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Common Changes in Cerebral Blood Flow in Patients With Social Phobia Treated With Citalopram or Cognitive-Behavioral Therapy
Tomas Furmark, PhD;
Maria Tillfors, PhD;
Ina Marteinsdottir, MD;
Håkan Fischer, PhD;
Anna Pissiota, MSc;
Bengt Långström, PhD;
Mats Fredrikson, PhD, DMSc
Arch Gen Psychiatry. 2002;59:425-433.
ABSTRACT
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Background Neurofunctional changes underlying effective antianxiety treatments
are incompletely characterized. This study explored the effects of citalopram
and cognitive-behavioral therapy on regional cerebral blood flow (rCBF) in
social phobia.
Methods By means of positron emission tomography with oxygen 15–labeled
water, rCBF was assessed in 18 previously untreated patients with social phobia
during an anxiogenic public speaking task. Patients were matched for sex,
age, and phobia severity, based on social anxiety questionnaire data, and
randomized to citalopram medication, cognitive-behavioral group therapy, or
a waiting-list control group. Scans were repeated after 9 weeks of treatment
or waiting time. Outcome was assessed by subjective and psychophysiological
state anxiety measures and self-report questionnaires. Questions were readministered
after 1 year.
Results Symptoms improved significantly and roughly equally with citalopram
and cognitive-behavioral therapy, whereas the waiting-list group remained
unchanged. Four patients in each treated group and 1 waiting-list patient
were classified as responders. Within both treated groups, and in responders
regardless of treatment approach, improvement was accompanied by a decreased
rCBF-response to public speaking bilaterally in the amygdala, hippocampus,
and the periamygdaloid, rhinal, and parahippocampal cortices. Between-group
comparisons confirmed that rCBF in these regions decreased significantly more
in treated groups than control subjects, and in responders than nonresponders,
particularly in the right hemisphere. The degree of amygdalar-limbic attenuation
was associated with clinical improvement a year later.
Conclusions Common sites of action for citalopram and cognitive-behavioral
treatment of social anxiety were observed in the amygdala, hippocampus, and
neighboring cortical areas, ie, brain regions subserving bodily defense reactions
to threat.
INTRODUCTION
COMMUNITY SURVEYS indicate that at least 20% of the US population have
anxiety disorders1 and that the annual societal
cost of these disorders exceeds $63 billion in 1998 dollars.2
This underscores the importance of developing efficacious antianxiety treatments,
which could be facilitated by a greater understanding of the brain regions
involved in anxiety reduction. In the past decade, it was learned that selective
serotonin reuptake inhibitors (SSRIs), such as fluoxetine, are helpful not
only in depression but also for patients with anxiety disorders.3
The SSRIs are generally considered to enhance serotonergic neurotransmission
in the brain, but the neural mechanisms whereby these drugs alleviate anxiety
symptoms are not well characterized. Similarly, psychological treatments such
as cognitive-behavioral therapy are effective in reducing anxiety, but little
is known about how successful psychotherapy exerts its beneficial effect in
the central nervous system.
Extensive evidence indicates that the amygdala plays a major role in
fear and anxiety reactions.4 In animals, anxiolytic
effects can be achieved by injections of benzodiazepines directly into the
amygdaloid complex.5-6 The hippocampus
is also a part of the neural anxiety network, participating in the consolidation
and retrieval of traumatic memories, behavioral inhibition, and contextual
analysis of distressing situations.7 Animal
studies suggest that the effects of anxiolytic drug administration are paralleled
by lesions to the hippocampus.8 Although it
can be hypothesized that the amygdala and hippocampus are important brain
targets for traditional antianxiety pharmacotherapy, it remains unclear whether
the SSRIs and efficacious psychotherapeutic techniques act on these or other
regions in the brain. Neuroimaging techniques such as positron emission tomography
(PET) provide the means to study these questions also in humans.
