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Original Article |

Decreased Frontal Serotonin2A Receptor Binding in Antipsychotic-Naive Patients With First-Episode Schizophrenia FREE

Hans Rasmussen, PhD; David Erritzoe, MD, PhD; Rune Andersen, MSc; Bjorn H. Ebdrup, MD; Bodil Aggernaes, MD, PhD; Bob Oranje, PhD; Jan Kalbitzer, MD; Jacob Madsen, PhD; Lars H. Pinborg, MD, DMSc; William Baaré, PhD; Claus Svarer, PhD; Henrik Lublin, MD, DMSc; Gitte M. Knudsen, MD, DMSc; Birte Glenthoj, MD, DMSc
[+] Author Affiliations

Author Affiliations: Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Faculty of Health Sciences, Copenhagen University Hospital, Psychiatric University Center Glostrup, Glostrup, Denmark (Drs Rasmussen, Ebdrup, Aggernaes, Oranje, Lublin, and Glenthoj and Mr Andersen); Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Faculty of Health Sciences (Drs Rasmussen, Erritzoe, Kalbitzer, Pinborg, Svarer, and Knudsen), and PET and Cyclotron Unit (Dr Madsen), Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; and Danish Center for Magnetic Resonance Imaging and Center for Integrated Molecular Brain Imaging, Faculty of Health Sciences, Copenhagen University Hospital Hvidovre Hospital, Hvidovre, Denmark (Dr Baaré).


Arch Gen Psychiatry. 2010;67(1):9-16. doi:10.1001/archgenpsychiatry.2009.176.
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Context  Postmortem investigations and the receptor affinity profile of atypical antipsychotics have implicated the participation of serotonin2A receptors in the pathophysiology of schizophrenia. Most postmortem studies point toward lower cortical serotonin2A binding in schizophrenic patients. However, in vivo studies of serotonin2A binding report conflicting results, presumably because sample sizes have been small or because schizophrenic patients who were not antipsychotic-naive were included. Furthermore, the relationships between serotonin2A binding, psychopathology, and central neurocognitive deficits in schizophrenia are unclear.

Objectives  To assess in vivo brain serotonin2A binding potentials in a large sample of antipsychotic-naive schizophrenic patients and matched healthy controls, and to examine possible associations with psychopathology, memory, attention, and executive functions.

Design  Case-control study.

Setting  University hospital, Denmark.

Participants  A sample of 30 first-episode, antipsychotic-naive schizophrenic patients, 23 males and 7 females, and 30 matched healthy control subjects.

Interventions  Positron emission tomography with the serotonin2A-specific radioligand fluorine 18–labeled altanserin and administration of a neuropsychological test battery.

Main Outcome Measures  Binding potential of specific tracer binding, scores on the Positive and Negative Syndrome Scale, and results of neuropsychological testing.

Results  Schizophrenic patients had significantly lower serotonin2A binding in the frontal cortex than did control subjects. A significant negative correlation was observed between frontal cortical serotonin2A binding and positive psychotic symptoms in the male patients. No correlations were found between cognitive functions and serotonin2A binding.

Conclusion  The results suggest that frontal cortical serotonin2A receptors are involved in the pathophysiology of schizophrenia.

Trial Registration  clinicaltrials.gov Identifier: NCT00207064

Figures in this Article

A growing body of evidence points toward impairment of the serotonin2A receptor function in schizophrenia. The initial serotonin hypothesis of schizophrenia was sparked by the observation that lysergic acid diethylamide (LSD), a drug with structural similarities to serotonin and a high affinity to serotonin2A receptors, has hallucinogenic properties similar to schizophrenic symptoms. This hypothesis is backed by 11111 of 151215 postmortem studies reporting decreased serotonin2A/C binding in cortical areas, especially in the frontal cortex. However, these reports were primarily based on chronically ill, medicated patients, and the techniques used to analyze postmortem tissue differed between studies.16

Indirect support for the involvement of the serotonin2A receptor in schizophrenia arises from the association between the receptor affinity profile and the clinical characteristics of new, atypical antipsychotic drugs. Atypical antipsychotic drugs have complex pharmacologic features. For example, clozapine has high affinity for a number of serotonin (serotonin2A, serotonin2C, serotonin6, serotonin7), dopamine (D4), muscarinic (M1, M2, M3, M4, M5), adrenergic (α1- and α2-subtypes), and other biogenic amine receptors.17 However, compared with typical antipsychotic drugs, which primarily bind to the dopamine 2 (D2) receptors, most atypical antipsychotics have higher affinity to cortical serotonin2A receptors than to striatal D2 receptors.18,19 This may account for the reduced extrapyramidal side effects of atypical antipsychotics and their effect on negative symptoms.20

It is unclear how serotonin2A activity is associated with the most commonly found clinical cognitive deficits in schizophrenia,21,22 for example, attention, executive functions, and spatial working memory. It has been proposed that working memory could be one of the central cognitive markers or endophenotypes of schizophrenia.2325 In general, the literature suggests that serotonin2A receptor antagonism improves cognition in schizophrenia.26 Recent research has shown that the affinity of antipsychotic drugs to the serotonin2A receptor is associated with cognition in a subtle way. Spatial working memory has been suggested to improve by stimulation rather than blockade of serotonin2A receptors in both preclinical and clinical studies.2729 Conversely, blockade of serotonin2A receptors by the serotonin2A antagonist ketanserin in healthy control subjects impaired memory more than combined escitalopram oxalate–ketanserin treatment.30 Atypical antipsychotic drugs with a high antagonistic action on serotonin2A may therefore benefit spatial working memory tasks less than low-affinity drugs.27 These studies support a linkage between impaired working memory and decreased serotonin2A availability or function in the human brain.

The introduction of selective serotonin2A receptor radioligands for positron emission tomography (PET) made it possible to examine the serotonin2A receptor density in the living human brain. However, few PET studies on first-episode antipsychotic-naive schizophrenic patients have been performed so far, and the results are inconsistent. Three studies found no difference in serotonin2A binding between schizophrenic patients and healthy control subjects,3133 and 1 study found a decreased binding potential in the left lateral frontal cortex in 6 patients.34 These studies are limited by small sample sizes and by their use of the radioligands setoperone labeled with fluorine 18 and N-methylspiperone labeled with carbon 11, which have a relatively low serotonin2A receptor selectivity.35

The radioligand altanserin labeled with fluorine 18 is highly selective for the serotonin2A receptor and allows measurements of serotonin2A receptor availability in both cortical and subcortical regions.31,36,37 In a previous preliminary study, our group reported the use of this radioligand in 15 antipsychotic-naive schizophrenic patients.35 We were unable to confirm our hypothesis of decreased frontal 5HT2A binding. However, in a post hoc analysis38 we found increased serotonin2A binding in the caudate nucleus. This result was considered a preliminary finding because of the modest receptor density of serotonin2A in subcortical brain regions. Larger sample sizes were deemed to be required to exclude type II errors.

The aim of the present PET study, therefore, is to use [18F]altanserin-PET to investigate cortical and subcortical serotonin2A binding in an extended group of first-episode antipsychotic-naive schizophrenic patients and matched healthy control subjects. Fifteen of the patients were identical to the patients included in our previous preliminary study.35

A decrease in serotonin2A binding in the frontal cortex in these patients compared with matched healthy control subjects was expected a priori. We also expected to confirm our preliminary finding of serotonin2A receptor upregulation in the caudate nucleus. As an additional and new approach, we explored possible associations between serotonin2A binding, psychopathology, and central cognitive deficits, specifically spatial working memory, attention, and executive functions.

The study was approved by the Ethics Committee of Copenhagen and Frederiksberg ([KF]11-061/03). The subjects participated after receiving a full explanation of the study and providing written informed consent according to the Declaration of Helsinki II.

