ORIGINAL ARTICLE

Reduced gray matter brain volumes are associated
with variants of the serotonin transporter gene in
major depression

T Frodl

1

, N Koutsouleris

1

, R Bottlender

1

, C Born

2

, M Ja¨ger

1

, M Mo¨rgenthaler

1

, J Scheuerecker

1

, P Zill

1

,

T Baghai

1

, C Schu¨le

1

, R Rupprecht

1

, B Bondy

1

, M Reiser

2

, H-J Mo¨ller

1

and EM Meisenzahl

1

1

Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University of Munich, Munich, Germany

and

2

Department of Radiology, Ludwig-Maximilians-University of Munich, Munich, Germany

The serotonergic system is involved in the pathophysiology of major depression as well as in
the early central nervous system development and adult neuroplasticity. The aim of the study
was to examine in 77 patients with major depression and 77 healthy controls the association
between the triallelic polymorphism in the promoter region of the serotonin transporter gene
(5-HTTLPR) and gray matter (GM) brain volumes measured with 1.5 T magnetic resonance
imaging. Voxel-based morphometry were estimated on magnetic resonance images and
genotyping was performed. We found that healthy controls have a strong association between
the 5-HTTLPR and GM volumes of the dorsolateral prefrontal cortex, left anterior gyrus cinguli,
left amygdala as well as right hippocampus, whereas there is no such association in patients
with major depression. Healthy subjects carrying the S- or L

G

-allele have smaller GM volumes

than those with the L

A

-allele, indicating that 5-HTTLPR contributes to the development of

brain structures. Patients with depression show reduced GM volumes, particularly when they
are homozygous for the L

A

-allele, suggesting that these patients are more vulnerable for

morphological changes during depressive episodes.
Molecular Psychiatry (2008) 13, 1093–1101; doi:10.1038/mp.2008.62; published online 1 July 2008

Keywords:

major depression; VBM; serotonin; imaging genetics; MRI; morphometry

Introduction

Dysfunction of neuronal plasticity could contribute to
the pathophysiology of mood disorders.

1

The under-

standing of these neuroplastic processes may offer the
possibility to define new pathology-related markers.
Such markers might be helpful to improve the
understanding of the neurobiology of major depres-
sion. Moreover, they might offer the opportunity to
obtain surrogate markers and to find new antidepres-
sants, as well as new substances, which may improve
the clinical outcome.

The neuroplasticity hypothesis of major depression

is supported by studies demonstrating that serotoner-
gic signaling is an important regulator of early central
nervous system development

2

and of adult neurogen-

esis.

3

This is supported by findings of reciprocal

regulations between the serotonergic system and
brain-derived neurotrophic factor (BDNF). Anti-
depressant treatment, which increases serotonergic
neurotransmission, for example, selective serotonin
reuptake inhibitors, and elevates BDNF in the

hippocampus and the frontal cortex,

4

has neurotrophic

effects

5

and increases hippocampal neurogenesis.

6

More-

over, serotonergic function is modulated by BDNF.

7

This hypothesis is also supported by preclinical

studies demonstrating that stress and depression lead
to reductions in total hippocampal volume, and
atrophy and loss of neurons in the adult hippocam-
pus.

8,9

Many in vivo neuroimaging studies have

detected reduced hippocampal volumes in elderly
and also in younger patients with major depression.
The results for other brain regions are rather incon-
sistent, perhaps because of problems with the exact
manual measurement of anatomical difficult brain
regions: enlarged amygdala volumes, as well as
reduced volumes of the anterior cingulum, prefrontal
cortex and basal ganglia, have been reported in only
some of the studies with regions of interest analysis.

10

Voxel-based morphometry (VBM) is extremely useful
because brain regions whose boundaries are difficult
to define can be analyzed. VBM has detected smaller
volumes of the medial frontal lobes in patients with
subthreshold depression,

11

as well as of the right

hippocampus and the middle frontal gyrus in patients
with major depression.

12

Neuroimaging genetics offer a good possibility to

combine the morphological and neurochemical as-
pects, for example, structural and serotonergic altera-
tions. Substantial relative decreases in hippocampal

Received 19 December 2007; revised 20 March 2008; accepted 12
May 2008; published online 1 July 2008

Correspondence:

Dr

T

Frodl,

Department

of

Psychiatry

and Psychotherapy Ludwig-Maximilians-University of Munich,
Nussbaumstr. 7, Munich 80336, Germany.
E-mail: [e-mail]

Molecular Psychiatry (2008) 13, 1093–1101

&

2008 Nature Publishing Group All rights reserved 1359-4184/08 $30.00

www.nature.com/mp

volume have been found in Met-carriers of the BDNF
polymorphism, in either healthy controls

13,14

or

patients with major depression.

