Metab Brain Dis (2006) 21:241–252
DOI 10.1007/s11011-006-9009-2
ORIGINAL PAPER
A comparison of the effects of citalopram and
moclobemide on resting brain perfusion in social
anxiety disorder
J. M. Warwick · P. Carey · G. Van der Linden ·
C. Prinsloo · D. Niehaus · S. Seedat · P. Dupont ·
D. J. Stein
Received: 30 June 2005 / Accepted: 10 October 2005 / Published online: 21 September 2006
C Springer Science+Business Media, Inc. 2006
Abstract Introduction: The serotonin specific reuptake inhibitor (SSRI) citalopram and
the reversible mono-amine oxidase-A inhibitor (RIMA) moclobemide have both been used
successfully for the treatment of social anxiety disorder (SAD). In this study we investigate
the effects of these compounds on resting brain function using single photon emission
computed tomography (SPECT).
Methods: Subjects meeting DSM-IV criteria for SAD underwent regional cerebral blood
flow (rCBF) SPECT using Tc-HMPAO at baseline and after 8 weeks of treatment with either
citalopram or moclobemide. Using statistical parametric mapping brain SPECT studies were
analysed to determine the effects of treatment on rCBF, to compare the effects of citalopram
and moclobemide, and to detect correlations between changes in rCBF and clinical response.
Results: Subjects received citalopram (n = 17) or moclobemide (n = 14) as therapy. Subjects in both treatment groups demonstrated a significant improvement of SAD symptoms
as measured by the Liebowitz Social Anxiety Scale total score. All subjects demonstrated a
decrease in rCBF in the insulae post therapy. Subjects receiving citalopram had decreased
superior cingulate rCBF after therapy compared to those receiving moclobemide.
Conclusion: Both SSRI’s and RIMA’s decreased rCBF in the insulae during treatment
of SAD; an effect that may be consistent with the role of these regions in processing
internal somatic cues evoked by emotional stimuli. Citalopram had a greater effect on
J. M. Warwick · P. Carey · G. Van der Linden · C. Prinsloo · D. Niehaus · S. Seedat · D. J. Stein
MRC Unit for Stress and Anxiety Disorders, Faculty of Health Sciences, Stellenbosch University,
Cape Town, South Africa
P. Dupont
Nuclear Medicine, Katolieke Universiteit,
Leuven, Belgium
J. M. Warwick ()
Nuclear Medicine, Tygerberg Hospital,
Francie van Zijl Drive, Tygerberg,
7505 Cape Town, South Africa
e-mail: jw@sun.ac.za
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Metab Brain Dis (2006) 21:241–252
superior cingulate perfusion, an effect that is consistent with evidence of high levels of 5-HT
transporters in this region.
Keywords Social phobia . SPECT . Citalopram . Moclobemide . Insula . Cingulate
Introduction
Social anxiety disorder (SAD) is recognized as a discrete anxiety disorder in the Diagnostic
and Statistical Manual of Mental Disorders (DSM-IV) (American Psychiatric Association,
1994). It is a condition characterised by fears of social interaction and performance situations.
These fears cause subjects to avoid these situations or endure them with extreme distress.
Unlike normal social anxiety, SAD results in significant distress and impairment (Wittchen
and Beloch, 1996). SAD, the most prevalent of the major anxiety disorders with a lifetime
prevalence of 10–15%, is associated with significant comorbidity and morbidity (Ballenger,
1998; Magee et al., 1996, Weiller et al., 1996).
The underlying neurocircuitry that mediates SAD is poorly understood, but may involve
regions implicated in anxiety (LeDoux, 1998; Nutt et al., 1998). Thus, neuroimaging studies of SAD demonstrated increased activity in the amygdalo-hippocampal complex during
anticipation (Lorderbaum et al., 2004; Tillfors et al., 2002), public speaking (Tillfors et al.,
2001), and conditioned response (Veit et al., 2002; Birbaumer et al., 1998; Schneider et al.,
1999) paradigms. The amygdalae are believed to play a role in fear conditioning whereas
the hippocampi may be responsible for processing the context of fear conditioning. Simultaneously activity in many cortical areas appears to decrease during anxiety provocation,
perhaps reflecting impaired cognitive processing at these times (Lorderbaum et al., 2004;
Tillfors et al., 2001; Tillfors et al., 2002; Van Ameringen et al., 2004).
A growing body of literature has also implicated specific neurotransmitter systems in
SAD. In particular, evidence has pointed to a role of the dopaminergic and serotonergic
systems (Stein et al., 2002). Selective serotonin reuptake inhibitors (SSRI’s) are effective for
the treatment of SAD (Van der Linden et al., 2000a), and as a class, represent the first-line
pharmacotherapy in SAD. SSRIs are thought to exert their effect in SAD by decreasing
the uptake of serotonin in the synaptic cleft, thus enhancing serotonergic transmission.