The principal aim of the present study was to examine neurofunctional
changes associated with anxiety alleviation in patients with social phobia
(social anxiety disorder). Individuals with social phobia fear scrutiny, performance
failure, and accompanying humiliation in social situations ranging from formal
public appearances to casual conversations. Social phobia is arguably the
most common anxiety disorder,1, 9
and public speaking is the most prevalent social fear.10
Although it is known that patients with social phobia respond favorably to
SSRIs11 and cognitive-behavioral therapy,12-13 the neural networks participating
in the response to these 2 forms of treatment are not well understood. Thus,
we used PET and water labeled with oxygen 15 (15O) to assess regional
cerebral blood flow (rCBF) in 18 patients with social phobia during a public
speaking task, before and after 9 weeks of citalopram medication or cognitive-behavioral
group therapy (CBGT). These treatments were compared with a waiting-list (WL)
control group. Additional aims were to explore whether treatment responders
and nonresponders differed in brain perfusion and whether neural change was
associated with long-term treatment outcome.
SUBJECTS AND METHODS
SUBJECTS
Eighteen previously untreated patients (10 men and 8 women; mean ±
SD age, 35.2 ± 7.3 years; range, 23-46 years) who fullfilled the DSM-IV14 criteria for social
phobia were recruited by means of newspaper advertising. The screening procedure
included telephone questioning, self-report questionnaires, structured clinical
diagnostic interviews15, and a public speaking
behavioral test. The structured clinical diagnostic interviews were performed
by an experienced psychiatrist (I.M.). Criteria for exclusion were as follows:
current psychiatric disorder (other than social phobia); neurologic disorders
such as epilepsy, stroke, and brain hemorrhage; somatic disease; long-term
use of prescribed medication; abuse of alcohol or narcotics; left-handedness;
and pregnancy. Participants refrained from use of tobacco, alcohol, and caffeine
for 12 hours before PET investigations. Participating women were premenopausal.
Patients were, as far as practically possible, matched for severity, sex,
and age in triplets. Severity matching was based on the Social Phobia Screening
Questionnaire.10 Age differences ranged from
7 to 12 years within triplets. One triplet did not have 3 members of the same
sex. Patients were then, by means of sealed envelopes, randomized to citalopram
(SSRI) medication, CBGT, or a WL control group, with 6 individuals in each
group. There were 3 patients with generalized and 3 with nongeneralized social
phobia in each group. Informed consent was obtained from all participants
after the procedure had been fully explained. The study was approved by the
Uppsala University Medical Faculty Ethical Review Board and the Uppsala University
Isotope Committee, Uppsala, Sweden.
TREATMENT
Subjects in the SSRI group were treated with citalopram by an experienced
psychiatrist. Dosage was adjusted according to the individual's clinical response
and experience of side effects. The daily mean (±SD) dosage was 40
± 9.8 mg. Subjects came for checkups at weeks 2, 4, and 7. Assessments
of compliance and side effect were then performed, but no systematic exposure
instructions were given. The mean (±SD) plasma levels of citalopram
and desmethylcitalopram at the time of the second PET assessment were 253
± 46.0 and 118 ± 22.8 nmol/L, respectively.
The CBGT incorporated simulated exposures to feared situations, cognitive
restructuring, and homework assignments according to principles described
by Hope and Heimberg.16 Because public speaking
was the only target situation for in-session exposure, the treatment period
was limited to 8 weekly sessions, each about 3 hours long. Sessions were led
by 2 clinical psychologists (T.F. and M.T.) trained in cognitive-behavioral
therapy. The treatment program was coplanned and supervised by a psychotherapist
with considerable experience of CBGT for social phobia.
After the 9-week treatment period, subjects in the citalopram group
could choose to continue medication and subjects in the CBGT group followed
an individual maintenance program, whereas WL control subjects were treated
with citalopram. No patients could receive any other form of treatment than
the one to which they were allocated in the study.
