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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 12 6271-6276
Copyright © 2004 by The Endocrine Society

Triiodothyronine Addition to Paroxetine in the Treatment of Major Depressive Disorder

Bente C. Appelhof1, Jantien P. Brouwer1, Richard van Dyck, Eric Fliers, Witte J. G. Hoogendijk, Jochanan Huyser, Aart H. Schene, Jan G. P. Tijssen and Wilmar M. Wiersinga

Departments of Endocrinology and Metabolism (B.C.A., J.P.B., E.F., W.M.W.), Psychiatry (J.H., A.H.S.), and Cardiology (J.G.P.T.), Academic Medical Centre, University of Amsterdam, 1100 DE Amsterdam, The Netherlands; and Department of Psychiatry (R.v.D., W.J.G.H.), Vrjie Universiteit Medical Centre, 1081 HV Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Bente C. Appelhof, M.D., Academic Medical Center of the University of Amsterdam, Department of Endocrinology and Metabolism, F5-161, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. E-mail: b.c.appelhof{at}amc.uva.nl.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
There is evidence that thyroid hormone T3 increases serotonergic neurotransmission. Therefore, T3 addition to antidepressants may improve treatment response in major depression. In nonrefractory depression, T3 addition to tricyclic antidepressants indeed accelerates treatment response. Current therapeutic practice favors selective serotonin reuptake inhibitors. This is the first study to investigate the efficacy of T3 addition to paroxetine in major depression.

One hundred thirteen patients with major depressive disorder were randomly assigned to 8 wk of double-blind outpatient treatment with low-dose T3 (25 µg), high-dose T3 (25 µg twice daily), or placebo in addition to paroxetine 30 mg daily.

A total of 106 patients started treatment and were included in the outcome analysis. Response rate after 8 wk (reduction of Hamilton Rating Scale for Depression score ≥ 50%) was 46% in all three treatment arms (P = 0.99). T3 addition did not accelerate clinical response to paroxetine, nor was an effect of T3 found when only women were analyzed. Patients on T3 addition reported more adverse events than patients on placebo comedication.

In conclusion, these results do not support a role for T3 addition to selective serotonin reuptake inhibitors in the treatment of nonrefractory major depressive disorder. On the contrary, more adverse reactions occurred in T3-treated patients.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
MAJOR DEPRESSION IS a serious and disabling illness, estimated by the World Health Organization to be the second most important worldwide cause of loss in disability-adjusted life-years by 2020 (26). The introduction of antidepressants about half a century ago has ameliorated treatment possibilities for major depressive disorder. However, both the delayed onset of therapeutic response to antidepressants of 2–6 wk and the lack of response to antidepressant therapy in 30–50% of patients remain important clinical problems. Therefore, the search for new treatment strategies that would either accelerate response or increase response rates is of importance.

Although the pathogenetic mechanisms of major depressive disorder have not yet been clarified, considerable experimental and clinical evidence supports a fundamental role of monoamines in the etiology of depression, including serotonin (1). Selective serotonin reuptake inhibitors (SSRIs), currently favored in therapeutic practice as a first step in the treatment of depression, increase the availability of serotonin at the synapse. This increase has been found to induce desensitization of inhibitory autoreceptors involved in the feedback mechanism of serotonin release, leading to higher central serotonergic activity, which is thought to elicit therapeutic response (1).

There is evidence from animal studies that T3 is also capable of increasing serotonergic neurotransmission by desensitization of the serotonin inhibitory 5-hydroxytryptamine1a autoreceptor in the raphe nucleus, in which the largest concentration of serotonergic neurons is found (2, 3). In addition, various antidepressant treatments, including SSRIs, stimulate type II deiodinase in the rat brain, whereas type III deiodinase is not increased or inhibited (4, 5). These effects should theoretically lead to increased cerebral T3 concentrations, enhancing serotonergic neurotransmission. These experimental data suggest that T3 might be of value in the treatment of major depression. A metaanalysis (6) investigating the combined treatment of T3 and tricyclic antidepressant (TCA) in patients with nonrefractory depression supported the efficacy of T3 in accelerating clinical response to TCAs, especially in women. So far, no randomized controlled trials have been published addressing the efficacy of T3 addition to SSRIs, although three case reports suggested that T3 augmentation may be effective in combination with SSRI treatment in nonresponders (7, 8, 9).

