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Original Article |

Brain Serotonin2 Receptors in Major Depression:  A Positron Emission Tomography Study FREE

Lakshmi N. Yatham, MBBS; Peter F. Liddle, PhD, MBBS; I-Shin Shiah, MD; Gayle Scarrow, BA; Raymond W. Lam, MD; Michael J. Adam, PhD; Athanasios P. Zis, MD; Thomas J. Ruth, PhD
[+] Author Affiliations

From the Division of Mood Disorders (Drs Yatham, Shiah, Lam, and Zis and Ms Scarrow), Division of Schizophrenia, Department of Psychiatry (Dr Liddle), and TRIUMF Positron Emission Tomography Program (Drs Adam and Ruth), The University of British Columbia, Vancouver; and Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (Dr Shiah).


Arch Gen Psychiatry. 2000;57(9):850-858. doi:10.1001/archpsyc.57.9.850.
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Published online

Background  Postmortem and brain imaging studies that measured brain serotinin2 (5-HT2) receptors in major depression reported an increase, decrease, and no change compared with controls. In this study, we assessed brain 5-HT2 receptors in 20 depressed patients (mean ± SD age, 40.1 ± 9.5 years; range, 22-60 years) and 20 healthy controls similar in age (37.2 ± 12.6 years; range, 19-59 years) using positron emission tomography and setoperone labeled with fluorine 18 ([18F]setoperone).

Methods  Patients with DSM-IV major depression and healthy controls underwent scanning with [18F]setoperone. All study subjects were drug free for at least 2 weeks. The 5-HT2 binding images were created using region-to-cerebellum ratios. The differences in 5-HT2 receptor binding potential between the two groups were determined with statistical parametric mapping software and region of interest analysis.

Results  There was a significant negative correlation between 5-HT2 receptor binding potential and age in both patients and controls, and the magnitude of this correlation was similar in both groups. Both statistical parametric mapping and region of interest analyses showed that, compared with healthy controls, depressed patients had significantly lower 5-HT2 receptor binding potential in frontal, temporal, parietal, and occipital cortical regions. Statistical parametric mapping analysis showed that the mean decrease in 5-HT2 receptor binding potential for the entire cluster in these regions was 22%, and it ranged from 22% to 27% for local maxima within the clusters of significant voxels.

Conclusion  This study suggests that brain 5-HT2 receptors are decreased in patients with major depression.

Figures in this Article

ALTHOUGH serotonin (5-hydroxytryptamine [5-HT]) has been implicated in the pathophysiology of depression, the precise nature of alterations in the 5-HT system that underlie depressive symptoms still remains elusive. The 5-HT acts on at least 14 subtypes of 5-HT receptors (5-HT1 to 5-HT7 subfamilies), and, of these, 5-HT2 receptors have been the most studied in suicide victims with or without a history of depression and in depressed patients who died of natural causes. Most,14 although not all,5,6 postmortem studies in suicide victims with mixed, uncertain, or no psychiatric diagnosis reported an increase in brain 5-HT2 receptor binding, particularly in frontal cortex, compared with control subjects. The findings, however, are inconsistent in those with an antemortem diagnosis of depression. Although 27,8 of 3 postmortem studies79 reported an increase in 5-HT2 receptors in frontal cortex of depressed patients who died of natural causes, only 110 of 5 studies1014 in suicide victims with an antemortem diagnosis of depression found an increase in 5-HT2 receptors compared with control subjects. Of the other 4 studies,1114 31113 showed no difference in 5-HT2 receptors, while 114 reported a trend for a decrease in depressed suicide victims compared with control subjects. Differences in age between patient and control groups at the time of death, cause of death, duration of drug-free periods or medication use before death, delay in brain tissue processing, and the type of ligand used may have contributed to variability in findings between postmortem studies.

Brain 5-HT2 receptors have also been examined in living depressed patients in 4 studies that used either single photon emission computed tomography or positron emission tomography (PET). In the only study that used single photon emission computed tomography to date, D'haenen et al15 reported an increase in uptake of 2-ketanserin labeled with iodine 123 (123I) in parietal cortex bilaterally and right greater than left asymmetry in the inferofrontal region of depressed patients compared with control subjects, suggesting an increased 5-HT2 receptor density in these regions in depressed patients. A PET study16 reported a decrease in uptake of altanserin labeled with fluorine 18 (18F) in the right anterior part of insular cortex and right posterolateral orbitofrontal cortex of depressed patients compared with control subjects. Of the other 2 PET studies17,18 that used setoperone labeled with fluorine 18 ([18F]setoperone) as a tracer, one17 reported a slight but significant decrease in [18F]setoperone binding in the frontal cortex of depressed patients compared with control subjects, while the other18 found no difference between the two groups. Therefore, the issue of whether 5-HT2 receptors are altered in major depression is still unclear.

The purpose of the present study was to further examine 5-HT2 receptor density in a large group of depressed patients and healthy control subjects similar in age using PET and [18F]setoperone. The [18F]setoperone has a high brain uptake, and its metabolites do not cross the blood-brain barrier in humans.19 Setoperone also has a high specific–to–nonspecific binding ratio. Setoperone has a high affinity for 5-HT2 receptors (Kd (equilibrium dissociation constant), 0.37 nmol/L), with relative selectivity to 5-HT2A subtype.20 It also binds to dopamine-2 (D2) receptors (Kd, 10-25 nmol/L), but the density of D2 receptors is very low in cortex.21 Setoperone signal in the striatum is displaced by pretreatment with 5-HT2 and D2 antagonists, but only 5-HT2 antagonists displace cortical signal.22,23 Therefore, [18F]setoperone is a suitable ligand for measuring 5-HT2 receptor binding in cortex in humans.