BEHAVIORAL MEASURES
Nine outcome measures, evaluating symptom changes from pretreatment
to posttreatment, were used. Four of these were public-speaking state anxiety
measures, ie, the patient's ratings of fear and distress on a scale of 0 to
100 (minimum-maximum) and the Spielberger state anxiety inventory (STAI-S17), administered immediately after each scanned speech.
Heart rate in beats per minute was also recorded during scans by means of
the PSYLAB6 integrated system for psychophysiology (Contact Precision Instruments,
London, England). In addition, patients completed a battery of social anxiety
questionnaires: the Social Phobia Scale (SPS18),
the Social Interaction Anxiety Scale (SIAS18),
the Personal Report on Confidence as a Speaker (PRCS19),
the Social Phobia Screening Questionnaire (SPSQ10),
and the Global Assessment of Functioning (GAF20)
Scale. The 5 questionnaires were completed before, immediately after, and
1 year after treatment. Data on heart rate and subjective anxiety during public
speaking could not be collected at 1-year follow-up.
All subjects were interviewed immediately after the final PET examination
by an independent assessor and were then asked to rate their phobic reactions
after as compared with before the treatment or waiting period and to express
any opinions about the treatment and assessments they had undergone.
PET ASSESSMENTS
An 8-ring brain PET scanner (GEMS PC2048-15B; General Electric Medical
Systems, Uppsala, Sweden)21 with a 10-cm axial
field of view and an axial-transaxial resolution of approximately 6 mm was
used. Subjects were positioned in the scanner and fixated in a commercial
headholder by means of a fast-hardening foam. A venous catheter was inserted.
Transmission measurements were performed with a rotating germanium 68 pin
source. Roughly 20 minutes before the initial emission scan, patients were
instructed to prepare a 2.5-minute speech about a vacation or travel experience.
While being scanned, subjects performed the speech in the presence of a silently
observing audience of 6 to 8 persons standing around the scanner bed. Patients
were instructed to observe the audience. To heighten observational anxiety,
the speech was recorded from close distance with a portable videocamera. Tracer
injections, approximately 0.41 mCi (15 MBq)/kg of body weight, corresponding
to 19 to 35 mCi (700-1300 MBq) of H215O dissolved in
3 to 4 mL of water, were performed at 12-minute intervals. Immediately after
injections, patients were asked to start speaking and continue until they
received instructions to stop. To improve signal-to-noise ratio, patients
spoke twice in front of the audience both before and after treatment. At pretreatment,
a final emission scan was acquired during which the couch was automatically
translated back and forth between 2 fixed positions to obtain a scan with
full axial coverage of the brain. This aids in the stereotactical normalization
of PET images and movement corrections.
The rCBF data were collected in fifteen 10-second frames during 150
seconds. Data from the first 70 seconds after arrival of the bolus to the
brain were summed, and images were reconstructed from the summation after
correction for dead time, scatter, and attenuation by means of the transmission
scan.22 All images were reconstructed to a
128x128 matrix with a pixel size of 2 mm by means of a 15-mm Hanning
filter. The rCBF data were normalized for global flow by means of linear scaling,23 thereafter reflecting relative (region to whole brain)
values. Global flow was estimated with a predefined mask outlining the brain,
but excluding all voxels that changed as a consequence of study conditions,
by means of F-map masking.24 Thus, brain regions
exhibiting a change in perfusion resulting from the experimental design were
excluded from the estimation of global flow, thereby ensuring independence
between local and global flow.24
All images were anatomically normalized to a standard stereotactic space,25 with the use of the software package CBA26 (Computerized Brain Atlas; Applied Medical Imaging
AB, Uppsala). This was performed automatically27
by first matching the scan with full axial coverage of the brain to the CBA
atlas template. Images from all other emission scans were automatically aligned
to the full coverage scan, bringing them into the stereotactic space25 and correcting for head movements between scans.28-29 Because movements in any direction
were always smaller than 5 mm, the attenuation correction was deemed satisfactory.29
The mean time from treatment onset to the second PET assessment was
62.7 days for the CBGT group and 66.5 days for the citalopram group. Subjects
in the WL group were reassessed after a mean waiting period of 60.0 days.
