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Journal of Affective Disorders 100 (2007) 271 277 www.elsevier.

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Preliminary communication

Free T4 index and clinical outcome in patients with depression


Osama Abulseoud , Natasha Sane, Anthony Cozzolino, Lindsay Kiriakos, Vishal Mehra, Michael Gitlin, Susan Masseling, Peter Whybrow, Lori L. Altshuler, Jim Mintz, Mark A. Frye
Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Received 17 June 2006; received in revised form 10 October 2006; accepted 13 October 2006 Available online 22 November 2006

Abstract Introduction: Many studies of patients with major depression have reported that a significant decrease in serum free T4 index is associated with specific treatments; what has been unanswered is whether these observations are generalizable. This study evaluated baseline thyroid function and its relationship to rapidity of treatment response as measured by hospital length of stay (HLOS). Methods: Admission thyroid indices and HLOS data were harvested from the medical record of patients hospitalized for depression, both unipolar and bipolar. The relationship between admission thyroid indices and HLOS was evaluated using survival models. Results: Controlling for age and year of discharge, an inverse relationship between FT4 index (FT4I) and HLOS was present in men, but not in women. The mean HLOS stratified by gender and median FT4I was 50% shorter in men with a relatively high FT4I in comparison to the other three groups. Limitations: This is a retrospective study limited by the absence of a structured diagnostic psychiatric interview and prospective controlled antidepressant evaluation. Conclusion: These data would suggest that a relatively elevated FT4 index in depressed men is associated with a faster antidepressant response time. Prospective study is encouraged to further clarify this potential thyroid/gender relationship and whether thyroid supplementation can accelerate the improvement in depression as measured by HLOS. 2006 Elsevier B.V. All rights reserved.
Keywords: Depression; Thyroid function; Treatment response; Gender

An extensive body of research over the past 25 years has documented an intimate relationship between the hypothalamicpituitarythyroid (HPT) axis and depression. Cross-sectional studies in patients with acute major depression have shown relative increases in levels of
Presented in part at the 154th Annual Meeting of the American Psychiatric Association, May 7 2001, New Orleans, LA. Supported in part by an unrestricted educational grant from Abbott Laboratories. Corresponding author. 300 Medical Plaza Los Angeles, CA 90095, USA. Tel.: +1 310 794 5841; fax: +1 310 794 9915. E-mail address: oabulseoud@mednet.ucla.edu (O. Abulseoud).

serum thyroxine (free, total or index) compared to healthy controls (Duval et al., 1994; Maes et al., 1993; Joffe and Singer, 1992; Kirkegaard and Faber, 1991, 1981; Kirkegaard et al., 1990; Mller and Bning, 1988; Linnoila et al., 1979; Whybrow et al., 1972). Furthermore, as presented in Table 1, 10/12 studies report a significant decrease in these same thyroxine measures associated with treatment. In 6 of these studies, regardless of treatment modality, the reduction was greater in responders than in non-responders (Gendall et al., 2003; Sokolov et al., 1996; Joffe and Singer, 1990; Joffe et al., 1996; Baumgartner et al., 1988; Kirkegaard and Faber, 1986). Neither gender,