15

Furthermore, the

L-allele of the 5-HTTLPR, which shows increased
5-HTT expression

and

increased

5-HT-reuptake

in vitro and in vivo,

16–18

is associated with hippocampal

volume reduction in major depression.

19,20

The L-allele of the 5-HTTLPR can be subtyped into

La and Lg alleles, the latter of which is thought to be
similar to the S-allele in terms of reuptake efficiency
perhaps explaining some of these discrepancies.

21

This polymorphism can then be handled as a triallelic
polymorphism. To avoid inconsistencies, we use the
term triallelic for this new polymorphism and
diallelic for the older polymorphism.

The aim of this study was to investigate the

influence of this functional triallelic 5-HTTLPR/
rs25531 on gray matter (GM) volumes of the brain in
patients with major depression and healthy controls
using voxel-based morphology. We hypothesized that,
compared to healthy controls, GM volume is particu-
larly reduced in the hippocampus, amygdala, anterior
gyrus cinguli (ACC) and the dorsolateral (DLPFC) and
dorsomedial prefrontal cortex (DMPFC) in patients
with major depression who are homozygous for the
L-allele of the 5-HTTLPR.

Materials and methods

Participants
Seventy-seven inpatients with major depression
(mean

age:

46.1±11.3

years,

Table

1)

were

recruited from the Department of Psychiatry of the
Ludwig-Maximilians-University, Munich. Psychiatric

diagnoses based on DSM-IV criteria and on the
structured clinical interview for DSM-IV (SCID)
were determined by a consensus of at least two
psychiatrists. Clinical variables were documented
using the 21-item Hamilton Depression Rating
Scale.

22

On the day of the magnetic resonance imaging,

patients were receiving the following medication: 17
patients serotonin reuptake inhibitors (7 sertraline,
7 citalopram, 2 paroxetine, 1 fluvoxamine), 8 tricyclic
antidepressants (1 amitriptyline, 2 amitriptylinoxide, 4
doxepine, 1 trimipramine), 34 other new antidepres-
sants (11 venlafaxine, 10 reboxetine, 13 mirtazapine),
2 maprotiline and 16 patients no antidepressant.

For comparison, 77 healthy control subjects were

matched with respect to age (mean age: 43.6±11.3
years), gender and handedness.

A structured interview was used to assess medical

history, trauma and other exclusion criteria for all
subjects. Exclusion criteria for patients and controls
were previous head injury with loss of consciousness,
cortisol medication in the medical history, previous
alcohol or substance abuse, neurological diseases or
age over 65 years. Comorbidity with other mental
illnesses and personality disorders were also ex-
cluded, as were patients with bipolar disorders.
Healthy controls had no history of neurological or
mental illnesses. No subject received an electrocon-
vulsive therapy before investigation. Handedness was
determined by the Edinburgh inventory.

23

Written informed consent was obtained from all

subjects subsequent to a detailed description of
the study. The study design was approved by
the local ethics committee and was prepared in

Table 1

Demographic and clinical data of patients with an episode of major depression and healthy controls

Patients (n = 77)

Controls (n = 77)

T-test

(mean±s.d.)

(mean±s.d.)

(P-value)

Age (years)

42.6±12.4

40.5±11.6

0.29

Female/male*

35/42

35/42

1.0

Handedness (R/L)*

65/12

72/5

0.07

Height (cm)

172.7±8.8

175.1±10.3

0.12

Weight (kg)

73.2±15.2

75.1±14.2

0.43

Alcohol (g day

1

)

9.8±18.1

8.4±11.3

0.57

Age of onset (years)

37.1±12.1

Duration of illness (years)

5.4±8.2

Number of depressive episodes

2.05±2.1

HDRS—baseline

22.8±6.1

Triallelic 5-HTTLPR*
L

A

L

A

/L

A

L

G

/L

G

L

G

/L

A

S/L

G

S/SS

14/18/11/23/1/10

10/10/1/34/8/14

0.002

Allele frequency
L

A

/L

G

/S

0.45/0.27/0.28

0.42/0.13/0.45

0.001

Functional consequence* (L

A

= L, L

G

= S)

LL/LS/SS

14/41/22

10/44/23

0.6

Abbreviation: HDRS, Hamilton Depression Rating Scale.
Mean and s.d.(±) are given.
No significant differences were found between patients and controls as measured with t-test or w

2

test.

