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Brain Serotonin 5-HT1A Receptor Binding in Schizophrenia Measured by Positron Emission Tomography and [11C]WAY-100635
Johannes Tauscher, MD;
Shitij Kapur, MD, PhD, FRCPC;
N. Paul L. G. Verhoeff, MD, PhD, FRCPC;
Douglas F. Hussey, BSc;
Zafiris J. Daskalakis, MD, FRCPC;
Sitra Tauscher-Wisniewski, MD;
Alan A. Wilson, PhD;
Sylvain Houle, MD, PhD, FRCPC;
Siegfried Kasper, MD;
Robert B. Zipursky, MD, FRCPC
Arch Gen Psychiatry. 2002;59:514-520.
ABSTRACT
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Background Results of postmortem studies show an elevation in serotonin-1A (5-hydroxytryptamine-1A
[5-HT1A]) receptor density in the prefrontal and temporal cortices
of patients with schizophrenia. This study examined 5-HT1A receptors
in vivo in patients with schizophrenia using positron emission tomography
and [carbonyl-11C]-N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-
N-(2-pyridinyl)cyclohexane carboxamide ([11C]WAY-100635).
Methods The 5-HT1A binding potential of 14 antipsychotic drug–naïve
patients with a DSM-IV diagnosis of schizophrenia
was compared with that of 14 age-matched healthy controls. Positron emission
tomography data were analyzed using 9 cortical regions of interest, which
were delineated on a coregistered magnetic resonance image and transferred
to the positron emission tomographic image, with the cerebellum as the reference
region for a simplified reference tissue model. We also performed a voxel-wise
comparison using statistical parametric mapping.
Results The region of interest–based analysis revealed a significant mean
± SD cortical 5-HT1A receptor binding potential increase
of 7.1% ± 6.4% in patients with schizophrenia (F = 2.975; P = .02); local differences were +20% in the left medial temporal cortex
(F = 9.339;P = .005) and +13% in the right mediotemporal
cortex (F = 4.453; P = .045). There were no significant
differences in regional tracer delivery or cerebellar [11C]WAY-100635
uptake. The voxel-based analysis also confirmed a group difference in the
left medial temporal cortex.
Conclusions The biological significance of elevated 5-HT1A receptor density
in schizophrenia remains unclear. Given the location of 5-HT1A
receptors on pyramidal cells, this elevation may reflect an abnormal glutamatergic
network. Our finding needs to be viewed in light of preclinical evidence supporting
a role for 5-HT1A receptors in mediating antipsychotic action and
extrapyramidal adverse effects of drugs.
INTRODUCTION
THERE IS CONSIDERABLE evidence for a role of the neurotransmitter serotonin
(5-hydroxytryptamine [5-HT]) in the pathophysiologic characteristics of schizophrenia.1-3 Recent interest in 5-HT
has been fueled by the fact that novel antipsychotic drugs such as clozapine,
olanzapine, quetiapine, risperidone, sertindole, and ziprasidone hydrochloride
are potent 5-HT2A receptor antagonists and relatively weaker dopamine
D2 antagonists.4 In addition, 5-HT1A and 5-HT2C receptors seem to contribute to the clinical
effects of some novel antipsychotic drugs.5
Results of most postmortem studies6-14
show a pronounced elevation of 20% to 79% in cortical 5-HT1A receptor
density in schizophrenia using [3H]-8-OH-DPAT or [3H]WAY-100635
as ligands. Human autoradiographic findings13
revealed the highest density of 5-HT1A receptors in the temporolimbic
cortex, followed by brainstem raphe nuclei, the frontal cortex, and other
neocortical regions, with very low or undetectable levels in the cerebellum.
