‘Supercharge’ antidepressants by adding thyroid hormones
Why hormones help, and new data on SSRI augmentation.
Antidepressant boosters
Thyroid hormones have been used extensively to treat MDD since the 1950s, when researchers reported that T3 monotherapy was efficacious for treating depression. These early studies had important methodologic limitations, including open designs and poorly defined diagnostic criteria and response.
For MDD, the most extensively researched uses of thyroid hormones are to augment therapy for antidepressant nonresponders and to accelerate partial response to antidepressants.
Tricyclics. Open studies primarily among outpatients in the 1970s and ‘80s suggested that thyroid hormones are a valid augmentation strategy for nonresponders to tricyclic antidepressants. Most—but not all—reported response rates >50% with T3 dosages of 20 to 50 mcg/d.22,23
Compared with outpatient studies, however, an open trial of T3 augmentation by Birkenhager et al24 found no evidence of efficacy in 14 severely depressed inpatients who had not responded to 6 weeks of tricyclics. These patients—mainly with melancholic and/or psychotic depression—showed greater response to a monoamine oxidase inhibitor (MAOI) or electroconvulsive therapy than to thyroid hormone.
Three of five double-blind controlled studies of thyroid hormone augmentation of tricyclics reported response rates of 50 to 65% (Table).14,18,25 Earlier controlled studies, including two negative studies26,27 had important methodologic limitations: all included few subjects (≤16), and two studies included both unipolar and bipolar patients. Joffe et al partially addressed these problems with two randomized, double-blind studies that were controlled with placebo or T4:
- In a 3-week trial, T3 was more effective than T4 when added to imipramine or desipramine.14
- In a 2-week trial, T3 was significantly more effective than placebo when added to imipramine or desipramine.25
In the latter study, T3 and lithium augmentation appeared equally effective. Conversely, T4 was more effective than lithium as the first augmentation strategy in a double-blind, crossover study by Spoov and Lahdelma.28
In conclusion, depressed patients given T3 with tricyclic antidepressants may be twice as likely as controls to respond to treatment, according to a meta-analysis of eight studies totaling 292 patients. This analysis by Aronson et al29 supports T3 augmentation while addressing the surveyed studies’ limitations.
Table
Treatment-resistant MDD: Controlled studies of thyroid hormone augmentation
| Study authors/design | Initial therapy | Augmentation | Results |
|---|---|---|---|
| Steiner et al, 1978 Randomized double-blind; 8 patients* | Several TCAs (6 weeks) | T3, 25 mcg/d, or placebo (35 days) | T3: 75% responders (3/4) Placebo: 75% (3/4) |
| Goodwin et al, 1982 Double-blind, mirror design; 12 patients* | Desipramine or imipramine (4 weeks) | T3, 25 to 50 mcg/d, or placebo (21 days) | T3: 33% responders (4/12) Placebo: 0% (0/6) |
| Gitlin et al, 1987 Double-blind with crossover; 16 patients | Imipramine (4 weeks) | T3, 25 mcg/d, or placebo (2 weeks); crossover (2 weeks) | No difference between T3 and placebo |
| Joffe and Singer, 1990 Randomized double-blind; 38 patients | Desipramine or imipramine (4 weeks) | T3, 37.5 mcg/d, or T4, 150 mcg/d (21 days) | T3: 53% responders (9/17) T4: 19% (4/21) |
| Joffe et al, 1993 Randomized double-blind; 33 patients | Desipramine or imipramine (5 weeks) | T3, 37.5 mcg/d, or placebo (14 days) | T3: 59% responders (10/17) Placebo: 19% (3/16) |
| Sopov and Lahdelma, 1998 Randomized double-blind with crossover; 22 patients* | TCA, MAOI antidepressants | T4, 200 mcg/d, or lithium, 500 mg/d, (4 weeks); then crossover (4 weeks) | T4: 64% responders (7/11) Lithium: 18% responders (2/11) |
| *Included patients with unipolar or bipolar depression | |||
| MAOI: monoamine oxidase inhibitor; SSRI: selective serotonin reuptake inhibitor; T3: triiodothyronine; T4: thyroxine; TCA: tricyclic antidepressant. | |||
MAO inhibitors. One small report has addressed the efficacy of thyroid hormones as adjuvants to MAOIs.30 In two patients, adding T3 to phenelzine enhanced the antidepressant response.
High-dose T4. Two open studies of patients with treatment-resistant bipolar or unipolar depression12,13 have examined the efficacy of high-dose T4 augmentation. These patients were taking a variety of antidepressants, including TCAs and SSRIs.
- In the study by Baurer et al,12 clinical remission (Hamilton Depression Scale [HAM-D] score ≤10) occurred in 4 of 5 patients with severe treatment-resistant unipolar depression who received adjunctive T4, mean 482±72 mcg/d, with antidepressants.
- In the study by Rudas et al,13 clinical remission (HAM-D ≤9) occurred in 7 of 9 patients with treatment-resistant MDD after T4, 150 to 300 mcg/d, was added to their antidepressant therapy. Side effects may limit this high-dose strategy, however, because 2 of the patients dropped out with thyrotoxicosis symptoms.
SSRIs. Three open trials to date have investigated using thyroid hormones to augment SSRIs in treatment-resistant MDD. In a prospective study by Agid and Lerer,31 10 of 25 (40%) patients who did not respond to SSRI treatment did so after T3 was added. No men improved, however, which led the authors to suggest that men and women might respond differently to T3 augmentation of SSRIs.
In our study, 7 of 20 patients (35%) with MDD who did not respond to 8 weeks of SSRI therapy did so when we added T3, 50 mcg/d, for 4 weeks (Figure). Response rates were high (5/5, 100%) in patients with atypical features by DSMIV criteria and low (1/8, 12.5%) in those with melancholic features.32