DATA ANALYSIS
Within groups, behavioral measures were evaluated by paired t tests (2-tailed). In addition, between-group differences were evaluated
by separate analyses of variance (ANOVAs). Because of small samples in each
group, inflating the risk of type II errors, the SSRI and CBGT groups were
merged (n = 12) in the ANOVA group factor. Posttreatment differences between
the citalopram and CBGT groups were evaluated separately by planned comparisons.
In all tests, the  level used was P<.05.
At 9 weeks, patients who improved 1 SD or more from the pretreatment
mean value on 7 to 9 outcome measures were labeled "much improved"; 4 to 6
measures, "moderately improved"; and 0 to 3 measures, "less improved." Patients
who were at least moderately improved were considered to be responders. At
1-year follow-up, patients who improved 1 SD or more from the pretreatment
mean value on 4 to 5 measures were labeled "much improved," and 0 to 3 measures,
"less improved," similar to the approach that was used to categorize responders
and nonresponders at 9 weeks.
The PET data were fitted to the general linear model30
by means of a pixelwise multiple linear regression. Image data were averaged
across the 2 repeated scans (both pretreatment and posttreatment) into mean
images to be compatible with a random-effects model.31
Image analyses were thus modeled as blocked ANOVAs where rCBF data, analogous
to the behavioral measures, were evaluated by means of within- and between-group
comparisons. Between-group differences were evaluated by groupxtime
interactions in the form of double subtractions, such as (CBGTpost -
CBGTpre) - (WLpost - WLpre).
Contrasts generated t-maps, subsequently converted to z-score maps through a probability-preserving transformation.32 Local changes were evaluated by means of the spatial
extent of connected clusters of voxels,33 with
a z-score more than 2.6 corresponding to P<.01 corrected for multiple comparisons. In addition to exploratory
whole-brain analyses, directed region of interest (ROI) evaluations were planned
a priori for the amygdala and hippocampus because of the large amount of previous
research ascribing important roles to these regions in fear and anxiety.4-8
For these areas, uncorrected P values are also reported.
Discriminant analysis was used to predict improvement at 1-year follow-up
from initial attenuation of subcortical rCBF. Mean voxel values for each subject
and condition were extracted from the subcortical ROIs implicated in the "Results"
section (the amygdala, hippocampus, periaqueductal gray area, and left thalamus).
The ROIs were anatomically predefined in the CBA.25-26
Change scores (after - before treatment) in relative rCBF were calculated
for each ROI and subject and then entered into a stepwise discriminant analysis34 with the use of Statistica 4.1 for Macintosh (Statasoft,
Inc, Tulsa, Okla).
To assess changes in verbal performance, number of spoken words before
and after treatment was analyzed by means of repeated-measurement ANOVA and
paired t tests (2-tailed). For each individual and
condition, the number of words was sampled from a randomly chosen 20-second
period from the videotape of the speech.
RESULTS
BEHAVIORAL MEASURES
There were no significant multivariate (Wilks  9,8
= 0.50, F = 0.89, P = .57) or univariate (F1,16 = 0.04-3.2, P = .85-.09) differences between
treated and nontreated subjects on behavioral outcome measures before treatment.
Means (±SD) at pretreatment were as follows: SPS, 28.9 ± 14.4;
SIAS, 34.3 ± 18.0; PRCS, 24.4 ± 3.1; SPSQ, 23.2 ± 10.7;
GAF, 76.5 ± 11.6; heart rate, 94.7 ± 15.5 beats/min; fear, 38.2
± 22.9; distress, 51.4 ± 24.6; and STAI-S, 56.6 ± 9.5.
Figure 1 displays within-group
changes with treatment (pretreatment-posttreatment) for behavioral measures
that were at least at the P .10 level according
to paired t tests. The CBGT group improved significantly
on the STAI-S, fear, distress, SPS, and PRCS (t5 = 3.7-5.9; P = .01-.002), whereas the citalopram
group improved significantly on the SPS and GAF scales (t5 = 2.8-3.6; P = .04-.02). On
several measures, these subjects also exhibited changes that were marginally
above the 2-tailed P<.05 level (Figure 1). The WL group did not change significantly
on any measure (t5 = 0.1-2.0; P = .95-.10).
