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Research Paper
Article de recherche
Peripheral thyroid hormones and response
to selective serotonin reuptake inhibitors
Michael Gitlin, MD; Lori L. Altshuler, MD; Mark A. Frye, MD; Rita Suri, MD;
Emily L. Huynh, BA; Lynn Fairbanks, PhD; Michael Bauer, MD; Stanley Korenman, MD
Gitlin, Altshuler, Frye, Suri, Huynh, Fairbanks, Bauer — Department of Psychiatry; Korenman — Department of
Endocrinology, UCLA School of Medicine, Los Angeles, Calif.
Objective: To examine the relation between baseline measurements of thyroid function and response to
selective serotonin reuptake inhibitors (SSRIs) and to consider the effect of these antidepressants on thyroid hormone levels. Methods: Nineteen subjects with major depression, but without a history of thyroid
treatment or lithium treatment, were treated openly with either sertraline or fluoxetine in a universityaffiliated tertiary care hospital. Hamilton Depression Rating Scale (Ham-D) scores were measured before
and after treatment. Clinical Global Impressions (CGI) scores were measured at study end. Thyroid data,
consisting of values for thyroid-stimulating hormone (TSH), triiodothyronine (T3, measured by radioimmunoassay [RIA]), thyroxine (T4, measured by RIA) and free T4, were collected before and after treatment.
Complete thyroid data were available for 17 subjects. Data were collected during 1997–1999. Results:
Baseline TSH correlated strongly with response to treatment as measured by change in Ham-D scores (r =
0.64, p = 0.003). Low TSH values correlated with greater improvement in depressive symptoms. Thyroid
hormone levels decreased with treatment, but these decreases did not correlate with clinical improvement. Conclusion: Baseline thyroid function, as measured by serum TSH, may predict a patient’s response
to antidepressant treatment with SSRIs. Optimal thyroid function, beyond simply being within the normal
laboratory values, may be necessary for an optimal response to antidepressants.
Objectif : Étudier le lien entre les mesures de base de la fonction thyroïdienne et la réponse aux inhibiteurs
spécifiques du recaptage de la sérotonine (ISRS), ainsi que l’effet de ces antidépresseurs sur les concentrations
d’hormone thyroïdienne. Méthodes : On a traité ouvertement à la sertraline ou à la fluoxétine 19 sujets atteints de dépression grave, mais qui n’avaient pas d’antécédents de traitement thyroïdien ou de traitement au
lithium, dans un hôpital de soins tertiaires affilié à une université. On a mesuré les scores selon l’échelle de dépression de Hamilton (HDRS) avant et après le traitement. On a mesuré les scores d’impression clinique globale à la fin de l’étude. On a recueilli, avant et après le traitement, des données sur la thyroïde, c.-à-d. des
valeurs pour la thyréostimuline (TSH), la triiodothyronine (T3) (mesurée par dosage radio-immunologique
[DRI]), la thyroxine (T4) (mesurée par DRI) et la T4 libre. On disposait de données complètes sur la thyroïde
pour 17 sujets. Les données ont été recueillies pour la période de 1997 à 1999. Résultats : On a établi un lien
solide entre la TSH de référence et la réponse au traitement mesurée par le changement des scores de la
HDRS (r = 0,64, p = 0,003). On a établi un lien entre de faibles valeurs de TSH et une plus grande amélioration
des symptômes de dépression. Les concentrations d’hormone thyroïdienne ont diminué avec le traitement,
mais il n’y avait pas de lien entre ces diminutions et l’amélioration clinique. Conclusion : La fonction thyroïdienne de référence mesurée par la concentration sérique de TSH peut permettre de prédire la réponse d’un
patient au traitement aux antidépresseurs, soit aux ISRS. Il se peut que la fonction thyroïdienne doive être optimale, outre se situer simplement dans la plage des valeurs normales de laboratoire, pour qu’il y ait réponse optimale aux antidépresseurs.
