02. Thyroid Psychopharmacology: T3 Augmentation, Levothyroxine Dosing, and Lithium-Induced Hypothyroidism

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Where T3 Fits in Treatment-Resistant Depression: Before the Antipsychotic

Flavio Guzman, M.D.: Let’s start with a hypothetical patient: major depressive disorder, two adequate antidepressant trials, currently euthyroid. Where does thyroid augmentation fit in this sequence?

James K. Rustad, M.D.: I would consider thyroid hormone before an atypical antipsychotic because the side effect profile is much more favorable.

With the atypical antipsychotics, you have to worry about both potential neurologic side effects and metabolic side effects.

With T3 (Cytomel), you don’t really have to worry about metabolic effects such as weight gain, increased glucose, and rising body mass index.

Strategically, trying a couple of medications and then augmenting with T3 is a reasonable approach, and the research backs that up.⁵

In level 3 of the STAR*D study, researchers compared augmentation with T3 at up to 50 mcg/day with lithium augmentation at up to 900 mg/day.

All participants entering level 3 had not experienced remission after at least two different medication treatments:

• Level 1: citalopram.
• Level 2: a switch to bupropion, sertraline, or venlafaxine, or augmentation with bupropion or buspirone.
• Level 3: T3 augmentation versus lithium augmentation.

After a mean treatment duration of about 10 weeks, remission rates were 25% with T3 augmentation and 16% with lithium augmentation.¹

This difference was not statistically significant, and T3 had superior tolerability, as lithium was more frequently associated with side effects and higher discontinuation rates.

So T3 and lithium are statistically about the same as augmentation strategies, but T3 is much more tolerable.

This should really be considered for treatment-resistant depression populations, as it converts non-responders to responders.

When it comes to adding T4 (thyroxine), some studies show evidence for T4 in rapid cycling bipolar disorder.³,⁶

However, more research is needed on the use of T4 in acute bipolar depression.

How to Prescribe T3 and T4: Doses, Titration, and Monitoring

Flavio Guzman, M.D.: Let’s say we decided that this patient is a good candidate for thyroid augmentation. Could you walk us through the actual prescribing process?

James K. Rustad, M.D.: T3 is liothyronine, and the brand name is Cytomel. It has a half-life of one day.

Dosing:

• The initiation dose is 12.5 to 25 mcg/day.
• Maximum dose is 50 mcg/day.
• An absolute high dose would be 62.5 mcg/day, in rare cases.

Response usually takes 2 to 14 weeks. You may see some early responders, but give it at least three to three and a half months before giving up on this treatment and moving on to something else.

Monitor with TSH labs before and after starting treatment.²

Some of the SSRIs can modify TSH. So even before treating with an SSRI, consider checking a TSH, so you know whether a change in TSH is related to the SSRI or to something else. Just as with SSRIs, you will want to monitor TSH on T3.

Administration details for T3:

• Timing of ingestion is in the morning and afternoon.
• It can be taken with food.
• Allow about 4 hours after taking calcium, iron, or antacids.

Flavio Guzman, M.D.: What about T4, levothyroxine? Do you think it has a place in psychiatry?

James K. Rustad, M.D.: The only evidence for it would be in rapid cycling bipolar disorder, so this isn’t necessarily something you would consider for treatment-resistant depression.³

The brand name is Synthroid, and the half-life is about 5 to 7 days.

Dosing:

• The initiation dose is 50 to 100 mcg/day.
• Maximum dose is 150 to 200 mcg/day.
• A high dose would be 500 mcg/day, which would be very, very high.

Time to response is about 2 to 3 months.

To monitor someone on levothyroxine, check TSH and free T4.

Administration details for levothyroxine:

• Timing of ingestion is in the morning, with a second dose at night if the dose is divided.
• It should be taken on an empty stomach, at least 30 minutes before food.
• Space it 4 hours from calcium, iron, and antacids, because they can affect this medication’s metabolism.
• It comes as a tablet, soft gel capsule, and liquid.

Thyroid Labs on Lithium: How Often to Check

Flavio Guzman, M.D.: Let’s talk about lithium now. Could you share your thinking on how to monitor for thyroid side effects and when to stop it?

James K. Rustad, M.D.: The short version is that if lithium is the appropriate treatment for the patient, you stay on the lithium.

You should not be switching to other mood stabilizers just to address something going on with the thyroid.

