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ORIGINAL ARTICLE
Meta-analysis of serotonin transporter gene promoter
polymorphism (5-HTTLPR) association with selective
serotonin reuptake inhibitor efficacy in depressed patients
A Serretti
1
, M Kato
1,2
, D De Ronchi
1
and T Kinoshita
2
1
Institute of Psychiatry, University of Bologna, Bologna, Italy and
2
Department of Neuropsychiatry, Kansai Medical University,
Osaka, Japan
The serotonin transporter gene promoter polymorphism (5-HTTLPR) has been repeatedly
associated with antidepressant response in mood disorder patients, but findings are not
consistent across studies. A meta-analysis was performed on 15 studies including data of 1435
subjects. We tested three phenotypes: remission rate, response rate and response rate within
4 weeks using the cochrane review manager. We observed a significant association of the s/s
variant of 5-HTTLPR with remission rate (P < 0.0001) and both s/s and s/l variants with response
rate (P = 0.0002). Response rate within 4 weeks was associated in both models (P = 0.003–
P < 0.00001). This effect is quite robust to ethnic differences although a significant
heterogeneity is present in Asian samples.
Molecular Psychiatry (2007) 12, 247–257. doi:10.1038/sj.mp.4001926; published online 5 December 2006
Keywords: depression; meta-analysis; 5-HTTLPR; polymorphism; treatment response; SSRI
Introduction
Mood disorders have a large impact on social health,
with considerable both direct and indirect costs.
1–4
Selective serotonin reuptake inhibitors (SSRIs) treat-
ment reduced their morbidity with a favorable side
effect profile. Unfortunately, not all individuals
benefit from treatment, and 30–40% of patients do
not show a complete response to treatment.
5,6
The first step of SSRIs action is to inhibit the
serotonin transporter (5-HTT) and thus modulate the
serotonergic activity. The human gene encoding 5-
HTT is located on chromosome 17q–11.1-q12, it spans
31 kb and consists of 14 exons. Heils et al.
7
reported a
functional polymorphism in the transcriptional con-
trol region upstream of the 5-HTT coding sequence
(5-HTTLPR). Since then, this polymorphism has been
the most widely studied in psychiatric genetics for its
high number of effects.
8
Of particular interest is the
association with SSRI efficacy. Our group performed
the first studies, and tested the hypothesis that 5-
HTTLPR was related to the response to fluvoxamine
and/or augmentation with pindolol in 102 inpatients
with major depression.
9
The carriers of the long allele
showed a better response to fluvoxamine compared to
those who were homozygous for the short allelic
variant. Following this pilot study, the association
between 5-HTTLPR and response in patients with
mood disorder has been investigated by a large
number of studies, but findings are not always
consistent. Significant associations between the long
variant and a good response have been reported, but
other studies did not confirm these findings.
10,11
Meta-analysis are a powerful and useful tool to
investigate discrepant findings
12
and this method
helped also in the possible association between 5-
HTTLPR and mood disorders.
13,14
However, no article has pooled and analyzed all the
data from studies testing associations of 5-HTTLPR
with treatment response. The purpose of this study
is the reevaluation of the association between 5-
HTTLPR and clinical response to SSRIs treatment in
patients with mood disorders pooling existing studies
through a meta-analysis.
Materials and methods
To identify studies eligible for this meta-analysis, we
searched Medline for all publications available up to
July 2006 studying the association between SSRIs
treatments and 5-HTTLPR in depressive patients with
the key words affective, depression, mood, treatment
response, serotonin transporter promoter region
(SERTPR) and 5-HTTLPR. We also used reference
lists from identified articles and reviews to find
additional articles not indexed by MEDLINE. Studies
were included in the current meta-analysis if they
evaluated the association between clinical response
to SSRIs treatments and 5-HTTLPR in patients
diagnosed with major depressive disorder or bipolar
disorder according to DSM criteria. Studies were
Received 26 July 2006; revised 31 August 2006; accepted 25
September 2006; published online 5 December 2006
Correspondence: Dr A Serretti, Institute of Psychiatry, University
of Bologna, Viale Carlo Pepoli 5, 40123 Bologna, Italy.
E-mail: alessandro.serretti@unibo.it
Molecular Psychiatry (2007) 12, 247–257
&
2007 Nature Publishing Group All rights reserved 1359-4184/07
$
30.00
www.nature.com/mp
excluded from the analysis if outcome was not
evaluated as response or remission rate on a depres-
sion scale, and studies with overlapping patient
samples were excluded to only include the study
with the large number of patients. Authors were
contacted when data were not reported in the article.
