Print ISSN 1738-3684 / On-line ISSN 1976-3026
Copyright © 2010 Korean Neuropsychiatric Association 215
Changes in Cerebral Cortex and Limbic Brain Functions
after Short-Term Paroxetine Treatment in Panic Disorder:
An [18F]FDG-PET Pilot Study
Hyun-Bo Sim, Eun-Ho Kang and Bum-Hee Yu
Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
ObjectiveaaPanic disorder (PD) is a common and often chronic psychiatric illness, and serotonin-specific reuptake inhibitors (SSRIs)
are the drugs of choice for the treatment of PD. Previous studies suggested the cerebral cortex and limbic brain structures played a major
role in the development of PD, but the therapeutic effect of SSRIs on specific brain structures remains unclear in PD. We examined the
changes in PD patients’ glucose metabolism using the [18F] Fluorodeoxy-glucose-positron emission tomography (FDG-PET) before and
after 12 weeks of paroxetine treatment.
MethodsaaWe assessed the brain glucose metabolism of 5 PD patients, using the [18F]FDG-PET, and treated them with paroxetine
(12.5-37.5 mg/day) for 12 weeks. Then, we compared before and after treatment PET images of the patients, using voxel-based statistical
analysis and a post hoc regions of interest analysis. Furthermore, we measured the patients’ clinical variables, including information from
the Panic Disorder Severity Scale (PDSS), Clinical Global Impression for Severity (CGI-S), and Hamilton Anxiety Rating Scale (HAMA).
ResultsaaAfter 12 weeks of paroxetine treatment, the patients showed significant clinical improvement in terms of PDSS, CGI-S and HAMA
scores (12.8±1.8 vs. 3.8±2.3, 4.6±0.5 vs. 2.0±1.4, and 15.2±4.0 vs. 5.0±1.2, respectively; all p values<0.05). After treatment, patients’ glu-
cose metabolism increased significantly in global brain areas: the right precentral gyrus, right middle frontal gyrus, right amygdala, right
caudate body, right putamen, left middle frontal gyrus, left precentral gyrus, left insula, left parahippocampal gyrus, and left inferior fron-
tal gyrus (All areas were significant at uncorrected p<0.001 and cluster level corrected p<0.05).
ConclusionaaIn these PD patients, cerebral cortex and limbic brain functions changed after short-term treatment with paroxetine. The
therapeutic action of paroxetine may be related to altered glucose metabolism at both the cerebral cortex and limbic brain areas.
Psychiatry Investig 2010;7:215-219
Key Wordsaa Brain imaging, Positron emission tomography, Panic disorder, Paroxetine.
Received: March 24, 2010 Revised: July 4, 2010
Accepted: July 16, 2010 Available online: August 13, 2010
Correspondence: Bum-Hee Yu, MD, PhD
Department of Psychiatry, Samsung Medical Center, Sungkyunkwan Univer-
sity School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea
Tel: +82-2-3410-3583, Fax: +82-2-3410-6957, E-mail: firstname.lastname@example.org
cc This is an Open Access article distributed under the terms of the Creative Commons
Attribution Non-Commercial License (http://creativecommons.org/licenses/by-
nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduc-
tion in any medium, provided the original work is properly cited.
Panic disorder (PD) occurs in approximately 3.5% of the ge-
neral population and in up to 20% of primary care patients.1,2
This relatively common syndrome remains a chronic illness,
despite the availability of effective anti-panic treatments, such
as serotonin-specific reuptake inhibitors (SSRIs). While most
patients show a clinical response to SSRIs, only 30-40% of them
experience a cure.3 Thus, for better treatments, clinicians need
more information about SSRIs’ therapeutic mechanism in PD.
