Supraphysiological Doses of L-Thyroxine in the Maintenance Treatment of Prophylaxis-Resistant Affective Disorders

Bauer, Michael; Berghöfer, Anne; Bschor, Tom; Baumgartner, Andreas; Kiesslinger, Ursula; Hellweg, Rainer; Adli, Mazda; Baethge, Christopher; Müller‐Oerlinghausen, B.

doi:10.1016/s0893-133x(02)00320-2

Cited by 46 publications

(63 citation statements)

References 31 publications

(19 reference statements)

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“…Although SPCs of T3 have been used in the treatment of chronic fatigue syndrome, 29 prophylaxis-resistant psychiatric illnesses, [30][31][32] and obesity, 33,34 the mechanism of T3 action at such concentrations is not known. Here, we focused our study on the role of SPCs of T3 in modulating cellular stress signaling pathways and stress-mediated antiviral responses.…”

Section: Discussionmentioning

confidence: 99%

“…24 An earlier report has indicated that thyroid hormone receptor (THR) agonist triiodo-l-thyronine (T3) at physiological concentrations can potentiate the inhibition of vesicular stomatitis virus (VSV) replication by IFN-g; 28 however, these authors did not observe any inhibition of VSV replication by T3 alone. Although supraphysiological concentrations (SPCs) of T3 have been used in the treatment of chronic fatigue syndrome, 29 prophylaxis-resistant psychiatric illnesses, [30][31][32] and obesity, 33,34 the mechanism of T3 function at SPCs and their role in modulating cellular stress pathways and stress-mediated antiviral responses are unknown. In this paper, we report that T3 hormone at SPCs activates ISR pathways that include PKR activation, SG formation, and activation of ER-mediated stress pathways.…”

Section: Introductionmentioning

confidence: 99%

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Integrated Stress Response Signaling Pathways Induced by Supraphysiological Concentrations of Thyroid Hormone Inhibit Viral Replication

Ishaq

Natarajan

2016

Signal Transduction Insights

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Supraphysiological concentrations (SPCs) of triiodo-l-thyronine (T3) have been used in the treatment of a number of nonviral diseases. However, the signaling mechanisms that regulate the function of T3 at these concentrations and their role in modulating cellular stress pathways and antiviral responses are unknown. Here, we have investigated the effects of SPCs of T3 on integrated stress response (ISR) signaling pathways and the replication of vesicular stomatitis virus (VSV). T3 amplified Poly IC-induced activation of RNA-dependent protein kinase, induced phosphorylation of eIF2α, stress granule (SG) formation, IRE1α phosphorylation, XBP1 splicing, and the expression of stress markers. T3 inhibited VSV replication by modulating SG formation and the expression of stress response markers. ISR activator guanabenz also inhibited VSV replication and amplified T3-induced anti-VSV response. To summarize, we have uncovered novel functions of T3 at SPCs as an activator of ISR signaling pathways and an inhibitor of VSV replication. This study offers a proof of principle of the concept that ISR activating agents like SPC of T3 and guanabenz can be potential antiviral agents.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Integrated Stress Response Signaling Pathways Induced by Supraphysiological Concentrations of Thyroid Hormone Inhibit Viral Replication

Ishaq

Natarajan

2016

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“…1,2 In this regard, adjunctive use of levothyroxine (L-T 4 ) at supraphysiological doses offers promise for patients who suffer rapid cycling [3][4][5][6] and prophylaxis-resistant bipolar disorders, [6][7][8][9] for patients with bipolar and unipolar disorder during a phase of refractory major depressive episode, 10 and patients with refractory chronic depression and dysthymia. 11 Despite knowledge of the role of thyroid hormones in the maturation and the differentiation of the brain, 12,13 and the association between thyroid status and behavioral disturbances in thyroid disease, 14,15 the action of thyroid hormones in the adult brain has received comparatively little attention.…”

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confidence: 99%

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

et al. 2005

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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 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.