SUBJECTS

The study was approved by The University of British Columbia Human Ethics Committee. Patients who fulfilled the DSM-IV criteria24 for major depression as determined by the Structured Clinical Interview for DSM-III-R, Patient Edition25 were recruited from the inpatient and outpatient departments of The University of British Columbia Hospital, Vancouver. Those with other comorbid diagnoses either on Axis I or Axis II were excluded. Patients with a history of substance or alcohol abuse within the previous 6 months were also excluded. The Hamilton Rating Scale for Depression (21 items)26 was used to assess the severity of depression in patients. Healthy control subjects similar in age were recruited through advertisements and screened by means of a Structured Clinical Interview for DSM-III-R, Nonpatient Edition.27 They had no lifetime history of psychiatric illness and no family history of mood disorders or schizophrenia in the first-degree relatives. Both patients and control subjects were physically healthy and were free of psychotropic medications for at least 2 weeks (5 weeks in the case of fluoxetine hydrochloride) before PET scan. All study subjects gave written informed consent for participation in the study. Study subjects underwent magnetic resonance imaging to exclude cerebral abnormality and for coregistration with PET images.

PET PROCEDURE

Subjects were scanned with a PET camera (ECAT/953B; Siemens, Knoxville, Tenn). This scanner collects 31 axial slices. The spatial resolution of PET images is about 5 mm (full width at half maximum). Setoperone labeled with 18F was synthesized as previously described.28 Each subject had a transmission scan for 10 minutes to correct PET images for attenuation. After this, a 15-frame emission scan was performed for 110 minutes as previously described,29 after subjects were injected with 148 to 259 MBq of [18F]setoperone intravenously.

DATA ANALYSIS
Determination of 5-HT2 Receptor Binding

Region of interest (ROI) analyses were performed by means of a multipurpose imaging tool,30 and voxel-based analyses were performed with statistical parametric mapping (SPM 96) software.31,32

The specific binding potential of [18F]setoperone can be estimated from the measured concentration of tracer in the cerebral ROI and the estimated concentration of tracer in the blood, provided it is possible to allow for nonspecific binding of tracer in the brain. The most direct approach is to measure the time course of arterial tracer concentration and brain tracer concentration for approximately 110 minutes after tracer administration. The variation with time allows separate estimates of specific and nonspecific binding. However, arterial blood sampling is cumbersome and impractical to implement in studies involving a large number of patients. Furthermore, the timing of the arterial measurements is crucial, and errors in the estimation of the arterial input of tracer can lead to serious inaccuracy of the estimation of specific binding.

Therefore, in many circumstances, it is preferable to use an indirect method to estimate the input of tracer and nonspecific binding. One approach33 is based on the observation that there is negligible specific binding of [18F]setoperone in the cerebellum for the following reasons: first, cerebellum is virtually devoid of 5-HT2 receptors in humans34; second, the time course of [18F]setoperone accumulation in cerebellum is not affected by saturating doses of 5-HT2 blocker ketanserin22,23; third, similar [18F]setoperone kinetics were found in cerebral cortex and cerebellum in ketanserin-pretreated subjects, indicating similar unbound radioligand in both structures.22,23

If it is assumed that nonspecific binding is identical in cortex and cerebellum, the ratio of binding in cortex (Ccx) to that in cerebellum (Ccb) at equilibrium, is given by the following equation: Ccx/Ccb = f2 × (Bmax/Kd) + 1, where Bmax is the total number of receptors and Kd is the equilibrium dissociation constant of the ligand-receptor complex; f2 = 1/[1 + (k5/k6)], where k5 and k6 are the transfer coefficients for association to and dissociation from nonspecific binding sites. Binding potential (BP) is defined as Bmax/Kd, and hence region to cerebellum ratio can be used to obtain a semiquantitative measure of BP for 5-HT2 receptors. Although the ratio method does not permit an independent determination of Bmax and Kd, it provides a very reliable index of BP. Furthermore, the region to cerebellum ratio at pseudoequilibrium correlates with the BP estimated by using k3-to-k4 ratio with kinetic tracer modeling with a measured arterial input.35

When the time-activity curves obtained from ROIs such as frontal, parietal, temporal, and cerebellar regions were plotted, the data showed that the specific region–to–cerebellum ratio did not change significantly in the period of 70 to 110 minutes, indicating a state of pseudoequilibrium during this period. Therefore, the cortex–to–cerebellum ratio in the frames from 70 to 110 minutes after [18F]setoperone injection was used to estimate the 5-HT2 receptor BP (5-HT2BP) for each study subject.

The SPM 9631,32 was used for aligning and coregistering PET images to magnetic resonance images and transforming both into the standard coordinate frame used for templates in SPM 96. Then, an [18F]setoperone BP image was created for each subject by dividing each pixel in the normalized mean image with that image's average cerebellar value. A mean activity value from 2 large ROIs (one on the right and one on the left) drawn on 3 contiguous cerebellar slices was used as that image's average cerebellar value. The binding images were smoothed by means of a 12-mm gaussian filter before statistical analysis was performed.

SPM Analysis

The SPM 96 was used to determine the significance of differences in 5-HT2BP between patients and healthy control subjects. Gray matter threshold was determined by the multipurpose imaging tool and set at 130% of the mean image intensity, as this threshold eliminated most white matter voxels without excluding any gray matter voxels. The significance of difference in 5-HT2BP for each voxel between the 2 groups was determined with age used as a covariate. We also assessed the significance of clusters of contiguous voxels in which the difference in 5-HT2BP exceeded a threshold of z = 2.33 corresponding to P<.01 (or P<.025, 2-tailed). The method implemented in SPM 96 as described by Worsley36 calculates the significance of clusters based on extent and peak z value within the cluster and then applies a correction for multiple comparisons performed. Cluster significance was also set at P<.01.