The brainstem receptors are somatodendritic autoreceptors, whereas the cortical
receptors are mainly postsynaptic. Cortical 5-HT1A receptors exert
inhibitory control over striatal glutamate release, and 5-HT1A
antagonists increase glutamate release in the striatum via corticostriatal
efferents.15 In addition, 5-HT1A
agonists increase the outflow of dopamine in the prefrontal cortex, without
a similar change in striatal dopamine release.16
Stimulation of 5-HT1A receptors seems to produce many of the same
effects as antagonism of 5-HT2A receptors.5
Earlier efforts to quantitatively analyze 5-HT1A receptors
using the agonist ligand 8-OH-DPAT were hampered by the fact that it labels
5-HT1A receptors only in their high-affinity state. This problem
has recently been overcome by the discovery of WAY-100635, a selective high-affinity
(Kd<1nM) 5-HT1A antagonist, which labels both low-
and high-affinity receptors.17 WAY-100635 has
been labeled at the [carbonyl-11C] position18
and can be used for the quantitative analysis of binding to 5-HT1A
receptors in humans.19 Using
[carbonyl-11C]-N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-
N-(2-pyridinyl)cyclohexane
carboxamide ([11C]WAY-100635) and positron emission tomography
(PET), cortical 5-HT1A binding can be quantitatively analyzed using
the cerebellum as an input function of a simplified reference tissue model
(SRTM).20-21 Using this method,
an age-dependent decline in cortical 5-HT1A receptor binding potential22 (BP) in healthy volunteers was recently demonstrated,23 consistent with findings from postmortem studies,24-26 which showed a decline
in 5-HT1A receptor numbers with age.
We present a PET study in 14 neuroleptic drug–naive patients with
a DSM-IV diagnosis of schizophrenia who experienced
a first psychotic episode. On the basis of human postmortem studies, we hypothesized
that in vivo 5-HT1A receptor BP as measured with
[carbonyl-11C]WAY-100635 and PET is higher in the frontal and temporal cortices
of patients with schizophrenia compared with an age-matched control group.
PARTICIPANTS AND METHODS
PARTICIPANTS
Fourteen right-handed patients (6 women and 8 men; mean age, 26 years;
age range, 22-37 years) with a DSM-IV diagnosis of
schizophrenia were included in the study. Each patient experienced a first
psychotic episode, had not received any psychotropic medication except for
benzodiazepines within 1 month of the PET scan, and had never been treated
with an antipsychotic agent. Patients were recruited from the Schizophrenia
and Continuing Care Program of the Centre for Addiction and Mental Health,
where they had been evaluated as either inpatients or outpatients. The diagnosis
of schizophrenia was ascertained using a Structured Clinical Interview for DSM-IV,27 which was performed
by an experienced psychiatrist (J.T., N.P.L.G.V., Z.J.D., or S.T.-W.).
Fourteen age-matched individuals (8 women and 6 men; mean age, 28 years;
age range, 19-36 years) comprised the control group. These 14 controls were
recruited from the community by advertisements and were part of a bigger pool
of healthy individuals described in an earlier [11C]WAY-100635
PET study.23
Patients were excluded from the study if they experienced a serious
medical or neurologic illness, had a significant head injury, or were pregnant.
Furthermore, exclusion criteria for control subjects were any Axis I psychiatric
diagnosis as confirmed by the Structured Clinical Interview for DSM-IV, nonpatient edition,28 or treatment
with psychotropic medications within 3 months of the study.
All patients gave written consent after the procedure had been fully
explained. The study and recruitment procedures were approved by the research
ethics board of the Centre for Addiction and Mental Health and the Department
of Psychiatry, University of Toronto.
IMAGE ACQUISITION AND ANALYSES
The selective 5-HT1A receptor antagonist [11C]WAY-100635
was synthesized according to modifications of the McCarron method29 using a short fluorocarbon resin tube loosely packed
with polypropylene wool as a substitute for the narrow polypropylene tubing
originally used.30 This procedure yielded syntheses
with high purity (>95%) and average specific activity of 47 GBq/µM (1270
mCi/µM) at the time of injection.
Positron emission tomographic images were obtained during 60 minutes
using a GEMS PC2048-15B camera (General Electric Medical Systems, Milwaukee,
Wis) in 15 one-minute frames followed by another 9 five-minute frames after
bolus injection of a mean ± SD of 9.8 ± 0.6 mCi (363 ±
22 MBq) of [11C]WAY-100635. The images were corrected for attenuation
with a 68Ge transmission scan and were reconstructed using filtered
back projection (Hanning filter, 5 mm full-width at half maximum), and 15
axial slices, each 6.5-mm thick, were obtained.
For the quantification of 5-HT1A receptor binding in human
brain, 2 approaches were used: one based on predefined regions of interest
(ROIs) and the other a voxel-wise analysis.
