Adjunctive thyroid hormone treatment in rapid cycling bipolar disorder: A double-blind placebo-controlled trial of levothyroxine (L-T4 ) and triiodothyronine (T3 )

Abstract

Objectives: This report describes the first comparative double-blind, placebo-controlled trial of levothyroxine (L-T₄ ) and triiodothyronine (T₃ ) as adjunctive treatments in rapid cycling bipolar disorder.

Methods: Thirty-two treatment-resistant, rapid cycling patients who had failed a trial of lithium were randomized into three treatment arms: L-T₄ , T₃ , or placebo. They were followed for ≥4 months with weekly clinical and endocrine assessments.

Results: There were no statistically significant differences between the groups in age, gender, duration of illness, or thyroid status. Markov chain analyses were employed to assess treatment effects on cycling patterns among mood states (euthymia, depression, mania, and mixed). Within groups, post-treatment the L-T₄ group spent significantly less time depressed or in a mixed state and greater time euthymic. The T₃ and placebo groups did not differ significantly pre- and post-treatment in any mood state, although the pattern of effects was the same for the T₃ group as for the L-T₄ group. Between groups, the L-T₄ group had a significantly greater increase in time euthymic and decrease in time in the mixed state than the placebo group. Other group differences were not significant, although they were in the expected direction.

Conclusions: The findings in this first double-blind study directly comparing the effects of L-T₄ and T₃ therapy against placebo provide evidence for the benefit of adjunctive L-T₄ in alleviating resistant depression, reducing time in mixed states and increasing time euthymic. Adjunctive T₃ did not show statistically significant evidence of benefit over placebo in reducing the time spent in disturbed mood states.

Keywords: bipolar disorder; levothyroxine; rapid cycling; thyroid; triiodothyronine.

Figure1:

Consolidated Standards of Reporting Trials (CONSORT) diagram.

Figure 2.

Mood states were assigned at weekly intervals based on each individual’s interpolated scores on HDRS and YMRS relative to their own pre-treatment median (as indicated by the grey lines).

Figure 3.

Individual mood state sequences were combined to estimate the transition matrices (i.e.probabilities of moving from any one state to any other state). The transition matrices were then used to calculate the long-run fraction of time participants would be expected to spend in each of the mood states under the specified treatment regimen. The pre-post differences in the stationary distributions were used to assess the treatment effects on euthymia, depression, mania, and mixed mood states.

Figure 4.

Figure presents the observed values and smoothed histograms of the bootstrap distributions of the change in percentage time spent in each mood state from baseline to post-treatment within each study arm. The various colors correspond to the treatment arms (black = placebo, blue = T3, red = L-T4). The 0 point on the x-axis indicates where there was no pre-post change in time spent in a particular state. Distributions to the right of 0 indicate an increase in time spent in that state from pre- to post-treatment, while distributions to the left of 0 indicate a decrease in time spent in that state. The dashed lines are observed data estimates for each group. P-values were computed as % of extreme tail to 0, doubled for two-sided test.

Figure 5.

The figure presents the observed values and smoothed histograms of the bootstrap distributions of the differential treatment effects on the percentage time spent in each mood state for each pair of study arms. The various colors correspond to the pairs (blue = T3 vs placebo, red = L-T4 vs placebo, green = LT4 vs T3). The 0 point on the x-axis corresponds to no difference between the groups in pre-post change in time spent in a particular state. Values to the right of 0 indicate a greater increase (or smaller decrease) in time spent in that state in the first treatment group vs the second, while distributions to the left of 0 indicate a greater decrease (or smaller increase). The dashed lines are observed data estimates for each group comparison. P-values were computed as the % of the extreme tail to 0, doubled for a two-sided test.