PARTICIPANTS

Thirty-three patients (26 male and 7 female) were recruited after voluntary first-time referral to a psychiatric unit of one of the affiliated university hospitals in the Capital Region of Copenhagen (Bispebjerg Hospital, Rigshospitalet, Psychiatric University Center Glostrup, or Psychiatric University Center Gentofte).

Thirty of the 33 patients fulfilled the diagnostic criteria for schizophrenia according to both the International Statistical Classification of Diseases, 10th Revision, and DSM-IV. Three patients proved to have a diagnosis of schizotypal personality disorder at a later stage of the study and were therefore excluded. All included patients (mean [SD] age, 26.4 [5.5] years) were antipsychotic naive. The diagnoses of schizophrenia were verified by means of the Schedules for Clinical Assessment in Neuropsychiatry interview.39

Thirty healthy control subjects (mean [SD] age, 26.4 [5.7] years) matched for age, sex, and parental socioeconomic status were recruited from the community by advertisement. None of the healthy control subjects had present or previous psychiatric disorder or any history of psychotropic medication as determined by the Schedules for Clinical Assessment in Neuropsychiatry interviews.

Six patients were previous (n = 4) or present (n = 2) users of antidepressant medication (in all cases selective serotonin reuptake inhibitors [SSRIs]). Benzodiazepines were allowed, albeit not on the day of the PET scan. Eight patients fulfilled lifetime criteria for substance abuse. All abuse diagnoses were clearly secondary to the diagnosis of schizophrenia. Substance dependence was an exclusion criterion. The DSM-IV diagnoses of substance abuse were as follows: alcohol abuse, in sustained full remission (n = 2); cannabis abuse, in a controlled environment (n = 1); other abuse, sustained full remission (n = 1); other abuse, moderate (n = 1); other abuse, in a controlled environment (n = 2); and other abuse, early partial remission (n = 1). In 4 of the patients the diagnosis “other abuse” covered mixed cannabis and alcohol abuse, and in the remaining patient the diagnosis covered a history of amphetamine and cocaine use. Three patients had no history of abuse for the past year, and 4 patients had no abuse for the past month. All subjects had negative results of urine screening for substance intake before the PET scan.

Eighteen of the patients (60%) and 6 of the control subjects (20%) were smokers. None of the participants had smoked 2 hours before the PET investigations. Smoking status was not a matching criterion because, in a recent study on 136 healthy subjects study, our group found no effect of smoking on serotonin2A binding.40

No subjects had a history of significant head injury or nonpsychiatric disorder. All subjects had normal results of a neurologic interview and examination, and structural magnetic resonance (MR) images of the brain were without clinical pathological findings as evaluated by a neuroradiologist.

PSYCHOPATHOLOGICAL RATINGS

Symptom severity was assessed by trained raters using the Positive and Negative Syndrome Scale (PANSS).41 All interviews were recorded on DVD for validation purposes. A subsample of 10 randomly selected PANSS ratings showed an intraclass correlation coefficient of 0.85 between the raters in a 2-way fixed-effect model.42

NEUROCOGNITIVE TESTING

Memory, executive functions, and attention were assessed with the following subtests from the Cambridge Neuropsychological Test Automated Battery43: Spatial Working Memory, Stockings of Cambridge, Intra-Extradimensional Set Shifting, and Rapid Visual Information Processing.

MR IMAGING

High-resolution 3-dimensional, T1-weighted, sagittal, magnetization-prepared rapid gradient-echo images of the whole head (inversion time, 800 milliseconds; echo time, 3.93 milliseconds; repetition time, 1540 milliseconds; flip angle, 9°; matrix, 256 × 256; 192 sections) using an 8-channel head array coil were acquired in all subjects on a 3-T imager (TRIO; Siemens, Erlangen, Germany) at the MR department of the Copenhagen University Hospital, Hvidovre, Denmark.

[18F]ALTANSERIN RADIOSYNTHESIS AND ADMINISTRATION

The radiosynthesis of [18F]altanserin has been described previously.44 Quality control was performed by means of thin-layer chromatography and high-performance liquid chromatography. The absence of residual solvents (methanol, tetrahydrofuran, and dimethyl sulfoxide) in the final formulation was confirmed by proton nuclear MR. For each PET study, 0.3 to 3.5 GBq of [18F]altanserin was produced with a radiochemical yield exceeding 95%. (To convert [18F]altanserin to curies, multiply by 2.7 × 10−3.) Catheters were inserted in both cubital veins for tracer infusion and blood sampling, respectively. The [18F]altanserin was administrated as a bolus to injection followed by continuous infusion to obtain a steady state of the tracer in blood and tissue. The bolus infusion ratio was 1.75 hours, as previously described.45 Subjects received a maximum dose of 3.7 MBq of [18F]altanserin per kilogram of body weight.

PET SCANNING

The PET scans were acquired in tracer steady-state conditions with an 18-ring scanner (GE-Advance; General Electric Co, Milwaukee, Wisconsin), operating in 3-dimensional acquisition mode, producing 35 image sections with an intersection distance of 4.25 mm. The total axial field of view was 15.2 cm, with an approximate in-plane resolution down to 5 mm. During steady state, the fraction of unmetabolized tracer in venous plasma was determined at 5 time points by means of high-performance liquid chromatography analysis. Reconstruction, attenuation, and scatter correction procedures were conducted as previously described.45

The subjects were placed in the scanner 90 minutes after the bolus injection of [18F]altanserin. The subjects were aligned in the scanner by means of a laser system so that the detectors were parallel to the orbitomeatal line and positioned to include the cerebellum in the field of view with the use of a short 2-minute transmission scan. An individual head holder was made to ensure relative immobility. All subjects were scanned in a resting state. A 10-minute transmission scan was obtained for correction of tissue attenuation with retractable germanium Ge 68/gallium Ga 68 pin sources. The transmission scans were corrected for tracer activity by a 5-minute emission scan performed in 2-dimensional mode. Dynamic 3-dimensional emission scans (5 frames of 8 minutes) were started 120 minutes after tracer administration.

Data were reconstructed into a sequence of 128 × 128 × 35 voxel matrixes, each voxel measuring 2.0 × 2.0 × 4.25 mm, with software provided by the manufacturer. A 3-dimensional reprojection algorithm with a 6-mm transaxial Hann filter and an 8.5-mm axial ramp filter was applied. Corrections for dead time, attenuation, and scatter were performed.

BLOOD SAMPLES

Five venous blood samples were drawn at midscan times 4, 12, 20, 28, and 36 minutes after the start of the dynamic scanning sequence. The samples were immediately centrifuged, and 0.5 mL of plasma was counted in a well counter for determination of radioactivity. Three of the 5 blood samples drawn at 4, 20, and 36 minutes were also analyzed for percentage of parent compound ([18F]altanserin) by means of reverse-phase high-performance liquid chromatography following a previously described method.46

In addition, the free fraction of [18F]altanserin in plasma, fP, was estimated by equilibrium dialysis, following a modified procedure.47 The dialysis was performed with Teflon-coated dialysis chambers (Amika; Harvard Bioscience, Holliston, Massachusetts) with a cellulose membrane that retains proteins larger than 10 000 Da. A small amount of [18F]altanserin (approximately 1 MBq) was added to 10-mL plasma samples drawn from the subjects. A 500-L portion of plasma was then dialyzed at 37°C for 3 hours against an equal volume of buffer because pilot studies had shown that a 3-hour equilibration time yielded stable values. The buffer consisted of 135mM sodium chloride, 3.0mM potassium chloride, 1.2nM calcium chloride, 1.0mM magnesium chloride, and 2.0mM phosphate (pH, 7.4). After the dialysis, 400 L of plasma and buffer was counted in a well counter, and the fP of [18F]altanserin was calculated as the ratio of disintegrations per minute in buffer vs plasma.

