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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?

SUBMITTER: Pilhatsch M

PROVIDER: S-EPMC6776578 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Pilhatsch Maximilian M J Stamm Thomas T Stahl Petra P Lewitzka Ute U Berghöfer Anne A Sauer Cathrin C Gitlin Michael M Frye Mark A MA Whybrow Peter C PC Bauer Michael M

International journal of bipolar disorders 20191004 1

<h4>Background</h4>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 o ...[more]

PMID: 31583561

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Project description:Adding supraphysiologic doses of levothyroxine (L-T4) to standard treatment for bipolar depression shows promise, but the mechanisms underlying clinical improvement are unknown. In a previous pilot study, L-T4 treatment reduced depression scores and activity within the anterior limbic network. Here we extended this work in a randomized, double-blind, placebo-controlled study of patients with bipolar depression. Cerebral glucose metabolism was assessed with positron emission tomography and [F-18]fluorodeoxyglucose before and after 6 weeks of treatment with L-T4 (n=15) or placebo (n=10) in 12 volumes of interest (VOIs): the bilateral thalamus, amygdala, hippocampus, dorsal striatum and ventral striatum, and midline cerebellar vermis and subgenual cingulate cortex. Radioactivity in the VOIs, normalized to whole-brain radioactivity was taken as a surrogate index of glucose metabolism, and markers of thyroid function were assayed. Changes in brain activity and their association with clinical response were assessed using statistical parametric mapping. Adjunctive L-T4 treatment produced a significant decline in depression scores during the 6-week treatment. In patients treated with L-T4, we found a significant decrease in regional activity at P<0.05 after Bonferroni correction in the left thalamus, right amygdala, right hippocampus, left ventral striatum and the right dorsal striatum. Decreases in the left thalamus, left dorsal striatum and the subgenual cingulate were correlated with a reduction in depression scores (P<0.05 after Bonferroni correction). Placebo treatment was associated with a significant decrease in activity only in the right amygdala, and no region had a change in activity that was correlated with change in depression scores. The groups differed significantly in the relationship between the changes in depression scores and in activity in the thalamus bilaterally and the left ventral striatum. The findings provide evidence that administration of supraphysiologic thyroid hormone improves depressive symptoms in patients with bipolar disorder by modulating function in components of the anterior limbic network.

Project description:OBJECTIVE:To evaluate the efficacy and tolerability of quetiapine monotherapy for anxiety symptoms in patients with bipolar disorder experiencing depression in the BipOLar DEpRession (BOLDER I and II) studies. METHOD:A post hoc analysis of anxiety symptoms in 1,051 acutely depressed patients with bipolar I or II disorder (DSM-IV) from 2 double-blind, randomized, placebo-controlled 8-week studies of quetiapine (300 or 600 mg once daily) was conducted. Anxiety symptoms were assessed using Hamilton Anxiety Rating Scale (HARS) total and psychic (items 1-6, 14) and somatic (items 7-13) anxiety subscale scores (mixed-model repeated measure and last-observation-carried-forward analysis of change from baseline at each assessment). The BOLDER I study was conducted between September 2002 and October 2003, and the BOLDER II study was conducted between June 2004 and August 2005. RESULTS:Mean baseline HARS total scores were similar across the treatment groups (300 mg/d: 18.9, 600 mg/d and placebo: both 18.6). There was a significantly greater improvement from baseline in mean HARS total scores at the first evaluation (week 1) in both quetiapine groups compared with placebo (300 mg/d: -4.6, P < .001 and 600 mg/d: -4.1, P = .003 vs placebo: -2.8). These improvements were sustained through week 8 with both quetiapine doses (300 mg/d: -10.1, P < .001 and 600 mg/d: -10.5, P < .001 vs placebo: -6.9). At week 8, there was also significant improvement from baseline in HARS psychic and somatic anxiety subscale scores compared with placebo (P < .001). The baseline severity of anxiety did not impact the improvement in depressive symptoms. Common adverse events included dry mouth, sedation, somnolence, and dizziness. CONCLUSIONS:In this pooled analysis, quetiapine monotherapy was more effective than placebo and generally well tolerated for the treatment of both depressive and anxiety symptoms in patients with bipolar disorder. TRIAL REGISTRATION:clinicaltrials.gov Identifiers: NCT00060489 (BOLDER I) and NCT00083954 (BOLDER II).