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Figure 1. Change scores (mean ± SE)
reflecting social phobia symptom changes with 9 weeks of treatment or waiting
time. CBGT indicates cognitive-behavioral group therapy; WL, waiting-list
control group; STAI-S, Spielberger State Anxiety Inventory17;
SPS, Social Phobia Scale18; PRCS, Personal
Report on Confidence as a Speaker19; SPSQ,
Social Phobia Screening Questionnaire10; and
GAF, Global Assessment of Functioning self-report.20
Heart rate and scores on the Social Interactional Anxiety Scale18
did not change markedly (P>.10) and are not displayed.
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Separate ANOVAs confirmed that treated subjects collectively improved
more than WL controls. Significant groupxtime interactions were noted
for the SPS (F1,16 = 4.9, P = .04), PRCS
(F1,16 = 6.9, P = .02), and GAF scale
(F1,16 = 5.5, P = .03). Follow-up Fisher
least significant difference tests showed that the treated subjects improved
significantly more than controls (SPS, P<.001;
PRCS, P<.01; GAF, P<.05).
Borderline significant groupxtime interactions were obtained on ratings
of distress (F1,16 = 4.1, P = .06) and
the STAI-S (F1,16 = 3.7, P = .07). Treated
subjects were more improved (P.05; Fisher least
significant difference) than WL subjects on both of these measures at posttreatment.
Planned comparisons did not show statistical differences between the
CBGT and citalopram groups on any outcome measure after therapy. The number
of responders was 4 each (67%) in the CBGT and citalopram groups, with 2 patients
being much improved and 2 moderately improved in both groups, suggesting that
the 2 interventions were about equally beneficial. One patient in the WL group
was also classified as a moderately improved responder, possibly because of
habituation effects. All responders (n = 9) confirmed symptom improvement
in individual posttreatment interviews.
REGIONAL CEREBRAL BLOOD FLOW
Therapeutic effects on rCBF were first evaluated by contrasting public
speaking after and before treatment within each group (CBGT, citalopram, WL)
separately. In CBGT- and citalopram-treated patients, symptom improvement
was accompanied by a significantly reduced rCBF response bilaterally in the
amygdala, hippocampus, and anterior and medial temporal cortex, including
the entorhinal, perirhinal, parahippocampal, and periamygdaloid areas. No
significant rCBF alterations were observed in WL controls. To verify that
brain perfusion changed as a function of treatment, the same contrast was
run for responders regardless of treatment modality. Consistently, responders
decreased their neural response to public speaking in the same regions. Significant
within-group decreases of temporal lobe rCBF are displayed in Table 1 and Figure 2A.
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Table 1. Brain Regions Exhibiting Significantly Decreased Within-Group
Activation After Treatment of Social Phobia
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Figure 2. A, Transverse positron emission
tomographic images, superimposed on a magnetic resonance reference image,
showing significant decreases in the regional cerebral blood flow response
to an anxiogenic public speaking task as a function of cognitive-behavioral
group therapy (CBGT; left) or citalopram treatment (middle), and for responders
regardless of treatment approach (right). Points of neural convergence were
observed in the amygdala, hippocampus, and surrounding temporal cortical regions.
B, Corresponding between-group differences in the amount of change in regional
cerebral blood flow with treatment. Images show a greater reduction in the
neural response to public speaking in CBGT relative to the waiting-list (WL)
group (left), citalopram relative to the WL group (middle), and responders
relative to nonresponders (right).