MR/PET CO-REGISTRATION

The PET images and 3-dimensional T1-weighted MR images were co-registered by means of a MATLAB-based program48 (MathWorks Inc, Natick, Massachusetts), in which PET and MR images are brought to fit through manual translation and rotation of the PET image with subsequent visual inspection in 3 planes.46

VOLUMES OF INTEREST AND PARTIAL VOLUME CORRECTION

Volumes of interest (VOIs) were automatically delineated on each individual's transaxial MR imaging sections in a strictly user-independent manner.49 This approach allowed automatic co-registration of a template set of 10 MR images to a new subject's MR image. The identified transformation parameters were used to define VOIs in the new subject MR imaging space, and through the co-registration these VOIs were transferred onto the PET images.

A frontal cortex region was defined for each subject and served as the primary VOI. The frontal cortex VOI consisted of a volume-weighted average of left and right cortical regions and included the orbitofrontal cortex, medial inferior frontal cortex, superior frontal cortex, and anterior cingulate cortex.49

Other regions included were the amygdala, caudate nucleus, entorhinal cortex, hippocampus, hypothalamus, insula, occipital cortex, parietal cortex, posterior cingulate cortex, putamen, sensorimotor cortex, superior temporal cortex, and thalamus. The cerebellum was used for estimation of nonspecific binding.

To enable partial volume correction of the PET data, MR images corrected for radiofrequency inhomogeneities by means of the N3 software50 were segmented into gray matter, white matter, and cerebrospinal fluid tissue classes with Statistical Parametric Mapping software (Wellcome Department of Cognitive Neurology, London, England). Partial volume correction was performed according to the Müller-Gärtner method.51,52 The white matter value was extracted from the uncorrected PET scan as the mean voxel value from a brain region containing predominantly white matter (centrum semiovale).

QUANTIFICATION OF SEROTONIN2A RECEPTOR BINDING

The outcome measure was the binding potential of specific tracer binding (BPP). The cerebellum was used as a reference region, since it represents nonspecific binding only. In the steady state, BPP is defined as follows:

BPP = [(CVOI − CReference)/CPlasma] = fp(Bmax/Kd),

where CVOI and CReference are the steady-state mean count densities in the VOI and in the reference region, respectively; CPlasma is the steady-state activity of nonmetabolized tracer in plasma; fp is the free fraction of radiotracer; Bmax is the density of receptor sites available for tracer binding; and Kd is the affinity constant of the radiotracer to the receptor.

STATISTICS

All analyses were performed with SPSS software (SPSS Inc, Chicago, Illinois). Between-group (patient or control) comparisons of all reported outcome measures were performed by parametric analysis after verifying that the data were normally distributed according to the Kolmogorov-Smirnov test. Potential outliers were detected with the Grubbs outlier test53 and subsequently excluded from analysis. The planned comparison in frontal serotonin2A binding between patients and controls was performed with an independent-sample t test (1-tailed, because of our directional hypothesis). In addition, an analysis of variance (ANOVA) was performed with between-factor group (patient or control) and within-factor region (frontal or other), to test whether a potential effect of group was more a global effect across all regions than a regional effect principally affecting frontal cortex. Furthermore, to test for additional regional group differences in binding, an ANOVA was performed with between-factor group (patient or control) and within-factor region (the regions specified in Table 1). Independent-sample t tests (2-tailed) were performed only when these ANOVAs indicated statistically significant results.

Table Graphic Jump LocationTable 1.  Mean Binding Potentials of Specific [18F]Altanserin Binding in Frontal Cortex and Subregions of Interest in Patients and Controls

Independent-sample t tests were further used to test for differences between patients and controls with regard to neurocognitive and psychopathological measures (2-tailed). Correlation analyses were performed with the Pearson product-moment correlation coefficient. The potential effect on the results of antidepressant medication, benzodiazepines, and substance abuse was examined by including these parameters in a multiple analysis of covariance as covariates.

SEROTONIN2A BINDING

The planned comparison of frontal cortical binding showed reduced serotonin2A binding in patients compared with controls (t58 = 2.54, P = .01).

The ANOVA on region and group disclosed significant main effects of group (F1,58 = 5.58, P = .02) and region (F17,42 = 82.19, P < .001), and a significant region × group interaction effect (F17,986 = 5.77, P < .001). Further analysis of these results indicated that serotonin2A binding in patients was significantly reduced not only in the frontal cortex but also in a number of other cortical—but not subcortical—regions (Table 1). Therefore, to test whether the frontal cortical region showed an even lower serotonin2A receptor binding than the other cortical regions, a post hoc ANOVA was performed with within-factor region (frontal cortex or other regions, Table 1) and between-factor group. This ANOVA demonstrated main effects of region (F1,58 = 1109, P < .001) and group (F1,58 = 6.00, P = .02) as well as a first-order interaction between region and group (F1,58 = 7.78, P = .007), indicating a more pronounced reduction in serotonin2A receptor binding in the frontal cortical region than in the other cortical regions (Figure 1).

Place holder to copy figure label and caption

Figure 1. Mean frontal cortical and total serotonin2A receptor binding in 30 antipsychotic-naive patients with first-episode schizophrenia and 30 matched healthy controls.

Graphic Jump Location

In the control group, the Grubbs test indicated 1 significant outlier with an increased binding in the frontal cortex. After exclusion of this outlier, the differences in serotonin2A binding remained significant. None of the results changed when the subjects with previous (n = 4) or current (n = 2) antidepressant treatment or cocaine and amphetamine abuse (n = 1) were excluded from the analyses. Data related to antidepressant medication is described in detail in Table 2. Furthermore, use of benzodiazepines did not covary significantly. The 2 groups did not differ significantly with regard to body mass index, injected radioactive dose, plasma free fraction, and specific radioactivity of [18F]altanserin (Table 3). The patients had significantly lower nonspecific binding than did the healthy control subjects.

Table Graphic Jump LocationTable 2.  Patients Receiving Antidepressant Medication
SEROTONIN2A BINDING AND NEUROCOGNITION

The cognitive data represent a subsample of a larger unpublished data set (R.A., B.O., Birgitte Fagerlund, PhD, Anders Gade, PhD, H.R., B.H.E., and B.G., unpublished data, 2009). Patients had significantly lower neurocognitive scores than healthy control subjects on the following tests: Spatial Working Memory strategy, Spatial Working Memory total errors, Spatial Working Memory between errors, Intra-Extradimensional Set Shifting total errors, and Intra-Extradimensional Set Shifting total number of trials on all stages attempted. There were no significant differences in Stockings of Cambridge or Rapid Visual Information Processing (Table 4). In the frontal cortex, no significant correlations were detected between serotonin2A binding and the neurocognitive measures. No significant correlations were found between the other VOIs and neurocognitive performance.

Table Graphic Jump LocationTable 4.  Neurocognitive Performance of Memory, Executive Functions, and Attention in Schizophrenic Patients Compared With Healthy Controls
SEROTONIN2A BINDING AND PSYCHOPATHOLOGY

In the patients, the PANSS mean (SEM) scores were as follows: positive, 20.0 (0.93); negative, 22.0 (1.20); general, 38.5 (1.30); and total, 80.0 (2.60). A significant negative correlation (r = −0.57, P < .01) was found between serotonin2A binding in the frontal cortex and positive symptoms in the larger group of male patients. An explorative post hoc analysis showed significant negative correlations between frontal serotonin2A binding and the following subitems of the positive PANSS scale: P1 delusions (r = −0.47, P = .03) and P6 suspiciousness (r = −0.53, P = .01) (Figure 2). No significant differences were found between the other VOIs and psychopathology. There was no sex effect on symptom severity or serotonin2A binding.