It is advisable to adopt a monitoring schedule with more frequent checks during the first year of lithium therapy:

• Check TSH every 3 to 6 months during the first year of lithium therapy.
• After the first year, move to regular assessments every other year.

In cases where severe and symptomatic thyroid dysfunction arose in patients treated with lithium, it was effectively managed with thyroid replacement therapy.

Patients with an optimal thyroid profile have been shown to experience better outcomes. So patients with bipolar disorder on lithium whose thyroid is optimally managed and normalized have better outcomes.

In conclusion, the studies showed that transient thyroid abnormalities in most patients normalize over time without the need to discontinue lithium or initiate long-term thyroid replacement therapy.

This is really crucial for the continued prescribability of lithium, which is a cornerstone in the treatment of bipolar disorder. It is effective, and it also has anti-suicidal properties.

Lithium-Induced Hypothyroidism: Treat the Thyroid, Keep the Lithium

Flavio Guzman, M.D.: Let’s say the labs confirm lithium-induced hypothyroidism. When do you think thyroid replacement is indicated?

James K. Rustad, M.D.: There are a couple of situations where intervention may be required:

• Treatment-refractory mood disorder, particularly rapid cycling, with modest TSH elevations (subclinical hypothyroidism). Here, thyroid supplementation with T4 may be indicated to remove one of the predisposing factors to mood instability and treatment refractoriness.
• Evidence of clinical hypothyroidism. Here thyroid hormone is required as replacement therapy.

It is important to note, again, that discontinuing lithium is not required when lithium-induced subclinical or clinical hypothyroidism supervenes.

Rather, thyroid replacement therapy should be used when indicated, and the bipolar disorder should be managed in the most appropriate way.

In summary, if lithium is still indicated for the patient, it should be continued along with thyroid replacement therapy.

Using alternative mood stabilizers to reverse a lithium-induced thyroid dysfunction is not the optimal management of a patient with bipolar disorder.

Hickam’s Dictum

Flavio Guzman, M.D.: Let’s close with the last question. What are one or two things you would like us as psychiatrists to do differently starting today?

James K. Rustad, M.D.: Correlation does not equal causality. Thyroid disorders could be contributory or comorbid with major depressive disorder, bipolar disorder, or generalized anxiety disorder.

So I want to tell people about Hickam’s dictum. We have all heard about Occam’s razor, where one explanation can account for many different phenomena.

Hickam’s dictum is the opposite of that: a patient can have as many diseases as they darn well please.

References

1. Nierenberg, A. A., Fava, M., Trivedi, M. H., Wisniewski, S. R., Thase, M. E., McGrath, P. J., Alpert, J. E., Warden, D., Luther, J. F., Niederehe, G., Lebowitz, B., Shores-Wilson, K., & Rush, A. J. (2006). A comparison of lithium and T3 augmentation following two failed medication treatments for depression: A STAR*D report. The American Journal of Psychiatry, 163(9), 1519–1530.
2. Rosenthal, L. J., Goldner, W. S., & O’Reardon, J. P. (2011). T3 augmentation in major depressive disorder: Safety considerations. The American Journal of Psychiatry, 168(10), 1035–1040.
3. Bauer, M. S., & Whybrow, P. C. (1990). Rapid cycling bipolar affective disorder: II. Treatment of refractory rapid cycling with high-dose levothyroxine: A preliminary study. Archives of General Psychiatry, 47(5), 435–440.
4. Rasmussen, M. J., Robbins, H., Fipps, D. C., Rustad, J. K., Pallais, J. C., & Stern, T. A. (2023). Neuropsychiatric sequelae of thyroid dysfunction: Evaluation and management. The Primary Care Companion for CNS Disorders, 25(6), Article 23f03570.
5. Nuñez, N. A., Joseph, B., Pahwa, M., Kumar, R., Resendez, M. G., Prokop, L. J., Veldic, M., Seshadri, A., Biernacka, J. M., Frye, M. A., Wang, Z., & Singh, B. (2022). Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis. Journal of Affective Disorders, 302, 385–400.
6. Walshaw, P. D., Gyulai, L., Bauer, M., Bauer, M. S., Calimlim, B., Sugar, C. A., & Whybrow, P. C. (2018). Adjunctive thyroid hormone treatment in rapid cycling bipolar disorder: A double-blind placebo-controlled trial of levothyroxine (L-T4) and triiodothyronine (T3). Bipolar Disorders, 20(7), 594–603.