Gbiomed.kuleuven.be
Metab Brain Dis (2010) 25:369–374DOI 10.1007/s11011-010-9218-6
Changes in regional brain volumes in social anxiety disorderfollowing 12 weeks of treatment with escitalopram
Naseema Cassimjee & Jean-Pierre Fouche & Michael Burnett & Christine Lochner &James Warwick & Patrick Dupont & Dan J. Stein & Karen J. Cloete & Paul D. Carey
Received: 23 April 2010 / Accepted: 24 August 2010 / Published online: 10 November 2010
# Springer Science+Business Media, LLC 2010
Abstract It has been suggested that antidepressants,
treatment with escitalopram. These preliminary findings
including the selective serotonin reuptake inhibitors have
require replication to determine their reliability, and
neurotrophic effects. Nevertheless, the impact of treatment
extension to determine whether or not they are disorder
with a selective serotonin re-uptake inhibitor on regional
brain volumes in social anxiety disorder has not beenstudied. 11 subjects with social anxiety disorder completed
Keywords Escitalopram . Regional brain volumes . Social
magnetic resonance imaging both before and after 12-
anxiety disorder . Structural magnetic resonance imaging
weeks of treatment with 20 mg/day escitalopram. Noincreases in structural grey matter were found, but therewere decreases in bilateral superior temporal cortex, vermis
and the left cerebellum volumes following 12 weeks of
Evidence for a range of effective medications for socialanxiety disorder (SAD) has emerged in recent years (Ipser
N. Cassimjee K. J. Cloete (*)
et al. Presently, the weight of evidence supports the
Department of Psychiatry, University of Stellenbosch,
use of selective serotonin reuptake inhibitors (SSRI) and
PO Box 19063, Tygerberg 7505, South Africae-mail:
[email protected]
serotonin norepinephrine reuptake inhibitors as first line
agents in SAD. It is increasingly thought that the primaryaction of the SSRIs is not limited to the inhibition of
synaptic serotonin reuptake, but also involves a complex
Cape Universities Brain Imaging Centre,University of Stellenbosch,
interaction of post-synaptic receptors, secondary messenger
Tygerberg, South Africa
systems and neurotrophic factors (NF), which act togetherto effect changes in the cellular milieu that result in a
M. Burnett C. Lochner J. Warwick D. J. Stein P. D. Carey
treatment response.
MRC Research Unit on Anxiety Disorders,Department of Psychiatry, University of Stellenbosch,
Mounting evidence supports the hypothesis that neuro-
Tygerberg, South Africa
trophins interact with neurotransmitters to alter synapticactivity (Lang et al. ; Schinder and Poo ). More
specifically, neurotrophins have a stimulatory or inhibitory
Division of Nuclear Medicine, University of Stellenbosch,Tygerberg, South Africa
effect on glutamatergic and gamma aminobutyric acid-ergicsystems, which in turn results in changes to the production,
secretion and activity of neurotrophins. Altered neuro-
Laboratory for Cognitive Neurology and Medical Imaging
trophin levels have been described in a variety of disorders,
Research Center,K.U. Leuven,
which have in turn been associated with altered brain
neuroplasticity (Spedding and Gressens ). Extension ofthis hypothesis into the clinical arena has indicated that
there is an association between lower levels of NF,
Department of Psychiatry, University of Cape Town,Cape Town, South Africa
increased psychiatric symptoms (Castrén and Rantamäki
Metab Brain Dis (2010) 25:369–374
; Martinowich et al. Vetencourt et al. ),
withdraw from fluoxetine due to lack of efficacy and was
with increased NF levels associated with a treatment
washed out for 5 weeks prior to the baseline treatment visit.
response (Rantamäki et al. ). In addition, early studies
No participant had failed more than a single trial of
of anxiety disorders (Bremner et al. and depression
pharmacotherapy defined as a minimum of 8 weeks at an
have suggested an association of NF levels with regional
adequate dose. No participants had previously been exposed
brain volumes (Campbell and MacQueen Frodl et
to escitalopram.