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Between-group comparisons confirmed that the rCBF response to public
speaking decreased significantly more in both treated groups relative to WL
control subjects in the previously implicated temporal lobe regions, albeit
mainly in the right hemisphere. Consistently, the rCBF response also decreased
more in responders relative to nonresponders in the right amygdala, hippocampus,
and rhinal and periamygdaloid areas (Table
2, Figure 2B). The citalopram
and CBGT groups differed only with regard to perfusion in the right thalamus
(x 17, y -14, z 11; z = 4.82), which increased
more with citalopram than CBGT.
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Table 2. Brain Regions Exhibiting Significantly Decreased Between-Group
Activation After Treatment of Social Phobia
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A change in perfusion was noted in a few other regions outside the temporal
lobe. In the CBGT group, rCBF decreased in the periaqueductal gray area (x
4, y -33, z -13; z = 3.17), while increases
were noted in the right cerebellum (x 16, y -51, z -11; z = 3.70) and the secondary visual cortex (area 19; x 37,
y -64, z -11; z = 2.88). In the citalopram
group, rCBF decreased in the left thalamus (x -10, y -14, z 6; z = 4.66) and left inferior frontal cortex (area 10/47;
x -17, y 35, z -10; z = 4.74). Responders
exhibited rCBF decreases in the right inferior frontal (area 47; x 19, y 14,
z -11; z = 3.79), right dorsolateral prefrontal
(area 9; x 37, y 0, z 21; z = 4.72), and bilateral
anterior cingulate (area 25/32; x -4, y 27, z -7; z = 5.11) cortices (Figure 3).
In the between-group comparison, rCBF decreased more in responders than nonresponders
in the right dorsolateral prefrontal (area 9; x 24, y 29, z 35; z = 5.19) and bilateral anterior cingulate (area 24/33; x 1, y 34,
z 14; z = 3.71) cortices (Figure 3).
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Figure 3. Sagittal positron emission tomographic
images displaying significantly reduced regional cerebral blood flow in the
rostral-ventral (subgenual) cingulate cortex corresponding to areas 25/32
for treatment responders (A) and a greater reduction in regional cerebral
blood flow in the responders relative to nonresponders in the affective division
of the anterior cingulate cortex corresponding to areas 24/33 (B).
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At 1-year follow-up, 7 of the originally treated patients were classified
as much improved, on the basis of the questionnaire results, whereas the remaining
5 patients were less improved. A stepwise discriminant analysis examined whether
initial attenuation of subcortical rCBF (after - before change scores)
was associated with the level of improvement a year later. The periaqueductal
gray area (P = .005), left thalamus (P = .006), right amygdala (P = .02), and left
amygdala (P = .06) combined to yield a significant
discrimination (Wilks = 0.16, F = 9.4, P<.006)
that was 100% accurate in predicting the 2 levels of improvement. Favorable
outcome at 1-year follow-up was associated with a greater initial attenuation
of the subcortical rCBF response to public speaking (Figure 4).
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Figure 4. Regional cerebral blood flow (rCBF)
redistribution after treatment (mean relative rCBF ± SE, after minus
before therapy) in 4 subcortical regions of interest. Discriminant analysis
showed that the initial degree of rCBF change in these regions was associated
with clinical status (much or less improved) in patients with social phobia
at 1-year follow-up assessment. Favorable long-term outcome was associated
with a greater initial suppression of subcortical rCBF. PAG indicates periaqueductal
gray area.
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VERBAL PERFORMANCE
An ANOVA evaluating data for treated subjects and controls did not show
significant time (F1,16 = 0.14, P = .71)
or group x time (F1,16 = 0.26, P
= .62) interaction effects with regard to number of spoken words. Paired t tests also indicated that the mean number of spoken words
did not change significantly from pretreatment to posttreatment for subjects
in the CBGT (+3.5 words; t5 = 0.72, P = .50), citalopram (-4.2 words; t5 = 2.2; P = .08), and WL (+2.2
words; t5 = 0.51, P = .63) groups.
