Am J Psychiatry 163:5, May 2006ajp.psychiatryonline.org
Cortical Serotonin 5-HT2A Receptor Binding and Social
Communication in Adults With Asperger’s Syndrome:
An in Vivo SPECT Study
Declan G.M. Murphy, M.R.C.Psych., M.D.
Eileen Daly, B.Sc.
Nicole Schmitz, Ph.D.
Fiona Toal, M.R.C.Psych.
Keiran Murphy, F.R.C.Psych., Ph.D.
Sarah Curran, M.R.C.Psych., Ph.D.
Kjell Erlandsson, Ph.D.
Jos Eersels, Ph.D.
Robert Kerwin, F.R.C.Psych., Ph.D.
Peter Ell, M.D., Ph.D.
Michael Travis, M.R.C.Psych.
Objective: The cause of autistic spectrum disorder (i.e., autism
and Asperger’s syndrome) is unknown. The serotonergic (5-HT)
system may be especially implicated. However, cortical 5-HT2A
receptor density in adults with the disorder has not been exam-
ined, to the authors’ knowledge.
Method: The authors investigated cortical 5-HT2A receptor
binding in eight adults with Asperger’s syndrome and in 10
healthy comparison subjects with single photon emission com-
puted tomography and the selective 5-HT2A receptor ligand
123I iodinated 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-
Results: People with Asperger’s syndrome had a significant re-
duction in cortical 5-HT2A receptor binding in the total, anterior,
and posterior cingulate; bilaterally in the frontal and superior
temporal lobes; and in the left parietal lobe. Also, reduced re-
ceptor binding was significantly related to abnormal social
Conclusions: The authors’ findings suggest that adults with As-
perger’s syndrome have abnormalities in cortical 5-HT2A receptor
density and that this deficit may underlie some clinical symptoms.
(Am J Psychiatry 2006; 163:934–936)
Autistic spectrum disorder (comprising the subtypes
of autism, Asperger’s syndrome, and pervasive develop-
mental disorder not otherwise specified) affects approxi-
mately 60 per 10,000 people and is characterized by perva-
sive abnormalities in socioemotional communication and
stereotypical and obsessional behaviors.
The cause of autistic spectrum disorder is poorly under-
stood and is most likely multifactorial; however, the sero-
tonergic (5-HT) system may be especially implicated. In
nonhuman primates and nonautistic humans, the 5-HT
system modulates social behavior, amygdala response to
facial emotion (1), and repetitive behaviors (see reference
2 for a review). Furthermore, the 5-HT2A receptor modu-
lates personality traits, such as harm avoidance (3). People
with autistic spectrum disorder are reported to have a sig-
nificant decrease in platelet 5-HT2A receptor binding (4,
5), and the 5-HT2A receptor gene is a functional candidate
gene in autism (see reference 6 for a review).
Thus, people with autistic spectrum disorder may have
abnormalities in 5-HT2A receptors. However, no one has
directly investigated in vivo brain 5-HT2A receptor binding
in non-mentally retarded adults, to our knowledge. There-
fore, we measured cortical 5-HT2A receptor binding in
adults with Asperger’s syndrome and in comparison sub-
jects with single photon emission computed tomography
(SPECT) and the selective 5-HT2A receptor ligand 123I io-
5-I-R91150). Based on prior work (4, 5), we tested the hy-
pothesis that in people with Asperger’s syndrome, cortical
5-HT2A receptors are significantly decreased.
We studied eight adult men with Asperger’s syndrome (full-
scale IQ measured with the WAIS-III: >80, range=80–120; age:
mean=26 years, SD=6) who were educated until they were at least
18 years and 10 healthy male comparison subjects who did not
differ significantly in age or education. All volunteers were diag-
nosed with ICD-10 criteria and the Autistic Diagnostic Inter-
view—Revised (7). For people with Asperger’s syndrome, the
mean scores on the Autistic Diagnostic Interview—Revised for
domain A (qualitative abnormalities in reciprocal social interac-
tion), domain B (qualitative abnormalities in communication),
and domain C (repetitive behavior) were, respectively, mean=18
(SD=3), mean=13 (SD=6), and mean=6 (SD=3).