There have been many biological investigations into the pa-
thophysiology of PD. Studies have implicated abnormal func-
tioning in catecholamines (noradrenergic and dopaminergic)
and serotonergic and GABAergic systems, as well as abnor-
mal chemoreceptor reactivity, in the pathophysiology of PD.4
Medications that are thought to interact with monoamines
and serotonergic systems, such as tricyclic antidepressants, mo-
noamine oxidase inhibitors, and SSRIs are effective in treat-
ing PD, suggesting monoamine neurotransmitters potential-
ly play a role in PD.5
There have been reports that PD patients show neural pro-
cessing abnormalities in several brain regions, such as the fron-
tal lobe, limbic system, and temporal lobe.6 Imaging investi-
gations, especially functional neuroimaging studies, are in the
highlight as research modalities for establishing the pathophys-
iological mechanisms of psychiatric illnesses. Among them,
online © ML Comm
216 Psychiatry Investig 2010;7:215-219
Paroxetine on Brain Function in Panic Disorder
PET permits visualization of regional brain metabolism and
neuroreceptor systems by means of a positron-labeled tracer
and a quantitation model. As PET is more sensitive to post-
treatment brain metabolism changes, compared to other mo-
dalities, it is preferred for clinical treatment studies in patients
A few studies have examined PD patients’ brain resting st-
ates in terms of brain glucose metabolism. Using resting state
PET, Reiman et al.8 showed unmedicated PD patients had ab-
normal asymmetry in cerebral blood flow (left less than right)
within a region of the parahippocampal gyrus, as compared
to normal controls. Bisaga et al.9 reported significantly increased
glucose metabolism in the left hippocampus and parahippo-
campal area in female PD patients.
Antidepressants, especially SSRIs, are widely used as first-
line pharmacological agents for PD treatment, but little is kn-
own about the change in brain function after antidepressant
treatment. This pilot study measured the changes in brain glu-
cose metabolism, using the [18F] Fluorodeoxy-glucose-positron
emission tomography (FDG-PET), in PD patients before and
after 12-weeks of paroxetine treatment and examined the ther-
apeutic effect of paroxetine on brain structures in PD.
Five patients who met the DSM-IV criteria for current PD
and had a Panic Disorder Severity Scale (PDSS) score over 7
participated in this study.10 All subjects were right-handed. The
patients were recruited from the outpatient psychiatric unit
of Samsung Medical Center in Seoul and diagnosed using the
Structured Clinical Interview for the DSM-IV.11 The clinical
evaluation included a physical examination, electrocardio-
gram, clinical laboratory tests including liver, kidney, and thy-
roid function tests, and urinalysis, to rule out serious medical
illnesses. We measured the clinical severity of the PD using
the PDSS, the Clinical Global Impression for Severity (CGI-S),
the Hamilton Rating Scale for Depression (HAM-D),12 the Ha-
milton Rating Scale for Anxiety (HAM-A),13 and the Spiel-
berger State-Trait Anxiety Inventory,14 both before and after
Exclusion criteria for all subjects included current major
medical or neurological disorders; coexisting major psychi-
atric illnesses, including current major depression; any anxi-
ety disorder other than PD; lifetime history of bipolar disor-
der, schizophrenia, and substance use disorders; and exposure
to psychotropic medications within 4 weeks of PET scanning
(within 8 weeks for fluoxetine). Subjects with a HAM-D score
>17 were also excluded.15 Additional exclusion criteria in-
cluded a personal or first-degree family history of major psy-
chiatric illnesses. All subjects abstained from alcohol and caf-
feine for 24 hours before the PET scan. The Institutional Re-
view Board of Samsung Medical Center approved this study,
and all subjects gave their informed consent before partici-
pating in the study.
We treated all PD patients with paroxetine medication for
12 weeks,16 following baseline evaluations. No cognitive be-
havioral treatment was combined with this pharmacothera-
py. The initial paroxetine dose for PD patients was 12.5 mg/
day for the first week. The physician determined doses admin-
istered during treatment based on adverse events and clinical
treatment responses. Two patients received adjunctive alpra-
zolam p.r.n. during the first 3 weeks. The mean final dose of
paroxetine was 27.0 mg.
We conducted the PET scans at the Department of Nucle-
ar Medicine of the Samsung Medical Center, obtaining PET
measurements of brain glucose metabolism at baseline and
again at the end of treatment for all participants. Baseline
scans took place during the week before the start of treat-
ment, and final scans within 1 week of the last treatment visit.
All PET sessions began at 8-9 : 00 AM. Using a GE Advance
PET scanner (GE Medical Systems, Milwaukee, WI), we ac-
quired the images with participants awake and rested, with
their eyes closed and ears unplugged. For each scan, we ad-
ministered 4.8 MBq/kg of [18F]FDG via a peripheral vein cath-
eter and recorded emission data over 15 minutes, starting 30
minutes after the [18F]FDG injection. A customized fitted
thermoplastic facemask minimized participants’ head move-
ments while allowing for accurate repositioning. We used a
Hanning filter (cut-off frequency=4.5 mm) to reconstruct the
PET images and displayed them in 128×128 matrix (pixel size=
1.95×1.95 mm with a slice thickness of 4.25 mm). We acquired
PD patients’ post-treatment PET images using the same scan-
ner and an identical protocol.