Correspondence to: Dr. Michael Gitlin, 300 UCLA Medical Plaza, Ste. 2200, Los Angeles, CA 90095; fax 310 206-4310;
[email protected]
Medical subject headings: depression; serotonin uptake inhibitors; thyroid hormones; thyrotropin; thyroxine; triiodothyronine.
J Psychiatry Neurosci 2004;29(5):383-6.
Submitted Mar. 6, 2003; Revised Aug. 26, 2003; Accepted Sept. 22, 2003
© 2004 Canadian Medical Association
J Psychiatry Neurosci 2004;29(5)
383
Gitlin et al
Introduction
There has long been an interest in the relation between
thyroid function and the course of a depressive
episode. As part of that interest, many studies have
evaluated both the predictive value of baseline thyroid
indices and subsequent response to antidepressant
treatment, as well as the change in these indices with
treatment.1–5 Up to 10% of individuals with depression
may present with elevated levels of thyroid-stimulating
hormone (TSH) and normal thyroxine (T4) and triiodothyronine (T3) levels (subclinical hypothyroidism).6,7
The clinical impact of an elevated TSH level is still unclear, but preliminary evidence suggests that it may
predict a poor response to antidepressants.7
With antidepressant treatment, the most common
change in thyroid hormones is a decrease in T4 and free
T4 without a significant reduction in TSH.2,5 Of note,
these changes are generally within the euthyroid range
of values. Some studies have shown that responders to
antidepressants show a greater decrease in T4 levels
compared with nonresponders.8,9
In this study, we explored these 2 areas by examining, first, the relation between baseline thyroid hormones and the clinical antidepressant response to selective serotonin reuptake inhibitors (SSRIs) and,
second, the change in thyroid hormone levels with
SSRI treatment.
Methods
All subjects in the current study were recruited from a
larger study of the dosing and efficacy of fluoxetine
versus sertraline in the treatment of major depression.10
Subjects who agreed to have their peripheral thyroid
hormones assayed before and after treatment with the
SSRI gave written informed consent and were included
in the current study. Nineteen subjects form the sample
described in this report. Inclusion criteria were a current diagnosis of major depressive episode, as defined
in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition,11 and age between 18 and 60 years.
The diagnosis was made by a structured interview
with trained raters. Exclusion criteria were as follows:
1) a history of substance abuse within the last 30 days;
2) current or recent treatment with an antidepressant;
3) history of previous manias or hypomanias; 4) previous failure of treatment with fluoxetine or sertraline;
and 5) a history of thyroid disease or current treatment
384
with thyroid hormones. No patient was treated with
lithium before study entry.
At study entry, baseline clinical assessments included the 21-item Hamilton Depression Rating Scale
(Ham-D)12 and the Clinical Global Impressions (CGI)
Severity of Illness and Global Improvement scales.13
Subjects were then treated with sertraline, 50 mg daily
(n = 8), sertraline, 100 mg daily (n = 4), or fluoxetine,
20 mg daily (n = 7), with medication and dose assigned alternately, that is, patient 1 received sertraline,
50 mg, patient 2, sertraline, 100 mg, and patient 3,
fluoxetine, but openly. At 6 weeks, subjects with a
Ham-D score above 7 and a CGI Global Improvement
score above 1 (less than “marked improvement”) had
their daily doses increased to sertraline, 100 mg daily,
sertraline, 200 mg daily, or fluoxetine, 40 mg daily, respectively. Total treatment time was 10 weeks. Although subjects were assessed every 2 weeks for
10 weeks, in this report, only the final CGI scores (both
severity and improvement subscales) and Ham-D will
be considered. Ham-D scores were assessed by research assistants and physicians who all had previous
rating training.