Place holder to copy figure label and caption

Figure 2. Correlation in male schizophrenic patients between mean frontal cortical serotonin2A receptor binding, positive symptoms on the Positive and Negative Syndrome Scale (PANSS), and 2 subitems. Negative correlations are evident for the PANSS positive scale (r = −0.57, P = .007) (A), as well as for subitems P1, delusions (r = −0.47, P = .03) (B), and P6, suspiciousness (r = −0.53, P = .01) (C).

Graphic Jump Location

In this study of serotonin2A binding in antipsychotic-naive, first-episode schizophrenic patients, we confirmed our hypothesis of lower frontal cortical serotonin2A binding in patients than in matched healthy control subjects. The serotonin2A binding was also reduced in a number of other cortical regions, but the reduction in the frontal cortical region was more pronounced. This is in agreement with the many postmortem studies suggesting decreased cortical serotonin2A receptor binding in schizophrenic patients. Moreover, the data demonstrated a significant negative correlation between frontal cortical serotonin2A binding and positive psychotic symptoms in male patients. We were not, however, able to confirm correlations between cognitive functions and serotonin2A binding, even though the patients performed significantly worse in spatial working memory and aspects of executive function than did the healthy controls.

Our results are based on what we believe to be the largest sample studied with PET, because earlier PET studies have reported results based on 6 to 15 patients.3135 The majority of these studies, including our own,54 were unable to identify differences in cortical serotonin2A binding between schizophrenic patients and healthy control subjects. In our previous study38 we found increased serotonin2A receptor binding in the caudate nucleus. This nucleus is a region with a relatively low serotonin2A receptor density; hence, the post hoc analyses were more prone to type II errors. The present study does not confirm our preliminary finding of increased binding in the caudate nucleus, but it does support the study by Ngan and colleagues,34 who reported reduced serotonin2A binding in the frontal cortex of 6 neuroleptic-naive schizophrenic subjects. Similarly, Hurlemann and colleagues55,56 reported decreased cortical serotonin2A binding in subjects at high risk of developing schizophrenia.

Decreased frontal serotonin2A binding and the relationship with positive psychotic symptoms may reflect either a primary pathophysiologic disturbance in schizophrenia or a compensatory downregulation of receptors in response to altered endogenous serotonin levels. Alternatively, the finding could indicate a downregulation compensating for hyperactive second messenger systems or hyperactivity in other systems on which the serotonin2A receptors have a modifying effect. Finally, the finding could imply that frontal serotonin2A receptors are important targets for antipsychotic drugs.

The correlation between serotonin2A binding and symptoms was present only in the male subjects. Various aspects of schizophrenia, including age at onset, pathophysiology, symptomatology, course of illness, and treatment response, have previously been shown to be related to sex. These sex differences supply evidence for a potential role of gonadal hormones and for an interaction of these hormones with neurotransmitters (for a review, see Halbreich and Kahn57). Indeed, we have previously reported sex differences in drug-naive schizophrenic patients with regard to the dopamine system, namely, a correlation between D2 receptor binding in the frontal cortex and positive psychotic symptoms in male patients only.58

As expected, patients showed significantly poorer performance in spatial working memory and aspects of executive functions than did healthy control subjects. This is in agreement with previous studies that have shown that spatial working memory and executive functions are centrally impaired neurocognitive domains in schizophrenia.21,22 However, we detected no correlations between the cognitive measures and serotonin2A binding in any of the VOIs. Hence, our data do not support previous findings relating serotonin2A receptor to cognition in general26 and spatial working memory in particular.27,28

The interaction between serotonin and cognition is complex. Indeed, the interactions between serotonin, dopamine, norepinephrine, and the cholinergic system have been suggested to mediate cognitive behavior.28 Moreover, studies differ in design with regard to subjects (rodents, healthy controls, or patients), type of serotonin manipulation (global, specific depletion, or stimulation), serotonin receptor subtype (currently 15 serotonin receptor subtypes have been identified), and the cognitive tests being used.27

There are some methodologic issues in the study that need to be addressed.

Six patients had previously received (n = 4) or were currently receiving (n = 2) SSRI treatment, which is known to affect serotonergic innervation. However, we have previously found that [18F]altanserin binding to serotonin2A receptors is insensitive to a citalopram hydrobromide challenge increasing extracellular serotonin.59 Furthermore, the effect of long-term SSRI treatment on serotonin2A density is unclear because SSRIs have different effects on serotonin2A receptors. Fluoxetine hydrochloride has been reported to have no effect on serotonin2A receptor number or to actually increase receptor number. Similarly, paroxetine hydrochloride has been shown to increase or have no effect on serotonin2A receptor density. In contrast, long-term citalopram treatment has been shown to downregulate serotonin2A receptors.60

For the foregoing reasons, we initially chose to include patients taking previous or current antidepressants but controlled for the potential effect in a post hoc analysis in which these patients were removed from the analyses. This did not change the results.

Similarly, 1 patient had a history of amphetamine and cocaine abuse. These substances are known to affect serotonergic innervation in the brain; however, the patient did not differ in serotonin2A receptor binding, and exclusion of this patient from the analyses did not alter the results.

Finally, there was a significantly lower binding in the cerebellum in patients than in control subjects. We have no explanation for this finding; the fraction of [18F]altanserin metabolites in venous blood was the same in both groups. However, lower nonspecific cerebellar binding in the patients is not likely to bias the results because a relative underestimation of nonspecific binding in the patients would lead to an overestimation of the composite measure BPP (see the equation in the “Methods” section).

In conclusion, this study of serotonin2A receptor binding in first-episode, antipsychotic-naive schizophrenic patients shows decreased binding in the frontal cortex and a negative correlation with positive symptoms in male patients. The results suggest that frontal cortical serotonin2A receptors are involved in the pathophysiology of schizophrenia. Because no correlations were found between binding and cognition, this study does not support the involvement of serotonin2A receptors in cognitive deficits in this early stage of the disease.

Correspondence: Hans Rasmussen, PhD, Psychiatric University Center Glostrup, Copenhagen University Hospital, Ndr Ringvej, DK-2600 Glostrup, Denmark (h.rasmussen@cnsr.dk).

Submitted for Publication: November 9, 2008; final revision received February 28, 2009; accepted May 8, 2009.

Financial Disclosure: None reported.

Funding/Support: This study was sponsored by the Danish Medical Research Council, H:S (Copenhagen Hospital Cooperation) Research Council, Copenhagen University Hospitals Rigshospitalet and H:S Bispebjerg, the John and Birthe Meyer Foundation, the Lundbeck Foundation, and an unrestricted grant from Astra Zeneca A/S.