ROI Analysis

A large region was drawn on each side for each of the cortical regions (ie, frontal, parietal, and temporal) on 3 contiguous slices. The ROIs for frontal and temporal regions were drawn on transverse planes at the anterior commissure/posterior commissure (AC/PC) line, and a plane above and a plane below the AC/PC line. For parietal region, ROIs were drawn on planes that were above the level of corpus callosum. The mean activity for each region was computed by averaging the values from right and left and from all 3 planes. Region-to-cerebellum ratios were used as a semiquantitative measure of 5-HT2BP for each region. An analysis of covariance was performed to compute the difference in 5-HT2BP in frontal, parietal, and temporal cortical regions between the 2 groups, with age used as a covariate.

Analysis by the Method of Blin et al

A study by Blin et al37 found small but significant linear increase in cerebellar nonspecific binding of setoperone with age in their study population. Therefore, in their data analysis, they used the "subtraction method (cortex − cerebellum)" instead of the ratio method (cortex-to-cerebellum) to calculate setoperone-specific binding, with the assumption that there is no differential age effect on nonspecific binding between cortex and cerebellum. They normalized for intersubject variations in the amount of radioactivity injected by expressing subtraction values as a percentage of injected dose. We have used this method as well to compare setoperone binding between patients and control subjects.

The differences in age and sex between the 2 groups were determined by means of the t and χ2 tests. Relationships between variables were assessed by means of Pearson correlation coefficient and/or regression analysis. All tests were 2 tailed, with significance set at P<.05. The data were analyzed by means of SPSS software.38 Data are given as mean (± SD) unless indicated otherwise.

A total of 20 patients (9 men and 11 women) and 20 control subjects (8 men and 12 women) participated in the study. Patients' ages ranged from 22 to 60 years, with a mean of 40.1 ± 9.5 years. Similarly, age range for healthy control subjects was 19 to 59 years, with a mean (±SD) of 37.2 ± 12.6 years. As expected, there was no difference in age (t38 = −1.09; P = .28) or sex (χ21 = 0.10; P = .75) between the 2 groups. The number of previous depressive episodes ranged from 0 to 12, with a mean of 2.9 ± 3.5 (Table 1). The patients' mean score on the Hamilton Rating Scale for Depression was 27.1 ± 5.5.

Table Graphic Jump LocationTable 1. Sociodemographic and Illness Characteristics for 20 Depressed Patients*

There was no significant difference in [18F]setoperone activity in the cerebellum between patients (0.077448 ± 0.0256) and control subjects (0.067074 ± 0.0284) (P = .23). Similarly, no significant difference was found for cerebellar [18F]setoperone activity normalized for injected dose between patients (0.000284 ± 0.000104) and control subjects (0.000248 ± 0.000102) (P = .28).

Age was a significant covariate for 5-HT2BP for both patients and healthy control subjects. Figure 1 depicts the relationship between age and 5-HT2BP for patients and control subjects for frontal and temporal cortical regions. There was a significant negative correlation between age and the 5-HT2BP (P<.001 for all regions examined), and this correlation was similar in both groups (see Table 2 for details).

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Figure 1.

Relationship between age and serotonin2 (5-HT2) receptor binding potential in frontal (A) and temporal (B) cortical areas in 20 depressed patients and 20 healthy control subjects. The lines indicate significant negative correlations between age and 5-HT2 receptor binding potential.

Graphic Jump Location
Table Graphic Jump LocationTable 2. Correlation Coefficients and Slopes of Linear Regression Between Age and Serotonin2 Receptor Binding Potential in Various Cortical Areas in 20 Depressed Patients and 20 Healthy Controls

The SPM analysis demonstrated that depressed patients had a significant decrease in 5-HT2BP compared with control subjects. The analysis disclosed an extensive cluster of voxels occupying lateral and medial frontal cortex bilaterally, extending back into insular, temporal, parietal, and occipital regions (Figure 2). This cluster had 37,244 gray matter voxels (Table 3, Figure 2, and Figure 3). Table 3 gives the location and z value for change in 5-HT2BP at those individual voxels where z exceeded 3.45 (P<.025 after stringent correction for multiple comparisons). The mean decrease in 5-HT2BP for the entire cluster was 21.7%, and it ranged from 22.1% to 27.4% for local maxima within the clusters of significant voxels (Table 3). The voxels that showed the most significant decrease in 5-HT2BP were located in the left inferior frontal gyrus, right anterior cingulate gyrus, left fusiform gyrus, right inferior temporal gyrus, right medial frontal gyrus, right cingulate gyrus, left superior frontal gyrus, and right inferior temporal gyrus (Table 3, Figure 2 and Figure 3).

Place holder to copy figure label and caption
Figure 2.

Statistical parametric maps of t values displayed as projections on the sagittal (A), coronal (B), and transverse (C) renderings of the brain. These projections illustrate regions of significantly decreased serotonin2 receptor binding potential in depressed patients compared with matched healthy control subjects.

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Place holder to copy figure label and caption
Figure 3.

Representative areas of significant decreases in serotonin2 receptor binding potential on the sagittal renderings of the brain (A, x = −38; B, x = 4; C, x = −48; D, x = 48) in 20 depressed patients. Coordinates are in millimeters from the origin at the midpoint of anterior commisure, in the coordinate frame used in statistical parametric mapping (SPM 96) software.