Serotonergic projections appear to have an important influence on the pathways that mediate
anxiety (Coplan and Lydiard, 1998), although the exact effects of SSRIs on this neurocircuitry
remain unclear.
Similarly, there is evidence demonstrating the efficacy of monoamine oxidase inhibitors,
including the reversible inhibitors of monoamine oxidase (RIMAs) in the treatment of SAD
(Liebowitz et al., 1992). These drugs have a less specific effect on neurotransmission; by
inhibiting the enzyme monoamine oxidase, they result in an increase in intrasynaptic levels
of a range of monoamines (noradrenaline, dopamine, and serotonin). Meta-analyses have
suggested that SSRIs may be more effective than RIMAs in the treatment of SAD (Van der
Linden et al., 2000a), and the latter agents are therefore more often used in clinical situations
where tolerability is a particular asset.
While both SSRI’s and RIMA’s have demonstrated clinical efficacy, little is known
about the neuro-anatomical mechanisms underlying the efficacy of these drugs in SAD.
In a previous region of interest (ROI) based study, after 8 weeks of citalopram treatment,
SAD patients had a decrease in resting rCBF in the temporal, frontal, and cingulate cortex
on the left side (Van der Linden et al., 2000b). Furmark et al. described attenuation of
the rCBF response to a public speaking task bilaterally in the amygdala, hippocampus,
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Metab Brain Dis (2006) 21:241–252
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and the periamygdaloid, rhinal, and parahippocampal cortices after 9 weeks of treatment
with either SSRI or cognitive behavioural therapy (Furmark et al., 2002). The authors are
not aware of any published work describing the effects of MAO inhibitors or RIMA’s on
rCBF.
A comparison of the effects on rCBF of SAD treatment with a SSRI and with a RIMA
could provide insights into their mechanisms of action in this condition. In this study the
effects on resting rCBF of the highly selective SSRI citalopram and the RIMA moclobemide
were compared and contrasted using brain SPECT. Data from 12 of these patients, receiving
only citalopram, has previously been reported using a ROI analysis (Van der Linden et al.,
2000b); in this study we extended the sample receiving citalopram, added subjects receiving
moclobemide, and used a voxel based analysis.
Methods
Subjects
Adult subjects with a primary diagnosis of generalised SAD were recruited from the Anxiety
Disorders Clinic of our tertiary hospital. All subjects were interviewed with the Structured
Clinical Interview for the Diagnosis of Axis-I Disorders to ascertain diagnosis according to
DSM-IV criteria (DSM IV) (First et al., 1996).
Subjects with other primary psychiatric disorders, significant medical illness or a neurological condition were excluded. A few patients had comorbid psychiatric disorders (2–panic
disorder, 1–trichotillomania (TTM), 1–generalised anxiety disorder (GAD) and body dysmorphic disorder, and 1–GAD and TTM). These conditions were considered secondary in
terms of temporal course, symptom severity, and associated distress and the subjects were
therefore included.
All data was acquired after receiving approval from the Institutional Review Board of
our University and all patients gave informed written consent after a full explanation of the
possible risks and benefits.
Pharmacotherapy
All patients underwent treatment for 8 weeks with either the selective serotonin reuptake
inhibitor citalopram, or the reversible inhibitor of monoamine oxidase-A moclobemide.
Subjects receiving citalopram were initiated on a dosage of 20 mg daily for the first two
weeks and then increased to 40 mg daily for the remaining 6 weeks. Moclobemide therapy
was initiated at 600 mg/day for first two weeks and then increased to 900 mg/day for the
remaining six weeks.
Measures
Ratings were carried out at baseline and every two weeks until the completion of pharmacotherapy. Social anxiety symptoms, depression, and disability were rated using the
Liebowitz Social Anxiety Scale (LSAS), Montgomery-Asberg Depression Rating Scale
(MADRS), and Sheehan Disability Scale (SDS) respectively. (Liebowitz, 1987; Montgomery
and Asberg, 1979; Sheehan, 1983).
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SPECT imaging
Single photon emission computed tomography (SPECT) was conducted before and after
pharmacotherapy. Subjects lay supine in a quiet dimly lit room for 30 min prior to injection
of the radiopharmaceutical. Apart from administration of the injection by a physician, they
remained alone in the room during this period. Subjects were asked to remain at rest for 10 min
after the injection of the radiopharmaceutical to allow uptake of the radiopharmaceutical in
the brain.