Project description:ObjectiveDespite the high prevalence of late-life depression and anxiety at threshold and subthreshold levels, their joint role in the disablement process remains unclear. This study aims to examine the association of comorbid occurring depression and anxiety across the full spectrum of symptom severity with disability onset in older adults.MethodsThe study included 3663 participants from the 2011 National Health and Aging Trends Study, who reported no limitations in self-care and mobility activities at baseline. Disability onset was defined as a report of receiving help from another person in any of the activities for 3 consecutive months. Depression and anxiety symptoms were measured using the four-item Patient Health Questionnaire, grouped into low, mild, and moderate/severe symptom groups. Cox proportional hazards models were used to estimate relative risks for disability onset over a 5-year period by depression/anxiety symptom groups.ResultsA total of 1047 participants developed disability (24.6%; 6.0 per 1000 person-months). At baseline, one-fifth of the sample reported symptoms that were mild (n = 579 [14.9%]; 31.6% with disability onset) or moderate/severe (n = 156 [4.2%]; 38.1% with disability onset). After adjustment for sociodemographics, there was a dose-response relationship between depression/anxiety symptom groups and disability onset (mild versus low: hazard ratio [HR] = 1.43, 95% confidence interval [CI] = 1.20-1.70; moderate/severe versus low: HR = 1.94, 95% CI = 1.45-2.59). The increased risk remained significant after adjustment for health status variables for the mild symptom group (HR = 1.26, 95% CI = 1.07-1.49), but not for the moderate/severe symptom group (HR = 1.30, 95% CI = 0.94-1.79), possibly reflecting lower statistical power.ConclusionsFindings suggest that the full spectrum of depression and anxiety symptoms are associated with increased risk for disability in late life. Their role in the disablement process warrants further investigation.

Project description:Depressive symptoms associated with bipolar disorder negatively impact health-related quality of life (HRQoL). The efficacy of lurasidone in reducing depressive symptoms has been previously demonstrated. The objective of this study was to examine the direct and indirect effect (mediated through improvement in depression symptoms) of lurasidone in improving patient HRQoL.A secondary analysis of data was conducted of two 6-week, double-blind, placebo-controlled trials assessing the effect of lurasidone (lurasidone monotherapy [20-60 mg/day or 80-120 mg/day]; lurasidone adjunctive to lithium or valproate [20-120 mg/day]) in patients with bipolar depression. Patient HRQoL was measured using the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q SF). Depression symptoms were measured using the Montgomery-Asberg Depression Rating Scale (MADRS). Analysis of covariance (ANCOVA) was used to estimate the effect of lurasidone on improvement in the Q-LES-Q SF percentage maximum score from baseline to 6 weeks. Path analysis was used to evaluate the total effect (?1), as well as the indirect (?2*?3) and direct (?4) effect of lurasidone on Q-LES-Q SF change through improvements in MADRS.A total of 340 and 485 patients from the monotherapy and adjunctive therapy, respectively, were included in the analysis. At 6-weeks, ANCOVA analyses demonstrated that lurasidone provided significant improvement in adjusted mean Q-LES-Q SF scores in comparison to placebo for monotherapy (22.9 and 22.7 vs. 15.2, both p?<?0.01) and adjunctive therapy (23.1 vs. 17.9, p?=?0.01). Path analyses indicated that lurasidone treatment predicted MADRS improvement (monotherapy: ?2?=?-0.44, p?<?0.001; adjunctive therapy: ?2?=?-0.34, p?=?0.003), which subsequently predicted improvement in Q-LES-Q SF (monotherapy: ?3?=?-0.73, p?<?0.001; adjunctive therapy: ?3?=?-0.75, p?<?0.001); however, the effect of lurasidone on improvement in Q-LES-Q SF was largely mediated by change in MADRS (monotherapy: ?4?=?0.11, p?=?0.13; adjunctive therapy: ?4?=?0.02, p?=?0.77).Lurasidone as a monotherapy and adjunctive to lithium or valproate is an effective treatment for improving HRQoL in patients with bipolar depression. However, improvement in HRQoL was not independent of improvement in depression, indicating that the effect of lurasidone on improving patient HRQoL may act through a reduction in depressive symptoms associated with bipolar disorder.Clinicaltrials.gov identifiers: NCT00868699 and NCT00868452 (both registered March 23, 2009).

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

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

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