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Table Graphic Jump LocationTable 3. Cluster Size, P and z Values, Coordinates With P and z Values, and Serotonin2 Receptor Binding Potential for Brain Regions With Highest Decreases in Binding in 20 Depressed Patients Compared With 20 Healthy Controls*

To minimize the possibility that the decrease in 5-HT2BP noted in our patients was caused by residual effects of previous antidepressant treatment, we carried out SPM analysis in a subgroup of 12 patients who had been drug free for 4 weeks or more and similar-aged control subjects. This analysis also showed a widespread decrease in 5-HT2BP in depressed patients with a peak z of 3.17.

As well, SPM analysis was done on binding images created by the method of Blin et al.37 The results again showed a widespread decrease in setoperone binding in all cortical areas. The peak z, however, was somewhat lower (ie, 3.00), which was anticipated, in that this method of creating binding images introduces a greater source of variance from the use of injected dose, as the amount of radioactivity that reaches into brain varies significantly from person to person.

The 5-HT2BP values obtained with the use of ROI analysis for patients and control subjects were compared by means of analysis of covariance with age as a covariate. The ROI analysis confirmed the SPM analysis, indicating a significant decline in 5-HT2BP in all 3 brain regions examined in depressed patients (frontal cortex: F2,39 = 76.7, P<.001; temporal cortex: F2,39 = 72.3, P<.001; parietal cortex: F2,39 = 35.9, P<.001).

The 5-HT2BP was not increased in depressed patients in any of the brain areas. There was no correlation between 5-HT2BP and scores on the 21-item Hamilton Rating Scale for Depression in depressed patients (data not shown).

To our knowledge, this is the largest study to date to assess the 5-HT2 receptor binding in living depressed patients using PET. The results showed that 5-HT2BP was significantly decreased in depressed patients compared with healthy control subjects. The decrease in 5-HT2BP was widespread and included frontal, parietal, temporal, and occipital regions.

Since we found a widespread decrease in 5-HT2BP in various cortical areas, one should consider the possibility of a difference in cerebellar radioactivity between patients and control subjects because this could affect the estimate of 5-HT2BP and confound the results. There were no differences in [18F]setoperone cerebellar activity or cerebellar activity expressed as a percentage of injected dose of radioactivity between patients and control subjects. Furthermore, a decrease in setoperone binding was also detected in depressed patients by the method of Blin et al.37 It is also unlikely that the observed decrease in 5-HT2BP in depressed patients could be accounted for by group differences in blood flow39,40 because the values of specifically bound radioligand at equilibrium are independent of initial radioligand delivery.41 Furthermore, for ligands that reach pseudoequilibrium from 30 minutes onward after injection, simulation studies have shown that the effects of cerebral blood flow on specific binding are negligible.42

The possibility exists that the decrease in 5-HT2BP observed in depressed patients in this study is caused by an increase in Kd rather than a decrease in Bmax. This possibility is not supported by previous postmortem studies, which reported no alterations in Kd in depressed patients,8,10 suggesting that the decrease in 5-HT2BP found in depressed patients in this study is likely to result from a decrease in brain 5-HT2 receptor density.

The results of this study confirmed previous observations that brain 5-HT2 receptors decline with age.6,18,4346 The patients and control subjects in this study were similar in age. Furthermore, we also used age as a covariate in both SPM and ROI analysis to remove any age effects on 5-HT2BP. We found that the magnitude of decline in 5-HT2BP was similar for both patients and control subjects, thus making any differential age effects an unlikely explanation for the findings.

The findings of this study are in contrast to a previous single photon emission computed tomographic study15 that reported an increase in uptake of 2-123I-ketanserin in parietal cortex bilaterally and right inferofrontal region of depressed patients compared with control subjects. Ketanserin is less selective than setoperone for 5-HT2 receptors relative to other cortical receptors47 and it has a very high nonspecific uptake, thus making the validity of the findings of this study questionable.

The results of the present study are in partial agreement with 2 previous PET studies16,17 but not the third.18 The 2 previous studies with positive findings, however, unlike the present study, reported only localized significant decreases in brain 5-HT2 receptor binding in depressed patients. Although Biver et al16 used voxel-based analysis as in the present study, that study had only 8 patients. Similarly, Attar-Levy et al17 studied only 7 patients and used ROI analysis.

Meyer et al18 used a method similar to that in the present study to calculate 5-HT2BP. They, however, were unable to find any differences in 5-HT2BP between patients and control subjects by means of ROI analysis. Patients in their study were drug free for more than 6 months, whereas in our study, 8 of 20 were drug free for only 2 weeks before scanning. Therefore, one could argue that the decrease in 5-HT2BP in depressed patients in our study could result from residual effects of antidepressant medication. However, a subgroup analysis in patients who had been drug free for 4 weeks or more also showed a decrease in 5-HT2BP. Furthermore, animal studies have shown that long-term administration of antidepressants decreases brain 5-HT2 receptor density.4854 The receptor density, however, returns to normal levels within 1 week to 10 days of discontinuation of antidepressants,49,50 thus making the residual effects of antidepressant medication an unlikely explanation. The differences in findings between the 2 studies may also result from other sampling differences. For instance, the mean age of patients in their study was 34 years, and many underwent scanning during their first major depressive episode. In contrast, the patients in our study were slightly older (mean age, 40 years), and many had recurrent chronic depression.