We analyzed the changes in the clinical psychological data
between the baseline and post-treatment by means of a paired
t-test and performed the statistical analyses of the PET data
using statistical parametric mapping (SPM) 2 (Wellcome De-
partment of Imaging Neuroscience, University College Lon-
don, London, England), implemented in Matlab version 7.0.
To determine the stereotactic coordinates of the peak differ-
ences, we used the Talairach and Tournoux17 atlas, after trans-
lating the MNI coordinates to coordinates according to the
Talairach template via the Matlab function mni2tal.m (http://
HB Sim et al.
spatially normalizing the pre-treatment and post-treatment
PET images to a standard FDG-PET template, we linearly
transformed each pre-treatment PET image to match the post-
treatment PET image. Also, we normalized all of the PET im-
ages to the standard FDG-PET template in SPM2, using a 12-
parameter affine and a non-linear transformation, and smoo-
thed them using a 14-mm, full-width, half-maximum Gaussian
kernel to increase the signal to noise ratio. We normalized the
count of each voxel to the total count of the brain (proportional
scaling) to remove the differences in global glucose metabolism
between individuals. To examine the statistical significance of
the differences between pre-treatment and post-treatment, we
utilized a paired t-test (statistical significances were set at un-
corrected p<0.001). Finally, we calculated the adjusted mean
activities of the regions of interest (ROIs), by the previously-de-
scribed method, from the clusters obtained from voxel-wise
t-statistics and performed a post-hoc ROI analysis to examine
the correlation between the change in brain activity and the ch-
ange in psychological variables.18
Table 1 shows the patients’ demographic and baseline clin-
ical characteristics (n=5). The patients’ mean age was 42.6
years, and 2 of the participants had agoraphobia. All patients
were naïve to psychotropic medications except paroxetine,
and 2 had taken benzodiazepines intermittently. No PD pa-
tients experienced a panic attack during PET scanning.
All patients responded to the 12 weeks of paroxetine treat-
ment (no panic attacks during the final 4 weeks and final PDSS
score <50% of baseline PDSS score). The patients showed
clinical improvement in terms of the CGI-S [4.6 (0.5) vs. 2.0
(1.4); p=0.025], the PDSS [12.8 (1.8) vs. 3.8 (2.3); p=0.002)],
the HAM-A [15.2 (4.0) vs. 5.0 (1.2); p=0.009)], and the HAM-
D [13.4 (2.6) vs. 4.4 (1.5); p=0.003)].
After the 12 weeks of paroxetine treatment, patients showed
a significantly increased [18F]FDG uptake compared to base-
line in 10 brain areas: the right precentral gyrus, the right mid-
dle frontal gyrus, the right amygdala, the right caudate body,
the right putamen, the left middle frontal gyrus, the left precen-
tral gyrus, the left insula, the left parahippocampal gyrus, and
the left inferior frontal gyrus (Table 2, Figure 1).
