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

Neuropsychiatric Institute & Hospital, University of California Los Angeles , CA, USA.
Molecular Psychiatry (Impact Factor: 14.5). 06/2005; 10(5):456-69. DOI: 10.1038/
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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 microg/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.

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    • "Several longitudinal studies indicate that the proportion of total time in depressive components of BD (averaging 75 % of a total of 54 % of weeks ill) is far greater than in manic or hypomanic phases, despite use of available treatments (Judd et al., 2002 ; Post et al., 2003a ; Joffe et al., 2005 ; Paykel et al., 2006 ; Kupka et al., 2007 ; Baldessarini et al., 2010a, c). Depressive components of BD are associated with high morbidity (Baldessarini et al., 2010a, b ; Leboyer et al., 2012), co-morbidity (Kilbourne et al., 2004 ; Bauer et al., 2005a, b), disability (Keck et al., 2008 ; Rosa et al., 2010), mortality (O ¨ sby et al., 2001 ; Angst et al., 2002 ; Roshanaei-Moghaddam and Katon, 2009 ; Baldessarini et al., 2010d) and high levels of clinical and economic burdens to patients and their families (Kupka et al., 2007 ; Baldessarini et al., 2010d). In addition, both types I and II BD are associated with very high rates of suicide (about 20 times above rates in the general population) and other violent causes of death especially among young patients (O ¨ sby et al., 2001 ; Tondo et al., 2003, 2007 ; Novick et al., 2010 ; Undurraga et al., 2012b), as well as similar total annual numbers of deaths associated with medical comorbidity in older patients, albeit at far-lower standardized mortality rates (2–3 times above rates in the general population) than for suicide (O ¨ sby et al., 2001 ; Tondo et al., 2003, 2007 ; Novick et al., 2010). "

    03/2015; 13(1):102-112. DOI:10.1176/appi.focus.130119
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    • "This study thus points to deficits in prefrontal signaling in BD, possibly resulting from reduced FFFSrelated punishment alerts, coupled with a diminished regulatory control of the BIS in manic state and vice versa in the depressed state. Further supporting this view is evidence from Positron Emission Tomography (PET) studies, showing increased sgACC, ACC and hippocampal metabolism in depressed BD patients during the resting state (Bauer et al., 2005; Mah et al., 2007). Altogether, imaging findings strongly support our proposal for the involvement of several RST systems in BD, suggesting that rather than a deficit in BAS alone, the coupled interaction of BAS with BIS/FFFS is impaired (Figure 2). "
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    ABSTRACT: Motivation is a key neurobehavioral concept underlying adaptive responses to environmental incentives and threats. As such, dysregulation of motivational processes may be critical in the formation of abnormal behavioral patterns/tendencies. According to the long standing model of the Reinforcement Sensitivity Theory (RST), motivation behaviors are driven by three neurobehavioral systems mediating the sensitivity to punishment, reward or goal-conflict. Corresponding to current neurobehavioral theories in psychiatry, this theory links abnormal motivational drives to abnormal behavior; viewing depression and mania as two abnormal extremes of reward driven processes leading to either under or over approach tendencies, respectively. We revisit the RST framework in the context of bipolar disorder (BD) and challenge this concept by suggesting that dysregulated interactions of both punishment and reward related processes better account for the psychological and neural abnormalities observed in BD. We further present an integrative model positing that the three parallel motivation systems currently proposed by the RST model, can be viewed as subsystems in a large-scale neurobehavioral network of motivational decision making.
    Frontiers in Behavioral Neuroscience 11/2014; 8:378. DOI:10.3389/fnbeh.2014.00378 · 3.27 Impact Factor
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    • "Comparatively, a significantly higher response to tricyclic antidepressants has been found for T3 (53 %) vs. T4 (19 %) (Joffe and Singer 1990). However, the latter study used low T4 doses, whereas more recent studies used supraphysiological doses (Bauer et al. 2005). Thus, the relatively elevated levels of FT3 and FT4 found in our study support the hypothesis of a compensatory response; this finding is in line with that of an early report that suggested a catecholamine–thyroid interaction in the central nervous system (Whybrow and Prange 1981). "
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    ABSTRACT: Thyroid hormones and their interactions with catecholamines play a potentially important role in alterations of mood and cognition. This study aimed to examine the neurobiological effects of catecholamine depletion on thyroid hormones by measuring endocrine and cerebral metabolic function in unmedicated subjects with remitted major depressive disorder (RMDD) and in healthy controls. This was a randomized, placebo-controlled, and double-blind crossover trial that included 15 unmedicated RMDD subjects and 13 healthy control subjects. The participants underwent two 3-day-long sessions at 1-week intervals; each participant was randomly administered oral α-methyl-para-tyrosine in one session (catecholamine depletion) and an identical capsule containing hydrous lactose (sham depletion) in the other session prior to a [(18)F]-fluorodeoxyglucose positron emission tomography scan. Serum concentrations of free T3 (FT3), free T4 (FT4), and TSH were obtained and assessed with respect to their relationship to regional cerebral glucose metabolism. Both serum FT3 (P = 0.002) and FT4 (P = 0.0009) levels were less suppressed after catecholamine depletion compared with placebo treatment in the entire study sample. There was a positive association between both FT3 (P = 0.0005) and FT4 (P = 0.002) and depressive symptoms measured using the Montgomery-Åsberg Depression Rating Scale. The relative elevation in FT3 level was correlated with a decrease in regional glucose metabolism in the right dorsolateral prefrontal cortex (rDLPFC; P < 0.05, corrected). This study provided evidence of an association between a thyroid-catecholamine interaction and mood regulation in the rDLPFC.
    Psychopharmacology 08/2013; 231(2). DOI:10.1007/s00213-013-3250-2 · 3.88 Impact Factor
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