Antidepressant medications such as tricyclics,4851 monoamine oxidase inhibitors,48,50,51 atypical antidepressants,48,51,52 and some selective serotonin reuptake inhibitors51,53,54 have been reported to down-regulate 5-HT2 receptors. A recent PET study from our group29 reported that desipramine hydrochloride treatment decreased 5-HT2 receptor density in depressed patients. Similarly, another effective treatment, electroconvulsive therapy, also caused similar decreases in 5-HT2 receptors in depressed patients.55 Since effective antidepressant treatments reduce brain 5-HT2 receptors, one would expect to find an increase in brain 5-HT2 receptors associated with major depression. Therefore, our finding of a decrease in 5-HT2 receptors in depressed patients was counterintuitive. Similar findings, however, have been reported with PET glucose and blood flow studies,39,5661 which showed a decrease in brain neuronal metabolism in frontal regions in drug-free depressed patients. Effective antidepressant treatments cause a further reduction in frontal metabolism, which is associated with recovery from depression.40,6264

Nevertheless, one must reconcile with the fact that 5-HT2 receptor density is decreased in at least some depressed patients, as shown in the present study and in 2 previous PET studies,16,17 and that the effective antidepressant treatments such as desipramine and electroconvulsive therapy further down-regulate29,49 rather than return 5-HT2 receptor density to normal levels in depressed patients. Given this, it is tempting to hypothesize that a decrease in baseline 5-HT2 receptor density might reflect a secondary compensatory response of the brain to the state of major depression. Such compensatory mechanism–induced down-regulation of 5-HT2 receptors would hypothetically be sufficient in some cases to induce spontaneous remission of a depressive episode, but in many cases, treatment with effective antidepressants is needed to accelerate down-regulation of 5-HT2 receptors to achieve recovery from depression.

Accepted for publication April 26, 2000.

Reprints: Lakshmi N. Yatham, MBBS, Mood Disorders Clinical Research Unit, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2A1 (e-mail: yatham@unixg.ubc.ca).