People were excluded if they had a history of physical or psy-
chiatric disorder affecting brain function (e.g., epilepsy), a genetic
disorder associated with autistic spectrum disorder (e.g., fragile X
syndrome), or clinically abnormal magnetic resonance imaging.
The study had ethical approval. No subject was taking any medi-
cation, and none reported past use of any psychotropic medica-
tion (e.g., selective serotonin reuptake inhibitors).
SPECT scans were performed at the Institute of Nuclear Medi-
cine, Middlesex Hospital, University College London Medical
School, with a three-headed PRISM 3000XP scanner (Phillips
Medical Systems, Cleveland) with low-energy ultra-high-resolu-
tion fan-beam collimators. A bolus dose of 180 MBq of 123I-5-I-
Am J Psychiatry 163:5, May 2006
R91150 was administered intravenously. Sequential whole-brain
images were acquired through a period of stable binding at pseu-
doequilibrium from 120 minutes to 280 minutes postinjection.
Whole-brain images were acquired with a resolution of 9–11
mm full width at half maximum. A transmission scan template,
with a corresponding 123I-5-I-R91150 specific emission scan tem-
plate, was generated. As previously described, data were analyzed
with the researcher automatically blind to subject status (e.g., see
reference 8). In brief, cerebellar and cortical regions of interest
based on the Talairach atlas were drawn on the emission scan
template brain, and subsequent automatic data analysis exam-
ined between-group differences independent of the operator.
The individual reconstructed and realigned image volumes were
coregistered to the template images by using a nine-parameter
(three-translation, three-rotation, and three-scaling) transforma-
tion based on the transmission image. Thus, mean activity per
voxel for each region of interest was generated automatically for
each subject. Average cerebellar uptake was used as a reference
region because it is virtually devoid of 5-HT2A receptors. Thus, an
estimated binding potential can be generated for each cortical re-
gion by calculating the cortical/cerebellar ratio for each cortical
region during the period of pseudoequilibrium.
Data were first examined for normality of distribution to con-
form to the assumptions of the statistics employed. Between-
group differences in mean 5-HT2A estimated binding potential
were examined by using a nonparametric test (Mann-Whitney U,
two-tailed), and statistical significance was defined as p<0.05.
Also, within those with Asperger’s syndrome, we carried out a pre-
liminary analysis (with a nonparametric test: Kendall’s tau) of the
relationship between estimated binding potential and clinical
symptoms as measured by the score on each of the three domains
of the Autistic Diagnostic Interview—Revised. To reduce the
number of statistical comparisons, we correlated only the esti-
mated binding potential of the brain regions that were signifi-
cantly different from those of the comparison subjects.
The individuals with Asperger’s syndrome had a signifi-
cantly lower mean 5-HT2A estimated binding potential
than the comparison subjects in the anterior and poste-
rior cingulate cortex, in the frontal and superior temporal
cortex bilaterally, and in the left parietal cortex (Table 1).
Also, estimated binding potential in the anterior and pos-
terior cingulate and the right frontal cortex was signifi-
cantly correlated with increased qualitative abnormalities
in reciprocal social interaction (domain A of the Autistic
Diagnostic Interview—Revised); in each of these three re-
gions, r=–0.837 and p<0.02.
Our findings suggest that people with Asperger’s syn-
drome have a significant reduction in cortical 5-HT2A re-
ceptors, supporting prior reports that people with autistic
spectrum disorder have reduced serotonergic “responsiv-
ity” (4) and platelet 5-HT2A receptor binding (4, 5).
