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Special Feature |
Department of Medicine and Division of Endocrinology and Metabolism, McMaster University (A.M.S., H.C.G., M.J.M., G.M.M.); Department of Medicine (A.M.S.) and Department of Psychiatry and Behavioral Neurosciences, Mood Disorders Program (M.J.M., G.M.M.), St. Joseph’s Healthcare; and Department of Medicine, Hamilton Health Sciences (H.C.G.), Hamilton, Ontario, Canada L8N 3Z5; and Department of Psychiatry, University of Medicine and Dentistry of New Jersey-New Jersey Medical School (R.T.J.), Newark, New Jersey 07103-2714
Address all correspondence and requests for reprints to: H. C. Gerstein, M.D., Department of Medicine, McMaster University, Room HSC 3V38, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5. E-mail: gerstein{at}mcmaster.ca.
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Abstract |
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Introduction |
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It has been suggested that the addition of T3 to T4 replacement therapy may improve mood, cognitive function, and general sense of well-being (11, 12, 13, 14, 15). Furthermore, T3 has been reported to augment the effect of antidepressant treatment in depressed patients who are already receiving levothyroxine replacement therapy (16, 17). These observations have led to a reexamination of the role of supplemental T3 therapy in the routine treatment of hypothyroidism, especially in individuals with depressive symptoms. However, previous studies examining the effect of T3 supplementation on the mood and well-being of hypothyroid patients included small numbers of participants with a range of different causes of hypothyroidism, were of brief duration, and generally enrolled participants who were taking supraphysiological doses of T4 and T3. This heterogeneity probably accounts for conflicting results that have been reported. Our aim was to determine whether nonthyroidectomized primary hypothyroid individuals with depressive symptoms experience an improved mood and/or sense of well-being when euthyroidism is maintained with a combination of T3 and T4 compared with T4 therapy alone.
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Subjects and Methods |
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Participants included consenting women and men, aged 25 to 75 yr, with an established diagnosis of primary hypothyroidism. Participants were recruited through general endocrine clinics as well as through public advertisements. Inclusion criteria included the use of a stable, unchanged dose of levothyroxine for 6 months before randomization, a baseline TSH concentration within normal limits, and evidence of depressive symptoms as defined by a score of more than 5 on the 30-item General Health Questionnaire (18, 19) on 2 occasions, at least 2 wk apart. The General Health Questionnaire is a self-report instrument designed to identify a person likely to have a psychiatric disorder and to indicate the degree of psychiatric dysfunction (18, 19).
Participants were excluded if they 1) had a history of hyperthyroidism, thyroidectomy, or thyroid cancer; 2) had a diagnosed mood disorder predating the hypothyroidism; 3) were taking a concurrent medication that may affect mental state (including psychotropic medications, ß-blockers, systemic glucocorticoids, or lithium); 4) had a concurrent medical illness that may affect mental state or that required active treatment (including type 1 diabetes mellitus or insulin-requiring type 2 diabetes mellitus); 5) were unable to complete questionnaires; or 6) were fertile women who were not using reliable birth control methods. None of the patients satisfied the criteria for current major depression based on scales described below. The study was approved by the ethics review board at McMaster University Medical Center.
Randomization procedure and therapy
Participants were centrally randomized to receive matched tablets containing T3 or placebo in addition to T4 (all formulated at the McMaster University Medical Center pharmacy). Treatment allocation was performed by the pharmacy, and coded pill bottles were provided to the investigator and the patients. The patients, investigators, and primary care physicians were all blinded to treatment allocation. Each participant received two different tablets, one with T4 (that was taken once daily) and one with T3 or placebo (that was taken twice daily). Both participants and investigators were unaware of the treatment allocation. All participants randomized to receive T3 had their prestudy dose of T4 dropped by 50%, and T3 was started at a dose of 12.5 µg, twice daily. Participants randomized to receive T4 therapy alone continued their usual dose of thyroid hormone as well as a placebo substitute for T3. Biochemical assays were performed at McMaster University Medical Center laboratory. TSH concentrations (using a third generation TSH assay, Axsym II, Abbott Laboratories, Chicago, IL), and free T4, free T3 (using fluorescent immunoassays, Axsym, Abbot Laboratories) were measured at screening, randomization, and 2, 4, 6, 9, 12, and 15 wk. The dose of T3 was titrated by one of the investigators (H.C.G.), who had no contact with either the participants or those assessing psychological outcomes, to maintain the TSH concentrations within the normal range (0.52–5.0 mU/liter).
