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augmentation of serotonergic antidepressants in female patients with refractory depression
Dorota Łojko, Janusz K. Rybakowski ⁎
Department of Adult Psychiatry, Poznan University of Medical Sciences, ul.Szpitalna 27/33, 60–572 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 30–60 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 μm 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: firstname.lastname@example.org (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 25–62.5 μg/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 25–50 μg/d in 12 patients with SSRI resistant
The patients were added 100 μg of L-thyroxine daily for four weeks. The assessment of depression severity with HDRS17 was done before and after 7.0. The rating was performed by two psychiatrists. During trial the patients had no formal psychotherapy. Patients with cardiovascular or endocrine diseases. In case of normal distribution. and one patient — fluoxetine (40 mg/d). none of the patients met the criteria for subclinical hypothyroidism.5 ± 1.8–19. J. differences between the groups of patients were assessed by one-way analysis of variance (ANOVA) and Student's t-test.3 pg/ml. Recent results of STAR⁎D project showed that augmentation of antidepressants in treatmentresistant depression with T3 (up to 50 μg/day) was slightly better than that with lithium (up to 900 mg/day). 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. The study was approved by Bioethics Committee. Joffe and Singer (1990) suggested that T4 augmentation was less effective than that with T3. (1996) reported an effective augmentation with thyroxine (dosage 50 μg/d) in older patients refractory to fluoxetine. Blood pressure and pulse were controlled twice daily. 2. Also. Patients included in the study had no history of thyroid axis disturbances and had either normal menstruations or were taking hormone replacement therapy. The last depressive episode was resistant to at least two adequate antidepressant treatments (duration of 6 weeks or more. 1960).254 D. and Spearman correlation test). Wilcoxon. 21 and 28 days of Lthyroxine augmentation.36–4.3–5. although both procedures were generally moderately effective (Nierenberg et al. TSH: 0. non-parametric tests were applied (Friedman ANOVA.. aged 30–60 (mean 46 ± 5) years. and the mean duration of current depressive episode was 5. They continued taking the same antidepressant and at the same dosage as before the thyroxine addition.0 mU/l). supraphysiological doses of L-thyroxine (250–450 μg/d) have been successfully used as an adjunctive treatment in refractory depression and in the maintenance of prophylaxis-resistant affective disorders (Bauer et al. The response was assumed as N 50% reduction in baseline HDRS.. Poznan University of Medical Sciences. the TRH stimulation test was performed. and Pearson correlation was employed. using adequate dose). and remission as 7 points or less on HDSR. with good inter-rater reliability. However. fulfilling DSM IV criteria for non-psychotic major depression. 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. The use of thyroxine (T4) for the augmentation of antidepressants has been much less common. . bipolar II — 3 patients). according to Thase and Rush (1995). To evaluate the normality of distribution the Shapiro–Wilk test was applied. free thyroxine (fT4). the last antidepressant preceding L-thyroxine addition should be serotonergic TCA (clomipramine) or SSRI. The results were within control range in 14 cases. Barak et al.4 pg/ml. Mann–Whitney. and thyroid-stimulating hormone (TSH) values before thyroxine addition were within the normal range (fT3: 2. Before entering the study. Furthermore. Results The mean intensity of depressive symptoms during four weeks of thyroxine addition in 17 patients is shown in Fig. According to the criteria of ΔTSH N 25 uU/ml where delta TSH was defined as the peak TSH value in 30 min after TRH stimulation minus baseline TSH (Degroot. The mean duration of patients' illness was 11 ± 8 years. All patients gave written consent. program. 1. Any other drugs were not permitted except for occasional small doses of benzodiazepines or zolpidem in the case of insomnia. Eleven patients received clomipramine (mean dosage 190 mg/d. They were also not taking drugs which might influence thyroid axis. Their free triiodothyronine (fT3). and patients with active suicidal tendencies were not included in the study. 2002). 14. 2006). To enter the study. which means stage 2-resistance. experienced in HDRS assessment. Rybakowski / Journal of Affective Disorders 103 (2007) 253–256 depression. alcohol or psychoactive substance abuse. fT4: 7. organic brain changes. 1998. 1989). 3. Subjects and methods The study was performed on 17 female patients. Łojko. 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).K. They presented with treatment-resistant depressive episode in the course of unipolar (10 patients) and bipolar mood disorder (7 patients: bipolar I — 4 patients. after 4 weeks of augmentation. except for counseling meeting once a week. Statistical analysis used Statistica 5. 5 patients — paroxetine (dosage 40 mg/d).3 months. range 150–225). Otherwise.
