Journal of Affective Disorders 103 (2007) 253 256 www.elsevier.

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Brief report

L-thyroxine

augmentation of serotonergic antidepressants in female patients with refractory depression

Dorota ojko, Janusz K. Rybakowski

Department of Adult Psychiatry, Poznan University of Medical Sciences, ul.Szpitalna 27/33, 60572 Poznan, Poland Received 13 August 2006; received in revised form 5 January 2007; accepted 9 January 2007 Available online 7 February 2007

Abstract Background: Triiodothyronine (T3) augmentation in treatment-resistant depression had been successfully performed with both tricyclic as well as with SSRI antidepressants. In this paper, the efficacy of addition of moderate dose of L-thyroxine (T4) to serotonergic antidepressants in refractory depression was evaluated. Methods: The study included 17 female patients, aged 3060 years, with treatment-resistant depressive episode in the course of unipolar or bipolar mood disorder. All patients had no history of thyroid axis disturbances and had T3, T4, and thyroid-stimulating hormone (TSH) values within the normal range. The antidepressants preceding thyroxine augmentation were serotonergic antidepressants (clomipramine 11 patients, paroxetine 5 patients, fluoxetine 1 patient). L-thyroxine was added in the dose of 100 m daily for 4 weeks. Results: After four weeks of L-thyroxine augmentation, the remission, assessed as 7 or less points on Hamilton Depression Rating Scale (HDRS) was obtained in eleven patients (64.7%). Five other patients (29.5%) had responded (reduction N 50% on HDRS) and one patient did not show an improvement. The efficacy of augmentation did not show any correlation with laboratory tests' results performed before (T3, T4, TSH and TSH stimulation test) as well as with any clinical factors (age, diagnosis, duration of illness, duration of episode). Conclusions: The addition of moderate dose of L-thyroxine may be a successful augmentation strategy in female depressed patients in whom the effect of serotonergic antidepressant had been unsatisfactory. It may be efficient despite of the lack of disturbances of thyroid axis in such patients. 2007 Elsevier B.V. All rights reserved.
Keywords: Depression; Thyroid; Thyroxine

1. Introduction Triiodothyronine (T3) augmentation in treatmentresistant depression has been performed with both tricyclic (TCA) as well as with SSRI antidepressants. In their meta-analysis, aggregating eight studies with a total 292 patients, Aronson et al. (1996) demonstrated
Corresponding author. Tel.: +48 61 8475 087; fax: +48 61 8480 392. E-mail address: rybakows@wlkp.top.pl (J.K. Rybakowski). 0165-0327/$ - see front matter 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2007.01.016

that patients with depression refractory to TCA, treated with T3, were twice likely to respond as controls. Altshuler et al. (2001) analyzed 6 controlled studies including 125 patients in whom T3 was added to TCA in doses 2562.5 g/d and found T3 being significantly more effective than placebo in accelerating clinical response. Furthermore, such an effect was better in women. Abraham et al. (2006) showed a favorable effect of minimum three weeks of T3 augmentation in doses 2550 g/d in 12 patients with SSRI resistant

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depression. Recent results of STARD project showed that augmentation of antidepressants in treatmentresistant depression with T3 (up to 50 g/day) was slightly better than that with lithium (up to 900 mg/day), although both procedures were generally moderately effective (Nierenberg et al., 2006). The use of thyroxine (T4) for the augmentation of antidepressants has been much less common. Joffe and Singer (1990) suggested that T4 augmentation was less effective than that with T3. However, Barak et al. (1996) reported an effective augmentation with thyroxine (dosage 50 g/d) in older patients refractory to fluoxetine. Also, supraphysiological doses of L-thyroxine (250450 g/d) have been successfully used as an adjunctive treatment in refractory depression and in the maintenance of prophylaxis-resistant affective disorders (Bauer et al., 1998, 2002). We put forward a hypothesis that addition of a moderate dose of L-thyroxine may exert an enhancing effect in female depressed patients showing refractoriness to treatment with serotonergic TCA or SSRI antidepressant. 2. Subjects and methods The study was performed on 17 female patients, aged 3060 (mean 46 5) years, fulfilling DSM IV criteria for non-psychotic major depression. They presented with treatment-resistant depressive episode in the course of unipolar (10 patients) and bipolar mood disorder (7 patients: bipolar I 4 patients, bipolar II 3 patients). Patients with cardiovascular or endocrine diseases, organic brain changes, alcohol or psychoactive substance abuse, and patients with active suicidal tendencies were not included in the study. The mean duration of patients' illness was 11 8 years, and the mean duration of current depressive episode was 5.5 1.3 months. The last depressive episode was resistant to at least two adequate antidepressant treatments (duration of 6 weeks or more, using adequate dose), which means stage 2-resistance, according to Thase and Rush (1995). To enter the study, the last antidepressant preceding L-thyroxine addition should be serotonergic TCA (clomipramine) or SSRI. Furthermore, the intensity of depression after 6 weeks of treatment with such antidepressant had to be 18 points or higher on the 17-item Hamilton Depression Rating Scale (HDRS-17) (Hamilton, 1960). Any other drugs were not permitted except for occasional small doses of benzodiazepines or zolpidem in the case of insomnia. During trial the patients had no formal psychotherapy, except for counseling meeting once a week.