Arora  RCMeltzer  HY Serotonin2 (5-HT2) receptor binding in the frontal cortex of schizophrenic patients. J Neural Transm 1991;85 (1) 19- 29
Bennett  JP  JrEnna  SJBylund  DBGillin  JCWyatt  RJSnyder  SH Neurotransmitter receptors in frontal cortex of schizophrenics. Arch Gen Psychiatry 1979;36 (9) 927- 934
PubMed
Burnet  PWEastwood  SLHarrison  PJ 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia. Neuropsychopharmacology 1996;15 (5) 442- 455
PubMed
Dean  BHayes  W Decreased frontal cortical serotonin2A receptors in schizophrenia. Schizophr Res 1996;21 (3) 133- 139
PubMed
Dean  BHayes  WHill  CCopolov  D Decreased serotonin2A receptors in Brodmann's area 9 from schizophrenic subjects: a pathological or pharmacological phenomenon? Mol Chem Neuropathol 1998;34 (2-3) 133- 145
PubMed
Dean  BHussain  THayes  WScarr  EKitsoulis  SHill  COpeskin  KCopolov  DL Changes in serotonin2A and GABAA receptors in schizophrenia: studies on the human dorsolateral prefrontal cortex. J Neurochem 1999;72 (4) 1593- 1599
PubMed
Gurevich  EVJoyce  JN Alterations in the cortical serotonergic system in schizophrenia: a postmortem study. Biol Psychiatry 1997;42 (7) 529- 545
PubMed
Laruelle  MAbi-Dargham  ACasanova  MFToti  RWeinberger  DRKleinman  JE Selective abnormalities of prefrontal serotonergic receptors in schizophrenia: a postmortem study. Arch Gen Psychiatry 1993;50 (10) 810- 818
PubMed
Matsumoto  IInoue  YIwazaki  TPavey  GDean  B 5-HT2A and muscarinic receptors in schizophrenia: a postmortem study. Neurosci Lett 2005;379 (3) 164- 168
PubMed
Mita  THanada  SNishino  NKuno  TNakai  HYamadori  TMizoi  YTanaka  C Decreased serotonin S2 and increased dopamine D2 receptors in chronic schizophrenics. Biol Psychiatry 1986;21 (14) 1407- 1414
PubMed
Pralong  DTomaskovic-Crook  EOpeskin  KCopolov  DDean  B Serotonin2A receptors are reduced in the planum temporale from subjects with schizophrenia. Schizophr Res 2000;44 (1) 35- 45
PubMed
Dean  BHayes  WOpeskin  KNaylor  LPavey  GHill  CKeks  NCopolov  DL Serotonin2 receptors and the serotonin transporter in the schizophrenic brain. Behav Brain Res 1996;73 (1-2) 169- 175
PubMed
Joyce  JNShane  ALexow  NWinokur  ACasanova  MFKleinman  JE Serotonin uptake sites and serotonin receptors are altered in the limbic system of schizophrenics. Neuropsychopharmacology 1993;8 (4) 315- 336
PubMed
Reynolds  GPRossor  MNIversen  LL Preliminary studies of human cortical 5-HT2 receptors and their involvement in schizophrenia and neuroleptic drug action. J Neural Transm Suppl 1983;18273- 277
PubMed
Whitaker  PMCrow  TJFerrier  IN Tritiated LSD binding in frontal cortex in schizophrenia. Arch Gen Psychiatry 1981;38 (3) 278- 280
PubMed
Dean  BCrossland  NBoer  SScarr  E Evidence for altered post-receptor modulation of the serotonin 2a receptor in schizophrenia. Schizophr Res 2008;104 (1-3) 185- 197
PubMed
Roth  BLSheffler  DJKroeze  WK Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov 2004;3 (4) 353- 359
PubMed
Meltzer  HYMatsubara  SLee  JC Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther 1989;251 (1) 238- 246
PubMed
Farde  LNyberg  SOxenstierna  GNakashima  YHalldin  CEricsson  B Positron emission tomography studies on D2 and 5-HT2 receptor binding in risperidone-treated schizophrenic patients. J Clin Psychopharmacol 1995;15 (1) (suppl 1)19S- 23S
PubMed
Meltzer  HYLi  ZKaneda  YIchikawa  J Serotonin receptors: their key role in drugs to treat schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2003;27 (7) 1159- 1172
PubMed
Weickert  TWGoldberg  TEGold  JMBigelow  LBEgan  MFWeinberger  DR Cognitive impairments in patients with schizophrenia displaying preserved and compromised intellect. Arch Gen Psychiatry 2000;57 (9) 907- 913
PubMed
Gur  RCRagland  JDMoberg  PJBilker  WBKohler  CSiegel  SJGur  RE Computerized neurocognitive scanning, II: the profile of schizophrenia. Neuropsychopharmacology 2001;25 (5) 777- 788
PubMed
Conklin  HMCurtis  CECalkins  MEIacono  WG Working memory functioning in schizophrenia patients and their first-degree relatives: cognitive functioning shedding light on etiology. Neuropsychologia 2005;43 (6) 930- 942
PubMed
Jindal  RDKeshavan  MS Neurobiology of the early course of schizophrenia. Expert Rev Neurother 2008;8 (7) 1093- 1100
PubMed
Meneses  A Involvement of 5-HT2A/2B/2C receptors on memory formation: simple agonism, antagonism, or inverse agonism? Cell Mol Neurobiol 2002;22 (5-6) 675- 688
PubMed
Roth  BLHanizavareh  SMBlum  AE Serotonin receptors represent highly favorable molecular targets for cognitive enhancement in schizophrenia and other disorders. Psychopharmacology (Berl) 2004;174 (1) 17- 24
PubMed
Tyson  PJRoberts  KHMortimer  AM Are the cognitive effects of atypical antipsychotics influenced by their affinity to 5HT-2A receptors? Int J Neurosci 2004;114 (6) 593- 611
PubMed
Tyson  PJLaws  KRFlowers  KATyson  AMortimer  AM Cognitive function and social abilities in patients with schizophrenia: relationship with atypical antipsychotics. Psychiatry Clin Neurosci 2006;60 (4) 473- 479
PubMed
Williams  GVRao  SGGoldman-Rakic  PS The physiological role of 5-HT2A receptors in working memory. J Neurosci 2002;22 (7) 2843- 2854
PubMed
Wingen  MKuypers  KPRamaekers  JG Selective verbal and spatial memory impairment after 5-HT1A and 5-HT2A receptor blockade in healthy volunteers pre-treated with an SSRI. J Psychopharmacol 2007;21 (5) 477- 485
PubMed
Lewis  RKapur  SJones  CDaSilva  JBrown  GMWilson  AAHoule  SZipursky  RB Serotonin 5-HT2 receptors in schizophrenia: a PET study using [18F]setoperone in neuroleptic-naive patients and normal subjects. Am J Psychiatry 1999;156 (1) 72- 78
PubMed
Okubo  YSuhara  TSuzuki  KKobayashi  KInoue  OTerasaki  OSomeya  YSassa  TSudo  YMatsushima  EIyo  MTateno  YToru  M Serotonin 5-HT2 receptors in schizophrenic patients studied by positron emission tomography. Life Sci 2000;66 (25) 2455- 2464
PubMed
Trichard  CPaillere-Martinot  MLAttar-Levy  DBlin  JFeline  AMartinot  JL No serotonin 5-HT2A receptor density abnormality in the cortex of schizophrenic patients studied with PET. Schizophr Res 1998;31 (1) 13- 17
