High-Dose Thyroxine Augmentation of Antidepressants
High-Dose Thyroxine Augmentation of Antidepressants
Abstract & Commentary
Synopsis: This open case series suggests that thyroxine (doses 150 to 300 mcg/d), in addition to previously ineffective psychotropic medications, may augment antidepressant effect in 50% of patients with chronic depression.
Source: Rudas S, et al. Treatment of refractory chronic depression and dysthymia with high-dose thyroxine. Biol Psychiatry 1999;45:229-233.
Based on prior reports demonstrating the efficacy of high-dose thyroxine (T4) in some previously treatment-resistant patients with rapid-cycling bipolar disorder (manic depression),1,2 this small open study examined the use of high-dose T4 in patients with chronic depression. Subjects consisted of nine outpatients with either chronic major depression or dysthymia (depression not of the severity of major depression, but persisting for more than 2 years). Some subjects had both disorders, and one patient (who subsequently proved to be a nonresponder to T4 augmentation) had bipolar disorder, but with predominant depressive symptoms. Subjects were part of Rudas and associates’ clinical program, and were reportedly the individuals who had exhibited the greatest degree of treatment resistance over the prior year. All had normal baseline thyroid hormone levels. All were extremely chronic, with a mean of 16.6 ± 7.8 prior episodes of depression.
Thyroxine 50 mcg was added to whatever psychotropic medications they had been taking in the preceding weeks. The dose of thyroxine was increased by 50 mcg every three days until the serum TSH level was completely suppressed, and the serum T4 level was double the baseline value. Dose escalation was also terminated if the patient exhibited clinical improvement or severe side effects. Assessments, definitions of treatment response, and statistical analysis were appropriate for the design and study question. Specifically, response was defined as a 50% or more reduction in the 21-item Hamilton Depression Rating Scale (HDRS) after eight weeks of treatment and a final score of less than 10. Partial remission was defined as a 50% or more reduction in the HDRS, but a final score of 10 or more.
Two patients withdrew because of side effects. The remaining seven patients received a final mean dose of 235 ± 58 mcg of T4 per day. Five patients were full responders, one a partial responder, and one a nonresponder. Response occurred after five weeks of T4 augmentation. For responders, the mean T4 level was 126.3 ± 16.4 mcg/L, and the mean free T4 level was 18.30 ± 8.52 ng/L. Side effects were restlessness, tremor, perspiration, and anxiety. Longer term (12-18 months) follow-up of five available subjects "was favorable in all patients, but not excellent," essentially varying from continued remission to the emergence of depressive symptoms that were less severe than previous episodes.
Comment by Lauren B. Marangell, MD
This small open study is noteworthy, but must be interpreted with some caution until the data are replicated with a larger number of patients in a standard double-blind, placebo-controlled design. Nonetheless, these data underscore the complex interconnection between thyroid hormones and mood. For example, it is well established that both hyper- and hypothyroidism can present as depression, and that physiologic doses of triiodothyronine (T3) are an effective augmentation strategy in 50% of presumably euthyroid patients with treatment-resistant depression. More recent data demonstrate a correlation between peripheral thyroid hormone levels within the normal range and brain activity, as assessed by positron-emission tomography, in patients with depression.3
A prior well-controlled study demonstrated the superiority of T3 compared to T4 in augmenting antidepressants when both hormones were administered in physiologic doses,4 as opposed to the current study, which used supraphysiologic doses of T4.
As Rudas et al point out, the use of high-dose T4 should be reserved for highly refractory patients, i.e., "last resort therapy." As such, it is advisable that a psychiatrist be involved in these cases. However, nonpsychiatrists will likely encounter greater numbers of patients who are being treated with thyroid hormones for psychiatric indications. It is important to note that all data to date suggest that thyroid hormones augment antidepressants or mood stabilizers. There are no data to suggest that thyroid hormone monotherapy will treat depression in the absence of thyroid disease.
References
1. Stancer HC, Persad E. Treatment of intractable rapid-cycling manic-depressive disorder with devothyroxine. Arch Gen Psychiatry 1982;39:311-312.
2. Bauer MS, Whybrow PC. Rapid cycling bipolar affective disorders: II. Treatment of refractory rapid cycling with high-dose levothyroxine: A preliminary study. Arch Gen Psychiatry 1990;47:435-440.
3. Marangell LB, et al. Inverse relationship of peripheral thyrotropin-stimulant hormone levels to brain activity in mood disorders. Am J Psychiatry 1997;154:224-230.
4. Joffe RT, Singer W. Comparison of triiodothyronine and thyronine in the potentiation of tricyclic antidepressants. Psychiatry Res 1990;32:241-251.
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