Patients included in the study had no history of thyroid axis disturbances and had either normal menstruations or were taking hormone replacement therapy. They were also not taking drugs which might influence thyroid axis. Their free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH) values before thyroxine addition were within the normal range (fT3: 2.35.3 pg/ml; fT4: 7.819.4 pg/ml; TSH: 0.364.0 mU/l). Before entering the study, the TRH stimulation test was performed. The results were within control range in 14 cases, and in 3 patients the values were slightly lower than in controls (control group was the group of healthy people the same age from other study). According to the criteria of TSH N 25 uU/ml where delta TSH was defined as the peak TSH value in 30 min after TRH stimulation minus baseline TSH (Degroot, 1989), none of the patients met the criteria for subclinical hypothyroidism. The patients were added 100 g of L-thyroxine daily for four weeks. They continued taking the same antidepressant and at the same dosage as before the thyroxine addition. Eleven patients received clomipramine (mean dosage 190 mg/d, range 150225), 5 patients paroxetine (dosage 40 mg/d), and one patient fluoxetine (40 mg/d). The assessment of depression severity with HDRS17 was done before and after 7, 14, 21 and 28 days of Lthyroxine augmentation. The rating was performed by two psychiatrists, experienced in HDRS assessment, with good inter-rater reliability. The response was assumed as N 50% reduction in baseline HDRS, and remission as 7 points or less on HDSR, after 4 weeks of augmentation. Blood pressure and pulse were controlled twice daily. Statistical analysis used Statistica 5.0. program. To evaluate the normality of distribution the ShapiroWilk test was applied. In case of normal distribution, differences between the groups of patients were assessed by one-way analysis of variance (ANOVA) and Student's t-test, and Pearson correlation was employed. Otherwise, non-parametric tests were applied (Friedman ANOVA, MannWhitney, Wilcoxon, and Spearman correlation test). The study was approved by Bioethics Committee, Poznan University of Medical Sciences. All patients gave written consent. 3. Results The mean intensity of depressive symptoms during four weeks of thyroxine addition in 17 patients is shown in Fig. 1.

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Fig. 1. HDRS scores (mean + SD) in 17 female depressive patients in the course of augmentation of antidepressants with L-thyroxine.

The mean baseline HDRS score before thyroxine addition was 26 4 points. A decrease in depression intensity was observed as early as after one week of L-thyroxine augmentation (20 4 points). After four weeks of L-thyroxine augmentation the mean score on HDRS was 8 + 4 points. Remission (HDRS 7) was obtained in eleven patients (64.7%), five other patients (29.5%) had responded (reduction N 50%) and one patient did not show an improvement. No correlation was observed between the degree of augmentation response, expressed as an index of (HDRS baseline HDRS 4 weeks) / HDRS baseline, and the values of laboratory tests and clinical characteristics of the patients (age, duration of illness and duration of the episode). Also no difference was found between augmentation response in unipolar and bipolar subjects. Baseline HDRS scores were similar in clomipramine and SSRI group (26 6 and 26 3, respectively). There was a significant difference in the intensity of depression after 14 days of thyroxine addition (14 + 4 vs 18 + 1, p = 0.04) and a trend after 28 days (7 + 3 vs 10 + 5, p = 0.07), favoring augmentation of clomipramine. L-thyroxine administration was well tolerated, only one patient complained of slight tachycardia. 4. Discussion Our findings may suggest a clinical efficacy of Lthyroxine augmentation of serotonergic antidepressants in female patients with refractory depression, reflected by remission following 4 weeks of thyroxine addition in nearly 2/3 of treated subjects. Obviously, these results require confirmation on greater number of patients and in double-blind study.

Thyroxine monotherapy remains the treatment of choice for clinical hypothyroidism. The effect of thyroxine and triiodothyronine combination on depressive symptoms in these patients did not differ from that of T4 alone (Joffe et al., 2004; Grozinsky-Glasberg et al., 2006). However, it is mainly T3 that has been used in treatment-refractory depression. Our results point to a significant therapeutic effect of addition of therapeutic dose of thyroxine (100 g/d) to antidepressants in refractory depressed female patients. All these patients were euthyroid and no significant association has been observed between baseline indices of thyroid function and a degree of therapeutic improvement in these patients. The issue of the relationship between thyroid indices and antidepressant response remains controversial. Gitlin et al. (2004) suggested that low baseline TSH values correlated with greater improvement in depressive symptoms after fluoxetine or sertraline treatment. On the other hand, in Cooper-Kazaz et al. (2006) study, among patients treated with sertraline plus T3, greater reductions in TSH values during therapy were associated with superior clinical outcome. In Gendall et al. (2003) paper, a decrease in deltamax TSH was correlated with response to fluoxetine, and increase in this parameter with response to nortriptyline. However, Schule et al. (2005) did not observe any changes in the indices of TRH or T3/TRH stimulation test after 4-week treatment with sertraline. Basic neurobiological mechanisms of augmentation of antidepressant effect with thyroid hormones are linked to their potentiation of serotonergic neurotransmission (Lifschytz et al., 2006). It was demonstrated that a combination of imipramine or fluoxetine with T3 induced a desensitization of 5HT1A and 5HT1 autoreceptors which can contribute to this effect (Gur et al., 2002; Lifschytz et al., 2004). In our study, the effect of thyroxine augmentation was slightly better in clomipramine, compared to typical SSRI-treated patients. Clomipramine, although predominantly serotonergic, is in fact a dual action antidepressant (serotonergic and noradrenergic) and its better effect than SSRI could be due to enhancing by thyroxine the noradrenergic component of the drug. In experimental studies, the administration of thyroxine reversed the deficit of noradrenergic system observed after thyroidectomy (Tejani-Butt and Yang, 1994). Our study was an open one and the number of patients studied was relatively small that can constitute main limitations. Bearing this in mind, we can nevertheless suggest that the addition of moderate dose of L-thyroxine may be a successful augmentation strategy in female

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