Subjects with any current psychiatric co-morbidity,
Taken together these studies raise the question of the link
including current depression, were excluded. Women of
between disorders with apparently lower NF levels, and the
childbearing potential were excluded if pregnant, and all
ability of pharmacotherapy agents to lead to changes in NF
subjects were required to be on contraception for the
levels, and consequently to changes in regional brain
duration of the study. Having a recent (6 months) history of
volume. Indeed, there is some evidence that antidepressant
substance abuse/misuse, a serious/unstable medical disorder,
treatment does lead to increases in regional brain volumes
a history of previous head injury, recent (90 days) electro-
(Chen et al. ; Fossati et al. ; Vermetten et al.
convulsive therapy, any metal implants, claustrophobia or a
). However, it remains unclear whether these findings
previous adverse response to magnetic resonance imaging
can be extended to other anxiety disorders, where different
(MRI), and use of any psychoactive substances other than
neuro-circuitry may be involved in mediating symptoms.
non-problematic alcohol or nicotine use (< 14 days prior to
Social anxiety disorder is an anxiety disorder character-
study initiation) were all criteria for exclusion from participa-
ized by marked and persistent fear of one or more
tion in the study.
performance situations (American Psychiatric Association
The study protocol was approved by the Committee
). Individuals fear being exposed to unfamiliar people/
for Human Research of the University of Stellenbosch
situations in which the possibility of scrutiny and ensuing
(M05/01/006) prior to study initiation. Following deter-
embarrassment is a possibility. This results in functionally
mination of eligibility, all participants were required to
impairing and distressing anticipation of social situations,
sign an information and consent document prior to any
consequent social avoidance, or endurance of situations
study specific procedure being conducted. Participants
with considerable discomfort. Previous work has suggested
were not re-imbursed for their participation in the study.
that an undefined dysfunction within the frontal and
However we did cover transport costs incurred to attend
amygdalo-hippocampal circuitry is responsible for mediat-
clinic visits.
ing symptoms of SAD (Aouizerate et al. ; Warwick etal. Research has also shown that effective treatment
alters brain regions broadly linked to these brain regionssuggesting disorder specific brain effects that correlate
To determine baseline and subsequent severity of SAD we
with the treatment effect (Furmark et al. ; Warwick
used the Liebowitz Social Anxiety Scale (LSAS) (Liebowitz
To assess sub-syndromal depressive symptomatology,
To date no studies in SAD have been reported in which
we used the Montgomery Äsberg Depression Rating Scale
the impact of treatment with an SSRI on regional brain
(MADRS) (Montgomery and Asberg ). Overall clinical
volumes is investigated. We hypothesized that after
severity of symptoms and response were assessed using the
12 weeks of treatment with escitalopram, brain volumes
Clinical Global Impression (CGI) scale (Guy ).
in frontal and temporal brain regions would increase inparticipants with SAD.
The clinical screening interview was conducted by a
Materials and methods
psychiatrist or psychiatric resident (PC and NC), and wasfollowed with a structural magnetic resonance scan prior to
the initiation of open-label escitalopram therapy. Subsequentstudy visits were scheduled on completion of 4, 8, and
Potentially eligible participants (n=14, 9=female, 5=male),
12 weeks of treatment. In addition, investigators made bi-
aged 18–65 years with MINI-defined DSM-IV SAD (Sheehan
weekly telephonic contact with participants to assess ongoing
et al. were recruited from our specialist anxiety disorder
safety and compliance with study procedures. A second MRI
clinic at Stellenbosch University. Participants had been
was conducted before discontinuation of study medication
previously diagnosed with SAD, and all but one were
after completion of a minimum of 12 weeks treatment.
medication free at the time of the study. The one participant
The clinical measures mentioned above were repeated at
on treatment at the time of screening voluntarily agreed to
each of these visits. Medication tolerability and compli-
Metab Brain Dis (2010) 25:369–374
ance (pill-count) with the treatment regime was assessed
mapping (ICBM) priors instead of study-specific priors. In
at each contact.
the longitudinal analysis, the second scan of each subject(Week 12 scan) was co-registered with the first scan
(baseline) without any re-slicing, and then warped to thebaseline scan using high-dimensional warping and also
Following completion of all scheduled baseline activities,
writing the Jacobian determinants for the deformation field
open-label treatment with escitalopram was initiated at a
of each warp. The deformation field was then applied to the
dose of 10 mg daily for the first 5 days. This dose was
follow-up image and this transformed image was then
increased to 20 mg daily for the remainder of the 12-week
averaged with the baseline image to create a mean image
treatment period. All participants who started treatment
for each subject. This mean image was then segmented into
completed the scheduled 12 weeks of treatment. Participants
grey matter, white matter and cerebrospinal fluid using the
were given the option of continuing treatment at 12 weeks.