Each participant underwent magnetic resonance imaging (MRI) (GE Signa
1.5-T scanner; spin-echo sequence T1- and proton density–weighted images;
and x, y, and z voxel dimensions 0.78, 0.78, and 3.00 mm, respectively). The
MRIs were coregistered to each PET image by using RView8/mpr software.31 For ROI analysis, brain regions were delineated on
the coregistered MRI using previously defined landmarks.32
Anatomic ROIs were drawn bilaterally in the dorsolateral prefrontal (DLPFC),
anterior cingulate (ACC), medial temporal (MTC), lateral temporal (LTC), and
parietal cortices and in the cerebellum by an operator masked to the condition.
The gray matter of the cerebellum was delineated on consecutive slices where
the middle cerebellar peduncle was clearly visible. The DLPFC was delineated
on axial MRI slices in which the caudate, putamen, and globus pallidus were
all clearly visualized. The ACC was delineated on the sameslices and identified
as a gray matter structure on both sides of the interhemispheric fissure extending
posterior to the anterior genu of the corpus callosum. The MTC was delineated
as a mediotemporal gray matter region corresponding to the hippocampus, amygdaloid
nucleus, and parahippocampal gyrus. The LTC included temporal gray matter
located laterally starting with the same slice, where the MTC was delineated,
and extending superior to slices in which the caudate, putamen, and globus
pallidus were clearly visualized. The parietal cortex was delineated on 3
slices corresponding to the inferior parietal lobule extending anterior to
the postcentral sulcus.
Decay-corrected time-activity curves (TACs) were obtained for each ROI
using the 60 minutes of the data acquisition period because 60-minute TACs
in the SRTM yielded test-retest agreement comparable to 90-minute TACs.23, 33 Because we were scanning acutely
psychotic patients, we tried to keep the scanning time as brief as possible.
Regional BP22 values were calculated
as an estimate of 5-HT1A receptor number in each ROI using the
kinetic modeling tool of PMOD Medical Imaging Software (version 2.20).34 To obtain BP values, the cerebellum was used as the
reference region for an SRTM.20
For the voxel-wise analysis, parametric 5-HT1A receptor BP
images were generated using the SRTM with PMOD. Parametric images were then
spatially normalized within the standard Montreal Neurologic Institute brain
space using Statistical Parametric Mapping version 99 (SPM99)35
and a ligand-specific template.36
STATISTICAL ANALYSIS
Statistical analyses of the ROI data were performed using SPSS for Windows
10.0.0 (SPSS Inc, Chicago, Ill). Parametric statistical analyses were applied
after it had been assured that skewness, kurtosis, outliers, and homogeneity
of variance of our data met the criteria for a normal distribution.37 In a first step, all regions were pooled together
to estimate the mean cortical 5-HT1A receptor BP of each group.
To test the hypothesis that 5-HT1A receptor BP is elevated in the
frontal andtemporal cortices of patients with schizophrenia, regional BP values
of patients and controls were compared using multivariate analysis of covariance,
with all regional BP values as dependent variables, group (patients vs controls)
as a fixed factor, and age as a covariate. Multiplying the area of each ROI
by the number of slices and their respective thickness of 6.5 mm provided
an approximation for the actual volume of interest (VOI). Additional separate
multivariate analyses of variance were performed to compare the VOI and R1 values between groups. R1 is the ratio of tracer delivery
to the tissue of interest (K) relative to the reference tissue (K'),
and it can be described by the following equation: R1 = K/K'.
To compare the uptake in the cerebellum between patients and controls, an
analysis of variance was performed, with the area under the curve of the cerebellar
TAC as the dependent variable. For the ROI analysis, an  level of P<.05 was considered significant, and all tests were
2-tailed. For the post hoc tests, a Bonferroni correction for multiple comparisons
was performed using 9 as the denominator because we compared [11C]WAY-100635
binding indices between patients and controls in 9 different cortical regions.