We hypothesized here that T3 not only accelerates but also increases response rates in nonrefractory depression. We therefore undertook a large, randomized, double-blind, placebo-controlled clinical trial to assess the efficacy and tolerability of T3 addition to paroxetine in patients with major depressive disorder.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
This study was carried out between October 1999 and June 2002 at two academic outpatient clinics (Departments of Psychiatry, Academic Medical Center, University of Amsterdam, and Vrije Universiteit Medical Center, Amsterdam). The protocol was approved by the institutional ethics review committees of both clinics.

Subjects

Patients were recruited from response to newspaper articles and advertisements, community clinicians, and the two psychiatric outpatient clinics. To be eligible for the study, patients had to be between 18 and 65 yr of age, fulfill the diagnostic criteria for major depressive disorder according to criteria in the Diagnostic and Statistical Manual (DSM) of mental disorders-IV (10), and have a score of 16 or more on the 17-item Hamilton Rating Scale for Depression (HRSD) (11) at baseline. The diagnosis of major depressive disorder was obtained at baseline by a clinician with use of the Structured Clinical Interview for Axis I Diagnostic and Statistical Manual of Mental Disorders-IV Disorders (12) and confirmed by a board-certified psychiatrist.

Exclusion criteria were bipolar disorder; a history of psychotic symptoms; severe cognitive disturbances; severe antisocial or borderline personality disorder; current suicidal risk; substance abuse; overt thyroid [free T4 (fT4)] outside reference range (10–23 pmol/liter) or adrenocortical disease (physical examination); angina pectoris; any serious unstable medical condition; or pregnancy or lactation. Patients were not allowed to have taken corticosteroids, thyroid hormone, or antithyroid or psychotropic drugs during the last 3 months before inclusion, with the exception of a low dose of benzodiazepines (equivalent to 30 mg oxazepam or 10 mg temazepam daily). During the study, patients were not allowed to take Hypericum perforatum (St. John’s wort) (13) or more than 5 U alcohol a day. After complete description of the study to the subjects, written informed consent was obtained.

Study design

After inclusion, the clinician provided participants with a consecutive study number, corresponding to an allocation code for study treatment. The randomization was organized by a computer-generated list such that for every 12 patients, three were assigned to receive 25 µg T3, three to receive 50 µg T3, and six to receive placebo, in addition to treatment with paroxetine. Study medication was provided in containers marked with the study number. To avoid possible severe complaints of anxiety and agitation due to the shared side effects of T3 and paroxetine, the 8-wk dosing schedule for paroxetine was titrated slowly: 10 mg/d during the first week, 20 mg/d during the second week, and 30 mg/d for the remaining 6 wk. Paroxetine was taken in the morning, together with half of the study medication dose (one tablet of 25 µg T3 or one tablet of placebo). The other half of the study medication dose was taken in the evening (25 µg T3 for the 50-µg T3 treatment arm, otherwise placebo). Placebo and T3 tablets were identical in appearance. Paroxetine (Seroxat) and T3 (Cytomel) were kindly supplied by GlaxoSmithKline, Zeist, The Netherlands. Placebo tablets were fabricated by and purchased from Terafarm (Zwijndrecht, The Netherlands).