ICBM priors of SPM5. The normalization parameters of the
Those that were discontinuing with the treatment were
grey matter partition were then applied to the mean images
tapered to 10 mg per day for 10 days, and then
as well as the Jacobian determinant data. The normalized
medication was stopped.
mean image was then segmented into its grey matterpartition using the ICBM template. This baseline data
(partition) for each subject was then multiplied by theJacobian determinants to create the follow-up data for each
Magnetic resonance imaging was conducted on the
subject. With data from both time-points being smoothed
3T Siemens Magnetom Allegra located in the Cape
using a 10 mm full width at half maximum Gaussian
Universities Brain Imaging Centre located at the University
of Stellenbosch's Tygerberg Campus. Scanning sessionslasted approximately 40 min. A high resolution 3D, T1-
Statistical analysis
weighted sequence was acquired and used in subsequentanalyses. One hundred and sixty, sagittal 1 mm slices of the
A paired two-sample t-test was used for the statistical
whole brain were acquired with imaging parameters as
analysis. The significance threshold was set at p<0.001 (at
follows: 179×256 matrix, TR=2300 ms, TE=3.93 ms, in-
the voxel level) combined with a family wise error
plane resolution of 1.0×1.0×1.0 mm and flip angle 12°.
corrected p<0.05 for the size of the clusters. To excludenon-brain voxels, a brain mask was used during the
MRI preprocessing
analysis. The contrast follow-up > baseline and the reversecontrast of baseline > follow-up was tested.
All of the 14 participants who started the study completedthe 12 weeks of treatment. One subject was excluded due topoor image quality of the MRI, and two participants were
not able to complete the Week 12 scan. Our final analysiswas conducted on the remaining 11 subjects using baseline
Eleven participants were included in the analysis. Participants
and week 12 scans. Preprocessing was performed in
demonstrated > 90% compliance overall, as determined by
MATLAB R2007b (Mathworks, Natick, MA) within the
pill count. The cohort comprised nine males and five females
statistical parametric mapping (SPM5) framework (Wellcome
with a mean age of 40.64 years (SD 11.74). All participants
Department of Imaging Neuroscience, University College
tolerated the higher (20 mg/day) dose of escitalopram as
London, UK). Although standard voxel-based morphometry
prescribed in the study protocol. Baseline severity of
processes in SPM5 are adequate for comparing grey matterdifferences across groups, potential artefacts might occur
Table 1 Clinical measures at baseline and week 12 demonstrate a
during longitudinal analysis resulting from intra subject global
markedly ill cohort with very limited depressive symptom co-
changes in brain size over time (Chételat et al. ). As such
morbidity and relatively modest overall improvements with 12 weeks
we implemented the longitudinal protocol described by
Chételat et al. This procedure first creates a
Mean (SD)— Mean (SD)—
customized whole brain template as described by Good et
al. ). The template was smoothed with an 8 mmGaussian full width at half maximum isotropic kernel.
Liebowitz Social Anxiety Scale
84.36 (21.92) 57.91 (32.74)
We then implemented the protocol as defined by
Montgomery Äsberg Depression
Chételat et al. (with the one exception being our
Clinical Global Impression -Severity
use of the SPM5 international consortium for brain
Metab Brain Dis (2010) 25:369–374
SAD was marked to severe with a mean LSAS score of
84.36 (SD 21.92). While a significant improvement was
noted overall (31% reduction in LSAS, p<0.009), themean LSAS score after Week 12 [57.91 (SD 32.74)] stillsuggests this cohort was moderately ill overall (Table Fewer than half (4/11) participants were classified asresponders with a CGI-Improvement score of "Much"(Score of 2, n=1) or "very much" (score of 1, n=3)improved. Treatment was well tolerated in all cases and noserious adverse effects were recorded.