Potential correlations between age and the measured activity in the
cerebellar ROI, between age and ROI size or regional BP values, and between
each ROI BP value and its respective area were examined using 2-tailed Pearson
product moment correlation coefficients. In addition, Pearson product moment
correlation coefficients were calculated to reveal possible correlations between
5-HT1A receptor BP in patients and duration of untreated psychosis
or severity of illness as measured using the Positive and Negative Syndrome
Scale for schizophrenia.38
For the voxel-by-voxel analysis, statistical parametric maps were generated
using SPM99. To test whether the measured 5-HT1A receptor BP differed
between patients and controls in any given voxel, 2-tailed t tests were applied. Results were displayed as statistical parametric
maps using an uncorrected height threshold of P<.01
(t test, >2.48). We applied 2 contrasts (patient
5-HT1A BP higher than that of controls and vice versa) to a search
volume of 93,209 voxels, each with a size of 2 x 2 x 2 mm.
RESULTS
The mean ± SD age of patients and controls was 26 ± 5
years and 28 ± 5 years, respectively. There was no significant difference
in age between groups (t26 = 1.071; P = .29).
The ROI-based analysis revealed a mean ± SD 5-HT1A
receptor BP increase of 7.1% ± 6.4% in patients with schizophrenia
across all 9 cortical ROIs (Figure 1
and Figure 2). A multivariate analysis
of covariance revealed a significant group effect (patients vs controls) on
the BP values measured in 9 cortical ROIs (F9,17 = 2.975; P = .02), but neither a significant effect of age (F9,17 = 0.814; P = .61) nor a significant age
x group interaction (F18,36 = 1.716; P = .08) was found. Post hoc tests of between-subject effects revealed
that 5-HT1A receptor BP values of patients were significantly higher
in the left MTC (F1 = 9.339; P = .005)
and the right MTC (F1 = 4.453; P = .045)
(Table 1). There were no significant
differences in BP values in any other ROI. Only the result in the left MTC
survived a Bonferroni correction for multiple comparisons (corrected P = .045).
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Figure 1. Serotonin-1A (5-hydroxytryptamine
[5-HT1A]) receptor binding potential values in 14 patients with
schizophrenia and 14 healthy controls in the mediotemporal cortex (MTC). Horizontal
lines indicate means.
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Figure 2. Composite mean serotonin-1A (5-hydroxytryptamine)
receptor binding potential images of 14 healthy controls and 14 age-matched
patients with schizophrenia indicating higher binding potential values in
the left and right mediotemporal regions of interest. Mean binding potential
images and magnetic resonance images had been spatially normalized to the
Montreal Neurologic Institute brain space. The axial slice is 40 mm below
the anterior commissure–posterior commissure line, in the plane where
Statistical Parametric Mapping version 99 indicated the most pronounced group
difference.
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5-HT1A Receptor Binding Potentials for the 9 Regions of
Interest*
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A multivariate analysis of variance revealed no significant group differences
in regional tracer delivery (R1) between patients and controls
(F9,18 = 1.427; P = .25). Mean VOI values
were 23 mL for the cerebellum, 21 mL for the left PFC, 22 mL for the right
PFC, 15 mL for the ACC, 12 mL for the left temporal cortex, 12 mL for the
right temporal cortex, 4 mL for the left MTC, 4 mL for the right MTC, 26 mL
for the left parietal cortex, and 27 mL for the right parietal cortex. There
was no significant difference in VOIs between patients and controls (F10,17 = 0.882; P = .57). Furthermore, there
was no significant difference in the area under the curve of the cerebellar
TAC between groups (F1 = 0.194; P = .66)
(Figure 3).
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Figure 3. Decay-corrected cerebellar time-activity
curves normalized to their peak values for 14 healthy control subjects and
14 patients with schizophrenia. Error bars represent 1 SD.
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Pearson correlation coefficients (r) did not
reveal any significant correlation between age and the area under the curve
of the cerebellum or BP in any cortical ROI, between age and VOI, or between
regional BP values and their respective VOIs. Furthermore, there was no significant
correlation between MTC 5-HT1A receptor BP and duration of untreated
psychosis in patients (left MTC: r = 0.06; P = .84; right MTC: r = -0.18; P = .57). Binding potential values were not significantly
correlated to severity of illness as measured using the Positive and Negative
Syndrome Scale for schizophrenia sum, positive, negative, and general scores,
with r = 0.05 to 0.37 and the corresponding P = .41 to .92.