*P < 0,05, only w

2

test.

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T Frodl et al

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Molecular Psychiatry

accordance with the ethical standards laid down in
the Declaration of Helsinki.

Magnetic resonance imaging procedures

Data acquisition.

Magnetic resonance images were

obtained with a Magnetom Vision scanner (Siemens,
Erlangen, Germany) operating at 1.5 T. All subjects
were scanned with a T1-weighted 3D-MPRAGE
sequence

(repetition

time,

11.6 ms;

echo

time,

4.9 ms; total acquisition time, 9 min; number of
acquisitions, 1; field of view, 230 mm; matrix,
512  512; section thickness, 1.5 mm) yielding 126
contiguous axial slices with a defined voxel size of
0.45  0.45  1.5 mm. After manually reorienting and
centering the images on the anterior commissure,
data preprocessing were performed with the SPM5
software package (Wellcome Department of Cognitive
Neurology, London, UK) running under MATLAB 6.5
(The MathWorks, Natick, MA, USA).

VBM preprocessing
This study employed the VBM5 toolbox, which
utilizes and extends the new unified segmentation
approach implemented in SPM5.

24

Unified segmenta-

tion provides a generative model of VBM preproces-
sing that integrates tissue classification, image
registration and magnetic resonance imaging inho-
mogeneous bias correction. Thus, the model avoids
the ‘circularity problem’ of the optimized VBM
procedure, as the initial image registration does not
require an initial tissue segmentation and vice versa.

25

The VBM5 toolbox extends the unified segmentation
model, as it increases the quality of segmentation by
applying a Hidden Markov Field model on the
segmented tissue maps.

26

The Hidden Markov Field

algorithm provides spatial constraints based on
neighboring voxel intensities within a 3  3  3 voxel
cube. It removes isolated voxels, which are unlikely
to be a member of a certain tissue class and also closes
holes in a cluster of connected voxels of a certain
class, resulting in a higher signal-to-noise ratio of the
final tissue probability maps. The VBM5 toolbox
offers the possibility to write the estimated tissue
probability maps without making use of the respec-
tive ICBM tissue priors (International Consortium for
Brain Mapping) from SPM5.

This study used this option, as it improved the

delineation of the subcortical structures and the sulci
in the final tissue maps. The final tissue maps of gray
matter (GM), white matter and cerebro-spinal fluid
were modulated with the deformation fields obtained
by normalization to standard space to analyze volume
differences between study populations. Finally, the
modulated GM partitions were smoothed with a
12 mm FWHM Gaussian kernel and used for statis-
tical analysis.

Genetics
DNA was extracted from a 5 ml blood sample using
the QIAamp Blood Isolation Kit (QIAGEN GmbH,

Hilden,

Germany)

according

to

the

supplier’s

instructions. We used the triallelic polymorphism
SNP-rs25531, because the L-allele can be subtyped
into La and Lg alleles, the latter of which is thought to
be similar to the S-allele in terms of reuptake
efficiency.

27

Genotyping was carried out by applying the PCR

amplification in a final volume of 25 ml consisting of
50-ng DNA, l mmol l

1

of each primer, 200-m

M

deoxy-

nucleotide triphosphate, 100-m

M

7-deaza-guanosine

triphosphate,

5%

dimethyl

sulfoxide,

10-m

M

Tris-hydrochloride

(pH

8.3),

50-m

M

potassium

chloride, 1.5-m

M

magnesium chloride and 2.5 U of

DNA polymerase (AmpliTaq Gold; PerkinElmer,
Langen, Germany). The PCR products were separated
on a 3% agarose gel (FMC NuSieve 3:1; Biozym
Diagnostic

GmbH,

Oldendorf,

Germany)

and

visualized by ethidium bromide staining.