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Table 1 Decrease in serum T4 associated with treatment response in depressed patients Author Gendall et al. (2003) N Results 190 Baseline serum TT4 in responders vs. non-responders in fluoxetine ( p b 0.05) group and FT4 in both groups; fluoxetine ( p b 0.01), and nortriptyline ( p b 0.04), respectively. Sokolov et al. 12 AD responders had baseline TT4 (114.5 (1996) 23.2) that by 16.0 13.6% in responders vs. non-responders (0.54 8.0%, p = 0.03) following desipramine treatment. Rao et al. 21 Elevated pretreatment TT4 in responders (1996) ( p b 0.05) vs. non-responders. Negative correlation between baseline FT4 and HDRS (week 2: r = 0.59, p b 0.05), and HDRS (week 3: r = 0.56, p b 0.05) in responders to either amitriptyline or mianserin. Joffe and Singer 28 Baseline TT4 higher in TCA responders (1990) versus non-responders (126.1 27.1 vs. 111.3 31.4, p b 0.05). TT4 and FT4I greater in responders TT4 (122.9 22.6) and FT4I (31.4 4.9, p b 0.001) vs. non-responders (108.5 24.6 and 29.6 6.5). Joffe et al. 30 20-week CBT in measures of TT4 in the (1996) 17 responders from 127.8 23.2 to 115.7 19.6 versus 13 non-responders 112.4 18.4 to 114.9 22.3 ( p = n.s.). Brady and Anton 13 DMI FT4I (8.2 2.4 to 6.9 1.4, p b 0.05) (1989) (15.8% decrease). Baumgartner 31 Delta TT4 baseline to endpoint was greater et al. (1988) in treatment TCA responders (TT4 responders: 15.3 14.4) vs. TT4 nonresponders (0.9 21.3, p = 0.05) and (FT4 responders 1.3 1.7 vs. FT4 0.2 2.3, p b 0.07. Kirkegaard and 17 FT4 was before ECT ( p b 0.01), and Faber (1986) after ECT ( p b 0.05) to levels similar to those found in controls. Kirkegaard and 80 Baseline TT4 and FT4I from 119 23 to Faber (1981) 112 27 ( p b 0.01) and from 116 37 to 103 26 ( p b 0.001) after ECT treatment respectively. Whybrow et al. 30 Significant in FT4I within the first week (1972) of treatment in both groups, those receiving T3 ( p b 0.05) and those receiving placebo ( p b 0.01). Fava et al. 200 No significant association was observed (1995) between T4 and the degree of clinical response to fluoxetine. Joffe and Singer 16 Phenalzine treatment was not associated (1987) with significant change in thyroid indices (baseline FT4I 33.8 6.5, post phenalzine 33.5 8.8). = decrease, = increase, AD = antidepressant, CBT = cognitive behavioral therapy, DMI = desipramine , ECT = electroconvulsive therapy, TT4 = total T4, FT4 = free T4, FT4I = free thyroxin index , HDRS = Hamilton Depression Rating Scale, MDD = major depressive disorder, TCA = tricyclic antidepressant, Tx. = treatment.

inpatient vs. outpatient status, nor unipolar vs. bipolar diagnosis was evaluated in these studies. It is unclear if this clinical observation of an activated HPT axis represents a primary pathological disturbance of depression (Joffe and Sokolov, 1994) or a compensatory homeostatic response (Bauer and Whybrow, 1988). Several lines of evidence support both arguments. Activation of the HPT axis in depression as exemplified by increased levels of CSF TRH (Banki et al., 1988; Kirkegaard et al., 1979), blunted TRH stimulation test (Duval et al., 1990; Kirkegaard and Faber, 1991; Baumgartner et al., 1988; Wahby et al., 1988; Langer et al., 1986), relative increases in T4 indices or transient hyperthyroxinemia (Duval et al., 1999; Kirkegaard and Faber, 1991; Baumgartner et al., 1988; Wahby et al., 1988; Langer et al., 1986), successful augmentation with tri-iodothyronine (T3), thereby decreasing serum T4 indices (Prange et al., 1969; Wilson et al., 1970, 1974; Coppen et al., 1972; Wheatley, 1972; Feighner et al., 1972), and antidepressant response to the antithyroid drug methamizole in refractory patients (Joffe et al., 1992), all suggest activation of the HPT axis as a primary pathological disturbance of depression. Conversely, low cerebrospinal fluid (CSF) TRH (Marangell et al., 1997), exaggerated TSH response to TRH stimulation (Gold et al., 1977; Amsterdam et al., 1996), low CSF transthyretin (Hatterer et al., 1993; Sullivan et al., 1999, 2006), and successful augmentation with thyroxine (T4) (Stancer and Persad, 1982; Leibow, 1983; Bauer and Whybrow, 1990; Hurowitz and Liebowitz, 1993; Baumgartner et al., 1994; Rudas et al., 1999) all favor hyperactivity of the HPT axis as a compensatory homeostatic mechanism. This retrospective study was conducted to evaluate thyroid function and its relationship to time to treatment response as represented by hospital length of stay (HLOS). In addition to evaluating whether relative activation of the HPT axis is indicative of rapidity of treatment response (i.e. HLOS), this study focused on possible gender differences. This is particularly relevant in this population given the higher prevalence rate of both unipolar depression (Kessler et al., 1994) and thyroid illness (Larsen, 1982) in women vs. men. Furthermore, gender differences in CSF TRH (Frye et al., 1999), thyroid correlates of mood severity (Frye et al., submitted for publication), and the clinical utility of thyroid supplementation in affective disorder (reviewed by MacQueen and Joffe, 2002), all have been reported. Additionally, Altshuler et al. (2001) published a metaanalysis on data examining T3 acceleration of antidepressant medication and concluded that depressed women may be more likely to benefit from the addition of T3 than depressed men.

