J Psychiatry Neurosci 2004;29(5)
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 thy-
roid 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 university-
affiliated 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 radioim-
munoassay [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 improve-
ment. 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 at-
teints 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 dé-
pression de Hamilton (HDRS) avant et après le traitement. On a mesuré les scores d’impression clinique glo-
bale 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 T4libre. 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 thyroï-
dienne 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 opti-
male, outre se situer simplement dans la plage des valeurs normales de laboratoire, pour qu’il y ait réponse op-
timale aux antidépresseurs.
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.
Correspondence to: Dr. Michael Gitlin, 300 UCLA Medical Plaza, Ste. 2200, Los Angeles, CA 90095; fax 310 206-4310;
J Psychiatry Neurosci 2004;29(5):383-6.
Medical subject headings: depression; serotonin uptake inhibitors; thyroid hormones; thyrotropin; thyroxine; triiodothyronine.
Submitted Mar. 6, 2003; Revised Aug. 26, 2003; Accepted Sept. 22, 2003
© 2004 Canadian Medical Association
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.1–5Up to 10% of individuals with depression
may present with elevated levels of thyroid-stimulating
hormone (TSH) and normal thyroxine (T4) and tri-
iodothyronine (T3) levels (subclinical hypothyroidism).6,7
The clinical impact of an elevated TSH level is still un-
clear, 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 T4and free
T4without a significant reduction in TSH.2,5Of note,
these changes are generally within the euthyroid range
of values. Some studies have shown that responders to
antidepressants show a greater decrease in T4levels
compared with nonresponders.8,9
In this study, we explored these 2 areas by examin-
ing, first, the relation between baseline thyroid hor-
mones and the clinical antidepressant response to se-
lective serotonin reuptake inhibitors (SSRIs) and,
second, the change in thyroid hormone levels with
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 cur-
rent diagnosis of major depressive episode, as defined
in the Diagnostic and Statistical Manual of Mental Disor-
ders, fourth edition,11and 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) previ-
ous failure of treatment with fluoxetine or sertraline;
and 5) a history of thyroid disease or current treatment
with thyroid hormones. No patient was treated with
lithium before study entry.
At study entry, baseline clinical assessments in-
cluded the 21-item Hamilton Depression Rating Scale
(Ham-D)12and 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 as-
signed 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, re-
spectively. Total treatment time was 10 weeks. Al-
though 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 re-
search assistants and physicians who all had previous
At baseline, thyroid indices were measured using
standard venipuncture techniques: TSH was assessed
using solid-phase immunoradiometric assay, T4by ra-
dioimmunoassay (RIA), T3by RIA and free T4by rabbit
anti-T4antibody (Diagnostic Products Kit). For all as-
says, 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 post-
treatment thyroid measurements. Our sample, there-
fore, includes 19 subjects at baseline (12 on sertraline
and 7 on fluoxetine) and post-treatment clinical evalua-
tion, of whom 17 underwent thyroid evaluations both
before and after treatment.
Hormone levels were screened for distributional
properties and determined to be appropriate for para-
metric analysis. Paired t tests were used to evaluate
changes in levels of TSH, T4, T3and free T4before 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, T3and free T4as the
independent variables (n = 19).
Gitlin et al
Rev Psychiatr Neurosci 2004;29(5)
Thyroid status and antidepressant response
J Psychiatry Neurosci 2004;29(5)
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, T3and free T4
after treatment. These differences were statistically
significant for T4and T3, but not for free T4or TSH.
Changes in Ham-D scores did not correlate signifi-
cantly 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 sig-
nificantly 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 re-
lation was not seen when dividing the sample into sub-
jects with remitting depression (Ham-D score < 8) ver-
sus subjects with nonremitting depression (Ham-D
score > 8) (t17= –1.06, p = 0.31). None of the other base-
line thyroid indices added significantly to the pre-
diction of response to treatment when correlations and
t tests for subjects with remitting depression versus
those with nonremitting depression were examined.
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
response to SSRI antidepressants. The relation was not
seen, however, when the sample was split into subjects
with remitting depression versus subjects with non-
The small number of subjects studied is a major limi-
tation 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 lim-
itation 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 com-
patible with a small, but consistent, literature that sug-
gests a relation between thyroid indices and clinical re-
sponse. In the most recent study, Cole et al14found that
a lower baseline free T4index and a higher TSH value
Baseline TSH, mU/L
0.00.51.0 1.52.0 2.53.0 3.5
r = –0.64
p = 0.003
Improvement in Ham-D score,
no. of points
Fig. 1: Correlation of improvement in Hamilton Depres-
sion 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
Mean test value (and SD)Statistical analysis
T3 (RIA), nmol/L
T4 (RIA), nmol/L
Free T4, pmol/L
Note: df = degrees of freedom; RIA = radioimmunoassay; SD = standard deviation; T3 = triiodothyronine; T4 =
thyroxine; TSH = thyroid-stimulating hormone.
*Paired t test.
were significantly associated with a poorer response to Download full-text
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 T4index was associated with a
shorter length of stay in hospital (as a measure of re-
sponse 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.1,5As 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 al16found no significant changes in
TSH or total T4with fluoxetine treatment but found an
association between the decline in T3levels and re-
sponse to fluoxetine. König et al17found an 11% de-
crease in thyroxine levels with paroxetine treatment.
As in other studies, we found that changes in TSH val-
ues after antidepressant treatment were less consistent
than those of T3and 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 re-
sponse to therapy with SSRIs.
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Gitlin et al
Rev Psychiatr Neurosci 2004;29(5)
Presented at the 153rd annual meeting of the American Psychiatric Asso-
ciation in Chicago on May 13–18, 2000.
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 re-
ceived 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 For-
est 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 GlaxoSmith-