There was a significant difference in the intensity of depression after 14 days of thyroxine addition (14 + 4 vs 18 + 1. the effect of thyroxine augmentation was slightly better in clomipramine. the administration of thyroxine reversed the deficit of noradrenergic system observed after thyroidectomy (Tejani-Butt and Yang. Lifschytz et al. we can nevertheless suggest that the addition of moderate dose of L-thyroxine may be a successful augmentation strategy in female . Also no difference was found between augmentation response in unipolar and bipolar subjects.K. Discussion Our findings may suggest a clinical efficacy of Lthyroxine augmentation of serotonergic antidepressants in female patients with refractory depression. 1. Our study was an open one and the number of patients studied was relatively small that can constitute main limitations. However. (2005) did not observe any changes in the indices of TRH or T3/TRH stimulation test after 4-week treatment with sertraline. In our study. In experimental studies.07). The issue of the relationship between thyroid indices and antidepressant response remains controversial. although predominantly serotonergic.. J. After four weeks of L-thyroxine augmentation the mean score on HDRS was 8 + 4 points. Rybakowski / Journal of Affective Disorders 103 (2007) 253–256 255 Fig. Clomipramine. (2003) paper. expressed as an index of (HDRS baseline − HDRS 4 weeks) / HDRS baseline. Schule et al.. and increase in this parameter — with response to nortriptyline. On the other hand. Baseline HDRS scores were similar in clomipramine and SSRI group (26 ± 6 and 26 ± 3.. 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. reflected by remission following 4 weeks of thyroxine addition in nearly 2/3 of treated subjects. p = 0. greater reductions in TSH values during therapy were associated with superior clinical outcome. Bearing this in mind. Łojko... Grozinsky-Glasberg et al. a decrease in deltamax TSH was correlated with response to fluoxetine. Our results point to a significant therapeutic effect of addition of “therapeutic” dose of thyroxine (100 μg/d) to antidepressants in refractory depressed female patients. No correlation was observed between the degree of augmentation response. in Cooper-Kazaz et al. and the values of laboratory tests and clinical characteristics of the patients (age. (2006) study. p = 0.5%) had responded (reduction N 50%) and one patient did not show an improvement. 2006). among patients treated with sertraline plus T3. In Gendall et al. 2006). duration of illness and duration of the episode). 2004). only one patient complained of slight tachycardia. HDRS scores (mean + SD) in 17 female depressive patients in the course of augmentation of antidepressants with L-thyroxine. Remission (HDRS ≤ 7) was obtained in eleven patients (64. Obviously. favoring augmentation of clomipramine. 1994). Thyroxine monotherapy remains the treatment of choice for clinical hypothyroidism. it is mainly T3 that has been used in treatment-refractory depression. 2002. A decrease in depression intensity was observed as early as after one week of L-thyroxine augmentation (20 ± 4 points). five other patients (29. Gitlin et al. these results require confirmation on greater number of patients and in double-blind study. The mean baseline HDRS score before thyroxine addition was 26 ± 4 points. compared to typical SSRI-treated patients.04) and a trend after 28 days (7 + 3 vs 10 + 5. 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. (2004) suggested that low baseline TSH values correlated with greater improvement in depressive symptoms after fluoxetine or sertraline treatment. Basic neurobiological mechanisms of augmentation of antidepressant effect with thyroid hormones are linked to their potentiation of serotonergic neurotransmission (Lifschytz et al. L-thyroxine administration was well tolerated. 2004. 4. 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. However.D. respectively). The effect of thyroxine and triiodothyronine combination on depressive symptoms in these patients did not differ from that of T4 alone (Joffe et al.7%).
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