The voxel-wise analysis produced no robust evidence for a pronounced
elevation in [11C]WAY-100635 uptake in the prefrontal or temporal
cortex in schizophrenia. Statistical parametric mapping showed only one activity
cluster denoting higher [11C]WAY-100635 uptake in patients with
schizophrenia, consisting of 86 voxels extending laterally from the Montreal
Neurologic Institute brain space coordinates –16, –6, and –40
mm (x, y, and z, respectively), with z = 2.99 and P26 = .001. Plotting this activity cluster on
an averaged composite MRI of all patients, which had been normalized to the
Montreal Neurologic Institute brain space, revealed a region in the left MTC
similar to the one in which we found the most pronounced difference between
patients and controls with the ROI-based approach (Figure 4).
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Figure 4. Activity cluster where Statistical
Parametric Mapping version 99 displayed a statistically significant (P<.01) higher
[carbonyl-11C]- N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-
N-(2-pyridinyl)cyclohexane carboxamide uptake in patients with schizophrenia
plotted on a composite magnetic resonance image that had been normalized to
the Montreal Neurologic Institute brain space.
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COMMENT
The main finding of this in vivo PET study was an increase in cortical
5-HT1A receptor BP in schizophrenia. The most pronounced difference
between patients and controls was a 20% increase in [11C]WAY-100635
binding in the left MTC of patients with schizophrenia found by ROI-based
PET analysis, which was confirmed by an additional voxel-wise analysis using
SPM99.
This in vivo PET study of 5-HT1A receptors in schizophrenia
did not detect a significant elevation in [11C]WAY-100635 binding
in the prefrontal cortex of patients, which is in contrast to results of postmortem
studies6-13
showing a 20% to 79% elevation in 5-HT1A receptor number in that
region.
Postmortem studies have several limitations. All patients in the postmortem
studies had received several years of antipsychotic drug treatment, and all
patients except 5 in the study by Hashimoto et al6
were receiving antipsychotic agents at the time of death. In contrast, all
patients in our study were antipsychotic drug naive. Hence, the more pronounced
increase in postmortem 5-HT1A receptors could be an effect of long-term
drug treatment.
In contrast to the postmortem studies with an average illness duration
of approximately 20 years, our sample consisted of first-episode patients
with a mean ± SD duration of untreated psychosis of 21 ± 18
months (range, 7 months to 5 years). Owing to this relatively restricted range,
we were not able to systematically investigate the effects of disease progression.
For tracer kinetic modeling, we used the cerebellum as the reference
region for an SRTM because the cerebellum is relatively devoid of 5-HT1A receptors.13 Furthermore, the SRTM
proved to be more reliable than kinetic modeling using arterial data21 and provided excellent test-retest reproducibility
with [11C]WAY 100635.21, 23
A test-retest study in 6 control subjects provided strong evidence that we
would be able to correctly identify a group difference of 20% to 79% with
acceptable sensitivity.23 Sixty- and 90-minute
TACs gave comparable results. With 60-minute TACs, the magnitude of the mean
error between 2 [carbonyl-11C]WAY-100635 PET scans of the same
individual ranged from 2% to 7% in cortical ROIs.23
Most postmortem studies selected limited and often arbitrary brain regions
to study. Only 2 groups6-7,12
studied samples from all cortical regions. All others investigated only the
prefrontal cortex9-11,13
or the prefrontal and temporal cortices.8 Although
all of the postmortem studies report "prefrontal" increases, the data came
from Brodmann areas (BAs) 98; 106;
11 and 129; 24, 9a, and 4412;
or 46.10, 13 To avoid an unjustified
restriction to frontal brain areas, we analyzed 5-HT1A receptor
BP in cortical ROIs drawn in the DLPFC, ACC, MTC, LTC, and parietal cortex.
However, we are aware of several limitations inherent to the ROI approach.
The intrinsic spatial resolution of our PET camera is 4.5 to 5.5 mm in the
transaxial plane. Therefore, we chose to delineate rather large areas comprising
several BAs. In the case of the DLPFC, this ROI roughly corresponds to portions
of BAs 9, 10, and 46, whereas in case of the ACC, we tried to confine this
ROI to BA 32 and frontal parts of BA 24.