At baseline, thyroid indices were measured using
standard venipuncture techniques: TSH was assessed
using solid-phase immunoradiometric assay, T4 by radioimmunoassay (RIA), T3 by RIA and free T4 by rabbit
anti-T4 antibody (Diagnostic Products Kit). For all assays, the intra-assay and interassay variation were less
than 10%. Thyroid tests were batch run. At the end
of the study, the same thyroid indices were measured
again. Two subjects did not complete the posttreatment thyroid measurements. Our sample, therefore, includes 19 subjects at baseline (12 on sertraline
and 7 on fluoxetine) and post-treatment clinical evaluation, of whom 17 underwent thyroid evaluations both
before and after treatment.
Hormone levels were screened for distributional
properties and determined to be appropriate for parametric analysis. Paired t tests were used to evaluate
changes in levels of TSH, T4, T3 and free T4 before and
after treatment for the 17 patients with values from
both time points. Response to treatment was measured
by the change in Ham-D scores from before and after
treatment, with positive values reflecting improvement
in Ham-D symptoms. A stepwise regression analysis
was used to predict improvement in Ham-D scores,
with baseline values for TSH, T4, T3 and free T4 as the
independent variables (n = 19).
Rev Psychiatr Neurosci 2004;29(5)
Thyroid status and antidepressant response
The 19 subjects were 10 women and 9 men, with a
mean age of 37.6 (standard deviation [SD] 9, range
27–58) years. Four subjects had a high school education
or less, 10 were college graduates and 5 had graduate
school experience. The mean Ham-D score was 20.7
(SD 1, range 14–31). After treatment, the mean Ham-D
score was 7.8 (SD 1.4, range 0–18). Thyroid values at
baseline and after treatment for the 17 subjects with
complete data are shown in Table 1. There was a slight
increase in TSH and a decrease in T4, T3 and free T4
after treatment. These differences were statistically
significant for T4 and T3, but not for free T4 or TSH.
Changes in Ham-D scores did not correlate significantly with changes in thyroid hormone values.
The patients’ condition improved by an average of
12.9 points on the Ham-D scale (range –1 to 31) after
treatment. The degree of improvement was related significantly to baseline TSH levels (r = 0.64, p = 0.003),
with low baseline TSH predicting a greater decline in
Ham-D scores (Fig. 1). This relation held even after
controlling for initial Ham-D scores. However, this relation was not seen when dividing the sample into subjects with remitting depression (Ham-D score < 8) versus subjects with nonremitting depression (Ham-D
score > 8) (t17 = –1.06, p = 0.31). None of the other baseline thyroid indices added significantly to the prediction of response to treatment when correlations and
t tests for subjects with remitting depression versus
those with nonremitting depression were examined.
response to SSRI antidepressants. The relation was not
seen, however, when the sample was split into subjects
with remitting depression versus subjects with nonremitting depression.
The small number of subjects studied is a major limitation of the study and suggests the need for caution in
the interpretation of our results. Insufficient statistical
power because of the small number of subjects might
explain some of the negative results seen. Another limitation of the study is the use of 2 SSRIs that, although
similar, may have had different effects on and relations
to thyroid measures. A third study limitation is the
lack of placebo controls, which may have contributed
to inflated response rates.
The association between a lower baseline TSH and
greater improvement in depressive symptoms is compatible with a small, but consistent, literature that suggests a relation between thyroid indices and clinical response. In the most recent study, Cole et al14 found that
a lower baseline free T4 index and a higher TSH value
Improvement in Ham-D score,
no. of points
Results
35
30
r = –0.64
p = 0.003
25
20
15
10
5
0
-5
Discussion
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Baseline TSH, mU/L
The results of this study suggest that a more active
hypothalamic–pituitary–thyroid system, as measured
by a lower serum TSH value, is associated with a better
Fig. 1: Correlation of improvement in Hamilton Depression Rating Scale (Ham-D) scores with low baseline
thyroid-stimulating hormone (TSH) values.
