Treatment of bipolar depression with supraphysiologic doses of levothyroxine: a randomized, placebo-controlled study of comorbid anxiety symptoms

Abstract

Background Symptoms of anxiety co-occur in a variety of disorders including in depressive episodes of bipolar disorder and in patients with thyrotoxicosis. Treatment of refractory bipolar disorder with supraphysiologic doses of levothyroxine (L-T4) has been shown to improve the phenotypic expression of the disorder and is associated with an increase of circulating thyroid hormones. However, it might be associated with somatic and mental adverse effects. Here we report the investigation of the influence of treatment with supraphysiologic doses of L-T4 on symptoms of anxiety in patients with refractory bipolar depression. Methods Post-hoc analysis from a 6-week, multi-center, randomized, double-blind, placebo-controlled study of the effects of supraphysiologic L-T4 treatment on anxiety symptoms in bipolar depression. Anxiety symptoms were measured weekly with the Hamilton anxiety/somatization factor (HASF) score of the Hamilton Depression Rating Scale (HAMD) and the State- and Trait Anxiety Inventory (STAI). Results Treatment of both groups was associated with a significant reduction in anxiety symptoms (p < 0.001) with no statistical difference between groups (LT-4: from 5.9 (SD = 2.0) at baseline to 3.7 (SD = 2.4) at study end; placebo: from 6.1 (SD = 2.4) at baseline to 4.4 (SD = 2.8) at study end; p = 0.717). Severity of anxiety at baseline did not show a statistically significant correlation to the antidepressive effect of treatment with supraphysiologic doses of L-T4 (p = 0.811). Gender did not show an influence on the reduction of anxiety symptoms (females: from 5.6 (SD = 1.7) at baseline to 3.5 (SD = 2.4) at study end; males: from 6.1 (SD = 2.3) at baseline to 4.0 (SD = 2.4) at study end; p = 0.877). Conclusions This study failed to detect a difference in change of anxiety between bipolar depressed patients treated with supraphysiologic doses of L-T4 or placebo. Comorbid anxiety symptoms should not be considered a limitation for the administration of supraphysiologic doses of L-T4 refractory bipolar depressed patients. Trial registration ClinicalTrials, ClinicalTrials.gov identifier: NCT01528839. Registered 2 June 2012—Retrospectively registered, https://clinicaltrials.gov/ct2/show/study/NCT01528839

Patterns of Thyroid Hormone Prescription in Patients with Bipolar or Schizoaffective Disorder: Findings from the LiSIE Retrospective Cohort Study

“…A recent RCT explored adjunctive treatment with supraphysiologic T4 doses in patients with bipolar depression. Compared to placebo, there was no statistically significant difference in reported anxiety, the primary outcome of this study [ 52 ]. Other observational studies have also failed to show any association between laboratory thyroid status and mood states in patients with BD [ 9 , 10 , 11 ].…”

Deiodinase variation and liothyronine treatment interaction to accelerate ECT response in major depression: Pilot data and implications for thyroid pharmacogenomic testing in mood disorders

“…There has been extensive review of thyroid function (i.e. peripheral TSH, FT4, Total T3, CSF FT4 and Total T3), thyrotropin releasing hormone (TSH) stimulation challenge, and intrathecal TSH treatment for mood disorders, often times without clear convergence of data clarifying the neuroendocrine pathophysiology of depression [23][24][25][26][27][28][29]. The lack of convergence may be related, in part, to not considering functional genetic variation in thyroid hormone metabolism.…”

Efficacy and acceptability of pharmacotherapy for comorbid anxiety symptoms in bipolar disorder: A systematic review and meta‐analysis

“…23 Two RCTs of ketamine 25,26 and one of methylene blue 24 reported a significant improvement of anxiety and depression symptoms compared with placebo. Single RCTs of minocycline plus aspirin 40 or levothyroxine 41 reported no differences in outcomes compared with placebo.…”