Supraphysiological doses of levothyroxine alter regional cerebral metabolism and improve mood in bipolar depression

Abstract

Supplementation of standard treatment with high-dose levothyroxine (L-T 4 ) is a novel approach for treatment-refractory bipolar disorders. This study tested for effects on brain function associated with mood alterations in bipolar depressed patients receiving high-dose L-T 4 treatment adjunctive to ongoing medication (antidepressants and mood stabilizers). Regional activity and whole-brain analyses were assessed with positron emission tomography and [ 18 F]fluorodeoxyglucose in 10 euthyroid depressed women with bipolar disorder, before and after 7 weeks of open-label adjunctive treatment with supraphysiological doses of L-T 4 (mean dose 320 lg/day). Corresponding measurements were acquired in an age-matched comparison group of 10 healthy women without L-T 4 treatment. The primary biological measures were relative regional activity (with relative brain radioactivity taken as a surrogate index of glucose metabolism) in preselected brain regions and neuroendocrine markers of thyroid function. Treatment-associated changes in regional activity (relative to global activity) were tested against clinical response. Before L-T 4 treatment, the patients exhibited significantly higher activity in the right subgenual cingulate cortex, left thalamus, medial temporal lobe (right amygdala, right hippocampus), right ventral striatum, and cerebellar vermis; and had lower relative activity in the middle frontal gyri bilaterally. Significant behavioral and cerebral metabolic effects accompanied changes in thyroid hormone status. L-T 4 improved mood (remission in seven patients; partial response in three); and decreased relative activity in the right subgenual cingulate cortex, left thalamus, right amygdala, right hippocampus, right dorsal and ventral striatum, and cerebellar vermis. The decrease in relative activity of the left thalamus, left amygdala, left hippocampus, and left ventral striatum was significantly correlated with reduction in depression scores. Results of the whole-brain analyses were generally consistent with the volume of interest results. We conclude that bipolar depressed patients have abnormal function in prefrontal and limbic brain areas. L-T 4 may improve mood by affecting circuits involving these areas, which have been previously implicated in affective disorders. Molecular Psychiatry (2005) 10, 456-469.

Modulation of adult hippocampal neurogenesis by thyroid hormones: implications in depressive-like behavior

“…2,68 TH treatment is also beneficial in bipolar disorders resistant to other forms of treatment. 69,70 Concerning cognitive functioning, there was no difference among the experimental groups in the long-term object recognition memory. A recent study 71 found that treatment with the antimitotic agent methylazoxymethanol acetate reduces neurogenesis in the hippocampus up to 65% and prevents the long-term memory improvement induced by environmental enrichment, as measured in this object recognition task.…”

Increased white matter connectivity in euthymic bipolar patients: diffusion tensor tractography between the subgenual cingulate and the amygdalo-hippocampal complex

“…The functional relevance of this structure in mood disorders has been underlined by different lines of evidence, including deep brain stimulation 9 and pharmacological treatment. 10 Furthermore, a pathmodelling meta-analysis of cerebral blood flow in depressive patients 11 has demonstrated that different effective connectivity patterns between the SC and the amygdalo-hippocampal (AH) complex distinguished treatment responders from nonresponders.…”

Glutamate as a spectroscopic marker of hippocampal structural plasticity is elevated in long-term euthymic bipolar patients on chronic lithium therapy and correlates inversely with diurnal cortisol

“…Direct clinical evidence for hippocampal pathology in bipolar illness stems from post-mortem histological analysis, [6][7][8][9] volumetric magnetic resonance imaging 10 and [(18)F]fluorodeoxyglucose-positron emission tomography. 11 Recently, magnetic resonance spectroscopy (MRS) has also provided evidence for hippocampal neurometabolite alterations in bipolar disorder. [12][13][14] After 50 years of clinical use, lithium salts have remained the most effective and widely used longterm preventive treatment for bipolar disorder to date.…”