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Yatham  LNLiddle  PFDennie  JShiah  ISAdam  MJLane  CLam  RWRuth  TJ Decrease in brain serotonin 2 receptor binding in patients with major depression following desipramine treatment: a positron emission tomography study with fluorine-18–labeled setoperone. Arch Gen Psychiatry. 1999;56705- 711
Link to Article
Pietrzyk  UHerholz  KFink  GJacobs  AMielke  RSlansky  IMurker  MHeiss  WD An interactive technique for three-dimensional image registration: validation for PET, SPECT, MRI, and CT brain studies. J Nucl Med. 1994;352011- 2018
Friston  KJFrith  CDLiddle  PFFrackowiak  RSJ Comparing function (PET) images: the assessment of significant change. J Cereb Blood Flow Metab. 1991;11690- 699
Link to Article
Friston  KJHolmes  APWorsley  KJPoline  JPFrith  CDFrackowiak  RSJ Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp. 1995;2189- 210
Link to Article
Mazoyer  B Investigation of the dopaminergic system with positron emission tomography: general issues in modelling. Baron  JCComar  DFarde  LMartinot  JLMazoyer  Beds.Brain Dopaminergic Systems Imaging With Positron Emission Tomography. Dordrecht, the Netherlands Kluwer1991;65- 83
Schotte  AMaloteaux  JMLanduron  PM Characterization and regional distribution of serotonin S2 receptors in human brain. Brain Res. 1983;276231- 235
Link to Article
Petit-Taboue  MCLandeau  BOsmont  ATillet  IBarre  LBaron  JC Estimation of neocortical serotonin-2 receptor binding potential by single-dose fluorine-18-setoperone kinetic PET data analysis. J Nucl Med. 1996;3795- 104
Worsley  KJ Local maxima and the expected Euler characteristic of excursion sets of χ2, F and t fields. Adv Appl Probability. 1994;2613- 42
Link to Article
Blin  JBaron  JCDubois  BCrouzel  CFiorelli  MAttar-Levy  DPillon  BFournier  DVidailhet  MAgid  Y Loss of brain 5-HT2 receptors in Alzheimer's disease: in vivo assessment with positron emission tomography and [18F]setoperone. Brain. 1993;116497- 510
Link to Article
Not Available, SPSS for Windows. Rels 7.5 Chicago, Ill SPSS Inc1996;
Bench  CJFriston  KJBrown  RGFrackowiak  RSJDolan  RJ Regional cerebral blood flow in depression measured by positron emission tomography: the relationship with clinical dimensions. Psychol Med. 1993;23579- 590
Link to Article
Kennedy  SHJavanmard  MVaccarino  FJ A review of functional neuroimaging in mood disorders: positron emission tomography and depression. Can J Psychiatry. 1997;42467- 475
Weinberger  DRJones  DWCoppola  RBerman  KFGibson  RReba  RC Concerning the distribution of cerebral muscarinic acetylcholine receptors in Alzheimer's disease [letter]. Arch Neurol. 1991;481117- 1118
Link to Article
Frost  JJMayberg  HSFisher  RSDouglass  KHDannals  RFLinks  JMWilson  AARavert  HTRosenbaum  AESnyder  SHWagner  HNJ µ-Opiate receptors measured by positron emission tomography are increased in temporal lobe epilepsy. Ann Neurol. 1988;23231- 237
Link to Article
Wong  DFWagner  HNDannals  RFLinks  JMFrost  JJRavert  HTWilson  AARosenbaum  AEGjedde  ADouglass  KHPetronis  JDFolstein  MFToung  JKTBurns  HD Effects of age on dopamine and serotonin receptors measured by positron emission tomography in the living human brain. Science. 1984;2261393- 1396
Link to Article
Wang  GJVolkow  NDLogan  JFowler  JSSchlyer  DMacGregor  RRHitzemann  RJGur  RCWolf  AP Evaluation of age-related changes in serotonin 5-HT2 and dopamine D2 receptor availability in healthy human subjects. Life Sci. 1995;56249- 253
Iyo  MYamasaki  T The detection of age-related decrease of dopamine D1, D2 and serotonin 5-HT2 receptors in living human brain. Prog Neuropsychopharmacol Biol Psychiatry. 1993;17415- 421
Link to Article
Marcusson  JOMorgan  DGWinblad  BFinch  CE Serotonin-2 binding sites in human frontal cortex and hippocampus: selective loss of S-2A sites with age. Brain Res. 1984;31151- 56
Link to Article
Crouzel  CGuillaume  MBarre  LLemaire  CPike  VW Ligands and tracers for PET studies of the 5-HT system: current status. Nucl Med Biol. 1992;19857- 870
Peroutka  SJSnyder  SH Long-term antidepressant treatment decreases spiroperidol-labeled serotonin receptor binding. Science. 1980;21088- 90
Link to Article
Peroutka  SJSnyder  SH Regulation of serotonin-2 (5-HT2) receptors labeled with [3H]spiroperidol by chronic treatment with the antidepressant amitriptyline. J Pharmacol Exp Ther. 1980;215582- 587
Kellar  KJCasio  CSButler  JAKurtzke  RN Differential effects of electroconvulsive shock and antidepressant drugs on serotonin-2 receptors in rat brain. Eur J Pharmacol. 1981;69515- 518
Link to Article
