Evidence-Based Reviews

‘Supercharge’ antidepressants by adding thyroid hormones

Current Psychiatry. 2006 July;5(7):15-25

Why hormones help, and new data on SSRI augmentation.

References

1. Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am 1996;19:179-200.

2. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006;163(1):28-40.

3. Nierenberg AA, McLean NE, Alpert JE, et al. Early nonresponse to fluoxetine as a predictor of poor 8-week outcome. Am J Psychiatry 1995;152:1500-3.

4. Nierenberg AA, Papakostas GI, Petersen T, et al. Nortriptyline for treatment-resistant depression. J Clin Psychiatry 2003;64(1):35-9.

5. Rozanov CB, Dratman MB. Immunohistochemical mapping of brain triiodothyronine reveals prominent localization in central noradrenergic systems. Neuroscience 1996;74:897-915.

6. Cheng LY, Outterbridge LV, Covatta ND, et al. Film autoradiography identifies unique features of [125I]3,3’5’-(reverse) triiodothyronine transport from blood to brain. J Neurophysiol 1994;72:380-91.

7. Gordon JT, Kaminski DM, Rozanov CB, Dratman MB. Evidence that 3,3’,5-triiodothyronine is concentrated in and delivered from the locus coeruleus to its noradrenergic targets via anterograde axonal transport. Neuroscience 1999;93:943-54.

8. Howland RH. Thyroid dysfunction in refractory depression: implications for pathophysiology and treatment. J Clin Psychiatry 1993;54:47-54.

9. Joffe RT. Peripheral thyroid hormone levels in treatment resistant depression. Biol Psychiatry 1999;45:1053-5.

10. Iosifescu DV, Howarth S, Alpert JE, et al. T3 blood levels and treatment outcome in depression. Int J Psychiatry Med 2001;31:367-73.

11. Joffe RT, Roy-Byrne PP, Udhe TW, Post RM. Thyroid function and affective illness: a reappraisal. Biol Psychiatry 1984;19:1685-91.

12. Bauer M, Hellweg R, Graf KJ, Baumgartner A. Treatment of refractory depression with high-dose thyroxine. Neuropsychopharmacology 1998;18:444-55.

13. Rudas S, Schmitz M, Pichler P, Baumgartner A. Treatment of refractory chronic depression and dysthymia with high-dose thyroxine. Biol Psychiatry 1999;45:229-33.

14. Joffe RT, Singer W. A comparison of triiodothyronine and thyroxine in the potentiation of tricyclic antidepressants. Psychiatry Res 1990;32:241-51.

15. Sandrini M, Vitale G, Vergoni AV, et al. Effect of acute and chronic treatment with triiodothyronine on serotonin levels and serotonergic receptor subtypes in the rat brain. Life Sci 1996;58:1551-9.

16. Gur E, Lerer B, Newman ME. Chronic clomipramine and triiodothyronine increase serotonin levels in rat frontal cortex in vivo: relationship to serotonin autoreceptor activity. J Pharmacol Exp Ther 1999;288:81-7.

17. Cleare AJ, McGregor A, Chambers SM, et al. Thyroxine replacement increases central 5-hydroxytryptamine activity and reduces depressive symptoms in hypothyroidism. Neuroendocrinology 1996;64:65-9.

18. Goodwin FK, Prange AJ, Post RM, et al. Potentiation of antidepressant effects by l-triiodothyronine in tricyclic nonresponders. Am J Psychiatry 1982;139:34-8.

19. Blier P. Pharmacology of rapid-onset antidepressant treatment strategies. J Clin Psychiatry 2001;62(suppl 15):12-7.

20. Smith CD, Ain KB. Brain metabolism in hypothyroidism studied with 31P magnetic-resonance spectroscopy. Lancet 1995;345:619-20.

21. Kato T, Murashita J, Shioiri T, et al. Effect of photic stimulation on energy metabolism in the human brain measured by 31P-MR spectroscopy. J Neuropsychiatry Clin Neurosci 1996;8:417-22.

22. Earle BV. Thyroid hormone and tricyclic antidepressants in resistant depressions. Am J Psychiatry 1970;126:1667-9.

23. Thase ME, Kupfer DJ, Jarrett DB. Treatment of imipramine-resistant recurrent depression: I. An open clinical trial of adjunctive l-triiodothyronine. J Clin Psychiatry 1989;50:385-8.

24. Birkenhager TK, Vegt M, Nolen WA. An open study of triiodothyronine augmentation of tricyclic antidepressants in inpatients with refractory depression. Pharmacopsychiatry 1997;30:23-6.

25. Joffe RT, Singer W, Levitt AJ, MacDonald C. A placebo-controlled comparison of lithium and triiodothyronine augmentation of tricyclic antidepressants in unipolar refractory depression. Arch Gen Psychiatry 1993;50:387-93.

26. Steiner M, Radwan M, Elizur A, et al. Failure of l-triiodothyronine to potentiate tricyclic antidepressant response. Curr Ther Res 1978;23:655-9.

27. Gitlin MJ, Weiner H, Fairbanks L, et al. Failure of T3 to potentiate tricyclic antidepressant response. J Affective Disord 1987;13:267-72.

28. Spoov J, Lahdelma L. Should thyroid augmentation precede lithium augmentation—a pilot study. J Affect Disord 1998;49:235-9.

29. Aronson R, Offman HJ, Joffe RT, Naylor CD. Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis. Arch Gen Psychiatry 1996;53:842-8.

30. Joffe RT. Triiodothyronine potentiation of the antidepressant effect of phenelzine. J Clin Psychiatry 1988;49:409-10.

31. Agid O, Lerer B. Algorithm-based treatment of major depression in an outpatient clinic: clinical correlates of response to a specific serotonin reuptake inhibitor and to triiodothyronine augmentation. Int J Neuropsychopharmacol 2003;6(1):41-9.