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1. Method A waiver for human subject was obtained for this retrospective study from the UCLA Institutional Review Board. As this was a retrospective study of time to treatment response for depression as represented by hospital length of stay (HLOS), the choice of primary medication treatment and general clinical management was made by the treating physician and was not part of this investigation. The medical records of 200 patients, aged 1845, discharged from the UCLA Neuropsychiatric Institute between January 1 1988 and December 31 1992 with a diagnosis of unipolar or bipolar depression were identified. The primary retrospective outcome measure was HLOS. Multiple exclusions to data analysis were set a priori to maximize the ability for HLOS to represent antidepressant response time. The time period was chosen to reflect a period of low managed care penetrance, thereby decreasing potential external confounds of hospital length of stay (HLOS). The age group was also chosen to further exclude the potential confound of perimenopause- and postmenopause-associated thyroid perturbation. Other exclusion criteria viewed as potential confounds to artificially attenuated or prolonged hospital length of stay were: premature hospital discharge (i.e. discharge against medical advice or transfer to another facility), direct transfer from an outside hospital, treatment of an acute concomitant medical illness, pregnancy, and active alcohol or drug abuse. Blind to diagnosis, treatment, thyroid admission data and HLOS, one investigator (MAF) measured clinical improvement at time of discharge as measured by the Clinical Global Impression; only those patients who were discharged with a very much improved or much improved on the depression rating were included in the sample. This left a group of 83 patients (27 men, 56 women). Admission thyroid function tests included thyroidstimulating hormone (TSH), free thyroxine index (FT4I), and total T3. All assays were completed by electrochemiluminescence immunoassay (Roche Diagnostics Corporation). FT4I is a general screening assay estimate of free T4 based on total T4 and T3 resin uptake, and in contrast to total T4, controls for possible fluctuations in binding globulins (i.e. menopause, malnutrition, liver failure, steroid treatment; Braunwald, 1987). As not all thyroid function tests were routinely completed, the demographic data were analyzed only for those patients who had a FT4 index at the time of admission (n = 50, 18 M/32 F). Demographic information obtained from the discharge summary included gender, age, discharge diagnosis,

hospital length of stay (days), length of index episode, number of prior antidepressant trials, presence of suicidality or psychosis, duration of illness, age of illness onset, and prior number of hospitalizations. Medications at the time of hospitalization, as recorded by class, were: selective serotonin reuptake inhibitor (1 M/5 F), tricyclic antidepressant (2 M/6 F), monoamine oxidase inhibitor (0 M/3 F), bupropion (1 M/4 F), venlafaxine (1 M/1 F), mood stabilizing agents such as lithium, carbamazepine, or divalproex sodium (1 M/7 F), benzodiazepine (3 M/9 F), and neuroleptics (1 M/4 F). 14/18 (77%) of men and 19/32 (59%) of women were medication-free at the time of hospital admission. Dose and duration of each treatment were not systematically recorded. The primary treatment intervention during the hospitalization was also recorded: selective serotonin reuptake inhibitor (5 M/9 F), tricyclic antidepressant, (2 M/11 F), monoamine oxidase inhibitor (3 M/2 F), bupropion (0 M/1 F), venlafaxine (3 M/9 F), moodstabilizing agent (3 M/1 F), benzodiazepine (2 M/3 F), and neuroleptic (0 M/6 F). Again, dose and duration of treatment were not recorded. 2. Statistical analysis The thyroid data were harvested and log transformed to achieve approximate normality of distribution. Similarly, a number of demographic variables (see Table 2) were square root transformed for analysis to correct positive skew. The mean standard deviation for each variable is reported. Because of the small sample size in each of the medication categories, statistical analyses on class of medication at admission or primary treatment intervention were not conducted. Gender differences in demographic and thyroid data were analyzed by 2 and t-tests. Time to improvement was analyzed using survival models. Accelerated failure time regression models were utilized with log of hospital length of stay (HLOS) as the dependent variable (SAS LIFEREG, Allison, 1995). Separate analyses were done using log TSH, log free T4I, and log T3 as independent variables. All of these analyses were adjusted for age
Table 2 Admission thyroid function data a, b Thyroid function FT4I, N = 50 Total T3, N = 45 TSH, N = 75 Men 9.6 1.7 132.7 30.2 1.67 0.68 Women 9.9 3.9 130.6 40.6 2.12 1.8 t = 0.69, p = 0.69 t = 0.87, p = 0.87 t = 0.12, p = 0.12

a Reference range: UCLA Clinical Laboratories FT4I = 511, TSH = 0.34.7 mIU/L, total T3 = 75175 ng/dL. b Similar results, not reported, on medication-free admissions.

