Triiodothyronine in the Treatment of Bipolar Depression

In the current treatment landscape where there are few solid strategies to address treatment resistance, augmentation with T3 has been recommended by several clinical practice guidelines.

The augmentation of antidepressants with thyroid hormone, particularly triiodothyronine (T3), is a well-established strategy for treatment-resistant unipolar depression.1 In patients with unipolar depression, T3 therapy has been demonstrated to reduce the time to onset of antidepressant effects, to enhance response when used throughout the length of antidepressant therapy, and to augment the effects of antidepressants in depression that has failed to respond adequately to antidepressant therapy.2,3 The evidence for T3 augmentation strategies in bipolar depression is less robust, but in the current treatment landscape where there are few solid strategies to address treatment resistance, augmentation with T3 has been recommended by several clinical practice guidelines.4-6

In an email interview with Psychiatry Advisor, Pascal Sienaert, MD, PhD, of Belgium’s Catholic University of Leuven, stated, “since we have very little evidence-based treatment steps in treating bipolar depression, a trial with T3 is warranted in treatment-resistant cases, whatever the thyroid status is.”

Dr Sienaert is coauthor of a recent literature review on the efficacy of adjunctive T3 in patients with treatment-resistant bipolar depression.7 Seven relevant studies were found through a targeted search of the medical literature. Authors Parmentier and Sienaert wrote that the studies they found were small and marred by methodologic flaws such as a low number of participants, failure in 5 of 7 studies to separate out the data on patients with bipolar disorder, inconsistent definitions of terms, and variability in assessment tools, baseline medication, and degree of treatment resistance. 

Only 1 randomized controlled trial was available for inclusion, and the results of the study did not demonstrate any difference in efficacy between T3 and placebo. Parmentier and Sienaert wrote: “Despite the limitations, 6 out of 7 studies suggest a meaningful antidepressant effect of adding T3 to an ongoing treatment with antidepressants in study groups containing patients with bipolar depression, some reporting very high success rates. Moreover, if bipolar subgroups were analyzed separately, the results turned out positive each time.”

Researchers and clinicians have long been aware of a bidirectional correlation between thyroid functioning and neuropsychiatric symptoms. Patients with thyroid disease have a high prevalence of comorbid mood disorders, particularly major depressive disorder.8 Correcting the underlying endocrine dysfunction in patients with thyroid disease frequently results in the resolution of psychiatric symptoms. Although most patients with unipolar or bipolar depression do not have overt thyroid dysfunction, some evidence suggests that subtler thyroid irregularities may be involved.8,9 

However, the exact mechanisms of action by which thyroid hormones have an impact on depression and mood are not fully understood. Some proposed mechanisms include modulatory effects on the serotonin and norepinephrine systems, direct effects on nuclear receptors controlling gene expression, increased basal 5-hydroxytryptamine levels in the frontal cortex, or adrenergic transmission and activity of second-messenger systems.8,10,11

Further elucidation of the pathophysiologic contribution of thyroid irregularities to bipolar disorder may ultimately provide clinical justification for the use of thyroid hormone in depression and might help determine which patients are likely to respond to T3 augmentation.12 One study found that thyroid autoimmunity, as indicated by the presence of thyroperoxidase antibodies, was more prevalent in a sample of outpatients with bipolar disorder than in psychiatric inpatients with any diagnosis or in normal controls.13 

Another study conducted in twins with bipolar disorder and normal twin controls found that autoimmune thyroiditis was linked with genetic vulnerability toward bipolar disorder as well as with the disorder itself. The authors concluded that autoimmune thyroiditis may represent a biologic marker for the transmission of the bipolar genotype.14 Yet another study of patients in the depressed phase of bipolar I disorder demonstrated that lower pretreatment values of free thyroxine index and higher pretreatment values of thyroid-stimulating hormone were significantly associated with slower treatment responses to antidepressants.15

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Dr Sienaert told Psychiatry Advisor that the current state of knowledge does not predict which patients with bipolar disorder are likely to respond to thyroid augmentation strategies. “We cannot say that some patients will respond better than others, or that certain patients are more optimal candidates. One could argue to select patients with subclinical hypothyroidism, but there is no reason to exclude patients without it.” Tammas Kelly, MD, associate professor of psychiatry at George Washington University and author of the book, The Art and Science of Thyroid Supplementation for the Treatment of Bipolar Depression, told Psychiatry Advisor that he uses high-dose thyroid supplementation in patients with bipolar depression whose disease has failed to stabilize on 3 different trials of other medications.

T3 is the most widely studied thyroid hormone used in the treatment of depression.3 It may be preferable to levothyroxine (T4) in bipolar disorder because of its rapid onset and offset of action. Evidence from the literature also suggests that T3 may be more efficacious than T4 in the adjunctive treatment of unipolar depression.7 However, Dr Kelly believes that distinguishing the 2 hormones in the treatment of bipolar depression is “not really valid.” He noted that the thyroid predominantly produces T4, which is then turned into T3 elsewhere in the body. “Ultimately it’s the T3 that gets used. There’s been no head-to-head study, but I’ve treated plenty of people with T3 or T4 and I can’t tell any difference as far as outcome. T3 is just easier to use. Others use T4 because it’s available and less expensive.”


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