Measurement of changes in mood, social functional status, and sense of well-being
The Symptom Check-List-90 (SCL-90), a self-report questionnaire (20, 21), as well as the Comprehensive Epidemiological Screens for Depression (CES-D) (22, 23) self-report scales were administered at baseline and 2, 4, 6, 9, 12, and 15 wk. Scores on the SCL-90 and CES-D are higher when symptoms are more severe. The Medical Outcomes Study (MOS) health status questionnaire was administered at baseline and 6 and 15 wk to assess functional status and well-being in 10 domains (physical functioning, physical role, bodily pain, general health, vitality, social functioning, emotional role, cognitive functioning scale, and mental health index) (24, 25, 26). Each subscale on the MOS has a range of possible scores from 0 (poorest health) to 100 (optimum health).
Statistical analyses
For each subject, TSH, free T3, free T4, SCL-90, and CES-D data from wk 2 and 4 were averaged as an early treatment measurement period, data from wk 6 and 9 were averaged as a midtreatment measurement period, and data from wk 12 and 15 were averaged as a late treatment measurement period. In the event of data missing from 1 of the 2 wk in a measurement period, data from the other week were used alone. MOS subscale scores were analyzed at baseline, 6 wk (midtreatment), and 15 wk (late treatment).
All individuals randomly allocated to study medication were analyzed according to the intention to treat principle regardless of their compliance with study medication. Baseline thyroid function study results were compared between treatment groups using independent sample t tests, and the change in thyroid function measurements over the course of the study between both treatment groups was compared using repeated measures ANOVA. The effect of the allocated therapies on the change with time in 1) SCL-90 depression and anxiety scores, 2) CES-D scores, and 3) MOS subscale scores in the two groups was compared using analysis of covariance with adjustment for the respective baseline scores.
Whenever a measurement was unavailable for a given treatment period (for example, if the individual dropped out of the study or did not perform the test), the mean value of the rest of the values for that individual’s treatment group was imputed in place of the missing value. All statistical analyses were performed using SPSS version 10 (SPSS, Chicago, IL).
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Results |
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A total of 40 individuals were randomized in the study. Twenty participants (mean age ± SD, 49.5 ± 11.8 yr), including 1 male, were allocated to continuation of T4 therapy, and 20 participants (mean age, 45.0 ± 10.1 yr), including 3 males, were allocated to the T4 plus T3 group. The mean duration of hypothyroidism was 8.5 ± 7.4 yr in the T4 group and 9.9 ± 6.8 yr in the T4 with T3 group. One participant in the T4 group did not undergo any measurements of SCL-90 and CES-D scales, and 2 participants in the T4 group did not undergo any measurements of MOS scales; these individuals were excluded from the analyses of these variables, but were included in the remaining analyses. Seven participants (all female) did not complete the full 15 wk of the study after the baseline assessment. Reasons for this in the T4 group included: side-effects (n = 2, 1 before wk 6 and 1 before wk 9), persistently high TSH levels (n = 1, between wk 6 and 9), and no explanation (n = 2, 1 before wk 2 and 1 before wk 9). Reasons for this in the T4 plus T3 group included side-effects in 2 participants (1 before wk 2 and 1 before wk 6).
The mean dose of levothyroxine before randomization was 120 µg (SD = 38 µg) for the T4 group and 132 µg (SD = 46 µg) for the T4 plus T3 group (P = 0.379). Baseline concentrations of TSH, free T4, and free T3 did not differ by group (Table 1
). At the last recorded visit of the participants, the mean doses of levothyroxine were 118 µg (SD =; 42 µg; n = 15 patients) for the T4 group compared with 67 µg (SD =; 23 µg) for the T4 with T3 group (n = 18 patients). Also at wk 15, the T4 with T3 group was taking a mean of 19 µg T3 (SD = 8 µg; n = 18 patients).
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Throughout the study, the combination of T4 plus T3 raised free T3 concentrations (P < 0.001) and decreased free T4 concentrations (P < 0.001) compared with the continuation of T4 treatment; this effect was seen within 2–4 wk of starting therapy (Table 1
). The mean TSH concentrations remained in the normal range throughout the study in both groups, with no significant overall effect of treatment group on this value (P = 0.06).
Assessment of mood and well-being throughout the study
After adjustment for baseline scores as well as the effect of repeated assessments, T3 plus T4 therapy did not significantly affect self-assessed mood as measured by the CES-D scale or the SCL-90 subscales (depression, anxiety, global severity index, positive symptom total, positive symptom distress index) compared with T4 plus placebo (Table 2; P > 0.05 for all indexes). Furthermore, the combination of T3 plus T4 did not lead to a greater change in personal sense of well-being and social functioning as measured by the MOS subscales (physical role, bodily pain, general health, vitality, social functioning, emotional role, mental health, cognitive functioning, mental health index) than continuation of T4 therapy (Table 3; P > 0.05 for all indexes).