Efficacy assessments were performed at 1, 2, 4, 6, and 8 wk after initiation of treatment by a clinician who was unaware of the treatment assignment and trained to have a high interrater reliability. Visits were limited to 60 min during which efficacy assessments were made with the 17-item HRSD, the Montgomery Åsberg Depression Rating Scale (MADRS) (14), the Hamilton Anxiety Rating Scale (HARS) (15), the Beck Depression Inventory (BDI) (16), and the Clinical Global Impression Scale (CGI) (17). The ratings of HRSD, MADRS, and HARS were obtained by means of a semistructured interview (18). The primary end point was the score on the 17-item HRSD at 8 wk. Response was defined as a 50% or greater reduction in the HRSD score from baseline to wk 8; remission was defined as an end point HRSD score of 8 or less. Secondary outcomes analyzed were: response in terms of the MADRS, HARS and BDI scales (≥50% reduction), response on the CGI (end point score 1 or 2), and remission as measured by the MADRS (end point score ≤ 12). For safety monitoring, blood pressure and heart rate were measured at every visit. Spontaneous mentioned adverse events were documented at every visit. At 1, 4, and 8 wk, patients were asked whether they had experienced any of 11 common adverse events of T3 and/or paroxetine, whether or not thought to be related to treatment. In case of severe complaints a board-certified psychiatrist was consulted to discuss whether participation should be discontinued.

Thyroid function tests were measured at baseline and end point. Hormone assays were conducted in the Endocrinology Laboratory of the Academic Medical Centre. T3 was measured by in-house RIA method (19), and fT4 and TSH were measured by time-resolved fluoroimmunoassay (Wallac Oy, Turku, Finland). Detection limits were 20 ng/dl (0.3 nmol/liter), 0.2 ng/dl (2 pmol/liter), and 0.01 µU/ml (0.01 mU/liter), respectively.

Interim analysis

The study was to enroll 150 patients with major depression. With 75 index patients and 75 controls, the study had sufficient power (90%) to detect an increase in response rates from 60 to 85%. After the first 100 participants had completed the trial, an interim analysis was to occur. A data-monitoring committee, composed of a psychiatrist, an endocrinologist, and a biostatistician, was established to provide an independent analysis of interim results. In May 2002 the data-monitoring committee advised to terminate trial enrollment because interim analysis revealed no effect whatsoever of T3 addition, compared with placebo addition.

Statistical analysis

Patients who withdrew during the baseline assessment phase before having received medication were not included in outcome analyses (Fig. 1Go). For patients who withdrew from the study protocol, data at the time of withdrawal were carried forward and used for outcome analysis. Paired t tests were performed for comparison of baseline vs. end point outcome measurements within treatment groups. Differences between groups were compared by means of {chi}2 and ANOVA as appropriate. More patients were randomized to placebo to allow for two contrasts in the analysis after overall ANOVA: 1) T3 addition vs. placebo addition, and 2) a dose-dependent effect of T3 addition. Because overall ANOVA did not show any significance, these further contrasts were not presented in this manuscript. Statistical significance was defined as a two-tailed P < 0.05.



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  		FIG. 1. Flow diagram of participants.

 

   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline clinical and demographic characteristics

Of the 189 patients assessed for eligibility, 76 patients were excluded (Fig. 1Go). A total of 113 patients met the criteria for eligibility and were randomized: 53 were assigned to placebo addition, 30 to addition of 25 µg T3, and 30 to addition of 50 µg T3. The three groups were similar at baseline with respect to a range of demographic and clinical characteristics (Table 1Go), with the exception of the number of patients with chronic major depression being somewhat higher in the 25-µg T3 group.


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  		TABLE 1. Demographic and baseline characteristics (all patients)

 
Seven patients withdrew from the study protocol before initiation of treatment, leaving 106 patients for outcome analysis (Fig. 1Go).

Efficacy

Table 2Go shows the mean baseline, end point, and difference scores of the HRSD, MADRS, and BDI scales as well as the response and remission rates for the primary end point. Analyses revealed a significant improvement in the HRSD scores from baseline to wk 8 (or the last follow-up visit) within all three groups (paired-samples t tests, all P < 0.001). Similar significant improvement was seen in the baseline vs. end point scores of all other psychiatric outcome measures (paired-samples t tests, all P < 0.001). The overall rate of response on the primary outcome measure, defined as a reduction in HRSD score of 50% or more, was 46% in all three treatment groups ({chi}2 = 0.002, df = 2, P = 0.99). Remission, defined as a HRSD score of 8 or less was 36% in the placebo group, compared with 32% in both T3 groups ({chi}2 =0.175, df = 2, P = 0.92). When the two T3 groups were pooled and compared with the placebo group, the absolute difference in response rate was 0.004 (95% confidence interval: –0.187 to 0.195). None of the primary or secondary outcome measures (including the HARS and CGI, data not shown) revealed any significant difference in treatment efficacy between the treatment groups. When women were analyzed separately (n = 68), response rates were 47, 53, and 47% in placebo, 25 µg T3, and 50 µg T3 groups, respectively ({chi}2 = 0.177, df = 2, P = 0.92). The group of patients with subclinical hypothyroidism, which was defined as an increased serum TSH (>4.0 mU/liter) and normal serum fT4 (between 10.0 and 23.0 pmol/liter) was too small to detect any significant differences in T3 efficacy (n = 12: 7, 2, and 3 in the control, low-dose T3, and high-dose T3 groups, respectively).