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“…56 ) In aggregate, only 29 subjects, some of whom were unipolar depressives, all from the same research group, have been evaluated in the studies published over the last 15 years. [57][58][59] (Some of the subjects in two earlier reports 57,58 are included in the later paper. 59 ) Nonetheless, high-dose thyroid hormone augmentation continues as a potential option for treatment-resistant bipolar disorder.…”

Section: High-dose Thyroid Augmentationmentioning

confidence: 99%

“…Mean doses of Lthyroxine in the two recent publications were 379 59 and 482 mcg, 58 between 3 and 4.5 Â the daily thyroid replacement dose in the United States. Thus, patients were treated with supraphysiological doses.…”

Section: High-dose Thyroid Augmentationmentioning

confidence: 99%

Treatment-resistant bipolar disorder

2006

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Despite the remarkable increase in medications validated as effective in bipolar disorder, treatment is still plagued by inadequate response in acute manic or depressive episodes or in long-term preventive maintenance treatment. Established first-line treatments include lithium, valproate and second-generation antipsychotics (SGAs) in acute mania, and lithium and valproate as maintenance treatments. Recently validated treatments include extended release carbamazapine for acute mania and lamotrigine, olanzapine and aripiprazole as maintenance treatments. For treatment-resistant mania and as maintenance treatments, a number of newer anticonvulsants, and one older one, phenytoin, have shown some promise as effective. However, not all anticonvulsants are effective and each agent needs to be evaluated individually. Combining multiple agents is the most commonly used clinical strategy for treatment resistant bipolar patients despite a relative lack of data supporting its use, except for acute mania (for which lithium or valproate plus an SGA is optimal treatment). Other approaches that may be effective for treatment-resistant patients include high-dose thyroid augmentation, clozapine, calcium channel blockers and electroconvulsive therapy (ECT). Adjunctive psychotherapies show convincing efficacy using a variety of different techniques, most of which include substantial attention to education and enhancing coping strategies. Only recently, bipolar depression has become a topic of serious inquiry with the dominant controversy focusing on the place of antidepressants in the treatment of bipolar depression. Other than mood stabilizers alone or the combination of mood stabilizers and antidepressants, most of the approaches for treatment-resistant bipolar depression are relatively similar to those used in unipolar depression, with the possible exception of a more prominent place for SGAs, prescribed either alone or in combination with antidepressants. Future work in the area needs to explore the treatments commonly used by clinicians with inadequate research support, such as combination therapy and the use of antidepressants as both acute and adjunctive maintenance treatments for bipolar disorder. With the first report of lithium's efficacy in 1949 by Cade, bipolar disorder has the longest record of treatment efficacy among the major Axis I disorders. Furthermore, after more than half a century of clinical research, multiple agents from many different pharmacological classes have shown at least some efficacy, while many other agents (albeit without a consistent database demonstrating their utility) are prescribed regularly by clinicians. Yet, despite this plethora of choices, treatment of bipolar disorder remains suboptimal from the points of view of clinicians and patients alike. Whether measured by recovery time from manic or depressive episodes or preventive efficacy of maintenance treatments, bipolar disorder is characterized by sluggish responses, inadequate responses, poor compliance and recurrences in controlled cli...

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Supraphysiological Doses of L-Thyroxine in the Maintenance Treatment of Prophylaxis-Resistant Affective Disorders

Abstract: This prospective open-label study examined the efficacy of adjunctive supraphysiological doses of L-thyroxine (T 4 ) in the

Cited by 46 publications

References 31 publications

Integrated Stress Response Signaling Pathways Induced by Supraphysiological Concentrations of Thyroid Hormone Inhibit Viral Replication

Integrated Stress Response Signaling Pathways Induced by Supraphysiological Concentrations of Thyroid Hormone Inhibit Viral Replication

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

Treatment-resistant bipolar disorder

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