To address our main hypothesis we assessed the contrast
‘Follow-up > baseline'. This showed no significant clustersmeeting our a priori thresholds. Even if we used a lessstringent threshold of p < 0.01 (voxel level) and anuncorrected p<0.05 (cluster level), we did not find anysignificant increase. However, the reverse contrast of
‘Baseline > Follow-up' demonstrated structural grey matter
decreases in the bilateral superior temporal cortex, vermisand the left cerebellum following 12 weeks of treatment
with escitalopram (Fig. Table Small group sizeprecluded a meaningful ‘responder vs non-responder'
The main findings in our study were structural grey matterdecreases in bilateral superior temporal cortex, vermis andleft cerebellum following 12 weeks of treatment withescitalopram. These findings are, to the best of ourknowledge, the first to demonstrate structural brain changesin response to SSRI treatment in SAD. The clinical measuresused in our study (LSAS, MADRS, CGI-severity) demon-strate a modest overall improvement following 12 weeks of
Contrary to our hypothesis, the findings here do not
replicate the effects on brain structure seen in previous
Fig. 1 Clusters corresponding to a significant decrease in grey matter
studies in mood and anxiety disorders when treated with
following 12 weeks of treatment with escitalopram in the right (a) and
left (b) superior temporal cortex. Clusters are overlayed on the single
's. The amygdalo-hippocampal brain regions, which
subject brain provided within SPM5 for visualisation
are usually associated with high levels of plasticity, did notappear to be impacted following SSRI treatment in our
Table 2 Group-wise contrast (Baseline > Follow-up) showing clusters of brain volume decreases following 12 weeks of treatment co-varied forbaseline LSAS scores
Coordinates x,y,z (mm)a
Cluster volume (mm3)
Right superior temporal cortex
Left superior temporal cortex
Left cerebellum crus
a Coordinates (x,y,z) in millimeters correspond to Montreal Neurological Institute spaceb Corrected for multiple comparisons
Metab Brain Dis (2010) 25:369–374
sample, as has been the case in previous functional work on
Aouizerate B, Martin-Guehl C, Tignol J (2004) Neurobiology and
pharmacotherapy of social phobia. Encephale 30:301–313
SAD (Furmark et al. ; Engel et al. ; Freitas-Ferrari
Bremner JD, Vermetten E (2004) Neuroanatomical changes associated
et al. or structural work on other anxiety disorders
with pharmacotherapy in posttraumatic stress disorder. Ann NY
(Bremner and Vermetten ; Engel et al. ). The
Acad Sci 1032:154–157
neuroplasticity of the adult brain may well be limited (Nass
Bremner JD, Vythilingam M, Vermetten E, Southwick SM, McGlashan
T, Nazeer A, Khan S, Vaccarino V, Soufer R, Garg PK, Ng CK,
). It is also possible that the sample size in our study
Staib LH, Duncan JS, Charney DS (2003) MRI and PET study of
was underpowered to find such differences.
deficits in hippocampal structure and function in women with
Changes in temporal lobe regional volumes after SSRI
childhood sexual abuse and posttraumatic stress disorder. Am J
treatment may, however, be consistent with various data
Psychiatry 160:924–932
Campbell S, MacQueen G (2006) An update on regional brain volume
pointing to the role of these structures in anxiety in general
differences associated with mood disorders. Curr Opin Psychiatry
and SAD in particular (Tillfors et al. ; Lorberbaum et
al. Furmark et al. Warwick et al. Engel et
Castrén E, Rantamäki T (2008) Neurotrophins in depression and
al. ; Freitas-Ferrari et al. It is notable that
antidepressant effects. Novartis Found Symp 289:43–52
Chen CH, Ridler K, Suckling J, Williams S, Fu CH, Merlo-Pich E,
citalopram reduced public speaking anxiety in patients with
Bullmore E (2007) Brain imaging correlates of depressive
social phobia, and that this symptom improvement was
symptom severity and predictors of symptom improvement after
associated with reduced regional cerebral blood flow mainly
antidepressant treatment. Biol Psychiatry 62:407–414
in the medial temporal lobe, but including the amygdala,
Chételat G, Landeau B, Eustache F, Mézenge F, Viader F, De La
Sayette V, Desgranges B, Baron JC (2005) Using voxel-based
hippocampus and surrounding rhinal cortices (Furmark et al.
morphometry to map the structural changes associated with rapid
Engel et al. ; Freitas-Ferrari et al. ).