PubMed
Ngan  ETYatham  LNRuth  TJLiddle  PF Decreased serotonin 2A receptor densities in neuroleptic-naive patients with schizophrenia: a PET study using [18F]setoperone. Am J Psychiatry 2000;157 (6) 1016- 1018
PubMed
Erritzoe  DRasmussen  HKristiansen  KTFrokjaer  VGHaugbol  SPinborg  LBaaré  WSvarer  CMadsen  JLublin  HKnudsen  GMGlenthoj  BY Cortical and subcortical 5-HT2A receptor binding in neuroleptic-naive first-episode schizophrenic patients. Neuropsychopharmacology 2008;33 (10) 2435- 2441
PubMed
Tan  PZBaldwin  RMVan Dyck  CHAl-Tikriti  MRoth  BKhan  NCharney  DSInnis  RB Characterization of radioactive metabolites of 5-HT2A receptor PET ligand [18F]altanserin in human and rodent. Nucl Med Biol 1999;26 (6) 601- 608
PubMed
Kristiansen  HElfving  BPlenge  PPinborg  LHGillings  NKnudsen  GM Binding characteristics of the 5-HT2A receptor antagonists altanserin and MDL 100907. Synapse 2005;58 (4) 249- 257
PubMed
Haugbøl  SPinborg  LHArfan  HMFrøkjaer  VMMadsen  JDyrby  TBSvarer  CKnudsen  GM Reproducibility of 5-HT2A receptor measurements and sample size estimations with [18F]altanserin PET using a bolus/infusion approach. Eur J Nucl Med Mol Imaging 2007;34 (6) 910- 915
PubMed
Wing  JKBabor  TBrugha  TBurke  JCooper  JEGiel  RJablenski  ARegier  DSartorius  NSchedules for Clinical Assessment in Neuropsychiatry, SCAN: Schedules for Clinical Assessment in Neuropsychiatry. Arch Gen Psychiatry 1990;47 (6) 589- 593
PubMed
Erritzoe  DFrokjaer  VGHaugbol  SMarner  LSvarer  CHolst  KBaaré  WFRasmussen  PMMadsen  JPaulson  OBKnudsen  GM Brain serotonin 2A receptor binding: relations to body mass index, tobacco and alcohol use [published correction appears in Neuroimage. 2009;47(2):780]. Neuroimage 2009;46 (1) 23- 30
PubMed
Kay  SRFiszbein  AOpler  LA The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987;13 (2) 261- 276
PubMed
McGraw  KOWong  SP Forming inferences about some intraclass correlation coefficients. Psychol Methods 1996;1 (1) 30- 46
Sahakian  BJOwen  AM Computerized assessment in neuropsychiatry using CANTAB: discussion paper. J R Soc Med 1992;85 (7) 399- 402
PubMed
Lemaire  CCantineau  RGuillaume  MPlenevaux  AChristiaens  L Fluorine-18-altanserin: a radioligand for the study of serotonin receptors with PET: radiolabeling and in vivo biologic behavior in rats. J Nucl Med 1991;32 (12) 2266- 2272
PubMed
Pinborg  LHAdams  KHSvarer  CHolm  SHasselbalch  SGHaugbøl  SMadsen  JKnudsen  GM Quantification of 5-HT2A receptors in the human brain using [18F]altanserin-PET and the bolus/infusion approach. J Cereb Blood Flow Metab 2003;23 (8) 985- 996
PubMed
Adams  KHPinborg  LHSvarer  CHasselbalch  SGHolm  SHaugbøl  SMadsen  KFrøkjaer  VMartiny  LPaulson  OBKnudsen  GM A database of [18F]-altanserin binding to 5-HT2A receptors in normal volunteers: normative data and relationship to physiological and demographic variables. Neuroimage 2004;21 (3) 1105- 1113
PubMed
Videbaek  CFriberg  LHolm  SWammen  SFoged  CAndersen  JVDalgaard  LLassen  NA Benzodiazepine receptor equilibrium constants for flumazenil and midazolam determined in humans with the single photon emission computer tomography tracer [123I]iomazenil. Eur J Pharmacol 1993;249 (1) 43- 51
PubMed
Willendrup  PPinborg  LHHasselbalch  SGAdams  KHStahr  KKnudsen  GMSvarer  C Assessment of the precision in co-registration of structural MR-images and PET-images with localized binding. Int Congr Ser20041265275280 doi:10.1016/j.ics.2004.04.065
Svarer  CMadsen  KHasselbalch  SGPinborg  LHHaugbøl  SFrøkjaer  VGHolm  SPaulson  OBKnudsen  GM MR-based automatic delineation of volumes of interest in human brain PET images using probability maps. Neuroimage 2005;24 (4) 969- 979
PubMed
Sled  JGZijdenbos  APEvans  AC A nonparametric method for automatic correction of intensity nonuniformity in MRI data. IEEE Trans Med Imaging 1998;17 (1) 87- 97
PubMed
Müller-Gärtner  HWLinks  JMPrince  JLBryan  RN McVeigh  ELeal  JPDavatzikos  CFrost  JJ Measurement of radiotracer concentration in brain gray matter using positron emission tomography: MRI-based correction for partial volume effects. J Cereb Blood Flow Metab 1992;12 (4) 571- 583
PubMed
Quarantelli  MBerkouk  KPrinster  ALandeau  BSvarer  CBalkay  LAlfano  BBrunetti  ABaron  JCSalvatore  M Integrated software for the analysis of brain PET/SPECT studies with partial-volume-effect correction. J Nucl Med 2004;45 (2) 192- 201
PubMed
Grubbs  FE Procedures for detecting outlying observations in samples. Technometrics 1969;11 (1) 1- 21
Erritzoe  DRasmussen  HKristiansen  KTFrokjaer  VGHaugbol  SPinborg  LBaaré  WSvarer  CMadsen  JLublin  HKnudsen  GMGlenthoj  BY Cortical and subcortical 5-HT(2A) receptor binding in neuroleptic-naive first-episode schizophrenic patients. Neuropsychopharmacology 2008;33 (10) 2435- 2441
PubMed
Hurlemann  RBoy  CMeyer  PTScherk  HWagner  MHerzog  HCoenen  HHVogeley  KFalkai  PZilles  KMaier  WBauer  A Decreased prefrontal 5-HT2A receptor binding in subjects at enhanced risk for schizophrenia. Anat Embryol (Berl) 2005;210 (5-6) 519- 523
PubMed
Hurlemann  RMatusch  AKuhn  KUBerning  JElmenhorst  DWinz  OKolsch  HZilles  KWagner  MMaier  WBauer  A 5-HT2A receptor density is decreased in the at-risk mental state. Psychopharmacology (Berl) 2008;195 (4) 579- 590
PubMed
Halbreich  UKahn  LS Hormonal aspects of schizophrenias: an overview. Psychoneuroendocrinology 2003;28(suppl 2)1- 16
PubMed
Glenthoj  BYMackeprang  TSvarer  CRasmussen  HPinborg  LHFriberg  LBaaré  WHemmingsen  RVidebaek  C Frontal dopamine D2/3 receptor binding in drug-naive first-episode schizophrenic patients correlates with positive psychotic symptoms and gender. Biol Psychiatry 2006;60 (6) 621- 629
PubMed
Pinborg  LHAdams  KHYndgaard  SHasselbalch  SGHolm  SKristiansen  HPaulson  OBKnudsen  GM [18F]altanserin binding to human 5HT2A receptors is unaltered after citalopram and pindolol challenge. J Cereb Blood Flow Metab 2004;24 (9) 1037- 1045
PubMed
Gray  JARoth  BL Paradoxical trafficking and regulation of 5-HT2A receptors by agonists and antagonists. Brain Res Bull 2001;56 (5) 441- 451
PubMed

