A New Treatment for Bipolar Depression: Part 3

BIPOLAR DISORDER

Dr Phelps is Medical Director at PsychEducation.org and Bipolar Disorder Section Editor for Psychiatric Times.

Editor’s note: This is Part 3 of a 3-part series on bipolar depression. Part 1 can be found here. Part 2 can be found here.

“What is the risk of driving thyroid stimulating hormone (TSH) below the lower limit of the normal lab range when using levothyroxine as an adjunct treatment for depression?” Here are new data and associated conclusions on that question posed in the October issue, at the end of Part 2 of this series.

Endogenous hyperthyroidism increases the risk of atrial fibrillation and decreased bone density. Population studies also note an increased risk of congestive heart failure and death.¹ But TSH suppressed by exogenous levothyroxine (high-dose thyroid [HDT]) may not carry the same risks as endogenous hyperthyroidism (eg, Grave disease).

HDT is used by endocrinologists as an adjunct treatment for high-risk differentiated thyroid cancer.² Dr Tam Kelly scrutinized this literature in two reviews, his monograph provides even more detail.^3-5

Bone risk

Two studies followed patients with bipolar disorder for nearly 6 years. Findings from these studies indicate no greater decline in women on HDT than controls matched for age and gender.^5p54,55 Together these studies followed 43 patients. Yes, that’s a small sample.

Meta-analyses from the much larger cancer literature were interpreted by a surgical team (they, too, need to know the risks and benefits of HDT). Thus, “detrimental effects on bone metabolism were very small or not significant in both premenopausal women and men; the results for postmenopausal women were less convincing.”⁶

At minimum, accelerated osteoporosis-if it is a risk at all-is associated with years of exposure, similar to tardive dyskinesia (which does not seem to dissuade us from aggressive use of dopaminergic agents). By comparison, the more immediate and potentially catastrophic risks of atrial fibrillation and cerebral infarction (from atrial clot fragments) may be more likely to drive decision-making by practitioners and patients.

Cardiac risk

Kelly⁵ reiterates and expands his earlier review.³ Trying to follow his analysis is like being back in residency learning how to critique study design, methodology, and statistical methods. I was still hesitant to adopt his conclusions. (Dr Kelly wisely invited me to “be skeptical of your skepticism.”) But an examination of his reviews by other specialists familiar with this literature has just arrived, with additional data on HDT’s cardiac risk.

Pilhatsch and colleagues⁷ published the results of a prospective study of cardiac outcomes in 23 patients on HDT (mean dose 463 µg/d).These patients had already been prescribed HDT for an average of 16 months before cardiac monitoring that included echocardiogram, holter, and stress testing, for an average of an additional 20 months. “None of the assessed cardiac parameters . . . was in a range predictive for cardiac dysfunction.” Again, the sample size was small, with no control group. Nevertheless, this article’s 10 authors, including Dr Peter Whybrow-one of the originators of using HDT for bipolar depression-repeatedly cite Kelly’s analyses in support of the relative safety of HDT.⁵

Conclusions and recommendations

Unless you have read Dr Kelly’s Art and Science of Thyroid Supplementation for the Treatment of Bipolar Depression, you should probably hold off on prescribing HDT for bipolar depression. However, while you continue to evaluate this option, three simple steps may better align your practice with available data on the efficacy and safety of levothyroxine in physiologic doses.

1. Consider levothyroxine as an augmentation in depressed patients with a TSH level greater than 2.5 mU/L, especially in bipolar depression (a nifty alternative to adding an antidepressant, with its attendant risks of inducing cycling and mixed states; or to buy time while slowly tapering an antidepressant).

2. Start with higher initial doses, such as 50 μg (“one half pill daily for a week then one daily”), at least for patients with significant depression.

3. Target a TSH level at least down to median for age. As reviewed in Part 2 of this series, remember: 1.5 mU/L to age 50; 1.6 mU/L to age 60; 1.7 mU/L to age 70; and 1.8 mU/L to age 80.

Any level of TSH between 1.0 mU/L and median is easily justified per the available literature. If there is no clearly associated risk, why not get there? Just as we “push” medications to the top of their dosage range (if fully tolerated yet not fully effective), we should suggest levothyroxine to a TSH around 1.0 mU/L to call its trial adequate.

This article was originally posted 8/30/18 and has since been updated.

Disclosures:

Dr Phelps stopped accepting honoraria from pharmaceutical companies in 2008 but he receives royalties for his books.

References:

1. Selmer C, Olesen JB, Hansen ML, et al. Subclinical and overt thyroid dysfunction and risk of all-cause mortality and cardiovascular events: a large population study. J Clin Endocrinol Metab. 2014;99:2372-2382.

2. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26:1-133.

3. Kelly T. An examination of myth: a favorable cardiovascular risk-benefit analysis of high-dose thyroid for affective disorders. J Affect Disord. 2015;177:49-58.

4. Kelly T. A favorable risk-benefit analysis of high dose thyroid for treatment of bipolar disorders with regard to osteoporosis. J Affect Disord. 2014;166:353-358.

5. Kelly T. The Art and Science of Thyroid Supplementation for the Treatment of Bipolar Depression. CreateSpace, 2018. .

6. Sugitani I, Fujimoto Y. Effect of postoperative thyrotropin suppressive therapy on bone mineral density in patients with papillary thyroid carcinoma: a prospective controlled study. Surgery. 2011;150:1250-1257.

6. Pilhatsch M, Berghöfer A, Mayer-Pelinski R, et al. Long-term treatment with supraphysiologic doses of levothyroxine in treatment-refractory mood disorders - A prospective study of cardiovascular tolerability. J Affect Disord. 2018;238:213-217.