An injection of 555 MBq (15 mCi) of technetium-99 m hexamethylpropylene amine
oxime (Tc-99 m HMPAO) was given into an arm vein through a previously placed intravenous
cannula. After completion of the 10 min rest period described above, SPECT imaging of
the brain was performed, with the subject’s head supported by a headrest, using a dual
detector gamma camera (Elscint Helix, GE Medical Systems, USA) equipped with fanbeam
collimators.
Data were acquired in the step-and-shoot mode, using a 360 degree circular orbit, with
the detectors of the gamma camera as close as possible to the subject’s head. The radius of
rotation was noted for each subject and the same measurements were used for the follow-up
study. Data were acquired using a 128 × 128 image matrix in 3 degree steps of 15 seconds
per step.
Data were reconstructed by filtered backprojection, using a Metz filter (power = 5,
FWHM = 14 mm). The Chang method (µ = 0.11/ cm) was used for attenuation correction (Chang, 1978). The final reconstructed voxel size was 1.7 × 1.7 × 3.9 mm3 . Image files
were converted from interfile to analyze format using conversion software (Medcon, Erik
Nolf, UZ Ghent, Belgium).
Spatial preprocessing
Statistical analyses were conducted on a voxel-by-voxel basis using Statistical Parametric
Mapping (SPM99, Wellcome Department of Cognitive Neurology, UK) (Friston et al., 1991).
The realign function was used to co-register baseline and post-treatment SPECT images for
each subject and to generate a mean image for each subject. Realigned images were then
normalised to the Montreal Neurological Institute (MNI) standard anatomical space with
4 × 4 × 4 mm3 voxels, and to a value of 50 using proportional scaling. This was achieved
using the transform function from the realigned mean image for each subject, to the template
image in MNI space using 12 affine transformations and 7 × 8 × 7 non-linear basis functions.
The normalised images were then smoothed using a 3D Gaussian kernel with a FWHM of
12 mm.
Analysis
A multi-group study design was performed using 2 groups (citalopram therapy and moclobemide therapy) with 2 conditions each (pre- and post-treatment). Contrasts were applied
to detect: (i) areas of significant change post-treatment compared to pre-treatment, and
(ii) areas of relative change in subjects receiving citalopram compared to those receiving
moclobemide.
A second study design, using the change in LSAS as a covariate, was performed to detect
correlations between the change in LSAS and the change in rCBF as a result of therapy.
Contrasts were applied to detect positive and negative correlations.
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Table 1
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Mean and standard deviation of various scales
Baseline
Post therapy
% change
p∗
Total Liebowitz Social Anxiety Scale (LSAS) scores at baseline and following pharmacotherapy
Citalopram
(n = 17)
95.2 ± 21.4
76.1 ± 26.9
20.1
<0.01
Moclobemide
(n = 14)
107.6 ± 20.7
69.4 ± 20.1
35.5
<0.001
Montgomery-Asberg Depression Rating Scale (MADRS) scores at baseline and following pharmacotherapy
Citalopram
(n = 17)
14.1 ± 5.3
7.1 ± 4.4
49.6
<0.0001
Moclobemide
(n = 14)
7.7 ± 6.5
3.8 ± 2.6
50.6
<0.01
Total Sheehan Disability Scale (SDS) scores at baseline and following pharmacotherapy
Citalopram
(n = 17)
17.9 ± 4.7
12.6 ± 7.3
29.6
<0.001
Moclobemide
(n = 14)
18.9 ± 4.4
13.6 ± 6.0
28.0
<0.01
∗ One-tailed
paired Student’s t-test.
An uncorrected p-value of p < 0.001 was chosen as a threshold for statistical significance.
A spatial extent threshold of 10 voxels was also used at all times. Clusters were located to
anatomical regions using MRIcro software (Chris Rorden, Nottingham University, UK).
Results
Thirty-one subjects (21 male, 10 female) with a mean (SD) age of 33 (9) years completed the
study. Seventeen subjects received citalopram and 14 subjects received moclobemide. The
two groups were clinically similar, although those receiving citalopram had higher MADRS
scores at baseline (p < 0.01). All but two subjects, one on alprazolam 1 mg/d and another
on propranolol 20 mg/d, were free of any other psychotropic medication during the study.
Clinical changes with pharmacotherapy for each drug are provided in Table 1. Pharmacotherapy using both drugs was associated with a significant reduction in social anxiety
symptom severity, depression symptoms, and disability.