Statistical analysis
An analysis of covariance was designed to investigate
focal GM volume (GMV) differences between the
patients with major depression and healthy controls
as well as between genotypes. Age and gender were
entered as covariates of no interest in the statistical
design. First, GMV differences (increases/decreases)
between patients with major depression and healthy
controls were assessed at the whole-brain level using
T contrasts (P < 0.05, family wise error correction
(FWE) corrected). Then, the overall genotype effects
were calculated again at the whole-brain level using T
contrasts (P < 0.05, FWE corrected).

Additionally, VBM analysis was performed to

examine the interactions between diagnosis and
genotype, with additional masking for higher GMV
in the S-allele within the patient group thresholded at
P < 0.05, uncorrected, as the exclusive mask.

The VBM results were also analyzed to test

differences between patients and controls within
each genotype and to test differences between
genotypes within the patients and within the controls
only. Additionally, small-volume-corrected VBM ana-
lyses were performed for the following regions of
interest: hippocampus, amygdala, ACC, DMPFC and
DLPFC at P < 0.01 for comparison of cross-sectional
GMV differences between patients and controls. For
these five regions of interest patient subgroups,
analyses were performed at P < 0.01, small volume
corrected: cross-sectional GMV differences between
the patients compared to controls, between patients
with each genotype and controls with the same
genotype, as well as in the patients and control group
between each genotype. Coordinates of peak signifi-
cant voxels were assigned to anatomical regions by
means of automated anatomical labeling.

28

Results

Age, gender, handedness, height, weight and alcohol
consumption were similar in patients and controls
(Table 1). The 5-HTTLPR distributions for the patients

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T Frodl et al

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Molecular Psychiatry

and controls were in Hardy–Weinberg equilibrium.
For each genotype, age, weight and height did not
differ between patients and controls. There was
no

significant

difference

in

illness

duration

(F(2/74) = 0.6;

P = 0.55)

or

depression

severity

(Hamilton Depression Rating Scale, F(2/74) = 1.5;
P = 2.3) between patients with a specific genotype.

Interestingly, with respect to the allele frequencies

of the 5-HTTLPR-rs25531 the L

G

-allele was more

frequent in our patients sample, whereas the S-allele
was less frequent compared to the healthy controls
(X

2

= 13.5; P = 0.001). As the L

G

-allele is considered

to be functionally comparable to the S-allele,
functional triallelic LL/LS/SS genotypes can be used.
Frequencies of these were not significantly different
between patients and controls (Table 1).

Using w

2

test, there was no significant difference

between genotypes with respect to different medica-
tion (no medication, selective serotonin reuptake
inhibitor, tricyclic, newer antidepressants).

In the overall VBM analyses, patients with major

depression had significantly smaller GMVs in the left
DLPFC, bilaterally in the supplementary motor area,
in the thalamus and the precentral area, and showed
trends bilaterally in the DMPFC, the right orbitofron-
tal cortex as well as the left insular cortex compared
to healthy controls (Figure 1).

Small volume correction for regions of interest

revealed that patients had significantly reduced
GMVs bilaterally in the ACC, DLPFC and in
the DMPFC compared to controls (Table 2). The
hippocampus and amygdala GMVs were not smaller
in patients.

Interaction between genotype and diagnosis
The interaction between diagnosis and genotype was
significant in the DLPFC right pronounced, left ACC,
left amygdala as well as right hippocampus: the
difference between controls homozygous for the
L

A

-allele and those homozygous for the S-allele

(L

G

L

G

, L

G

S, SS) was larger than the difference between

patients homozygous for the L

A

-allele and those

homozygous for the S-allele (Table 3).

Effects of diagnosis within genotypes
Patients homozygous for the L

A

-allele had signifi-

cantly smaller GMVs in the hippocampus, amygdala,
ACC, DLPFC and DMPFC than healthy controls with
the same genotype. Heterozygous patients differed
significantly from controls with the same genotype
with respect to the DLPFC, and patients homozygous
for the S-allele (L

G

L

G

, L

G

S, SS) had significantly

smaller subregions within the hippocampus DLPFC
and DMPFC compared to controls with the same
genotype (Figure 2).

Genotype effects within the depressive group
Patients homozygous for the L

A

-allele had signifi-

cantly

reduced

bilateral

hippocampal

volumes

than those patients being homozygous for S-allele
(L

G

L

G

, L

G

S, SS). No significant differences were

observed between heterozygous patients and patients
homozygous for either the S-(L

G

or S) or L

A

-allele

(Table 4).