Table 1: Thyroid values of study subjects (n = 17) before and after
antidepressant treatment
Mean test value (and SD)
Thyroid test
TSH, mU/L
T3 (RIA), nmol/L
T4 (RIA), nmol/L
Free T4, pmol/L
Before
treatment
1.23
1.58
95.88
19.18
(0.17)
(0.10)
(7.34)
(0.90)
After
treatment
1.51
1.41
78.50
16.99
(0.29)
(0.07)
(5.28)
(0.77)
Statistical analysis
t-test
value*
df
p value
–1.54
2.15
2.53
1.78
16
16
16
16
0.14
0.05
0.02
0.09
Note: df = degrees of freedom; RIA = radioimmunoassay; SD = standard deviation; T3 = triiodothyronine; T4 =
thyroxine; TSH = thyroid-stimulating hormone.
*Paired t test.
J Psychiatry Neurosci 2004;29(5)
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Gitlin et al
were significantly associated with a poorer response to
treatment of bipolar depression. No other variables,
whether demographic, clinical or treatment with
lithium, explained this association. Similarly, Sane et al15
found a higher free T4 index was associated with a
shorter length of stay in hospital (as a measure of response to antidepressant treatment) in men who had
been admitted to hospital with major depression.
Furthermore, in this study, changes in peripheral
thyroid hormone levels decreased with antidepressant
treatment. The reduction in peripheral thyroid indices
after antidepressant treatment is also consistent with
most, but not all, previous studies.1,5 As noted here, the
lack of statistical significance for the changes in free T4
may reflect the small sample in our study.
Few studies have evaluated the association between
SSRI treatment for depression and changes in thyroid
indices. Shelton et al16 found no significant changes in
TSH or total T4 with fluoxetine treatment but found an
association between the decline in T3 levels and response to fluoxetine. König et al17 found an 11% decrease in thyroxine levels with paroxetine treatment.
As in other studies, we found that changes in TSH values after antidepressant treatment were less consistent
than those of T3 and T4.
In summary, the results of our study suggest that
more active thyroid function, even within the normal
range as measured by TSH values, may predict the response to therapy with SSRIs.
Presented at the 153rd annual meeting of the American Psychiatric Association in Chicago on May 13–18, 2000.
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Joffe RT, Sokolov STH. Thyroid hormones, the brain, and affective disorders. Crit Rev Neurobiol 1994;8(1/2):45-63.
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Gold MS, Pottash AC, Mueller EAN, Extein I. Grades of thyroid failure in 100 depressed and anergic inpatients. Am J Psychiatry 1981;138:253-5.
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Joffe RT, Levitt AJ. Major depression and subclinical (Grade 2)
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American Psychiatric Association. Diagnostic and Statistical
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Cole DP, Thase ME, Mallinger AG, Soares JC, Luther JF,
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Psychiatry 2002;159:116-21.
15.
Sane NS, Frye MA, Kiriakos LR, Cossolino A, Altshuler LL,
Mehra V, et al. Serum-free T4 and shorter hospital length of
stay in depressed male patients [presentation]. American Psychiatric Association annual meeting; 2001 May 5–10; New Orleans (LA).
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Shelton C, Winn S, Ekhatore N, Loosen P. The effects of antidepressants on the thyroid axis in depression. Biol Psychiatry
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König F, Hauger B, von Hippel C, Wolfersdorf M, Kaschka
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Acknowledgement: This study was supported in part by a grant
from Eli Lilly and Company.
Competing interests: None declared for Dr. Frye, Ms. Huynh, Dr.
Fairbanks and Dr. Korenman. Dr. Gitlin is in the speaker’s bureau for
Eli Lilly and Pfizer. Dr. Altshuler has been a consultant for, has received honoraria from and sits on the advisory boards of Abbott,
Bristol-Myers Squibb, Eli Lilly, Forest Laboratories and Janssen. She
has received grant/research support from Abbott, Eli Lilly and Forest Laboratories and is in the speaker’s bureau of Abbott. Dr. Suri has
received an honorarium for a speaking engagement with Pfizer. Dr.
Bauer has received travel assistance from Eli Lilly and GlaxoSmithKline.
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