHP, afterhyperpolarization; 5-HT, 5-hydroxytryptamine.