Genotype effects within healthy controls
Healthy controls homozygous for the L

A

-allele had

significantly larger GMVs in the ACC, DLPFC right
pronounced, right DMPFC, left amygdala and left
hippocampus than those homozygous for the S-allele
(Table 4).

Discussion

The main finding from this study is that healthy
controls

show

a

strong

association

between

5-HTTLPR

polymorphism

and

GMVs

in

all

investigated brain regions, with the smallest volumes
being found in healthy subjects homozygous for the
S-allele (L

G

L

G

, L

G

S, SS), whereas in patients with

major depression this association is only seen in
subregions of the hippocampus. The explanation for
this discrepancy may be that patients with depression
who are homozygous for the L

A

-allele have prominent

GM reductions compared to controls with the same
genotype. Patients have the largest volume reductions
compared to controls in cortical brain regions such as
the DLPFC, DMPFC, ACC as well as in the amygdala
and anterior hippocampus when they are homo-
zygous for the L

A

-allele. Patients homozygous for the

S-allele (L

G

L

G

, L

G

S, SS) or heterozygous patients

(L

A

S, L

A

L

G

) only differ in small regions from controls

with the same genotype. For example, only the
middle hippocampal volume was found to be reduced
in patients carrying the S-allele compared to controls
with the same genotype.

This finding is very interesting because the normal

influence of 5-HTTLPR on the brain may be dimin-
ished in patients with major depression, indicating
that other factors may have a greater influence on
these processes, for example psychosocial factors or
early life events.

29

Interestingly, patients had higher L

G

-allele frequen-

cies and less S-alleles (L

G

L

G

, L

G

S, SS) compared to

healthy controls. Unfortunately, our sample is too
small to conclude that the L

G

-allele may be a risk

factor for major depression or to analyze the different
influences between L

G

-allele and S-allele (L

G

L

G

, L

G

S,

SS) on the brains of patients with major depression
and healthy controls.

These data suggest that the main GM alterations are

seen in patients homozygous for the functional
L

A

-allele of the 5-HTTLPR-rs25331. In our earlier

study, the homozygous L-allele of the 5-HTTLPR was
found to be associated with reduced hippocampal
volumes in patients with major depression and not in
controls.

19

Moreover, patients with a late-onset

geriatric depression who were homozygous for the
L-allele of the 5-HTTLPR had smaller hippocampal
volumes than other groups.

30

One possible explanation may be that the higher

reuptake of serotonin in subjects homozygous for the

Brain volumes and serotonin transporter in depression

T Frodl et al

1096

Molecular Psychiatry

Figure 1

Overall brain gray matter (GM) volume reduction in patients compared to controls. Regions where GM density is

reduced in patients with major depression compared to healthy controls. P-values are corrected for multiple comparisons
(FDR, P < 0.01). Numbers below slices represent the vertical distance in millimeter to the anterior commissure.

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T Frodl et al

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Molecular Psychiatry

L

A

-allele is an additional factor that aggravates stress-

induced neurotoxic effects during depression. In
addition to its role as a neurotransmitter, serotonin
acts as a trophic factor modulating developmental
processes such as neuronal division, differentiation,
migration, synaptogenesis

31,32

and adult neurogen-

esis.

33

Moreover, several studies found interactions

between the serotonergic system and BDNF, as the
5-HTT function is modulated by BDNF,

34

which, in

turn, was found to be elevated in the hippocampus
and the frontal cortex after antidepressant treat-
ment.

35

Upregulation of the cAMP response ele-

ment-binding

protein

due

to

effective

therapy

increases the expression of BDNF, which seems to
have neurotrophic effects.

36

One might therefore expect that the high-activity

L

A

-allele with its increased number of 5-HTT trans-

porter proteins, concomitant decrease in serotonin
levels and reduced effects on neuroplastic processes
would be more likely to cause structural changes

during major depression. Importantly, this may not be
a common phenomenon because healthy control
subjects with the S-allele (L

G

L

G

, L

G

S, SS) have the

smallest hippocampal volumes. Therefore, the pre-
sence of major depression or other factors that play a
part in the pathophysiology of major depression
seems to be necessary for the changes seen in patients
homozygous for the L

A

-allele.

Another possibility for the association of brain

volume and the 5-HTTLPR polymorphism comes
from the studies reporting that the L-allele of the
5-HTTLPR may be related to Alzheimer disease.