Hardy–Weinberg equilibrium was examined in stu-
dies where genotype frequencies were included.
9,15–25
Given the lack of unequivocal data for 5-HTTLPR
genotype pooling, we tested both dominant and
recessive hypotheses: l/l versus l/s-s/s and l/l-l/s
versus s/s. Outcome was defined with three pheno-
types: remission rate, response rate, and response rate
within 4 weeks. Subjects with pindolol augmentation
were excluded given the observed influence of
pindolol on the 5-HTTLPR effect.
9
Remission was defined as a final Hamilton Rating
Scale for Depression (HAM-D) total score of 7 or less.
Response was defined as at least 50% decrease in
HAM-D or Montgomery and Asberg Depression
Rating Scale (MADRS) total score. In one study,
17
response was defined as a 60% or greater decrease in
MADRS. Remission is a quite robust outcome defini-
tion but response is more sensitive although quite
non-specific. Moreover, the length of evaluation of
response varied largely between studies. We therefore
investigated separately response within 4 weeks of
treatment and response at any length of observation
(2–12 weeks). We focused on the response rate within
4 weeks because it is a sensitive measure to evaluate
speed of response. Many studies presented the out-
come of 4 weeks, while only three studies presented
outcome within 2 weeks, and 6 weeks was too a long
period to investigate speed of response.
26
Remission was instead calculated at 6 weeks when
possible, and in defect of data we used different
observation lengths. When outcome data were not
available in the article, we requested data from the
author or estimated the number of response and
remission from the presented figures. Data were
entered into the Cochrane Collaboration review
manager software (RevMan version 4.2) and analyzed
by RevMan analysis 1.01. Heterogeneity between the
studies was assessed with w
2
test. Individual and
pooled odds ratio (OR) and associated 95% CIs were
calculated. A fixed-effect model was used in all
analyses. We used the fixed-effect despite a moderate
heterogeneity across studies given that we had no
a priori reason to hypothesize data coming from
different populations and because of the main aim of
the present analysis being the identification of the
best estimate of a single effect size more than the
range of effect sizes across populations.
12
Results
The literature search and selection produced 19
studies,
9,15–25,27–33
but only 15 studies were included
in current meta-analysis, as listed in Table 1. Studies
by Kraft et al.
28
and Minov et al.
30
were excluded
because they included patients treated by a mixture of
antidepressants. The paper by Lee et al.
29
was not
included because it did not use HAM-D or MADRS
but Clinical Global Impressions of Improvement (CGI)
score. The paper by Murphy et al.
31
was not included
because data were not available. Two studies
17,19
used
the DSM-III-R diagnostic criteria and all the other
studies applied the DSM-IV diagnostic criteria.
Analysis in the whole sample
Figure 1 presents ORs for the individual studies and
the pooled analyses in the l/l and l/s genotype versus
the s/s genotype subjects for the remission rate,
response rate and response rate within 4 weeks.
All studies except two showed an OR higher than 1.
The pooled OR of seven studies of remission rate
including 745 subjects was highly significant (2.21,
CI = 1.53–3.21, P < 0.0001) and there was no evidence
for heterogeneity across studies. Pooled OR of nine
studies of response rate including 944 subjects was
not significant (1.20, CI = 0.90–1.60, P = 0.21) but with
a significant heterogeneity across studies (P = 0.001).
When we considered only the five studies reporting
response rate within 4 weeks including 633 subjects
the effect of the 5-HTTLPR s/s genotype was again
significant (1.72, CI = 1.20–2.47, P = 0.003) with no
heterogeneity across studies.
We then pooled the l/l genotype versus the l/s and
s/s genotype and results were presented in Figure 2.
Pooled OR of seven studies of remission rate includ-
ing 745 subjects was 1.42 (CI = 0.98–2.04, P = 0.06)
with no heterogeneity across studies. On the other
hand, that of 10 studies of response rate including
1031 subjects was 2.01 (CI = 1.39–2.89, P = 0.0002)
with heterogeneity across studies, whereas the effect
in seven studies of response rate within 4 weeks
including 771 subjects was significant (OR = 2.57,
CI = 1.70–3.88, P < 0.00001) without heterogeneity
across studies.
To investigate whether ethnicity played a role in
confounding the association between 5-HTTLPR and
SSRIs response, we examined studies with Caucasian
and Asian subjects separately.
