A New Treatment for Bipolar Depression: Part 1

September 7, 2018

Old data have recently been gathered and systematically presented-reinforced by a new study, but perhaps contradicted by another. So it’s time to revisit this story.

Do you accept the idea that a treatment with no known risks, such as a dawn simulator, requires less evidence for efficacy than a risky medication? That does not appear to be the thinking in recent treatment guidelines, which put high-risk medications first line because of the number of studies that support their efficacy (quetiapine, olanzapine/fluoxetine, and lurasidone).1

But this is not how patients think. Especially in bipolar II, where they have often lived with symptoms for years, they are not looking for immediate efficacy as much as long-term tolerability. A treatment with no long-term risks and very low probability of adverse effects is appealing. By contrast, clinicians know all too well that mentioning a risk of weight gain and diabetes can take a medication right out of contention.

With all this in mind, imagine a new treatment for bipolar depression that:

    • Has not caused medical problems in over 20 years of research

    • Does not cause weight gain or diabetes

    • Has no adverse effects for most people (and if they occur, are short-lived with dose reduction), including no daytime sedation or fatigue, even during titration

Such a treatment would likely be among patients’ top options (unless their depression was severe, in which case, a treatment with strong efficacy data could also be a top consideration).

We might have such a well-tolerated, low-risk medication in our hands now. It has been under study since 1990.2 It has evidence for efficacy at a mechanistic level, and two small positive randomized trials.3,4 Have I got your attention, then? I certainly hope so.

My goal in Part 1 of this 3-part series is to open your thinking. I’ll admit, I myself am having trouble with this. I’m writing in part to convince myself, or at least explore my hesitations. If this is such a great treatment, I ought to have been using it a lot myself and I have not. I’m still not certain what’s holding me back. But old data have recently been gathered and systematically presented-reinforced by one new study, but perhaps contradicted by another. So it’s time to revisit this story.

What treatment am I talking about? Good old thyroid hormone. With only one randomized trial in bipolar depression when the recent guidelines were prepared, it keeps getting overlooked-almost.3 The CANMAT treatment guidelines5 list adjunctive thyroid hormone as a third-line treatment option for bipolar depression, down there along with monotherapy using divalproex, fluoxetine, and tranylcypromine.

Thyroid hormone has been under study in mood disorders since at least 1981 when Dr Peter Whybrow6 pointed out the connection between thyroid hormone and catecholamines. He and colleague Dr Michael Bauer went on to demonstrate that even mild elevations in thyroid stimulating hormone (TSH) were associated with rapid cycling in bipolar disorder.7 In 1990 they presented 11 cases of refractory rapid cycling they had treated with high doses of thyroid hormone.8 “Levothyroxine was added to the baseline medication regimen, and the dosage was increased until clinical response occurred or until side effects precluded further increase.” TSH was suppressed; and T4 levels went to around 150% of normal, Whybrow reported.9 In the randomized trial, the dose was 300 mcg daily, with a starting dose and weekly increases of 100 mcg.4

You’re asking yourself: “How come these patients don’t just become hyperthyroid, if you’re giving them supraphysiologic doses of thyroid hormone?” Of course that’s a key question. Whybrow and Bauer and colleagues have found that patients with rapid cycling bipolar disorder “respond differently to the hormone and tolerate it better than healthy individuals.”9 In other words, despite their TSH of less than 0.1, patients who respond do not develop tachycardia, palpitations, tremor, GI hypermotililty, or weight loss.

This will prove critical. Endogenous hyperthyroidism is associated with decreased bone mineral density and increased rates of atrial fibrillation. Are patients on supraphysiologic thyroid for bipolar depression subject to the same risks?

Suppose they aren’t. Suppose there were no evidence of increased atrial fibrillation, nor decreased bone density, with this well-tolerated treatment that is inexpensive and doesn’t cause weight gain or other metabolic consequences? Would you use it, given one positive randomized trial?

We physicians and psychiatric nurse practitioners are human. We closely monitor social norms, including how our colleagues are treating patients. I suspect that the lack of a psychiatric norm around using supraphysiologic thyroid is the limiting factor here, not an adverse risk-to-benefit ratio. But if you’ll even contemplate this “new”-old-treatment, then I have a book recommendation for you. After publishing detailed reviews of the putative risks of arrhythmias and decreased bone density with supraphysiologic thyroid, Dr Tammas Kelly has written a guide to this approach: The Art and Science of Thyroid Supplementation for the Treatment of Bipolar Depression.10

Kelly’s book may help lower the barriers that impede the use of supraphysiologic thyroid. In any case, it’s a fascinating and well-written summary. I read more than half of it standing right where I removed it from the shipping box. More on this in Parts 2 and 3.


This article was originally published on 7/5/18 and has since been updated.


Dr. Phelps is Director of the Mood Disorders Program at Samaritan Mental Health in Corvallis, Ore. He is the Bipolar Disorder Section Editor for Psychiatric Times. Dr. Phelps stopped accepting honoraria from pharmaceutical companies in 2008 but receives honoraria from McGraw-Hill and W.W. Norton & Co. for his books on bipolar disorders, including Bipolar, Not So Much, a book he coauthored with Chris Aiken, MD.


1. Guzman, F. Bipolar Disorder Treatment Guidelines: A 2018 Update. Psychopharmacology Institute. https://psychopharmacologyinstitute.com/guidelines/bipolar-disorder-guidelines. Accessed June 20, 2018.

2. Bauer MS, Whybrow PC. Rapid cycling bipolar affective disorder: II: treatment of refractory rapid cycling with high-dose levothyroxine: a preliminary study. Arch Gen Psychiatry. 1990;47:435-440.

3. Bauer M, Berman S, Stamm T, et al. Levothyroxine effects on depressive symptoms and limbic glucose metabolism in bipolar disorder: a randomized, placebo-controlled positron emission tomography study. Mol Psychiatry. 2016;21:229-236.

4. Walshaw PD, Gyulai L, Bauer M, et al. Adjunctive thyroid hormone treatment in rapid cycling bipolar disorder: a double-blind placebo-controlled trial of levothyroxine (L-T4 ) and triiodothyronine (T3 ). Bipolar Disord. June 4, 2018; Epub ahead of print.

5. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20:97-170.

6. Whybrow PC, Prange AJ Jr. A hypothesis of thyroid-catecholamine-receptor interaction: its relevance to affective illness. Arch Gen Psychiatry. 1981;38:106-113.

7. Bauer MS, Whybrow PC, Winokur A. Rapid cycling bipolar affective disorder: I: association with grade I hypothyroidism. Arch Gen Psychiatry. 1990;47:427-432.

8. Bauer MS, Whybrow PC. Rapid cycling bipolar affective disorder: II: treatment of refractory rapid cycling with high-dose levothyroxine: a preliminary study. Arch Gen Psychiatry. 1990;47:435-440.

9. Whybrow PC. The therapeutic use of triiodothyronine and high dose thyroxine in psychiatric disorder. Acta Med Austriaca. 1994;21:47-52.

10. Kelly T. The Art and Science of Thyroid Supplementation for the Treatment of Bipolar Depression. 2018. https://www.amazon.com/Science-Thyroid-Supplementation-Treatment-Depression/dp/1979168415. Accessed June 20, 2018.

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