The process of coregistering introduces another source of error, which
also contributes to the anatomic inaccuracy of the ROI approach. Moreover,
if any given pathologic condition afflicts only parts of an ROI, a possible
BP increase or decrease will be diluted, and, therefore, the chance to miss
a group difference is high. On these grounds we chose to corroborate the results
of the ROI analysis by applying an additional voxel-wise SPM99 analysis. Because
of the restricted field of view of our PET camera (15 slices of 6.5 mm each,
which translates into 9.75 cm with regard to the z-axis), even the voxel-wise
approach cannot be considered to cover the entire brain. Nevertheless, SPM99
revealed an elevated 5-HT1A receptor BP in the left MTC of patients,
confirming the strongest result of the ROI-based approach.
We matched our control group for age but not for sex because it had
been shown post mortem and in vivo using PET and [11C]WAY-100635
that 5-HT1A density declines with age, whereas in both studies
sex did not significantly affect 5-HT1A receptor BP.23-24
Based on the results of postmortem studies, we expected at least a 25%
BP elevation in the frontal cortices of patients in vivo. Using values from
controls (mean ± SD frontal BP, 3.2 ± 0.4), we estimated that
our study had a power of 0.98 (1 - ß) to detect a 25% elevation
in frontal 5-HT1A receptor BP in patients at <.05. However,
this study did not reveal such an elevation in frontal brain regions. On the
other hand, to decide whether the 4% to 5% "nonsignificant" difference reported
in the DLPFC is truly within chance or due to a type II error, we would have
to increase our sample size 10-fold, which is not feasible because of practical
limitations.
There is preclinical evidence39-40
to support a role for 5-HT1A agonism in the antipsychotic action
and extrapyramidal adverse effects of drugs. The 5-HT1A agonist
8-OH-DPAT enhanced the antipsychotic-like effect of the D2/D3 antagonists raclopride41 and haloperidol42 and antagonized the catalepsy induced by the D1 agonist SCH23390 in rats.43 Several
atypical antipsychotic drugs are partial agonists at the 5-HT1A
receptor, including clozapine, ziprasidone, quetiapine, and tiospirone hydrochloride.
Clinical studies of adding 5-HT1A partial agonists may help to
clarify the possible importance of 5-HT1A agonism in the treatment
of schizophrenia.
The biological significance of elevated 5-HT1A receptor numbers
in schizophrenia as indicated by several postmortem studies and this in vivo
PET study remains unclear. It has been suggested that given the location of
most of the 5-HT1A receptors on pyramidal cells, it may reflect
an abnormal glutamatergic network.44 Although
we did not confirm a pronounced 5-HT1A receptor elevation in frontal
cortices of patients, the ROI-basedapproach demonstrated a 20% higher 5-HT1A receptor BP in the left MTC and a 13% elevation in the right MTC.
Underlining the robustness of the result in the left MTC was the fact that
it survived a correction for multiple comparisons in 9 cortical ROIs and was
confirmed using a voxel-wise analysis with SPM99. The left temporal cortex
is an anatomic region known to be afflicted in schizophrenia,45
but the significance and functional relevance of our finding of locally elevated
[11C]WAY-100635 uptake in patients with schizophrenia remains unclear
and warrants replication in the future.
AUTHOR INFORMATION
Submitted for publication February 26, 2001; final revision received
August 16, 2001; accepted September 11, 2001.
This research was supported by the EJLB Foundation (Montreal, Quebec)
and the Austrian Research Fund (Vienna).
We thank all patients and healthy volunteers for their participation;
Corey Jones, BSc, Kevin Cheung, Alex Kecojevic, HBSc, Li Jin, and Armando
Garcia for technical assistance; and Barb Brownlee, MSc, for proofreading.
Corresponding author and reprints: Johannes Tauscher, MD, Department
of General Psychiatry, University of Vienna, Währinger Gürtel 18-20,
A-1090 Vienna, Austria (e-mail: johannes.tauscher{at}akh-wien.ac.at).
From the PET Centre (Drs Tauscher, Kapur, Verhoeff, Wilson, and Houle
and Mr Hussey) and the Schizophrenia and Continuing Care Program (Drs Daskalakis,
Tauscher-Wisniewski, and Zipursky), Centre for Addiction and Mental Health
and the Department of Psychiatry, University of Toronto (Drs Kapur, Verhoeff,
Daskalakis, Tauscher-Wisniewski, Wilson, Houle and Zipursky), Toronto Ontario;
and the Department of General Psychiatry, University of Vienna, Vienna, Austria
(Drs Tauscher and Kasper).
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