Analysis in Caucasian subjects
The pooled analyses and OR in the l/l and l/s
genotype versus the s/s genotype within Caucasian
subjects are presented in Figure 3. There was no
evidence for heterogeneity and all OR were higher
than 1. Pooled OR of five studies of remission rate
including 544 subjects was highly significant (2.37,
CI = 1.56–3.58, P < 0.0001), while the pooled OR of
four studies of response rate including 345 subjects
(1.53, CI = 0.90–2.59, P = 0.11) and the one of two
studies of response rate within 4 weeks including
208 subjects (1.37, CI = 0.65–2.88, P = 0.40) were not
significant, although greater than 1. Figure 4 pre-
sented the pooled analyses in the l/l genotype versus
the l/s and s/s genotype. Pooled OR of five studies
of remission rate including 544 subjects was
not significant (1.37, CI = 0.93–2.00, P = 0.11), whereas
the pooled OR of five studies of response rate
5-HTTLPR and SSRI meta-analysis
A Serretti et al
248
Molecular Psychiatry
including 432 subjects (1.74, CI = 1.10–2.76, P = 0.02)
and those of four studies of response rate within 4
weeks including 346 subjects (1.75, CI = 1.07–2.88,
P = 0.03) was significant. Overall in Caucasians, we
observed an association of the s/s genotype with
nonremission and of the s containing genotype with
nonresponse but with some reduction in the signifi-
cance possibly due to the smaller number of studies
included.
Analysis in Asian subjects
Figure 5 presented results for Asian subjects.
Pooled OR of two studies of remission rate including
201 subjects demonstrated a nonsignificant trend of
favorable response to SSRIs in the l/l or l/s genotype
carrier (1.70, CI = 0.74–3.93, P = 0.21) with no evi-
dence for heterogeneity. Pooled OR of the five studies
of response rate including 599 subjects was not
significant (1.09, CI = 0.78–1.53, P = 0.62) but with
evidence for large heterogeneity (P < 0.0001). In fact
the neutral OR of 1.09 is due to the sum of three
studies showing a worse response effect of the s/s
genotype and two studies reporting a protective effect
of the s/s genotype. However, analyzing response rate
within 4 weeks there was no evidence for hetero-
geneity across three studies including 425 subjects
Table 1 Characteristics of studies investigating the association between SSRIs treatments and 5-HTTLPR in mood disorder
patients
Reference Type of SSRIs
(dose: mg/day)
N (Male/Female) Mean age
(years)
Ethnicity Inclusion
criteria
Evaluation
Arias et al.
15
Citalopram
(20–40)
131 (31/100) 40.0 Caucasian MD Response rate: 4w
Remission rate: 12w
Durham et al.
27
Sertraline
(50–100)
106 (47/59) 69.7 Mostly
Caucasian
MD Response rate: 2, 4, 6,
8w
Remission rate: 12w
Hong et al.
16
Fluoxetine
(20–40)
224 (93/131) 44.0 Asian MD Response rate: 4w
Joyce et al.
17
Fluoxetine
(10–80)
86 (not reported) 31.8
whole group
Caucasian MD þ BPII Response rate: 6w
Kato et al.
18
Fluvoxamine
(50–150) or
paroxetine
(20–40)
80 (44/36) 43.9 Asian MD Response rate: 2, 4, 6w
Remission rate: 6w
Kim et al.
19
Fluoxetine
(20–50) or
paroxetine
(20–60)
120 (78/42) 54.2 Asian MD þ BPI, II,
dysthymia
Response rate: 6w
Kirchheiner
et al.
20
Citalopram,
fluoxetine,
fluvoxamine,
paroxetine or
sertraline
(common
doses)
77 (22/55) 44.0 Caucasian MD þ BP Response rate: 3w
Pollock et al.
32
Paroxetine
(20–30)
51 (not reported) 72.0
whole group
Caucasian MD Response rate: 2w
Rausch et al.
33
Fluoxetine
(0–40)
51 (not reported) Not reported Caucasian MD Response rate: 12w
Serretti et al.
21
Fluvoxamine
(up to 300) or
paroxetine
(up to 40)
220 (75/145) 50.6 Caucasian MD þ BP Remission rate: 6w
Smeraldi et al.
9
Fluvoxamine
(100–300)
53 (16/37) 49.0 Caucasian MD þ BP Remission rate: 6w
Yoshida et al.
22
Fluvoxamine
(50–200)
54 (22/32) 51.2 Asian MD Response rate: 6w
Yu et al.