37–39

The larger reduction in GMVs in patients homozy-
gous for the L-allele may then be explained by a larger
susceptibility to neurodegenerative changes. How-
ever, this seems to be unlikely, although not exclu-
sive, because our patients were young.

The effect of stress on the brain is relevant for the

discussion of these findings. It is well known from
clinical and experimental studies that stress is one of

Table 2

Gray matter volume reduction in patients with major depression compared to healthy controls with SVC for ACC,

hippocampus, amygdala, DLPFC, DMPFC (P < 0.01, uncorrected)

k

k (%)

FWE

FDR

T

P

x

y

z

Left ACC

219

1.96

0.057

0.028

3.21

0.001

2

36

28

Right ACC

1200

11.42

0.031

0.028

3.44

< 0.001

4

42

28

Left DLPFC

12667

32.56

0.006

0.004

4.34

< 0.001

25

5

61

Right DLPFC

13570

33.23

0.038

0.004

3.78

< 0.001

43

4

51

Left DMPFC

6302

26.33

0.004

0.002

4.26

< 0.001

0

32

46

Right DMPFC

2886

16.9

0.004

0.002

4.24

< 0.001

1

32

46

Left amygdala

9

0.51

0.017

0.126

3.27

0.001

16

2

17

Right amygdala

NS

Left hippocampus

7

0.09

0.041

0.166

3.33

0.001

15

2

16

Right hippocampus

1

0.01

0.053

0.166

3.24

0.001

26

40

3

Abbreviations: ACC, anterior gyrus cinguli; DLPFC, dorsolateral prefrontal cortex; DMPFC, dorsomedial prefrontal cortex;
FDR, false discovery rate; FWE, family wise error correction; k, number of suprathreshold voxels in anatomical region;
k (%), percentage of suprathreshold voxels in anatomical region, T-test; NS, not significant; SVC, small volume correction.

Table 3

Difference in GM volume between L

A

/L

A

and S/S (L

G

L

G

, L

G

S, SS) is greater for controls compared to the difference

between L

A

/L

A

and S/S (L

G

L

G

, L

G

S, SS) for patients with SVC for ACC, hippocampus, amygdala, DLPFC, DMPFC (P < 0.01,

uncorrected)

k

k (%)

FWE

FDR

T

P

x

y

z

Left ACC

49

0.44

0.153

0.347

2.79

0.003

12

31

26

Right ACC

NS

Left DLPFC

11

0.03

0.591

0.266

2.54

0.006

34

1

50

Right DLPFC

926

2.27

0.175

0.266

3.21

0.001

29

35

29

Left DMPFC

NS

Right DMPFC

NS

Left amygdala

21

1.19

0.117

0.128

2.47

0.007

29

0

26

Right amygdala

NS

Left hippocampus

NS

Right hippocampus

17

0.22

0.269

0.253

2.52

0.006

35

12

27

Abbreviations: ACC, anterior gyrus cinguli; DLPFC, dorsolateral prefrontal cortex; DMPFC, dorsomedial prefrontal cortex;
FDR, false discovery rate; FWE, family wise error correction; GM, gray matter; k, number of suprathreshold voxels in
anatomical region, k (%), percentage of suprathreshold voxels in anatomical region, T-test; NS, not significant; SVC, small
volume correction.

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Figure 2

Small-volume-corrected (SVC) gray matter volume (GMV) reduction in patients compared to controls for each

genotype pair. Regions where GMV is reduced in patients with the L

A

L

A

genotype compared to healthy controls with the

L

A

L

A

genotype (red), L

A

S, L

A

L

G

genotypes (green), (L

G

L

G

, L

G

S, SS genotypes (yellow), respectively with SVC (P < 0.01,

uncorrected). Numbers below slices represent the vertical distance in millimeter to the anterior commissure. Significantly
reduced GMVs in patients compared to controls are detected bilaterally in the hippocampus, bilaterally in the anterior gyrus
cinguli (ACC), in the left amygdala and the right dorsomedial prefrontal cortex (DMPFC).

Brain volumes and serotonin transporter in depression
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the major factors that contribute to the development
of depression. Several studies have found that the
S-allele of 5-HTTLPR increases the vulnerability to
depression only in the presence of significant adverse
life events. Relative to homozygous individuals for
the L-allele, young adult carriers of the S-allele were
more vulnerable to major depression when exposed to
adverse events.