conversion in MCI: a longitudinal MRI study. Neuroimage
Although there is little work on the role of the cerebellum
in anxiety disorders, previous research has suggested an
Engel K, Bandelow B, Gruber O, Wedekind D (2009) Neuroimaging
in anxiety disorders. J Neural Transm 116:703–716
association between anxiety disorders and cerebellar-
Fossati P, Radtchenko A, Boyer P (2004) Neuroplasticity: from MRI
vestibular dysfunction (Levinson ), and a positron
to depressive symptoms. Eur Neuropsychopharmacol 14:S503–
emission tomography study demonstrated that anticipatory
anxiety in SAD subjects was associated with decreased
Freitas-Ferrari MC, Hallak JEC, Trzesniak C, Filho AS, Machado-
de-Sousa JP, Chagas MHN, Nardi AE, Crippa JAS (2010)
cerebellar perfusion bilaterally (Tillfors et al. ; Freitas-
Neuroimaging in social anxiety disorder: a systematic review
Ferrari et al. These areas also correspond with changes
of the literature. Prog Neuropsychopharmacol Biol Psychiatry
demonstrated by Kilts et al. ). Nevertheless, the relative
lack of involvement in cerebellum in previous anxiety
Frodl T, Schule C, Schmitt G, Born C, Baghai T, Zill P, Bottlender R,
Rupprecht R, Bondy B, Reiser M, Möller HJ, Meisenzahl EM
disorder imaging studies, and the less reliable GM segmen-
(2007) Association of the brain-derived neurotrophic factor
tation of the cerebellum, raises the question of whether the
Val66Met polymorphism with reduced hippocampal volumes in
cerebellum findings here are artefactual.
major depression. Arch Gen Psychiatry 64:410–416
Our study is limited by the fact that we do not have direct
Furmark T, Tillfors M, Marteinsdottir I, Fischer H, Pissiota A,
Långström B, Fredrikson M (2002) Common changes in cerebral
evidence of changes in potentially relevant mediating
blood flow in patients with social phobia treated with citalopram
molecular pathways, such as altered neurotrophin factor
or cognitive-behavioral therapy. Arch Gen Psychiatry 59:425–
levels in response to treatment, and as such cannot make any
direct inference about the mechanism of change. Our small
Furmark T, Appel L, Michelgård A, Wahlstedt K, Ahs F, Zancan S,
Jacobsson E, Flyckt K, Grohp M, Bergström M, Pich EM,
sample size also precluded us drawing conclusions about the
Nilsson LG, Bani M, Långström B, Fredrikson M (2005)
relationship between treatment response, and changes in
Cerebral blood flow changes after treatment of social phobia
brain volume. The preliminary findings here require replica-
with the neurokinin-1 antagonist GR205171, citalopram, or
tion to determine their reliability, and extension to determine
placebo. Biol Psychiatry 58:132–142
Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ,
whether or not they are disorder specific.
Frackowiak RS (2001) A voxel-based morphometric study ofageing in 465 normal adult human brains. Neuroimage 14:21–36
We would also like to acknowledge equipment
Guy W (1976) ECDU assessment manual for psychopharmacology.
support from Siemens. Funding for this study was received from the
National Institute of Mental Health, Research Branch, pp 313–331
Medical Research Council of South Africa and the Harry Crossley
Ipser JC, Kariuki CM, Stein DJ (2008) Pharmacotherapy for social
anxiety disorder: a systematic review. Expert Rev Neurother8:235–257
Kilts CD, Kelsey JE, Knight B, Ely TD, Bowman FD, Gross RE,
Selvig A, Gordon A, Newport DJ, Nemeroff CB (2006) Theneural correlates of social anxiety disorder and response topharmacotherapy. Neuropsychopharmacol 3:2243–2253
American Psychiatric Association (2000) Diagnostic and statistical
Lang UE, Jockers-Scherubl MC, Hellweg R (2004) State of the art of
manual of mental disorders, 4th ed Text Revision (DSMIV-TR).