However, we studied adults and used parental reports of
abnormal behavior and an analysis based on regions of in-
terest. Hence, we do not know if our findings will general-
ize across the autistic spectrum (e.g., to children) or if ab-
normalities in 5-HT2A estimated binding potential of
specific subregions of the cortex relate to particular sub-
types of social behavior (e.g., gaze avoidance or processing
of facial emotion). Also, we carried out a number of statis-
tical comparisons. Nevertheless, we compared group dif-
ferences in mean estimated binding potential with two-
tailed nonparametric statistical tests; seven of 15 regions
were significantly different, and four more were nearly sig-
nificant. Therefore, our findings are unlikely to be fully ex-
plained by type 1 error.
Reduced 5-HT2A estimated binding potential of the cin-
gulate, frontal, and temporal cortex was correlated with
qualitative abnormalities in reciprocal social interaction.
TABLE 1. Serotonin 5-HT2A Regional Cortical Receptor Binding Potential in Subjects With Asperger’s Syndrome and Healthy
Am J Psychiatry 163:5, May 2006
These regions are crucial to human social communication.
Also, in the general population, cortical 5-HT2A receptor
density is related to personality traits for harm avoidance
(3). Furthermore, as noted above, the 5-HT2A receptor gene
is close to a region on chromosome 13q reported to be
linked to autism (6). Hence, differences in cortical 5-HT2A
receptor availability may partially explain some symptoms
in people with Asperger’s syndrome. Furthermore, differ-
ences in the 5-HT system are of relevance to the treatment
of autistic spectrum disorder (e.g., randomized trials of 5-
HT reuptake inhibitors improve global severity ratings ).
5-HT acts as a trophic or differentiation factor in the
brain (10). We found that people with Asperger’s syn-
drome had lower estimated binding potential in regions
that are also anatomically abnormal in the disorder (11).
Furthermore, in people with Asperger’s syndrome, abnor-
mal neuronal integrity of a frontal region, including the
anterior cingulate, is also related to problems in social
communication (12). Thus, our findings may be con-
founded by differences in brain anatomy, and/or differ-
ences in the serotonergic system may affect brain devel-
opment in autistic spectrum disorder.
Others have reported a link between repetitive behav-
iors and the serotonergic system. We found no relation-
ship between these behaviors and cortical 5-HT2A density
in Asperger’s syndrome. This may reflect a lack of power or
our inability to detect subtle regional differences in recep-
tor density by using approaches based on regions of inter-
est. Also, people with Asperger’s syndrome had signifi-
cantly lower estimated binding potential in all of the brain
regions we examined, but this only reached statistical sig-
nificance in some regions. We do not suggest that people
with Asperger’s syndrome have regionally specific differ-
ences in 5-HT2A receptions. It is more likely that they have
generalized abnormality, but it may affect some brain re-
gions more than others.
Previous work in animals with 123I-5-I-R91150 has indi-
cated a higher nonspecific binding in primates than in rats
(13). However 123I-5-I-R91150 has been validated for use
in humans and has been used successfully in clinical pop-
ulations (e.g., see reference 14).
In summary, adults with Asperger’s syndrome have ab-
normalities in cortical 5-HT2A receptor density; this may
be related to some clinical symptoms. Further work
should directly relate differences in brain 5-HT receptors
to behavior in larger groups.
Received Nov. 19, 2004; revisions received Feb. 8 and April 8, 2005;
accepted April 26, 2005. From the Institute of Psychiatry, Depart-
ment of Psychological Medicine, London; the Department of Psychi-
atry, College of Surgeons, Dublin; Middlesex Hospital, University Col-
lege London, London; and Radionuclide Center, Vrije Universiteit,
Amsterdam. Address correspondence and reprint requests to Dr.
Murphy, P50, Institute of Psychiatry, DeCrespigny Park, London,
SE58AF U.K.; firstname.lastname@example.org (e-mail).
Supported by the South London and Maudsley National Health Ser-
vice Trust, the Health Foundation, and the Medical Research Council
United Kingdom AIMS Program.
1. Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman
D, Egan MF, Weinberger DR: Serotonin transporter genetic vari-
ation and the response of the human amygdala. Science 2002;
2. Stein D: Obsessive-compulsive disorder. Lancet 2002; 360:397–
3. Moresco FM, Dieci M, Vita A, Messa C, Gobbo C, Galli L, Rizzo G,
Panzacchi A, De Peri L, Invernizzi G, Fazio F: In vivo serotonin
5HT(2A) receptor binding and personality traits in healthy sub-
jects: a positron emission tomography study. Neuroimage
4. McBride PA, Anderson GM, Hertzig ME, Sweeney JA, Kream J,
Cohen DJ, Mann JJ: Serotonergic responsivity in young male
adults with autistic disorder: results of a pilot study. Arch Gen
Psychiatry 1989; 46:213–221
5. Cook EHJ, Arora RC, Anderson GM, Berry-Kravis EM, Yan SY,
Yeoh HC, Sklena PJ, Charak DA, Leventhal BL: Platelet seroto-
nin studies in hyperserotonemic relatives of children with au-
tistic disorder. Life Sci 1993; 52:2005–2015
6. Veenstra-VanderWeele J, Kim SJ, Lord C, Courchesne R, Akshoo-
moff N, Leventhal BL, Courchesne E, Cook EH Jr: Transmission
disequilibrium studies of the serotonin 5-HT2A receptor gene
(HTR2A) in autism. Am J Med Genet 2002; 114:277–283
7. Lord C, Rutter M, Le Couteur A: Autism Diagnostic Interview—
Revised: a revised version of a diagnostic interview for caregiv-
ers of individuals with possible pervasive developmental disor-
ders. J Autism Dev Disord 1994; 24:659–685
8. Busatto GF, Pilowsky LS, Costa DC, Mertens J, Terriere D, Ell PJ,
Mulligan R, Travis MJ, Leysen JE, Lui D, Gacinovic S, Waddington
W, Lingford-Hughes A, Kerwin RW: Initial evaluation of 123I-5-
I-R91150, a selective 5-HT2A ligand for single-photon emission
tomography, in healthy human subjects. Eur J Nucl Med 1997;
9. McDougle CJ, Naylor ST, Cohen DJ, Volkmar FR, Heninger GR,
Price LH: A double-blind, placebo-controlled study of fluvox-
amine in adults with autistic disorder. Arch Gen Psychiatry
10. Whitaker-Azmita PM: Serotonin and brain development: role
in human developmental diseases. Brain Res Bull 2001; 56:
11. McAlonan GM, Daly E, Kumari V, Critchley HD, van Amelsvoort
T, Suckling J, Simmons A, Sigmundsson T, Greenwood K, Russell
A, Schmitz N, Happe F, Howlin P, Murphy DGM: Brain anatomy
and sensorimotor gating in Asperger’s syndrome. Brain 2002;
12. Murphy DGM, Critchley HD, Schmitz N, McAlonan GM, van
Amelsvoort T, Robertson D, Daly E, Rowe A, Russell A, Simmons
A, Murphy KC, Howlin P: Asperger syndrome: a proton mag-
netic resonance spectroscopy study of brain. Arch Gen Psychi-
atry 2002; 59:885–891
13. Abi-Dargham A, Zea-Ponce Y, Terriere D, Al-Tikriti M, Baldwin R,
Hoffer P, Charney DS, Leysen JE, Laruelle M, Mertens J, Innis RB:
Preclinical evaluation of [I-123]R93274 as a SPECT radiotracer
for imaging serotonin 5-HT2A receptors. Eur J Pharmacol 1997;
14. Jones HM, Travis MJ, Mulligan R, Bressan RA, Visvikis D, Gacinovic
S, Ell PJ, Kerwin RW, Pilowsky LS: In vivo 5-HT2A receptor block-
ade by quetiapine: an R91150 single photon emission tomogra-
phy (SPET) study. Psychopharmacology (Berl) 2001; 157:60–66