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and date of hospital discharge within the 5-year study period (to control for any secular trends affecting HLOS during the study period). To control for medication possibly affecting thyroid function, a second set of analyses were conducted using only those patients who were medication-free at the time of admission. Fig. 1 is based on linear regression of log FT4I on log HLOS, adjusting for age and date of discharge. Chisquare (2) statistics from accelerated failure time survival regression with the same covariates (SAS LIFEREG) are also reported. To summarize the survival regression data in a more clinically meaningful way, the sample was stratified by gender and median FT4I into 4 groups (high FT4I men, low FT4I men, high FT4I women, and low FT4I women). KaplanMeier survival analysis was then completed within each of these four groups to estimate the mean HLOS and its standard error. 3. Results The demographic data of those patients who had admission FT4I data includes 18 males (17 unipolar depression and 1 BP depression) age 32.4 7.75 years and 32 females (26 unipolar depression and 6 BP depression), age 32.8 8.44 years. There was no significant difference by gender except for hospital length of stay (HLOS), which was shorter in men vs.

women (11.83 6.46 days vs. 17.56 9.91 days). There was no significant difference in the percentage of patients who were medication-free at the time of admission (men: 14/18 or 77%; women: 19/32 or 59%, 2 = 0.61, p = 0.44). As presented in Table 2, there were no significant gender differences in absolute values of admission free T4 index (FT4I), total T3, or TSH. Similar results were obtained from analyzing only patients who were medication-free at time of admission. Survival regression modeling including gender and each thyroid function revealed a significant interaction between gender and log FT 4 I ( 2 = 8.30, df = 1, p = 0.004). As presented in Fig. 1, separate gender analyses revealed an inverse relationship between FT4I and HLOS in men ( = 1.86 0.25, 2 = 17.78, df = 1, p = 0.0001) but not in women ( = 0.06 0.25, 2 = 0.06, p = 0.81). Survival regression modeling showed no significant interaction by gender for either TSH or T3; thus, these models were estimated without the interaction by gender. Neither TSH (2 = 0.08, df = 1, p = 0.78) nor T3 (2 = 1.23, df = 1, p = 0.27) had a significant association with HLOS. In a smaller medication-free sample (figure not presented), a similar inverse relationship was observed between FT4I and hospital length of stay in men (2 = 26.81, df = 1, p = 0.0001), but not in women (2 = 0.81, p = 0.37). The mean HLOS values were calculated stratified by gender and median FT4I. The four cells were: relatively high FT4I male HLOS = 9.3 days (n = 12, S.E. = 1.1); relatively high FT4I female HLOS = 16.8 days (n = 13, S.E. = 2.2); relatively low FT4I male HLOS = 17.5 days (n = 6, S.E. = 3.4); and relatively low FT4I female HLOS = 16.8 days (n = 19, S.E. = 1.5). The mean HLOS or time to improvement was approximately 50% shorter in men with a relatively high FT4I in comparison to the other three groups. 4. Discussion Despite the lack of difference in absolute mean FT4I level by gender, these data suggest that men who have a relatively elevated FT4 Index are more likely than men with a relatively low FT4 index or women regardless of FT4I index to have a faster time to antidepressant treatment response as represented by hospital length of stay. The difference in hospital length of stay (9.3 vs. 16.8 17.5 days) suggests a faster or accelerated treatment response. This study is consistent with the previous seminal observation by Whybrow et al. (1972) where noniodothyronine measures of thyroid function (faster ankle reflex time and lower serum cholesterol) highly correlated with treatment response to imipramine for unipolar

Fig. 1. FT4I and HLOS in major depression. Figures are based on linear regression analyses of log FT4I on log HLOS using residuals adjusted for age and date of discharge. 2 statistics are based on accelerated failure time regression analyses with the same covariates (men: = 1.86 0.25, 2 = 17.78, df = 1, p = 0.0001; women: = 0.06 0.25, 2 = 0.06, p = 0.81). Labels on the axes are antilogs, and thus display the original scales (intervals become increasingly wide as the numbers increase in value).

