V. Faria et al 1
March 23rd 2012, Word count: 283; Tables: 1; Figures: 1.
Amygdala Subregions tied to SSRI and Placebo Response
in Patients with Social Anxiety Disorder
Authors: Vanda Faria, MSc1; Lieuwe Appel, PhD2; Fredrik Åhs, PhD3; Clas Linnman, PhD4;
Anna Pissiota, MSc1; Örjan Frans, PhD1; Massimo Bani, PhD5; Paolo Bettica, PhD5; Emilio
Merlo Pich, MD5; Eva Jacobsson, PhD6; Kurt Wahlstedt, MD, PhD6; Mats Fredrikson, PhD,
DMSc1; Tomas Furmark, PhD1
SUPPLEMENTAL RESULTS
Anxiolytic effects on amygdala blood flow common to SSRIs and placebo
The common anxiolytic deactivation of the right ventrolateral and left basomedial/basolateral
amygdala subregions was confirmed in a more conservative between-group conjunction
analysis (SSRI responders vs. nonresponders, pre vs. post) & (Placebo responders vs.
nonresponders, pre vs. post) at the uncorrected p-level (x28, y-2, z-26, z=2.00, Puncorr =0.023;
x-16, y-6, z-14, z=1.66, Puncorr =0.049).
Dosage of paroxetine: Follow-up analyses
To further check the validity of the data merging we extracted voxel values from the left
lateral amygdala (x-26, y0, z-18), which was tied to a general SSRI neurophysiologic effect in
V. Faria et al 2
the present study, and compared the neural changes resulting from paroxetine 7.5 mg vs.
placebo from the same third trial and vs. paroxetine 20 mg from trial 2.
ANCOVA, with amygdala pretreatment values as covariate, revealed a significant effect of
group (F2,31=4.14, P=.02) indicating a different neural response in the selected treatment
arms. Further testing suggested greater attenuation from pre- to posttreatment in paroxetine
7.5 mg vs. placebo (t(21)=3.26, P=.0038) and paroxetine 20mg vs. placebo (t(22)=4.30,
P=.0003) while low vs. high doses of paroxetine did not differ (t(21)=-.73, P=.47) – see
Supplemental Figure S1. Thus, paroxetine 7.5 mg yielded a neurophysiologic effect on
amygdala blood flow that was differentiated from placebo and in vicinity of the 20 mg
standard therapeutic dose, supporting that this group could be pooled together with the other
SSRI-arms.
Changes with treatment on the LSAS (main clinical outcome measure) did not differ
significantly across these three arms (F2,31=.68, P=.52). The mean (±SD) values at pre- and
posttreatment were as follows: Paroxetine 7.5 mg: pre 66.00±28.71, post 45.00±18.39;
Paroxetine 20 mg: pre 66.41±20.40, post 39.25±29.07; Placebo: 64.08±28.11, post
47.83±25.03.
V. Faria et al 3
Supplemental Figure S1. Mean amygdala changes from pre to posttreatment in the SSRIneurophysiologic division of the left lateral amygdala (x-26, y0, z-18) in patients treated with
placebo (n=12) or paroxetine 7.5 mg (n=11) in the third trial and paroxetine 20 mg (n=12) in
the second trial.
V. Faria et al 4
SUPPLEMENTAL TABLE
Supplemental Table S1. Brain regions that changed within responders and nonresponders as
a function of treatment
MNI Coordinate¤
Brain region
SSRI Responders, n=20
Decreases (pre>post)
R Amygdala
L Amygdala
x
y
z
z value
P value
R Insula
R Hippocampus
L Hypothalamus
L Brainstem
L Uncus (28)‡
26
-28
-16
36
28
-8
-6
-28
-4
0
-6
2
-10
-6
-8
4
-26
-22
-14
0
-26
-8
-10
-26
4.55
4.24
2.50
3.39
3.94
3.79
3.45
4.97
0.000
0.000
0.006†
0.054
0.001
0.000
0.048
0.013
Increases (pre<post)
L Insula
-46
-14
2
4.09
0.005
SSRI Nonresponders, n=15
Decreases (pre>post)
L Amygdala
L Insula
L Hippocampus
L Brainstem
L Parahippocampal Gyrus (30)‡
-26
-36
-28
-12
-16
-6
2
-12
-30
-34
-14
-6
-18
-8
-8
4.57
3.64
3.65
3.76
4.78
0.000
0.025
0.003
0.018
0.029
Increases (pre<post)
R Orbitofrontal cortex (11)
L Anterior Cingulate cortex (32)
L Ventromedial Prefrontal Cortex (10)
R Postcentral gyrus (2)‡
24
-14
-14
36
42
40
50
-42
-16
16
-4
68
3.71
4.46
4.25
4.64
0.016
0.001
0.003
0.051
Placebo Responders, n=11
Decreases (pre>post)
L Amygdala
R Amygdala
-18
28
-8
-2
-16
-26
2.86
2.95
0.026
0.020
Increases (pre<post)
n.s
V. Faria et al 5
Placebo Nonresponders, n=26
Decreases (pre>post)
L Amygdala
L Hippocampus
R Hippocampus
R Orbitofrontal cortex (11)
R Anterior Cingulate Cortex (32)
-28
-28
26
4
4
0
-28
-14
28
30
-22
-14
-20
-12
-8
2.14
2.81
2.79
3.44
3.72
0.016†
0.037
0.039
0.040
0.029
Increases (pre<post)
R Insula (13)
34
-22
16
3.52
0.037
Abbreviations: L, left side; R, right side; SSRI, selective serotonin reuptake inhibitor; n.s, not
significant. Approximate Brodmann areas within parentheses.
¤ Based on the Montreal Neurologic Institute coordinate system.
† p uncorrected for multiple comparisons.
‡Whole brain approach; All the other unmarked regions are ROI-based.