Hypothyroidism, more commonly subclinical, appears a common abnormality, while the hypothalamic-pituitary-thyroid (HPT) axis abnormalities are quite common among patients with bipolar disorder. On the other hand, lithium has been used successfully in treating bipolar disorders, but lithium influence on the thyroid gland is one of the key side effects in the long-term therapy. Lithium administration leads to a decrease of production and release of thyroid hormones, which results in increased levels of thyroid stimulating factor (TSH), and excessive TSH response to stimulation with TRH. Inhibition of thyroid hormone release, a process mediated by cyclic adenosine monophosphate, appears to be the critical mechanism in the development of lithium-induced hypothyroidism. Lithium also inhibits thyroidal iodine uptake and iodotyrosine coupling, alters thyroglobulin structure, and interferes with the deiodination of T4 to T3, by inhibiting type-II deiodinase in the brain. Lithium may also demonstrate an immunostimulant effect, either by inducing, or by exacerbating a preexisting autoimmune disease. Additionally, lithium alters cellular responsiveness to thyroxine, and influences thyroid hormone receptor gene expression. Deficits in any one or more of these mechanisms may result in reduced bioavailability of thyroid hormones at cerebral target regions despite normal peripheral serum levels of thyroid hormones. Rethinking lithium mechanisms of action, and especially lithium induced hypothyroidism, may help to enhance our understanding of the thyroid-bipolar disorder connection. In the course of lithium therapy, excessive TSH response to TRH occurs in at least 50% of bipolar patients. This “disordered” thyroid-hypothalamic-pituitary axis seems to be temporary in most patients, which suggests that the axis is adjusting to the new «state» during therapy. Moreover, rapid cycling bipolar disorder is associated with a latent hypofunction of the HPT system, which becomes manifest even with short-term lithium challenge. Lithium-treatment exaggeration of TSH responses to TRH, indicate that lithium push forward these patients in a temporary “more hypo-thyroid” status”. It is possible that the lithium induced ‘central hypothyroidism’ may enhance the HPT axis activation, resulting to the thyroid system re-activation, and to the thyroid hormones’ availability and effect re-adaptation. This compensatory process may results to the correction of a possible peripheral resistance to thyroid hormones, as well as to the correction of an isolated CNS hypothyroidism. We may hypothesize that these compensatory mechanisms, which operate to prevent the development of hypothyroidism or goiter, represent a therapeutic process of lithium therapy in bipolar disorder, acting through a thyroid system resetting.

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Orestis Giotakos