the neurotrophin hypothesis in psychiatric disorders: implications
American Psychiatric Publishing, Washington DC
and limitations. J Neural Transm 111:387–411
Metab Brain Dis (2010) 25:369–374
Levinson HN (1989a) A cerebellar-vestibular explanation for fears/
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J,
phobias: hypothesis and study. Percept Mot Skills 68:67–84
Weiller E, Hergueta T, Baker R, Dunbar GC (1998) The Mini-
Levinson HN (1989b) The cerebellar-vestibular predisposition to
International Neuropsychiatric Interview (M.I.N.I.): the develop-
anxiety disorders. Percept Mot Skills 68:323–338
ment and validation of a structured diagnostic psychiatric interview
Liebowitz MR (1987) Social phobia. Mod Probl Pharmacopsychiatry
for DSM-IV and ICD-10. J Clin Psychiatry 59:22–33
Spedding M, Gressens P (2008) Neurotrophins and cytokines in
Lorberbaum JP, Kose S, Johnson MR, Arana GW, Sullivan LK,
neuronal plasticity. Novartis Found Symp 289:222–233
Hamner MB, Ballenger JC, Lydiard RB, Brodrick PS, Bohning
Tillfors M, Furmark T, Marteinsdottir I, Fredrikson M (2002) Cerebral
DE, George MS (2004) Neural correlates of speech anticipatory
blood flow during anticipation of public speaking in social
anxiety in generalized social phobia. NeuroReport 15:2701–2705
phobia: a PET study. Biol Psychiatry 52:1113–1119
Martinowich K, Manji H, Lu B (2007) New insights into BDNF
Vermetten E, Vythilingam M, Southwick SM, Charney DS, Bremner
function in depression and anxiety. Nat Neurosci 10:1089–1093
JD (2003) Long-term treatment with paroxetine increases verbal
Montgomery SA, Asberg M (1979) A new depression scale designed
declarative memory and hippocampal volume in posttraumatic
to be sensitive to change. Br J Psychiatry 134:382–389
stress disorder. Biol Psychiatry 54:693–702
Nass R (2002) Plasticity: mechanisms, extent and limits. In:
Vetencourt JFM, Sale A, Viegi A, Baroncelli L, De Pasquale R,
Segalowitz SJ, Rapin I (eds) Handbook of neuropsychology,
O'Leary OF, Castrén E, Maffei L (2008) The antidepressant
2nd ed, vol 8(1), Child neuropsychology, part 1. Elsevier,
fluoxetine restores plasticity in the adult visual cortex. Science
Amsterdam, pp 29–68
Rantamäki T, Hendolin P, Kankaanpää A, Mijatovic J, Piepponen P,
Warwick JM, Carey P, Van der Linden G, Prinsloo C, Niehaus D,
Domenici E, Chao MV, Männistö PT, Castrén E (2007)
Seedat S, Dupont P, Stein DJ (2006) A comparison of the effects
Pharmacologically diverse antidepressants rapidly activate
of citalopram and moclobemide on resting brain perfusion in
brain-derived neurotrophic factor receptor TrkB and induce
social anxiety disorder. Metab Brain Dis 21:241–252
phospholipase-Cgamma signaling pathways in mouse brain.
Warwick JM, Carey P, Jordaan GP, Dupont P, Stein DJ (2008) Resting
brain perfusion in social anxiety disorder: a voxel-wise whole
Schinder AF, Poo M (2000) The neurotrophin hypothesis for synaptic
brain comparison with healthy control subjects. Prog Neuro-
plasticity. Trends Neurosci 23:639–645
psychopharmacol Biol Psychiatry 32:1251–1256
Source: https://gbiomed.kuleuven.be/english/research/50000666/50488664/pdf/2010-cassimjee-metab-brain-dis-sad.pdf
Laboratorios Silanes, S.A. de C.V. Información para prescribir Nombre del producto y F.F.: Versión de IPP: N° de Registro: Versión número: CLOSTEDAL* 86718 SSA-IV N° de Autorización: tabletas KEAR 06330060101992/RM2006 INFORMACIÓN PARA PRESCRIBIR AMPLIA (IPP-A)
The new england journal of medicine Alastair J.J. Wood, M.D., Editor Management of Overactive Bladder Joseph G. Ouslander, M.D. From the Division of Geriatric Medicine veractive bladder is a symptom complex that includes uri- and Gerontology, Wesley Woods Center, nary urgency with or without urge incontinence, urinary frequency (voiding