COMMENT
Social phobia symptom severity was significantly and about equally reduced
after 9 weeks of either cognitive-behavioral or SSRI treatment, whereas WL
control subjects did not improve. Alleviation of social anxiety was associated
with an attenuated neural activity during public speaking in the amygdala,
hippocampus, and the neighboring rhinal, parahippocampal, and periamygdaloid
cortices. This neural pattern was observed within both treated groups, and
in responders regardless of treatment approach, but not in WL control subjects.
Between-group comparisons confirmed that the rCBF response to the anxiogenic
public speaking task was significantly more suppressed after treatment in
the citalopram and CBGT groups relative to WL control subjects, and in responders
relative to nonresponders, particularly in the right hemisphere.
Furthermore, discriminant analysis showed that rCBF diminution in the
amygdala, in conjunction with the periaqueductal gray area and left thalamus,
could accurately discriminate much improved from less improved patients a
year later. Hence, the degree of limbic response attenuation with treatment
was associated with long-term clinical outcome. Because of small samples,
this should be interpreted cautiously. However, according to the discriminant
score plot, the closest distance between the much improved and less improved
groups was roughly 1 SD, suggesting that the groups were well separated with
regard to predicting variables and that the accurate discrimination was statistically
reliable. Significant response decrement in limbic brain territories could
thus be crucial for long-term improvement.
In individuals with social phobia, the amygdala and hippocampus have
previously been implicated in the processing of conditioned aversive stimuli,
as well as facial and unpleasant odor stimulation.36-37
It has been proposed that the amygdaloid-hippocampal region forms an alarm
system that is activated by threatening stimulation.38
Presumably, the rhinal, parahippocampal, and periamygdaloid cortices transit
sensory and/or memory information into this system.4
Suppression of neural activity in the amygdalohippocampal and surrounding
cortical regions might be an important mechanism by which both pharmacologic
and psychological therapies exert their anxiolytic effect. Exposure-based
behavior therapy may act by permitting systematic habituation of neuronal
activity in these brain structures.8 Consistently,
recent studies suggest that repetition of emotionally salient stimuli results
in neural habituation in the medial temporal lobe including the amygdala39-40 and hippocampus.39
The SSRIs could produce similar effects, eg, by correcting for median raphe
nucleus malfunction with resultant attenuation of cortical and amygdalohippocampal
activation.41 An increase of serotonin may
inhibit thalamic and cortical inputs from activating the amygdala.42
In a recently completed report, our group43
noted that the amygdalohippocampal activity during public speaking stress
was more elevated in untreated patients with social phobia than in normal
healthy volunteers. However, neural activation patterns in the 2 groups differed
also in widespread cortical areas including the secondary visual, retrosplenial,
parietal, temporal pole, insular, and orbitofrontal cortices.43
Thus, pretreatment abnormalities and therapeutic change patterns overlap only
partly, suggesting that treatment involves both normalization and other adaptive
metabolic changes in the brain. Some anomalies may persist after therapy.
This has been noted also in mood disorders.44
Resting-state amygdala hypermetabolism in depressed patients appears to decrease
toward normality after antidepressant pharmacotherapy,45
suggesting that the amygdala could be a general target for treatments of negative
affect.
Only a few regions outside the temporal lobe exhibited altered activity
after treatment. Patients who received CBGT showed decreased neuronal activity
in the periaqueductal gray area, which is involved in defense behaviors in
animals and probably also in humans.46 Moreover,
a decrement in rCBF was noted in the left thalamus (citalopram group), the
affective division of the anterior cingulate cortex47
(responders), and the inferior and medial prefrontal cortices (responders).
The thalamus relays afferent anxiogenic information to the amygdala and cortical
areas.7 Both the left inferior frontal48 and anterior cingulate49
cortices participate in affective regulation and perception of facial emotions.