Goodwin  GMGreen  ARJohnson  P 5-HT2 receptor characteristics in frontal cortex and 5-HT2 receptor-mediated head twitch behavior following antidepressant treatment to mice. Br J Pharmacol. 1984;83235- 242
Link to Article
Blackshear  MASanders-Bush  E Serotonin receptor sensitivity after acute and chronic treatment with mianserin. J Pharmacol Exp Ther. 1982;221303- 308
Stoltz  JFMarsden  CAMiddlemiss  DN Effect of chronic antidepressant treatment and subsequent withdrawal on [3H]-5-hydroxytryptamine and [3H]-spiperone binding in rat frontal cortex and serotonin mediated behavior. Psychopharmacology. 1983;80150- 155
Link to Article
Eison  ASYocca  FDGianutsos  G Effect of chronic administration of antidepressant drugs on 5-HT2–mediated behavior in the rat following noradrenergic or serotonergic denervation. J Neural Transm. 1991;8419- 32
Link to Article
Yatham  LNDennie  JLane  CShiah  ISLiddle  PF A PET study of effects on desipramine or ECT on 5-HT2 receptors in depression.  Abstracts of the XXIst Collegium Internationale Neuro-Psychopharmacologicum (CINP) Congress July 12-16, 1998 Glasgow, ScotlandAbstract 278
Buchsbaum  MSDeLisi  LEHolcomb  HHCappelletti  JKing  ACJohnson  JHazlett  E Anteroposterior gradients in cerebral glucose use in schizophrenia and affective disorders. Arch Gen Psychiatry. 1984;411159- 1166
Link to Article
Baxter  LRPhelps  MEMazziotta  JCSchwartz  JMGerner  RHSelin  CESumida  RM Cerebral metabolic rates for glucose in mood disorders. Arch Gen Psychiatry. 1985;42441- 447
Link to Article
Post  RMDeLisi  LEHolcomb  HHUhde  TWCohen  RBuchsbaum  MS Glucose utilization in the temporal cortex of affectively ill patients: positron emission tomography. Biol Psychiatry. 1987;22545- 553
Link to Article
Dolan  RJBench  CJBrown  RGScott  LCFriston  KJFrackowiak  RSJ Regional cerebral blood flow abnormalities in depressed patients with cognitive impairment. J Neurol Neurosurg Psychiatry. 1992;55768- 773
Link to Article
Biver  FGoldman  SDelvenne  VLuxen  ADe Maertelaer  VHubain  PMendlewicz  JLotstra  F Frontal and parietal metabolic disturbances in unipolar depression. Biol Psychiatry. 1994;36381- 388
Link to Article
Bench  CJFrackowiak  RSJDolan  RJ Changes in regional cerebral blood flow on recovery from depression. Psychol Med. 1995;25247- 251
Link to Article
Nobler  MSSackeim  HAProhovnik  IMoeller  JRMukherjee  SSchnur  DBPrudic  JDevanand  DP Regional cerebral blood flow in mood disorders, III: treatment and clinical response. Arch Gen Psychiatry. 1994;51884- 897
Link to Article
Volkow  NDBellar  SMullani  NJould  LDewey  S Effects of electroconvulsive therapy on brain glucose metabolism: a preliminary study. Convulsive Ther. 1988;4199- 205
Scott  AIFDougall  NRoss  MO'Carroll  RERiddle  WEbmeier  KPGoodwin  GM Short-term effects of electroconvulsive treatment on the uptake of 99mTc-exametazime into brain in major depression shown with single photon emission tomography. J Affect Disord. 1994;3027- 34
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Relationship between age and serotonin2 (5-HT2) receptor binding potential in frontal (A) and temporal (B) cortical areas in 20 depressed patients and 20 healthy control subjects. The lines indicate significant negative correlations between age and 5-HT2 receptor binding potential.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Statistical parametric maps of t values displayed as projections on the sagittal (A), coronal (B), and transverse (C) renderings of the brain. These projections illustrate regions of significantly decreased serotonin2 receptor binding potential in depressed patients compared with matched healthy control subjects.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Representative areas of significant decreases in serotonin2 receptor binding potential on the sagittal renderings of the brain (A, x = −38; B, x = 4; C, x = −48; D, x = 48) in 20 depressed patients. Coordinates are in millimeters from the origin at the midpoint of anterior commisure, in the coordinate frame used in statistical parametric mapping (SPM 96) software.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Sociodemographic and Illness Characteristics for 20 Depressed Patients*
Table Graphic Jump LocationTable 2. Correlation Coefficients and Slopes of Linear Regression Between Age and Serotonin2 Receptor Binding Potential in Various Cortical Areas in 20 Depressed Patients and 20 Healthy Controls
Table Graphic Jump LocationTable 3. Cluster Size, P and z Values, Coordinates With P and z Values, and Serotonin2 Receptor Binding Potential for Brain Regions With Highest Decreases in Binding in 20 Depressed Patients Compared With 20 Healthy Controls*