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depression. These data further suggest that this relative thyroid activation and associated shorter length of hospitalization is not specific for a particular type of treatment as previously studied in patients treated with carbamazepine, tricyclic antidepressants, thyroid augmentation, and cognitive psychotherapy, but is a more broadly based indicator of rapidity of treatment response. Research data has also suggested that the baseline free T4 index can predict time to remission. In a study of 65 outpatients with bipolar depression who received standardized antidepressant treatment by Cole et al. (2002), low free T4 index was associated with a slower response to treatment (i.e., longer time to remission). Those individuals who had had FT4I above the reported mean achieved remission 4 months earlier than those with a FT4I below the mean. Although exclusively a bipolar sample, this observation is similar to ours and suggests that free T4 index can be viewed as a marker for both rapidity of acute response and remission in patients with depression. This study has several limitations including most importantly, the retrospective design of a medical chart review and treatment response with no control group. Second, diagnostic heterogeneity (bipolar and unipolar patients), lack of structured diagnostic interview using operationalized criteria for depression and any associated Axis I, II or III comorbidity, and unknown socioeconomic status may limit the conclusions that can be made regarding this study. Third, the treatment intervention was uncontrolled based on clinical assessment rather than random or standardized assignment, with no measure of dosage or treatment adequacy. In addition, patients on lithium or antipsychotics (which could have caused thyroid disturbance) were not independently analyzed due to the small number. However, despite this latter limitation, the same inverse relationship between FT4 Index and HLOS was observed in patients who were medication-free at admission. A final limitation is that a comprehensive assessment of thyroid function (i.e. free T3 and T4, sex and thyroid binding globulin, thyroid antibodies, TRH neuroendocrine challenge) was not obtained. Our finding of a free T4 index-associated differential time to response based on gender is, to our knowledge, unique. Few studies have evaluated thyroid function in depression comparing gender. In a separate study of iodothyronines and depression severity by Frye et al. (submitted for publication), multiple T4 indices were highly correlated to depression severity in men but not in women. These preliminary observations would suggest that men, but not women, may be able to more effectively mobilize thyroid reserve in depression (i.e. a stronger correlation to severity of depression) and that this mobilization may be associated with an accelerated treatment

response. This is particularly relevant given the recent meta-analysis of thyroid supplementation accelerating tricyclic antidepressant response. In this review by Altshuler et al. (2001), the effect size of T3 acceleration increased as the percentage of women participating in each of the 6 controlled studies increased. This difference may be related to a biological difference in thyroid function in general or specifically in mood disorders. One final factor that could have contributed to the differential time course of treatment response by gender is the possibility that men and women are treated differently for depression. The sample size is too small in this study to make any conclusions about different medication and treatment response. However, in a controlled evaluation of sertraline vs. imipramine for patients with unipolar depression, women were more likely than men to respond to sertraline and men were more likely than women to respond to imipramine (Kornstein et al., 2000). Furthermore, the time to response for women who were randomized to imipramine was longer than men. In our small study, more women were treated with a tricyclic antidepressant than men; this may explain the longer length of hospitalization for women, but does not explain the lack of thyroid correlation. These data suggest that in men there is a relationship between thyroid function at admission and rapidity of treatment response for depression as measured by hospital length of stay. The non-specific measure of hospital length of stay and the previous reports of a similar T4 relationship and response to carbamazepine (Roy-Byrne et al., 1984), tricyclic antidepressants (Rao et al., 1996; Joffe and Singer, 1990), cognitive psychotherapy (Joffe et al., 1996), and T3 augmentation to desipramine (Sokolov et al., 1997) suggest that this is not a relationship related to drug mechanism per se, but rather to depression. Given these results, it might be clinically relevant to check free T4 in addition to the routine check of TSH upon admission and to utilize thyroid augmentation strategies perhaps more in women with depression. Prospective study is encouraged to clarify the significance of thyroid axis overdrive, potential gender difference in ability to mobilize thyroid reserve in depression, and whether thyroid supplementation (T3 or T4) can attenuate this difference to enhance the treatment response in depression. References
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