23
Fluoxetine
(20–60)
121 (70/51) 44.7 Asian MD Response rate: 4w
Remission rate: 4w
Zanardi et al.
24
Paroxetine (40) 58 (15/43) 47.7 Caucasian MD þ BP Remission rate: 4w
Zanardi et al.
25
Fluvoxamine
(100–300)
88 (25/63) 52.0 Caucasian MD þ BP Remission rate: 6w
Abbreviations: MD, major depression; BP, bipolar disorder.
5-HTTLPR and SSRI meta-analysis
A Serretti et al
249
Molecular Psychiatry
and pooled OR was significant in the same direction
of Caucasians with the s/s genotype associated with
poor response (1.85, CI = 1.22–2.79, P = 0.004). The
alternative pooling of the l/l genotype versus the l/s
and s/s genotype are presented in Figure 6. Pooled OR
of the two studies of remission rate including 201
subjects was not significant (2.28, CI = 0.59–8.86,
P = 0.23). However, pooled OR of the five studies of
response rate including 599 was significant (2.52,
CI = 1.37–4.62, P = 0.003) with large heterogeneity,
whereas pooled OR of the three studies of response
rate within 4 weeks including 425 subjects was highly
significant (5.96, CI = 2.70–13.17, P < 0.0001) with no
heterogeneity.
Discussion
In this study, we retrieved 15 studies that included
data from 1435 subjects to evaluate the association
between 5-HTTLPR and clinical response to SSRIs
treatment in patients with mood disorders. The
results of our study indicate a significant association
between 5-HTTLPR and clinical response in both
remission rate and response rate. These findings
Figure 1 Outcome data for l/l and l/s versus s/s in remission rate, response rate and response rate within 4 weeks in the
whole sample.
5-HTTLPR and SSRI meta-analysis
A Serretti et al
250
Molecular Psychiatry
suggest that 5-HTTLPR could be a predictor of
response to SSRIs treatment.
The results also showed a more robust effect of
5-HTTLPR for remission rate when comparing the
l/l and l/s versus the s/s and for response rate when
comparing the l/l versus the l/s and s/s pooled
genotypes. Nevertheless both comparisons showed a
similar direction of effect. It is interesting to note that
the effect of 5-HTTLPR for response within 4 weeks
was the most robust and consistent in all comparisons
except one analysis in Caucasian with some reduction
in the significance due to the smaller number of
studies included. This could suggest a major effect on
speed of response of both s/s and s/l genotypes, while
only the homozygote s/s effect could influence the
overall remission rate. The dominance of 5-HTTLPR
Figure 2 Outcome data for l/l versus l/s and s/s in remission rate, response rate and response rate within 4 weeks in the
whole sample.
5-HTTLPR and SSRI meta-analysis
A Serretti et al
251
Molecular Psychiatry
has not been addressed unequivocally, even though a
dominant s allele effect has been repeatedly re-
ported
34–36
other studies did not confirm this model
37
and SNPs are usually supposed to have a codominant
effect.
38
Our results favour the view of a dominant s
effect, as indicated on response and early response.
However, the remission effect was more clear with
both s allele copies (s/s). We repeated the analysis
excluding the first published study, which may
inflate the overall estimate of effect to test for
publication bias, but the outcome was similar to
those with all together. OR in the l/l and l/s genotype
versus the s/s genotype were 2.06 (P = 0.0003) in
the whole population and 2.18 (P = 0.0005) within
Caucasian whereas that in the l/l versus l/s and s/s
genotype were 1.26 (P = 0.23) in the whole population
and 1.20 (P = 0.38) within Caucasian. Consequently,
the publication bias should have not influenced our
results.
There are several differences among the studies
included in this meta-analysis to discuss that could
explain the significant heterogeneity we observed in
some comparisons: different kind and dose of SSRIs,
different subtype of affective disorder, different
Figure 3 Outcome data for l/l and l/s versus s/s in remission rate, response rate and response rate within 4 weeks in
Caucasian subjects.
5-HTTLPR and SSRI meta-analysis
A Serretti et al
252
Molecular Psychiatry
ethnic populations, and different lengths of assess-
ment. Moreover other SNPs within the gene could be
the causal variant and this might lead to the observed
differences.
39,40
A wider list of polymorphism should
be investigated to achieve a better resolution given
that other control regions may be present for the 5-
HTT expression, not to mention possible enhancers or
silencers located in other regions far from the gene
locus. In fact, Hamilton et al.