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Discussion |
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The importance of these findings is strengthened by the fact that this was a prospective, double-blinded, randomized, controlled trial of longer duration than other published studies. Furthermore, 1) it included a uniform group of individuals with a history of primary hypothyroidism who were receiving typical stable doses of levothyroxine before randomization; 2) it included people with depressive symptoms who would be expected to have the greatest likelihood of showing a benefit if one truly existed; and 3) it avoided overreplacement of thyroid hormone. Conversely, the fact that only 40, mainly female, participants were studied, the high drop-out rate, the lack of an objective assessment of mood and cognitive status by a psychiatrist, and the need to impute missing scores because of missed appointments would have reduced the ability to detect any benefit of therapy. Nevertheless, these limitations are similar to those encountered in daily clinical practice. As such, these provide no support for changing current approaches to the management of hypothyroidism.
We found that the SCL-90 and CES-D scores in both treatment groups improved with repeated assessments. Several explanations may account for this observation. First, it may reflect a placebo effect in both groups. Second, familiarity with the test or research staff may have led to an improvement in participants’ scores on repeat testing. Third, the interactions at clinic visits may have provided some therapeutic benefits in both groups. Of note is that the analysis of covariance models did account for the effect of time in the study (i.e. early, middle, or late).
How do these findings compare with those from other controlled trials? In a previous 5-wk, cross-over design, randomized, controlled trial, 33 patients (who were receiving a mean prestudy levothyroxine dose of 175 µg, daily) were randomized to continuing baseline T4 dosing or replacement of 50 µg of the levothyroxine dose for T3 (12.5 µg, twice daily) (11). In this study among 17 comparisons of cognitive functioning and mood, the scores in 6 pairs favored the addition of T3; however, 2 of 33 (6%) of subjects reported feeling nervous on combined therapy (11). However, more than half of the participants in this study had a previous diagnosis of thyroid cancer, and in such individuals higher doses of levothyroxine are typically used to suppress the TSH (11). These suppressive doses may have accounted for the positive results reported in this study. Indeed, the results reported in a follow-up paper describing these participants suggest that the dose of thyroid hormone may be important. In this study a subgroup of 11 subjects with autoimmune thyroid disease in whom the TSH level was kept in the normal range (TSH, 0.71 ± 1.41 mU/liter; mean ± SD) experienced no improvement in cognitive functioning or mood, as measured by the digit symbol test, digit span test, visual scanning test, Beck Depression Inventory, Spielberger State Anxiety Inventory, and Profile of Mood States, although visual analog scale assessments of sadness, confusion, fearfulness, and irritability were noted to be improved (P = 0.02 for each) (12). Conversely, in the subgroup of 15 people with thyroid cancer in whom TSH concentrations were suppressed (TSH, 0.09 mU/liter at the conclusion of the study), improvement was noted in some aspects of the digit symbol test, visual scanning time, and Profile of Mood States subscales (global score, fatigue-inertia, depression-dejection, anger-hostility) as well as in visual analog assessments of sadness, confusion, irritability, tension, and agitation (12). Furthermore, in these cross-over design studies (11, 12) the effect of time on mood/well-being scores could not be fully examined, given the short duration of the treatment periods. Thus, the longer-term, parallel-design study that we have presented is preferred to examine the effects of time on mood/well-being in hypothyroid patients.
At least three other trials of T3 therapy for hypothyroidism were not able to detect a substantial benefit. In a 5-wk cross-over study of similar design, in which 10 µg T3 were substituted for 50 µg of the usual T4 dose in 10 subjects with a history of thyroidectomy for Graves’ disease, no significant improvement in mood was noted, as measured by the Beck Depression Index, Profile of Mood States, and visual analog scale examining tension, sadness, and confusion or on cognitive functioning, as measured by the digit symbol test and digit span test (13). In another recent randomized controlled trial, T3 use did not improve mood or cognitive functioning (27). In a third, double-blinded, randomized, controlled trial comparing the use of T4 alone to T4 plus T3 (50 µg T4 replaced with 7.5 µg T3, twice daily) for 4 months, there was also no significant difference between groups in the results of nine different psychological tests and hypothyroid scores (28). All of the above studies are limited by the fact that multiple statistical comparisons were performed, thereby increasing the risk of a type I error, sample sizes were small (with limited power to detect an effect of therapy), and follow-up periods were relatively short. Furthermore, the positive results in subjects with thyroid cancer in whom TSH was suppressed may not be generalizable to patients with autoimmune thyroid failure, in whom traditional goals are to keep TSH in the normal range.
In conclusion, our data do not support the routine use of T3 in addition to T4 to maintain euthyroidism in hypothyroid patients who are receiving stable doses of levothyroxine hormone, but who complain of depressive symptoms. Moreover, the long-term safety of combining T3 with T4 therapy is unknown and was not studied herein. Until a future large, multicenter, blinded, randomized, controlled trial proves otherwise, there is insufficient evidence to support changing the current approach of routinely using T4 alone to maintain euthyroidism in hypothyroid individuals.
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Footnotes |
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Abbreviations: CES-D, Comprehensive Epidemiological Screens for Depression; MOS, Medical Outcomes Study.
Received January 28, 2003.
Accepted May 8, 2003.
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