40

Young adults homozygous for the S-

allele also had significantly greater sensitivity to
depressogenic effects of stressful life events than
carriers of the L-allele.

41

An increased risk for major

depression was detected in maltreated children
homozygous for the S-allele.

42

Moreover, S-alleles

independently predicted greater depression severity
and greater severity of major depression with moder-
ate-to-severe life events compared with the higher
expressing L-allele.

43

These studies indicate a role of

the S-allele in predisposing to major depression.
However, one recent study found that the high-
activity L-allele was associated with a higher risk of
depression in the presence of adverse life events in a
large sample of 247 young adult female twins from
Missouri.

44

Also, controversial is the neurobiological interpre-

tation. It seems puzzling that lower serotonin uptake
resulting from a genetic predisposition would be
associated with a higher risk of depression because
lowering serotonin uptake by treatment with seroto-
nin selective reuptake inhibitors relieves depression.
Therefore, more studies are necessary to explore the
role of the serotonin transporter in the neurobiology
of major depression.

The primary limitation of this study is its

case–control design, which is sensitive to population
stratification. However, as cases and controls with a

certain 5-HTTLPR genotype did not differ with
respect to age, gender, illness duration, age of onset,
medication and origin, it does not seem likely that the
population stratification had any negative effects.
Another important factor is medication. There was no
difference in medication between genotypes, how-
ever, we cannot exclude from our study an interaction
between medication, genotype and brain volumes,
because our sample is too heterogeneous with respect
to medication and too small, to analyze this effect.
Further studies are therefore necessary.

In summary, healthy subjects with the L

G

L

G

, L

G

S or

SS genotype have smaller GMVs than those being
homozygous for the L

A

-allele. A hypothetical expla-

nation may be that the S-allele may have impact
on neurodevelopmental processes, perhaps due to
increased sensitivity to childhood and adolescent
stressful life events as suggested from genetic studies.
Patients with depression show the most reduced
GMVs compared to controls with the same genotype
when they are homozygous for the L

A

-allele, suggest-

ing that these patients are more vulnerable for
morphological or even neuroplastic changes during
depressive episodes.

Acknowledgments

This study was supported by the German Federal
Research Ministry within the promotion ‘German
Research Networks in Medicine’ as part of the project
‘German Research Network on Depression’ and Maike
Moergenthaler carried out her doctoral thesis within
this study. Moreover, we thank Mrs Jaquie Klesing for
native english editing.

Table 4

Difference in GM volume between patients with L

A

/L

A

and those with S/S genotype (L

G

L

G

, L

G

S, SS) as well as

difference in GM volume in healthy controls with L

A

/L

A

compared to those with S/S genotype (L

G

L

G

, L

G

S, SS) with SVC for ACC,

hippocampus, amygdala, DLPFC, DMPFC (P < 0.01, uncorrected)

k

k (%)

FWE

FDR

T

P

x

y

z

Major depression

Left hippocampus

185

2.48

0.02

0.097

3.59

< 0.001

26

38

4

Right hippocampus

281

3.71

0.012

0.097

3.76

< 0.001

30

38

5

Healthy controls

Left ACC

40

0.36

0.24

0.144

2.55

0.006

11

29

25

Right ACC

94

0.89

0.218

0.144

2.61

0.005

11

36

28

Left DLPFC

20

0.05

0.62

0.248

2.5

0.007

27

7

62

Right DLPFC

867

2.12

0.063

0.248

3.6

< 0.001

28

34

29

Left DMPFC

NS

Right DMPFC

54

0.32

0.122

0.16

3.08

0.001

12

22

41

Left amygdala

35

1.99

0.078

0.114

2.66

0.004

17

6

18

Right amygdala

NS

Left hippocampus

65

0.87

0.212

0.22

2.64

0.005

17

6

20

Right hippocampus

NS

Abbreviations: ACC, anterior gyrus cinguli; DLPFC, dorsolateral prefrontal cortex; DMPFC, dorsomedial prefrontal cortex;
FDR, false discovery rate; FWE, family wise error correction; GM, gray matter; k, number of suprathreshold voxels in
anatomical region; k (%), percentage of suprathreshold voxels in anatomical region, T-test; NS, not significant; SVC, small
volume correction.

Brain volumes and serotonin transporter in depression

T Frodl et al

1100

Molecular Psychiatry

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