“Hyperthyroidism plays a major role in psychiatric morbidity in Graves’ disease, and is associated with long-term mood disturbances. Although hyperthyroidism has been considered to induce psychiatric symptoms by enhancement of the sensitivity and turnover in catecholaminergic neurotransmission, the precise mechanism of cognitive and behavioral dysfunction in hyperthyroidism is not known. According to Gonen, the direct influence of thyroid hormones on brain functions stems from the wide distribution of T3 receptors throughout the brain. Improvement of some clinical features (attention and concentration) with beta-blocker therapy suggests a role for a hyperthyroid-induced hyperactivity of the adrenergic nervous system, possibly disrupting the adrenergic pathways between the locus ceruleus and frontal lobe that subserve attention and vigilance, and thereby accounting for many physical and mental symptoms. Another possibility is hyperthyroidism may cause oxidative stress, resulting in neuronal injury and hastening the presentation of degenerative or vascular dementia. A 2002 study suggests another possible mechanism, involving activational and translational regulation of functional proteins in the brain.
Whatever the precise mechanisms, thyroid hormones clearly inﬂuence adult brain functioning, and may interact with mood regulation via targets in speciﬁc brain circuits. Singh et al. formulate, “differential thyroidal status is known to cause decrease in cell number and induces irreversible morphometric changes in adult brain resulting in different neuronal abnormalities”. This is underscored by recent studies, which document a thyroid hormone effect on the neurotransmitters serotonin and norepinephrine, with changes in neurotransmitter synthesis and receptor sensitivity being noted. De Groot points out, in spite of the fact that epinephrine levels and catecholamine excretion are actually not elevated, propranolol (it is presumed, acting by inhibition of alpha-adrenergic sympathetic activity) reduces anxiety and tremor in a very useful manner, indicating some of the central nervous system irritability is a manifestation of elevated sensitivity to circulating epinephrine. Thompson mentioned T3 can increase the activity of serotonin in the brain, while serotonin has been shown to inhibit thyroid function. Thus, although a complex system of interaction between thyroid hormone and neurotransmitters has been recognized and examined, no clear-cut explanation for the effect of thyroid hormone on depression has emerged.
Graves’ ophthalmopathy may also contribute to psychiatric morbidity, presumably through the psychosocial consequences of a changed appearance. However, the observation that a substantial proportion of patients have altered mental states even after successful treatment of hyperthyroidism, has led some researchers to suggest the autoimmune process itself may play a role in the presentation of mental symptoms and psychiatric disorders in Graves’ disease, whether or not ophthalmopathy is present. Persistent stimulation of thyroid-stimulating hormone receptors (TSH-Rs) may be involved. In Graves’ disease, the TSH-R gives rise to antibodies, and in some patients, these antibodies persist after restoration of euthyroidism. The cerebral cortex and hippocampus are rich in TSH-Rs. Antibody stimulation of these brain receptors may result in increased local production of T3.
Role of and relationship to Norepinephrine?