Figures

Place holder to copy figure label and caption

Figure 1. Mean frontal cortical and total serotonin2A receptor binding in 30 antipsychotic-naive patients with first-episode schizophrenia and 30 matched healthy controls.

Graphic Jump Location
Place holder to copy figure label and caption

Figure 2. Correlation in male schizophrenic patients between mean frontal cortical serotonin2A receptor binding, positive symptoms on the Positive and Negative Syndrome Scale (PANSS), and 2 subitems. Negative correlations are evident for the PANSS positive scale (r = −0.57, P = .007) (A), as well as for subitems P1, delusions (r = −0.47, P = .03) (B), and P6, suspiciousness (r = −0.53, P = .01) (C).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Mean Binding Potentials of Specific [18F]Altanserin Binding in Frontal Cortex and Subregions of Interest in Patients and Controls
Table Graphic Jump LocationTable 2.  Patients Receiving Antidepressant Medication
Table Graphic Jump LocationTable 4.  Neurocognitive Performance of Memory, Executive Functions, and Attention in Schizophrenic Patients Compared With Healthy Controls

References

Arora  RCMeltzer  HY Serotonin2 (5-HT2) receptor binding in the frontal cortex of schizophrenic patients. J Neural Transm 1991;85 (1) 19- 29
Bennett  JP  JrEnna  SJBylund  DBGillin  JCWyatt  RJSnyder  SH Neurotransmitter receptors in frontal cortex of schizophrenics. Arch Gen Psychiatry 1979;36 (9) 927- 934
PubMed
Burnet  PWEastwood  SLHarrison  PJ 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia. Neuropsychopharmacology 1996;15 (5) 442- 455
PubMed
Dean  BHayes  W Decreased frontal cortical serotonin2A receptors in schizophrenia. Schizophr Res 1996;21 (3) 133- 139
PubMed
Dean  BHayes  WHill  CCopolov  D Decreased serotonin2A receptors in Brodmann's area 9 from schizophrenic subjects: a pathological or pharmacological phenomenon? Mol Chem Neuropathol 1998;34 (2-3) 133- 145
PubMed
Dean  BHussain  THayes  WScarr  EKitsoulis  SHill  COpeskin  KCopolov  DL Changes in serotonin2A and GABAA receptors in schizophrenia: studies on the human dorsolateral prefrontal cortex. J Neurochem 1999;72 (4) 1593- 1599
PubMed
Gurevich  EVJoyce  JN Alterations in the cortical serotonergic system in schizophrenia: a postmortem study. Biol Psychiatry 1997;42 (7) 529- 545
PubMed
Laruelle  MAbi-Dargham  ACasanova  MFToti  RWeinberger  DRKleinman  JE Selective abnormalities of prefrontal serotonergic receptors in schizophrenia: a postmortem study. Arch Gen Psychiatry 1993;50 (10) 810- 818
PubMed
Matsumoto  IInoue  YIwazaki  TPavey  GDean  B 5-HT2A and muscarinic receptors in schizophrenia: a postmortem study. Neurosci Lett 2005;379 (3) 164- 168
PubMed
Mita  THanada  SNishino  NKuno  TNakai  HYamadori  TMizoi  YTanaka  C Decreased serotonin S2 and increased dopamine D2 receptors in chronic schizophrenics. Biol Psychiatry 1986;21 (14) 1407- 1414
PubMed
Pralong  DTomaskovic-Crook  EOpeskin  KCopolov  DDean  B Serotonin2A receptors are reduced in the planum temporale from subjects with schizophrenia. Schizophr Res 2000;44 (1) 35- 45
PubMed
Dean  BHayes  WOpeskin  KNaylor  LPavey  GHill  CKeks  NCopolov  DL Serotonin2 receptors and the serotonin transporter in the schizophrenic brain. Behav Brain Res 1996;73 (1-2) 169- 175
PubMed
Joyce  JNShane  ALexow  NWinokur  ACasanova  MFKleinman  JE Serotonin uptake sites and serotonin receptors are altered in the limbic system of schizophrenics. Neuropsychopharmacology 1993;8 (4) 315- 336
PubMed
Reynolds  GPRossor  MNIversen  LL Preliminary studies of human cortical 5-HT2 receptors and their involvement in schizophrenia and neuroleptic drug action. J Neural Transm Suppl 1983;18273- 277
PubMed
Whitaker  PMCrow  TJFerrier  IN Tritiated LSD binding in frontal cortex in schizophrenia. Arch Gen Psychiatry 1981;38 (3) 278- 280
PubMed
Dean  BCrossland  NBoer  SScarr  E Evidence for altered post-receptor modulation of the serotonin 2a receptor in schizophrenia. Schizophr Res 2008;104 (1-3) 185- 197
PubMed
Roth  BLSheffler  DJKroeze  WK Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov 2004;3 (4) 353- 359
PubMed
Meltzer  HYMatsubara  SLee  JC Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther 1989;251 (1) 238- 246
PubMed
Farde  LNyberg  SOxenstierna  GNakashima  YHalldin  CEricsson  B Positron emission tomography studies on D2 and 5-HT2 receptor binding in risperidone-treated schizophrenic patients. J Clin Psychopharmacol 1995;15 (1) (suppl 1)19S- 23S
PubMed
Meltzer  HYLi  ZKaneda  YIchikawa  J Serotonin receptors: their key role in drugs to treat schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2003;27 (7) 1159- 1172
PubMed
Weickert  TWGoldberg  TEGold  JMBigelow  LBEgan  MFWeinberger  DR Cognitive impairments in patients with schizophrenia displaying preserved and compromised intellect. Arch Gen Psychiatry 2000;57 (9) 907- 913
PubMed
Gur  RCRagland  JDMoberg  PJBilker  WBKohler  CSiegel  SJGur  RE Computerized neurocognitive scanning, II: the profile of schizophrenia. Neuropsychopharmacology 2001;25 (5) 777- 788
PubMed
Conklin  HMCurtis  CECalkins  MEIacono  WG Working memory functioning in schizophrenia patients and their first-degree relatives: cognitive functioning shedding light on etiology. Neuropsychologia 2005;43 (6) 930- 942
PubMed
Jindal  RDKeshavan  MS Neurobiology of the early course of schizophrenia. Expert Rev Neurother 2008;8 (7) 1093- 1100
PubMed
Meneses  A Involvement of 5-HT2A/2B/2C receptors on memory formation: simple agonism, antagonism, or inverse agonism? Cell Mol Neurobiol 2002;22 (5-6) 675- 688
PubMed
Roth  BLHanizavareh  SMBlum  AE Serotonin receptors represent highly favorable molecular targets for cognitive enhancement in schizophrenia and other disorders. Psychopharmacology (Berl) 2004;174 (1) 17- 24
PubMed
Tyson  PJRoberts  KHMortimer  AM Are the cognitive effects of atypical antipsychotics influenced by their affinity to 5HT-2A receptors? Int J Neurosci 2004;114 (6) 593- 611
PubMed
Tyson  PJLaws  KRFlowers  KATyson  AMortimer  AM Cognitive function and social abilities in patients with schizophrenia: relationship with atypical antipsychotics. Psychiatry Clin Neurosci 2006;60 (4) 473- 479
PubMed
Williams  GVRao  SGGoldman-Rakic  PS The physiological role of 5-HT2A receptors in working memory. J Neurosci 2002;22 (7) 2843- 2854
PubMed
Wingen  MKuypers  KPRamaekers  JG Selective verbal and spatial memory impairment after 5-HT1A and 5-HT2A receptor blockade in healthy volunteers pre-treated with an SSRI. J Psychopharmacol 2007;21 (5) 477- 485
PubMed
Lewis  RKapur  SJones  CDaSilva  JBrown  GMWilson  AAHoule  SZipursky  RB Serotonin 5-HT2 receptors in schizophrenia: a PET study using [18F]setoperone in neuroleptic-naive patients and normal subjects. Am J Psychiatry 1999;156 (1) 72- 78