Previous studies of anxiety disorder emphasized the role of
the limbic brain and the cerebral cortex regions.19-22 In line
with our results, Boshuisen et al.23 reported PD patients had
hypoactivity in the precentral gyrus, the inferior frontal gyrus,
Table 1. Demographic and clinical characteristics (N=5)
VariableBaseline After treatmentp value
PD duration (months)
Clinical Global Impression for Severity
Panic Disorder Severity Scale
Hamilton Rating Scale for Anxiety
Hamilton Rating Scale for Depression
Spielberger State Anxiety inventory
Spielberger Trait Anxiety inventory
*p<0.05. PD: panic disorder, SD: standard deviation
04.6 (0.5) 2.0 (1.4)0.025*
12.8 (1.8) 3.8 (2.3)0.002*
15.2 (4.0)5.0 (1.2)0.009*
13.4 (2.6)4.4 (1.5)0.003*
40.0 (16.3) 35.0 (13.0)0.382
43.6 (18.3)35.8 (6.0)00.303
218 Psychiatry Investig 2010;7:215-219
Paroxetine on Brain Function in Panic Disorder
and the anterior insula, both during anticipatory anxiety and
at rest after pentagastrin challenge. Unfortunately, our study
did not include a control group, and we did not know which
brain structures of the patients were abnormal compared with
those of normal subjects. However, our results suggest a link
between cerebral cortex regions and SSRI treatment in terms
of brain glucose metabolism. Similar to previous studies, we
could detect the functional changes after treatment in the hip-
pocampal and parahippocampal areas or the amygdala in
patients with PD. Functional or structural abnormalities of the
hippocampus, parahippocampus, and amygdala are often re-
ported in PD.6 Our findings suggest that cerebral cortex re-
gions, as well as limbic brain areas including the amygdala, hip-
pocampus, and parahippocampal gyrus, may play a more im-
portant role in PD treatment. This study is the first to examine
the effect of a single SSRI on brain metabolism in PD patients
and suggests that paroxetine treatment may work its therapeu-
tic action by increasing the activities of not only the limbic br-
ain but also cerebral cortex regions, including the prefrontal
Gorman et al.6 suggested a possible mechanism for the two
different main treatment modalities, SSRIs and cognitive be-
havior therapy (CBT), in PD patients. The hypothesis is that
medications, particularly those that influence the serotonin
system, desensitize the fear network, from the level of the am-
ygdala through its projections into the hypothalamus and the
brainstem.24 Effective psychosocial treatments may also re-
duce contextual fear and cognitive misattributions at the level
of the prefrontal cortex and hippocampus.25 Prasko et al.26
examined the effects of SSRIs, as well as CBT, on PD patients
in terms of basal glucose metabolism, using [18F]FDG-PET.
They reported SSRIs cause metabolic changes at the cortical
level, such as decreases in the inferior temporal gyrus and the
right hemisphere’s superior and inferior frontal gyri, increas-
es in the inferior frontal gyrus and middle temporal gyrus,
and (increases in) insulin in the left hemisphere. They did not
detect changes in [18F]FDG uptake in the limbic regions (hip-
pocampus, parahippocampal gyrus, and amygdala). Howev-
er, their study had some limitations, such as using a priori hy-
pothesized ROIs and using different medications on each patient.
Icreased metabolism in the right amygdala and left parahip-
pocampal gyrus after paroxetine treatment seems paradoxi-
cal, because the amygdala and parahippocampal gyrus im-
portant structures in fear acquisition and consolidation. Many
studies have shown that acutely increasing 5-HT levels, either
globally or regionally, in the brain of an experimental animal
increases fear and avoidance.27 In some studies, long-term ad-
ministration of 5-HT precursors or agonists appear to main-
tain this fear increase,28 although some contradictory data ex-
ist. This stimulating effect of serotonin seems to be related to
increased metabolism in the amygdala and the parahippo-
campal gyrus.29 However, the stimulating effect of serotonin
in PD patients is usually temporary, and SSRIs are effective in
reducing panic symptoms. Thus, in PD, paroxetine’s effect may
result from increased frontal cortex activity, whereas the par-
oxetine’s role in the amygdala and the parahippocampal gyrus
is still in debate.
Our study had several limitations. First, as this was a pilot
study, our sample size was too small. Examining the exact pa-
thophysiology of PD woud require a larger patient sample size,
with a control group. Second, this study’s design was semi-
naturalistic, and the medication dosages were flexible, accord-
ing to the physician’s decisions. Finally, the relatively short
pharmacotherapy duration may be a potential limitation in as-
sessing our results.
In conclusion, PD patients’ cerebral cortex and limbic brain
functions changed after short-term treatment with paroxetine.
Table 2. Regions where [18F] FDG uptake increased after parox-
etine treatment in patients with panic disorder, by voxel-wise
Right precentral gyrus, BA4
Right middle frontal gyrus, BA6
Right caudate body
Left middle frontal gyrus, BA6
Left precentral gyrus, BA6
Left insula, BA13
Left parahippocampal gyrus, BA34
Left inferior frontal gyrus, BA47
*all results were significant at uncorrected p<0.001. BA: Brodmann
area, FDG: Fluorodeoxy-glucose
Figure 1. Statistical parametric map illustrating brain areas with
increased activity, in panic disorder patients (N=5) after 12 weeks
of paroxetine treatment.
HB Sim et al.
Paroxetine’s therapeutic action may be related to altered glu-
cose metabolism in both the cerebral cortex and limbic brain
This study was supported by the Choi Shin Hae Research Fund of Korean
Neuropsychiatry Research Foundation in 2007.
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