The results of the SPM analysis are summarised in Table 2. Comparison of pre- and
post-treatment scans for the whole group showed decreased activity in 2 significant clusters
located in the regions of right and left insulae. (Fig. 1) Comparing the effects of citalopram
with moclobemide demonstrates a significantly greater decrease in perfusion in the superior
cingulate in those subjects receiving citalopram. (Fig. 2).
Using the change in LSAS as a covariate, a significant correlation was detected between the
LSAS change score and decreased rCBF in the posterior cingulate. On closer examination of
this region it was found that across patients when comparing the pre- and post-therapy scans,
the response to therapy in this region was heterogenous with a mixture of decreasing and
increasing rCBF. This correlation therefore represented a mixture of a progressively smaller
increases in rCBF (in subjects with increased rCBF with treatment) and a progressively
larger decrease in rCBF (in subjects with decreased rCBF with treatment), with increasing
LSAS change score. Conversely two other clusters, in the right mid-temporal cortex and
the cuneus, showed a significant correlation between change in LSAS and increased rCBF
following therapy. (Fig. 3).
Furthermore, although not attaining the high level of significance required for the voxelwise analyses above, an analysis of the individual voxels with the most significant deactivations in the insulae of the combined group following therapy, demonstrated a positive
correlation with the change in LSAS (p < 0.05).
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Table 2 Changes in rCBF following pharmacotherapy, differences between citalopram and moclobemide
therapy, and correlations between change in LSAS and rCBF changes with therapy
Region
Decreased for both drugs:
Right insula
Left insula
Decreased in citalopram, not in
moclobemide
Mid cingulate
Correlation between change in LSAS and
decrease in rCBF
Posterior cingulate
Right insula∗
Left insula∗
Correlation between change in LSAS and
increase in rCBF
Right mid-temporal cortex
Cuneus
MNI coordinates x,y,z (mm)
Voxels
t
36, 12, − 4
− 44, 4, 4
27
11
5.07
4.21
4, 12, 44
18
4.69
− 8, − 36, 24
36, 12, − 4
− 44, 4, 4
16
4.39
2.05
2.22
60, − 52, 16
− 4, − 84, 24
10
21
4.40
3.90
∗ Not
significant for voxelwise analysis of whole brain volume, but p < 0.05 for single voxels at sites of
maximum insular deactivation with therapy.
Discussion
A first finding in this study was that resting rCBF in subjects with social anxiety disorder
decreased in the insulae bilaterally following therapy with both the SSRI citalopram and
the RIMA moclobemide. This was also noted when looking at the drugs separately (results
not shown), although this did not reach statistical significance, probably due to the small
size of the individual treatment groups. Furthermore, when looking at the voxels with the
most significant deactivation in the left and right insulae, there was a significant relationship
between the magnitude of the deactivation and the clinical response based on a change in
the LSAS. Thus, insular deactivation may not merely reflect treatment with the medications
here, but may be directly related to effective pharmacotherapy.
It is interesting that despite differences in their pharmacological actions both of these
drugs were both clinically effective and both had common effects on rCBF. Little is known
about the effects of SAD on resting rCBF. Only one study has been published comparing
resting rCBF in SAD patients with a control group (Stein and Leslie, 1996). This study found
no differences between the two groups, but only limited areas of the brain were examined
using manually placed regions of interest. In particular the study did not focus on insular
perfusion. It is possible that resting rCBF may be increased in the insulae in SAD patients,
with normalisation following successful pharmacotherapy. However there is no experimental
data to substantiate or refute this.
Other studies have demonstrated that SSRI’s alter brain perfusion (Carey et al., 2004;
Furmark et al., 2002; Geday et al., 2005) and metabolism (Smith et al., 2002; New et al.,
2004). The overlapping effects on rCBF of these two drugs with differing primary mechanisms of action, suggests that at least some of their direct or secondary actions seem to
overlap and to effect a clinical response in SAD. Brain perfusion is however an indirect measure of neuronal metabolism and neuronal activity. Although these processes can become
decoupled under certain circumstances, they are normally linked (Kessler, 2003). Thus, it
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Fig. 1 Two clusters of significantly decreased rCBF in the left and right insulae in all subjects following
pharmacotherapy with citalopram or moclobemide. The clusters are superimposed onto a representative
T1-weighted MRI study in MNI space. (Courtesy of MRIcro, Chris Rorden, Nottingham University, UK)
can be speculated that in SAD the effects of SSRI’s and RIMA’s on neuronal function may
converge to a common pathway involving the insulae.