PubMed
Okubo  YSuhara  TSuzuki  KKobayashi  KInoue  OTerasaki  OSomeya  YSassa  TSudo  YMatsushima  EIyo  MTateno  YToru  M Serotonin 5-HT2 receptors in schizophrenic patients studied by positron emission tomography. Life Sci 2000;66 (25) 2455- 2464
PubMed
Trichard  CPaillere-Martinot  MLAttar-Levy  DBlin  JFeline  AMartinot  JL No serotonin 5-HT2A receptor density abnormality in the cortex of schizophrenic patients studied with PET. Schizophr Res 1998;31 (1) 13- 17
PubMed
Ngan  ETYatham  LNRuth  TJLiddle  PF Decreased serotonin 2A receptor densities in neuroleptic-naive patients with schizophrenia: a PET study using [18F]setoperone. Am J Psychiatry 2000;157 (6) 1016- 1018
PubMed
Erritzoe  DRasmussen  HKristiansen  KTFrokjaer  VGHaugbol  SPinborg  LBaaré  WSvarer  CMadsen  JLublin  HKnudsen  GMGlenthoj  BY Cortical and subcortical 5-HT2A receptor binding in neuroleptic-naive first-episode schizophrenic patients. Neuropsychopharmacology 2008;33 (10) 2435- 2441
PubMed
Tan  PZBaldwin  RMVan Dyck  CHAl-Tikriti  MRoth  BKhan  NCharney  DSInnis  RB Characterization of radioactive metabolites of 5-HT2A receptor PET ligand [18F]altanserin in human and rodent. Nucl Med Biol 1999;26 (6) 601- 608
PubMed
Kristiansen  HElfving  BPlenge  PPinborg  LHGillings  NKnudsen  GM Binding characteristics of the 5-HT2A receptor antagonists altanserin and MDL 100907. Synapse 2005;58 (4) 249- 257
PubMed
Haugbøl  SPinborg  LHArfan  HMFrøkjaer  VMMadsen  JDyrby  TBSvarer  CKnudsen  GM Reproducibility of 5-HT2A receptor measurements and sample size estimations with [18F]altanserin PET using a bolus/infusion approach. Eur J Nucl Med Mol Imaging 2007;34 (6) 910- 915
PubMed
Wing  JKBabor  TBrugha  TBurke  JCooper  JEGiel  RJablenski  ARegier  DSartorius  NSchedules for Clinical Assessment in Neuropsychiatry, SCAN: Schedules for Clinical Assessment in Neuropsychiatry. Arch Gen Psychiatry 1990;47 (6) 589- 593
PubMed
Erritzoe  DFrokjaer  VGHaugbol  SMarner  LSvarer  CHolst  KBaaré  WFRasmussen  PMMadsen  JPaulson  OBKnudsen  GM Brain serotonin 2A receptor binding: relations to body mass index, tobacco and alcohol use [published correction appears in Neuroimage. 2009;47(2):780]. Neuroimage 2009;46 (1) 23- 30
PubMed
Kay  SRFiszbein  AOpler  LA The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987;13 (2) 261- 276
PubMed
McGraw  KOWong  SP Forming inferences about some intraclass correlation coefficients. Psychol Methods 1996;1 (1) 30- 46
Sahakian  BJOwen  AM Computerized assessment in neuropsychiatry using CANTAB: discussion paper. J R Soc Med 1992;85 (7) 399- 402
PubMed
Lemaire  CCantineau  RGuillaume  MPlenevaux  AChristiaens  L Fluorine-18-altanserin: a radioligand for the study of serotonin receptors with PET: radiolabeling and in vivo biologic behavior in rats. J Nucl Med 1991;32 (12) 2266- 2272
PubMed
Pinborg  LHAdams  KHSvarer  CHolm  SHasselbalch  SGHaugbøl  SMadsen  JKnudsen  GM Quantification of 5-HT2A receptors in the human brain using [18F]altanserin-PET and the bolus/infusion approach. J Cereb Blood Flow Metab 2003;23 (8) 985- 996
PubMed
Adams  KHPinborg  LHSvarer  CHasselbalch  SGHolm  SHaugbøl  SMadsen  KFrøkjaer  VMartiny  LPaulson  OBKnudsen  GM A database of [18F]-altanserin binding to 5-HT2A receptors in normal volunteers: normative data and relationship to physiological and demographic variables. Neuroimage 2004;21 (3) 1105- 1113
PubMed
Videbaek  CFriberg  LHolm  SWammen  SFoged  CAndersen  JVDalgaard  LLassen  NA Benzodiazepine receptor equilibrium constants for flumazenil and midazolam determined in humans with the single photon emission computer tomography tracer [123I]iomazenil. Eur J Pharmacol 1993;249 (1) 43- 51
PubMed
Willendrup  PPinborg  LHHasselbalch  SGAdams  KHStahr  KKnudsen  GMSvarer  C Assessment of the precision in co-registration of structural MR-images and PET-images with localized binding. Int Congr Ser20041265275280 doi:10.1016/j.ics.2004.04.065
Svarer  CMadsen  KHasselbalch  SGPinborg  LHHaugbøl  SFrøkjaer  VGHolm  SPaulson  OBKnudsen  GM MR-based automatic delineation of volumes of interest in human brain PET images using probability maps. Neuroimage 2005;24 (4) 969- 979
PubMed
Sled  JGZijdenbos  APEvans  AC A nonparametric method for automatic correction of intensity nonuniformity in MRI data. IEEE Trans Med Imaging 1998;17 (1) 87- 97
PubMed
Müller-Gärtner  HWLinks  JMPrince  JLBryan  RN McVeigh  ELeal  JPDavatzikos  CFrost  JJ Measurement of radiotracer concentration in brain gray matter using positron emission tomography: MRI-based correction for partial volume effects. J Cereb Blood Flow Metab 1992;12 (4) 571- 583
PubMed
Quarantelli  MBerkouk  KPrinster  ALandeau  BSvarer  CBalkay  LAlfano  BBrunetti  ABaron  JCSalvatore  M Integrated software for the analysis of brain PET/SPECT studies with partial-volume-effect correction. J Nucl Med 2004;45 (2) 192- 201
PubMed
Grubbs  FE Procedures for detecting outlying observations in samples. Technometrics 1969;11 (1) 1- 21
Erritzoe  DRasmussen  HKristiansen  KTFrokjaer  VGHaugbol  SPinborg  LBaaré  WSvarer  CMadsen  JLublin  HKnudsen  GMGlenthoj  BY Cortical and subcortical 5-HT(2A) receptor binding in neuroleptic-naive first-episode schizophrenic patients. Neuropsychopharmacology 2008;33 (10) 2435- 2441
PubMed
Hurlemann  RBoy  CMeyer  PTScherk  HWagner  MHerzog  HCoenen  HHVogeley  KFalkai  PZilles  KMaier  WBauer  A Decreased prefrontal 5-HT2A receptor binding in subjects at enhanced risk for schizophrenia. Anat Embryol (Berl) 2005;210 (5-6) 519- 523
PubMed
Hurlemann  RMatusch  AKuhn  KUBerning  JElmenhorst  DWinz  OKolsch  HZilles  KWagner  MMaier  WBauer  A 5-HT2A receptor density is decreased in the at-risk mental state. Psychopharmacology (Berl) 2008;195 (4) 579- 590
PubMed
Halbreich  UKahn  LS Hormonal aspects of schizophrenias: an overview. Psychoneuroendocrinology 2003;28(suppl 2)1- 16
PubMed
Glenthoj  BYMackeprang  TSvarer  CRasmussen  HPinborg  LHFriberg  LBaaré  WHemmingsen  RVidebaek  C Frontal dopamine D2/3 receptor binding in drug-naive first-episode schizophrenic patients correlates with positive psychotic symptoms and gender. Biol Psychiatry 2006;60 (6) 621- 629
PubMed
Pinborg  LHAdams  KHYndgaard  SHasselbalch  SGHolm  SKristiansen  HPaulson  OBKnudsen  GM [18F]altanserin binding to human 5HT2A receptors is unaltered after citalopram and pindolol challenge. J Cereb Blood Flow Metab 2004;24 (9) 1037- 1045
PubMed
Gray  JARoth  BL Paradoxical trafficking and regulation of 5-HT2A receptors by agonists and antagonists. Brain Res Bull 2001;56 (5) 441- 451
PubMed

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