References

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Blin  JPappata  SKiyosawa  MCrouzel  CBaron  JC Fluorine-18-setoperone: a new high-affinity ligand for positron emission tomography study of the serotonin-2 receptors in baboon brain in vivo. Eur J Pharmacol. 1988;14773- 82
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Blin  JSette  GFiorelli  MBletry  OElghozi  JLCrouzel  CBaron  JC A method for the in vivo investigation of the serotonergic 5-HT2 receptors in the human cerebral cortex using positron emission tomography and 18F-labeled setoperone. J Neurochem. 1990;541744- 1754
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American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Washington, DC American Psychiatric Association1994;
Spitzer  RLWilliams  JBWGibbon  MFirst  MB Structured Clinical Interview for DSM-III-R, Patient Edition.  Washington, DC American Psychiatric Association1990;
Hamilton  M A rating scale of depression. J Neurol Neurosurg Psychiatry. 1960;2356- 62
Link to Article
Spitzer  RLWilliams  JBWGibbon  MFirst  MB Structured Clinical Interview for DSM-III-R, Nonpatient Edition.  Washington, DC American Psychiatric Association1992;
Adam  MJLu  SJivan  SHuser  J Simplified purification and synthesis of F-18 setoperone [abstract]. J Labeled Compounds Radiopharm. 1997;40258
Yatham  LNLiddle  PFDennie  JShiah  ISAdam  MJLane  CLam  RWRuth  TJ Decrease in brain serotonin 2 receptor binding in patients with major depression following desipramine treatment: a positron emission tomography study with fluorine-18–labeled setoperone. Arch Gen Psychiatry. 1999;56705- 711
Link to Article
Pietrzyk  UHerholz  KFink  GJacobs  AMielke  RSlansky  IMurker  MHeiss  WD An interactive technique for three-dimensional image registration: validation for PET, SPECT, MRI, and CT brain studies. J Nucl Med. 1994;352011- 2018
Friston  KJFrith  CDLiddle  PFFrackowiak  RSJ Comparing function (PET) images: the assessment of significant change. J Cereb Blood Flow Metab. 1991;11690- 699
Link to Article
Friston  KJHolmes  APWorsley  KJPoline  JPFrith  CDFrackowiak  RSJ Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp. 1995;2189- 210
Link to Article
Mazoyer  B Investigation of the dopaminergic system with positron emission tomography: general issues in modelling. Baron  JCComar  DFarde  LMartinot  JLMazoyer  Beds.Brain Dopaminergic Systems Imaging With Positron Emission Tomography. Dordrecht, the Netherlands Kluwer1991;65- 83
Schotte  AMaloteaux  JMLanduron  PM Characterization and regional distribution of serotonin S2 receptors in human brain. Brain Res. 1983;276231- 235
Link to Article
Petit-Taboue  MCLandeau  BOsmont  ATillet  IBarre  LBaron  JC Estimation of neocortical serotonin-2 receptor binding potential by single-dose fluorine-18-setoperone kinetic PET data analysis. J Nucl Med. 1996;3795- 104
Worsley  KJ Local maxima and the expected Euler characteristic of excursion sets of χ2, F and t fields. Adv Appl Probability. 1994;2613- 42
Link to Article
Blin  JBaron  JCDubois  BCrouzel  CFiorelli  MAttar-Levy  DPillon  BFournier  DVidailhet  MAgid  Y Loss of brain 5-HT2 receptors in Alzheimer's disease: in vivo assessment with positron emission tomography and [18F]setoperone. Brain. 1993;116497- 510
Link to Article
Not Available, SPSS for Windows. Rels 7.5 Chicago, Ill SPSS Inc1996;
Bench  CJFriston  KJBrown  RGFrackowiak  RSJDolan  RJ Regional cerebral blood flow in depression measured by positron emission tomography: the relationship with clinical dimensions. Psychol Med. 1993;23579- 590
Link to Article
Kennedy  SHJavanmard  MVaccarino  FJ A review of functional neuroimaging in mood disorders: positron emission tomography and depression. Can J Psychiatry. 1997;42467- 475
Weinberger  DRJones  DWCoppola  RBerman  KFGibson  RReba  RC Concerning the distribution of cerebral muscarinic acetylcholine receptors in Alzheimer's disease [letter]. Arch Neurol. 1991;481117- 1118
Link to Article
Frost  JJMayberg  HSFisher  RSDouglass  KHDannals  RFLinks  JMWilson  AARavert  HTRosenbaum  AESnyder  SHWagner  HNJ µ-Opiate receptors measured by positron emission tomography are increased in temporal lobe epilepsy. Ann Neurol. 1988;23231- 237
Link to Article
Wong  DFWagner  HNDannals  RFLinks  JMFrost  JJRavert  HTWilson  AARosenbaum  AEGjedde  ADouglass  KHPetronis  JDFolstein  MFToung  JKTBurns  HD Effects of age on dopamine and serotonin receptors measured by positron emission tomography in the living human brain. Science. 1984;2261393- 1396
Link to Article
Wang  GJVolkow  NDLogan  JFowler  JSSchlyer  DMacGregor  RRHitzemann  RJGur  RCWolf  AP Evaluation of age-related changes in serotonin 5-HT2 and dopamine D2 receptor availability in healthy human subjects. Life Sci. 1995;56249- 253
Iyo  MYamasaki  T The detection of age-related decrease of dopamine D1, D2 and serotonin 5-HT2 receptors in living human brain. Prog Neuropsychopharmacol Biol Psychiatry. 1993;17415- 421
Link to Article
Marcusson  JOMorgan  DGWinblad  BFinch  CE Serotonin-2 binding sites in human frontal cortex and hippocampus: selective loss of S-2A sites with age. Brain Res. 1984;31151- 56
Link to Article
Crouzel  CGuillaume  MBarre  LLemaire  CPike  VW Ligands and tracers for PET studies of the 5-HT system: current status. Nucl Med Biol. 1992;19857- 870
Peroutka  SJSnyder  SH Long-term antidepressant treatment decreases spiroperidol-labeled serotonin receptor binding. Science. 1980;21088- 90
Link to Article
Peroutka  SJSnyder  SH Regulation of serotonin-2 (5-HT2) receptors labeled with [3H]spiroperidol by chronic treatment with the antidepressant amitriptyline. J Pharmacol Exp Ther. 1980;215582- 587
Kellar  KJCasio  CSButler  JAKurtzke  RN Differential effects of electroconvulsive shock and antidepressant drugs on serotonin-2 receptors in rat brain. Eur J Pharmacol. 1981;69515- 518
Link to Article
Goodwin  GMGreen  ARJohnson  P 5-HT2 receptor characteristics in frontal cortex and 5-HT2 receptor-mediated head twitch behavior following antidepressant treatment to mice. Br J Pharmacol. 1984;83235- 242
Link to Article
Blackshear  MASanders-Bush  E Serotonin receptor sensitivity after acute and chronic treatment with mianserin. J Pharmacol Exp Ther. 1982;221303- 308
Stoltz  JFMarsden  CAMiddlemiss  DN Effect of chronic antidepressant treatment and subsequent withdrawal on [3H]-5-hydroxytryptamine and [3H]-spiperone binding in rat frontal cortex and serotonin mediated behavior. Psychopharmacology. 1983;80150- 155
Link to Article
Eison  ASYocca  FDGianutsos  G Effect of chronic administration of antidepressant drugs on 5-HT2–mediated behavior in the rat following noradrenergic or serotonergic denervation. J Neural Transm. 1991;8419- 32
Link to Article
Yatham  LNDennie  JLane  CShiah  ISLiddle  PF A PET study of effects on desipramine or ECT on 5-HT2 receptors in depression.  Abstracts of the XXIst Collegium Internationale Neuro-Psychopharmacologicum (CINP) Congress July 12-16, 1998 Glasgow, ScotlandAbstract 278
Buchsbaum  MSDeLisi  LEHolcomb  HHCappelletti  JKing  ACJohnson  JHazlett  E Anteroposterior gradients in cerebral glucose use in schizophrenia and affective disorders. Arch Gen Psychiatry. 1984;411159- 1166
Link to Article
Baxter  LRPhelps  MEMazziotta  JCSchwartz  JMGerner  RHSelin  CESumida  RM Cerebral metabolic rates for glucose in mood disorders. Arch Gen Psychiatry. 1985;42441- 447
Link to Article
Post  RMDeLisi  LEHolcomb  HHUhde  TWCohen  RBuchsbaum  MS Glucose utilization in the temporal cortex of affectively ill patients: positron emission tomography. Biol Psychiatry. 1987;22545- 553
Link to Article
Dolan  RJBench  CJBrown  RGScott  LCFriston  KJFrackowiak  RSJ Regional cerebral blood flow abnormalities in depressed patients with cognitive impairment. J Neurol Neurosurg Psychiatry. 1992;55768- 773
Link to Article
Biver  FGoldman  SDelvenne  VLuxen  ADe Maertelaer  VHubain  PMendlewicz  JLotstra  F Frontal and parietal metabolic disturbances in unipolar depression. Biol Psychiatry. 1994;36381- 388
Link to Article
Bench  CJFrackowiak  RSJDolan  RJ Changes in regional cerebral blood flow on recovery from depression. Psychol Med. 1995;25247- 251
Link to Article
Nobler  MSSackeim  HAProhovnik  IMoeller  JRMukherjee  SSchnur  DBPrudic  JDevanand  DP Regional cerebral blood flow in mood disorders, III: treatment and clinical response. Arch Gen Psychiatry. 1994;51884- 897
Link to Article
Volkow  NDBellar  SMullani  NJould  LDewey  S Effects of electroconvulsive therapy on brain glucose metabolism: a preliminary study. Convulsive Ther. 1988;4199- 205
Scott  AIFDougall  NRoss  MO'Carroll  RERiddle  WEbmeier  KPGoodwin  GM Short-term effects of electroconvulsive treatment on the uptake of 99mTc-exametazime into brain in major depression shown with single photon emission tomography. J Affect Disord. 1994;3027- 34
Link to Article

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