Decreased flow in these areas might reflect downgraded emotional evaluative
functions, suggesting that the affective value assigned to facial or other
exteroceptive stimuli is lessened after treatment. Reduced prefrontal and
cingulate activity could also reflect an alteration of the emotional experience38 or a reduction in catastrophic or negative thinking.41
In patients with social phobia, Van der Linden and coworkers50 recently reported that 8 weeks of citalopram medication
reduced resting-state neuronal activity in the left-sided temporal, midfrontal,
and cingulate cortices, whereas bilateral increases were noted in occipital
regions. Other brain imaging reports on antianxiety treatments are scarce,
but landmark PET studies suggest that both pharmacotherapy51
and behavioral therapy51-52 normalize
resting-state glucose metabolism in the right caudate nucleus in patients
with obsessive-compulsive disorder. To our knowledge, the present investigation
is the first study incorporating comparative evaluations of the effects that
SSRI and psychological treatments exert on brain activity during provoked
anxiety states.
An important limitation of the present study is the small number of
subjects in each group, restricting statistical power and enhancing the risk
of type II errors (false-negative results). Even so, a consistent pattern
of change in behavioral measures and rCBF was demonstrated in both within-
and between-group analyses. Because both CBGT- and citalopram-treated subjects
improved while WL control subjects did not, it is unlikely that the beneficial
effects can be attributed to repeated testing, statistical regression, or
other potentially confounding factors. The number of spoken words did not
change from before to after treatment for the groups, making it unlikely that
rCBF changes reflect verbal performance shifts rather than anxiety reduction.
We argue that the consistent pattern shown by the subtractive and discriminant
analyses supports a true causal link between the alterations in brain activity
and symptom change.
Future imaging studies could compare treatment groups not only with
WL control groups but also with attentional (eg, educational-supportive) psychotherapy
and pill placebo groups. Future studies could also investigate whether the
combination of cognitive-behavioral and SSRI treatments amplifies the effect
on brain activity. Moreover, the direct physiological effects of citalopram
and other SSRIs could be unraveled by administering these drugs to normal
healthy volunteers. A recent report, however, indicated that long-term administration
of fluoxetine did not change regional or global CBF in healthy volunteers.53
In conclusion, the neural sites of action for citalopram and cognitive-behavioral
treatments of social anxiety converged in the amygdala, hippocampus, and neighboring
cortical areas, possibly representing a final common pathway in successful
antianxiety treatments. Thorough suppression of amygdalar-limbic activity
with therapy was associated with favorable long-term outcome and may be a
prerequisite for clinical improvement.
AUTHOR INFORMATION
Submitted for publication December 1, 2001; final revision received
June 13, 2001; accepted August 13, 2001.
This study was supported by the Swedish Council for Research in Humanities
and Social Sciences (Dr Fredrikson), the Bank of Sweden Tercentenary Foundation
(Dr Fredrikson), and the Wenner-Gren Foundation (Dr Fischer), Stockholm, and
Uppsala University (Dr Fredrikson) and the Swedish Brain Foundation (Dr Fischer),
Uppsala, Sweden.
This study was presented in part as a poster at the Fifth and Sixth
International Conferences on Functional Mapping of the Human Brain, Düsseldorf,
Germany, June 25, 1999, and San Antonio, Tex, June 14, 2000.
We thank Scott L. Rauch, PhD, and Arne Öhman, PhD, for comments
on the manuscript; Jesper Andersson, PhD, Lennart Thurfjell, PhD, and Håkan
Stattin, PhD for valuable discussions; and the staff of Uppsala University
PET-Center, Uppsala, for excellent research conditions.
Corresponding author and reprints: Tomas Furmark, PhD, Department
of Psychology, Uppsala University, Box 1225, SE-751 42 Uppsala, Sweden (e-mail: tomas.furmark{at}psyk.uu.se).
From the Department of Psychology, Uppsala University, Uppsala, Sweden
(Drs Furmark, Fredrikson, and Tillfors and Ms Pissiota); Department of Neuroscience,
Psychiatry (Dr Marteinsdottir), and Uppsala University PET-Center (Drs Fischer
and Långström), University Hospital, Uppsala; and Psychiatric Neuroimaging
Research Group, Massachusetts General Hospital and Harvard Medical School,
Boston, Mass (Dr Fischer).
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