28,41
reported a signifi-
cant association of a functional SNP (rs25531)
42,43
located just upstream of the 5-HTTLPR with anti-
depressant response to fluoxetine treatment and in
linkage disequilibrium (LD) with 5-HTTLPR. In the
presence of the g allele of this SNP, the l allele of
5-HTTLPR seems to be associated with nonresponse,
while this is the case for the s allele in presence of the
a allele of the SNP. In partial agreement, we found the
same polymorphism influencing response, although
in a different direction.
44
These effects may be one of
the sources of heterogeneity between studies.
Ethnicity and length of assessment might have also
played a role in determining the heterogeneity among
studies. Different allele frequencies between Cauca-
sians and Asians, the s allele being present in 42% of
Caucasians, but in 79% of Asians,
45
are a strong cause
of heterogeneity. In fact, when Caucasians were
analyzed separately, the heterogeneity disappeared
but it still remained when Asians were analyzed
Figure 4 Outcome data for l/l versus l/s and s/s in remission rate, response rate and response rate within 4 weeks in
Caucasian subjects.
5-HTTLPR and SSRI meta-analysis
A Serretti et al
253
Molecular Psychiatry
alone. The reason of this large amount of hetero-
geneity in Asian population could not be understood
well, however, the length of assessment could be one
of the sources. Observation length ranged from 2 to 12
weeks, this wide range mostly influences the outcome
in term of response given its lower robustness
compared to remission. In fact, there was no evidence
for heterogeneity among studies that assessed re-
sponse rate within 4 weeks both in Caucasians and in
Asians. Indeed some evidence suggest that the
association between 5-HTTLPR and treatment re-
sponse is due to acceleration, more than overall
response rate.
24,32,46
The results of our study suggest
the period of assessment could be an important factor
to evaluate the response rate, while on the other hand
the remission rate seemed less influenced by the
period of assessment because our results showed no
heterogeneity in all remission comparison. This could
be due to the fact that remission was evaluated in a
longer length of observation: only two studies within
4 weeks.
23,24
Finally, as previously discussed, a
causative SNP located nearby the 5-HTTLPR could
be the cause for association in the opposite direction
in Asians.
We used a fixed-effect model for the meta-analysis.
The two populations gene frequency differences may
not fully justify the a priori population independence,
as well as other minor methodological differences in
the studies. Moreover the discrepant Asian results
argue against a true population independence from
Figure 5 Outcome data for l/l and l/s versus s/s in remission rate, response rate and response rate within 4 weeks in Asian
subjects.
5-HTTLPR and SSRI meta-analysis
A Serretti et al
254
Molecular Psychiatry
Caucasians. Therefore, we presented the fixed-effect
model to address the best estimate of a single effect
size. However, the differences between the fixed-
effects and the random-effects models were minimal
in this analysis (data not shown).
To the best of our knowledge, our study is the first
article investigating the association of 5-HTTLPR
with response to SSRI treatment with a meta-analytic
technique. Smits et al.
11
collected and analyzed
studies about association of 5-HTTLPR with treat-
ment in depression. They result in a somewhat less
favorable effect of SSRIs among Caucasian population
with the s/s variants of the 5-HTTLPR as opposed to
those with the l/l and l/s variant and no available
evidence in Asian population. Our results were
consistent with their ones, the conceivable difference
between our study and theirs is that they analyzed a
smaller number of studies focusing on the mean
decrease in HAM-D and MADRS score. Another
partial meta-analysis has been reported but in the
context of a wider review and including only a small
part of the studies here included and with a large
heterogeneity of treatments.
47
In conclusion, our meta-analysis confirmed the
significant association of the l variant of 5-HTTLPR
with a better response to SSRIs and this effect seemed
independent from ethnic differences. The subjects
with s/s genotype have difficulties to reach remission,
Figure 6 Outcome data for l/l versus l/s and s/s in remission rate, response rate and response rate within 4 weeks in Asian
subjects.
5-HTTLPR and SSRI meta-analysis
A Serretti et al
255
Molecular Psychiatry
and take a long time, over 4 weeks, to respond as well
as the subjects with s allele take a long time to
respond. The pooled OR in this meta-analysis
resulted in up to 2.57 in all populations that seems
a moderate effect and it is in line with minor effect
genes.
48
Other genes are expected to influence this
complex trait and a comprehensive knowledge could
enable clinical use of a gene profile as predictor to
allow identification of the best therapeutic tools and
avoid lengthy treatment trials.
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