Previous work in SAD has implicated the insulae with demonstration of increased activity
during anticipation (Lorderbaum et al., 2004) and conditioned response (Veit et al., 2002)
paradigms. In apparent contrast, decreased activity during a public speaking task has been
demonstrated (Tillfors et al., 2001). It is possible that the insulae activate the amygdalohippocampal complexes during anticipation of an unpleasant task or while a conditioned
response is evoked (Veit et al., 2002). However during exposure to the feared situation, the
insulae no longer play this role. After successful pharmacotherapy, social stimuli are less
likely to be experienced as aversive, and there is apparently a decrease in baseline activity
in this region. We were unable to demonstrate an effect of SSRI treatment on the amygdalohippocampal complex in SAD, perhaps because of the relatively poor spatial resolution
of SPECT compared with PET. A primary effect of antidepressants on the insulae cannot
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Fig. 2 Single cluster of significantly decreased rCBF in the superior cingulum in subjects receiving citalopram
compared to those receiving moclobemide. The cluster is superimposed onto a representative T1-weighted
MRI study in MNI space. (Courtesy of MRIcro, Chris Rorden, Nottingham University, UK)
however be ruled out on the basis of the data at hand. Changes in the insulae after SSRIs
may also not be limited to SAD; decreased resting glucose metabolism was noted in the right
insula of elderly patients with depression following 8 weeks of citalopram therapy (Smith
et al., 2002). This raises the question of whether specific serotonin receptors in the insulae
are involved in the response to SSRIs. At the same time, caution is required in suggesting
that the citalopram or moclobemide act directly on specific receptors in particular regions in
order to change perfusion there. These agents have a range of secondary effects in addition
to their initial effects on synaptic neurotransmitters. Despite this, autoradiographic work has
demonstrated high densities of serotonin transporters in the limbic system and the insulae
(Varnäs et al., 2004). Studies with serotonergic ligands in SAD might be useful in shedding
light on this issue.
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Fig. 3 Single cluster of significant correlation between magnitude of change of LSAS and decrease in rCBF
in the region of the posterior cingulate. Two clusters of significant correlation between magnitude of change
of LSAS and increase in rCBF in the right mid-temporal cortex and cuneus. The clusters are superimposed
onto a representative T1-weighted MRI study in MNI space. (Courtesy of MRIcro, Chris Rorden, Nottingham
University, UK)
A second finding was that patients receiving citalopram demonstrated a significant decrease in resting perfusion to the mid-cingulate compared to those receiving moclobemide.
In the group as a whole, there was a correlation between improved symptoms and deactivation of the posterior cingulate. Deactivation of the cingulate is consistent with an earlier
ROI based report of SAD patients treated with citalopram using a sub-set of the subjects
used in this study (Van der Linden et al., 2000b) and with a mixed population of anxiety
disorders in a population that also included a subset of the patients in the current study
(Carey et al., 2004). The greater effect of citalopram on the cingulate is consistent with
innervation of cingulate cortex by inhibitory serotonergic neurons arising from the raphe
nuclei in the brainstem, with autoradiographic studies demonstrating a high concentration of
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serotonin transporters in this region (Varnäs et al., 2004), and imaging studies showing a high
level of occupancy of the serotonin transporter at therapeutic levels of SSRI’s (Kent et al.,
2002).
It has been suggested that therapeutic interventions in SAD may exert their effect by
suppression of neuronal activity in the amygdalo-hippocampal and surrounding cortical
regions, including the cingulate (Furmark et al., 2002). The amygdalae receive inhibitory
inputs from the cingulate that are believed to mediate the extinction of fear conditioning.
Consequently amygdala hyperactivity in SAD may result in a compensatory increase in
cingulate activity that is no longer needed following successful pharmacotherapy.
A number of limitations of the current study can be noted. First, two subjects, one on
alprazolam 1 mg/d and another on propranolol 20 mg/d, were receiving other psychotropic
medication during the study. However some evidence exists suggesting that rCBF is unaffected by the chronic administration of these drugs (Roy-Byrne et al., 1993; Madsen et al.,
1990). Second, the difference in the severity of the baseline depression symptoms between
the 2 groups is a potential confound, so that a more marked decrease in cingulate perfusion
in the citalopram group may be a reflection of the treatment of more severe depressive
symptoms in this group. Third, the relatively small sample size and the limitations of SPECT
may have lead to an inability to detect and identify true differences, as well as false positive
findings. The choice of significance threshold is a compromise to attempt to minimise the
presence of type 1 and type 2 errors. Nevertheless, the findings contribute to a growing
literature on the functional imaging of anxiety disorders.
Future work will also need to assess particular neuroreceptor systems before and after
pharmacotherapy of SAD. In particular, reasonably available and validated SPECT ligands
exist that may be used to evaluate the serotonergic and dopaminergic systems in these patients
(de Win et al., 2005).
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