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  		TABLE 2. Scores on psychiatric outcome measures at baseline and endpoint

 
For treatment responders, the time interval to response did not significantly differ among the three groups: the mean time to response was 5.3 wk in the placebo group (n = 23), compared with 5.8 and 6.3 wk in the 25-µg T3 (n = 13) and 50-µg T3 (n = 13) groups, respectively (F = 0.745, df = 2, 46, P = 0.48). The course of the HRSD scores during the 8 wk of the trial was similar for all treatment groups (Fig. 2Go). No different times to response were found if women (n = 33) were analyzed separately: 5.0, 5.0, and 3.9 wk in the placebo, 25 µg T3, and 50 µg T3, respectively (F = 0.590, df = 2, 30, P = 0.56).



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  		FIG. 2. Course of HRSD scores during treatment (n = 106). For each visit the mean HRSD score was calculated for each treatment group. The last HRSD score of noncompleters was carried forward. In the case of a sporadic missing visit, the HRSD score was calculated as the metric mean between the score of the preceding and following visit.

 
Attrition rates, adverse events, and endocrine measures

Nine of the 106 patients (8%) did not complete the study, and attrition rates were similar in the three groups (Fig. 1Go). Eight patients dropped out as a result of adverse events, evenly distributed among the treatment groups (8% in the placebo group, 7% in each T3 group).

One patient sought other treatment. Of the eight patients who discontinued due to adverse events, six did so within the first 2 wk of medication.

Table 3Go lists the occurrence of 11 common adverse events of T3 and/or paroxetine, as measured at end point. T3-related adverse events (palpitations, sweating, nervousness, and tremor) were expected to occur more often in patients receiving T3. Indeed, differences in occurrence of adverse events were evident for these four, significantly so for palpitation, sweating, and nervousness. In nine of 28 (32.1%) patients in the 50-µg T3 arm, the adverse events clearly interfered with the functioning of the patient or outweighed the therapeutic effect, as measured by the CGI efficacy index (17). This occurred less often in the 25-µg T3 group (four of 28, 14.3%) and placebo group (nine of 50, 18.0%), although the difference was not significant ({chi}2 = 3.2, df = 2, P = 0.207).


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  		TABLE 3. Adverse events at 8 wk (treatment completers only)

 
As expected, there was a dose-dependent increase in serum T3 concentrations and a concordant decrease in serum fT4 concentrations as measured at end point. Mean serum T3 concentrations were 109 ± 27 ng/dl (1.68 ± 0.42 nmol/liter, placebo group), 185 ± 65 ng/dl (2.84 ± 1.00 nmol/liter, 25-µg T3 group), and 202 ± 71 ng/dl (3.10 ± 1.09 nmol/liter, 50-µg T3 group). Mean serum fT4 concentrations were 0.9 ± 0.1 (11.6 ± 1.7 pmol/liter, placebo group), 0.6 ± 0.2 (7.8 ± 2.4 pmol/liter, 25-µg T3 group), and 0.4 ± 0.2 (5.2 ± 2.6 pmol/liter, 50-µg T3 group).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the present study, the largest trial investigating T3 addition to antidepressants thus far, we found that addition of the thyroid hormone T3 to paroxetine had no advantage over addition of placebo in the treatment of nonrefractory major depressive disorder. Treatment with T3 did not accelerate the response to treatment; neither did T3 addition influence response or remission rates. In fact, the main difference between treatments appears to be that patients in the T3-addition groups experienced more adverse effects, compared with those on paroxetine alone, especially those who received 50 µg T3 daily.