32. Iosifescu DV, Nierenberg AA, Mischoulon D, et al. An open study of triiodothyronine augmentation of selective serotonin reuptake inhibitors in treatment-resistant major depressive disorder. J Clin Psychiatry 2005;66:1038-42.

33. Abraham G, Milev R, Stuart Lawson J. T3 augmentation of SSRI resistant depression. J Affect Disord 2006;91(2-3):211-15.

34. Altshuler LL, Bauer M, Frye MA, et al. Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature. Am J Psychiatry 2001;158:1617-22.

Prescribing thyroid hormones with antidepressants—whether to augment the antidepressant effect or accelerate patient response—is a well-researched strategy for treatment-resistant major depressive disorder (MDD). Thyroid hormones are known to boost response to tricyclics, and preliminary evidence shows they may be useful adjuvants to selective serotonin reuptake inhibitors (SSRIs) as well.

Thyroid hormones enter the brain slowly across the blood-brain barrier and choroid plexus. They accumulate in the locus ceruleus and other structures and are distributed widely along noradrenergic pathways.

Effective treatments are available for MDD, although 30% to 40% of patients do not respond to one or more antidepressant trials (Box).^1-4 This article offers:

new information about why triiodothyronine (T3) and thyroxine (T4) can “super-charge” antidepressant response
tips on how to use thyroid hormones in patients with MDD, including effective dosages, patient monitoring, and treatment durations.

Box

Treatment-resistant depression: A common clinical problem

30% to 40% of patients with major depressive disorder (MDD) do not respond sufficiently to usual antidepressant treatment¹
Even under optimal treatment conditions, only one-third of patients achieve remission²
Among patients who fail to respond to two pharmacologic interventions, remission rates with the next antidepressant are as low as 12%³
A patient becomes less likely to respond clinically with each additional nonresponse to antidepressant treatment⁴

Why thyroid hormones?

Thyroid hormones enter the brain slowly across the blood-brain barrier and the choroid plexus—cerebrospinal fluid barriers. T4 is the main source of brain T3—after attack by 5’deiodinase—but circulating T3 also crosses the blood-brain barrier through active transport.

Thyroid hormones accumulate in the locus ceruleus and other central noradrenergic structures and are distributed widely in the brain along noradrenergic pathways.^5-7 The mechanism of their therapeutic effect for MDD is not well understood, and various hypotheses have been proposed.

Subclinical hypothyroidism. Early studies such as by Howland⁸ of treatment-refractory MDD suggested that thyroid hormone augmentation might correct a hypothyroid state. However, blood thyroid hormone levels are not associated with resistance to antidepressant treatment, according to studies of MDD populations.^9-10 Also, thyroid hormones’ therapeutic action in MDD appears unlikely to be related to treating subclinical hypothyroidism because patients’ euthyroid status was verified in all adjuvant studies since 1980.

Joffe et al¹¹ proposed that MDD is characterized by a relative excess of T4 versus T3—probably related to a deficit in converting T4 to T3 in the periphery—and administering T3 would therefore correct this imbalance. They offered no strong evidence for an increased T4 level, however, and later studies failed to detect the postulated blood T3 abnormalities in MDD.^9-10 Also—as suggested by studies with high-dose T4 augmentation^12,13—the adjuvant antidepressant effect of thyroid hormones is not restricted to T3, although T3 may be more efficacious than T4.¹⁴

Neurotransmitter effects. Thyroid hormones’ role in increasing serotonin (5-HT) release could partially explain the benefit of adjuvant thyroid hormone therapy in MDD. Researchers found:

T3 increased cortical 5-HT levels, probably by reducing the autoinhibitory effect of the presynaptic 5-HT_1A receptor¹⁵
adding T3 to clomipramine therapy increased 5-HT levels to a greater extent than T3 or clomipramine used alone¹⁶
Low 5-HT activity, shown in hypothyroid patients, increased after T4 replacement.¹⁷

This 5-HT release theory cannot explain why thyroid hormones have a rapid clinical effect in MDD. Most studies report the hormones have clinical efficacy in MDD within 4 weeks.¹⁸ Similarly, selective serotonin reuptake inhibitors (SSRIs) increase 5-HT levels within hours of treatment onset, but the clinical effect occurs 4 to 6 weeks later.¹⁹ Therefore, increased 5-HT levels cannot fully explain thyroid hormones’ early effect.

Close interaction between thyroid hormones and the noradrenergic system also has been examined. Brain T3 is primarily localized in the central noradrenergic systems, with axonal anterograde transport of T3 from the locus ceruleus. T3 is processed and accumulated in the noradrenergic system, carried via axonal transport, then delivered from nerve cell bodies to its neuronal targets.^5,7 T3 thus functions as a coneurotransmitter with norepinephrine.

Cellular energy metabolism. We recently reported that thyroid hormones’ antidepressant effect may be related to brain cellular energy metabolism. Thyroid hormones increase cellular levels of adenosine triphosphate (ATP) and phosphocreatine (PCr) in the hypothyroid brain.²⁰ Brain imaging—phosphorus-31 nuclear magnetic resonance spectroscopy (31P-MRS)—of subjects with MDD shows decreased brain levels of ATP and increased PCr.²¹

Our group showed that the antidepressant effect of T3 augmentation of SSRIs is correlated with significant increases in ATP levels and decreases in PCr. This effect—which appears to represent re-normalization of brain bioenergetics in treatment responders—did not occur in nonresponders (Iosifescu et al, presented at APA, 2004).

The effect of thyroid hormones on bioenergetic metabolism is compatible with the hypothesized effects on noradrenergic and serotonergic systems.^5,7 These mechanisms may represent different links in the same chain of events.