This negative result is in disagreement with the previously mentioned positive metaanalysis about the acceleration of response. With regard to this discrepancy, several issues deserve some discussion.

The choice of T3 dose was based on previous T3 addition studies that virtually all used a dose between 25 and 50 µg daily. It has been argued that 25 µg T3 might be insufficient to increase antidepressant efficacy (20), so we chose to include a treatment group receiving 50 µg T3. This dose slightly exceeds the human daily production rate of T3, which is estimated between 22 and 47 µg/d (21). The failure to find a difference between the effects of T3 and placebo is therefore unlikely to be the result of an insufficient dose of T3.

Serum levels of T3 showed a dose-dependent increase in serum T3 concentrations, indicating that compliance was not a major issue.

We investigated an outpatient population with a mean HRSD score of 21. Although this is similar to at least one of the studies finding a response accelerating effect of T3 addition (22), it seems that most other positive trials were carried out among inpatients, even though this is often not clearly described in the publications. Maybe a population of inpatients, who may be assumed to suffer from more severe illness, is more likely to benefit from T3 addition. However, in this study we did not find severity of depression (as measured by baseline HRSD score) to be related to treatment response, neither in the control nor T3 groups.

At baseline, chronic major depression, which has been reported to predict treatment response, was more prevalent in the 25-µg T3 group. However, in our study, there was no difference in response rates between patients with chronic and nonchronic depression in the group as a whole (46 vs. 47%, respectively) or in the placebo group (50 vs. 44%, respectively). It is therefore unlikely that chronicity was a confounder in this study.

In the studies included in the metaanalysis (6), the advantage of T3 addition was present only in the first 3–4 wk of treatment; thereafter the difference with placebo disappeared. In our study we cannot be sure that a beneficial T3 effect did not exist after 3 wk of treatment because no measurement of severity of depression was performed at 3 wk. But as is shown in Fig. 2Go, HRSD scores were quite similar in wk 1 and 2 and even somewhat higher in the T3-treated groups at 4 wk of treatment, compared with the placebo group. In our opinion this makes an advantage of T3 addition at 3 wk very unlikely.

Altshuler et al. (6) found that women in particular benefited from the T3 addition. We therefore performed a separate response analysis for the subgroup of women in our study but, again, found no advantage of T3 addition. Whether T3 addition is specifically beneficial in depressed patients with subclinical hypothyroidism remains unanswered in this study because of the low prevalence of subclinical hypothyroidism.

Could the lack of increase in efficacy in this study be due to the fact that T3 was used in addition to a SRRI? Thus far the efficacy of T3 addition has been only investigated in combination with tricyclic antidepressants. The mechanism of action of T3 in the treatment of major depression is not well understood. Animal studies, finding that T3 influences the (nor)adrenalin as well as serotonin system in rat brain (23, 24), give little cause to assume that T3 addition might be effective in combination with TCAs but not with SSRIs. Besides, most TCAs are known to inhibit both norepinephrine and serotonin reuptake.

In conclusion, the results of this study indicate that the addition of T3 to SSRIs does not enhance treatment response in any way in nonrefractory depressed patients. On the contrary, in this study T3 addition seems to cause an increase in complaints of adverse events.


   Acknowledgments
 
Paroxetine and T3 were kindly supplied by GlaxoSmithKline.


   Footnotes
 
This work was supported by a grant from the Academic Medical Center Anton Meelmeijer Fund (fund no. SAG 05002).

The authors state that they had full access to all the data in the study and had final responsibility for the decision to submit for publication.

1 B.C.A. and J.P.B. contributed equally to this work. Back

Abbreviations: BDI, Beck Depression Inventory; CGI, Clinical Global Impression Scale; fT4, free T4; HARS, Hamilton Anxiety Rating Scale; HRSD, Hamilton Rating Scale for Depression; MADRS, Montgomery Åsberg Depression Rating Scale; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

Received June 16, 2004.

Accepted September 14, 2004.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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