A voxel-by-voxel analysis of [18F]setoperone PET data shows no substantial serotonin 5-HT2A receptor changes in schizophrenia

Several postmortem studies have reported regionally localized decreases in serotonin(2A) receptors (5-HT(2A)R) in schizophrenia. This was not confirmed by two recent [18F]setoperone positron emission tomography (PET) studies. In these two studies relatively large regions of interest (ROIs) were used; hence, 5-HT(2A)R changes may have been missed in some brain areas. Therefore, data from one study were analyzed on a voxel-by-voxel basis using Statistical Parametric Mapping (SPM). We also used this method to examine the relationship between 5-HT(2A)R binding potential (BP) and five PANSS-derived factors: negative, positive, activation, dysphoric and autistic preoccupation. Thirteen schizophrenic patients (10 antipsychotic-naïve, 3 antipsychotic-free; 11 M, 2 F; age 31+/-7 years) and 35 age-matched control subjects (15 M, 20 F; age 30+/-7 years) were scanned. The 5-HT(2A)R BP was determined for each voxel using the pseudoequilibrium ratio method on PET data obtained between 65 and 90 min after [18F]setoperone bolus injection. The resulting parametric 5-HT(2A)R BP images were spatially normalized using a ligand specific template. Analyses of covariance were done using SPM99 with age as covariate. In tests for the effect of schizophrenia and for partial correlations between 5-HT(2A)R BP and the five factors, corrected P values <0.05 at cluster or voxel level were considered significant. No significant differences were detected between patients and control subjects, and no significant correlations were observed between 5-HT(2A)R BP and any of the five factors. Thus, in agreement with the previous ROI studies, voxel-by-voxel analysis confirmed the lack of substantial 5-HT(2A)R BP differences between schizophrenic patients and control subjects.

[1]  Marie-Laure Paillère-Martinot,et al.  No serotonin 5-HT2A receptor density abnormality in the cortex of schizophrenic patients studied with PET , 1998, Schizophrenia Research.

[2]  J. Kleinman,et al.  Selective abnormalities of prefrontal serotonergic receptors in schizophrenia. A postmortem study. , 1993, Archives of general psychiatry.

[3]  C Crouzel,et al.  Loss of brain 5-HT2 receptors in Alzheimer's disease. In vivo assessment with positron emission tomography and [18F]setoperone. , 1993, Brain : a journal of neurology.

[4]  Ralph Myers,et al.  Assessment of Spatial Normalization of PET Ligand Images Using Ligand-Specific Templates , 1999, NeuroImage.

[5]  M. Jüptner,et al.  Review: Does Measurement of Regional Cerebral Blood Flow Reflect Synaptic Activity?—Implications for PET and fMRI , 1995, NeuroImage.

[6]  T. Crow,et al.  Tritiated LSD binding in frontal cortex in schizophrenia. , 1981, Archives of general psychiatry.

[7]  J. Krystal,et al.  [123I]Iomazenil SPECT benzodiazepine receptor imaging in schizophrenia , 1999, Psychiatry Research: Neuroimaging.

[8]  Paul J. Harrison,et al.  5-HT1A and 5-HT2A Receptor mRNAs and Binding Site Densities Are Differentially Altered in Schizophrenia , 1996, Neuropsychopharmacology.

[9]  J. Joyce,et al.  Alterations in the cortical serotonergic system in schizophrenia: A postmortem study , 1997, Biological Psychiatry.

[10]  M. Richardson,et al.  Benzodiazepine receptors in focal epilepsy with cortical dysgenesis: An 11C‐flumazenil PET study , 1996, Annals of neurology.

[11]  M Laruelle,et al.  Alterations of benzodiazepine receptors in type II alcoholic subjects measured with SPECT and [123I]iomazenil. , 1998, The American journal of psychiatry.

[12]  S. Kapur,et al.  Serotonin 5-HT2 receptors in schizophrenia: a PET study using [18F]setoperone in neuroleptic-naive patients and normal subjects. , 1999, The American journal of psychiatry.

[13]  T. Kuno,et al.  Decreased serotonin S2 and increased dopamine D2 receptors in chronic schizophrenics , 1986, Biological Psychiatry.

[14]  C. Halldin,et al.  PET imaging of central 5-HT2A receptors with carbon-11-MDL 100,907. , 1998, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[15]  Karl J. Friston,et al.  Cerebral benzodiazepine receptors in hippocampal sclerosis. An objective in vivo analysis. , 1996, Brain : a journal of neurology.

[16]  J. Kleinman,et al.  Serotonin Uptake Sites and Serotonin Receptors Are Altered in the Limbic System of Schizophrenics , 1993, Neuropsychopharmacology.

[17]  S. Kapur,et al.  Reliability of a simple non-invasive method for the evaluation of 5-HT2 receptors using [18F]-setoperone PET imaging. , 1997, Nuclear medicine communications.

[18]  Charles F. Reynolds,et al.  Reduced binding of [ 18 F ]altanserin to serotonin type 2A receptors in aging: persistence of effect after partial volume correction , 1998, Brain Research.

[19]  M. Nöthen,et al.  Association between schizophrenia and T102C polymorphism of the 5-hydroxytryptamine type 2a-receptor gene , 1996, The Lancet.

[20]  G. Aghajanian,et al.  Pyramidal cells in piriform cortex receive a convergence of inputs from monoamine activated GABAergic interneurons , 1993, Brain Research.

[21]  C Crouzel,et al.  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 , 1990, Journal of neurochemistry.

[22]  J. Baron,et al.  Estimation of neocortical serotonin-2 receptor binding potential by single-dose fluorine-18-setoperone kinetic PET data analysis. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[23]  T. Woo,et al.  A subclass of prefrontal gamma-aminobutyric acid axon terminals are selectively altered in schizophrenia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[24]  P. Maquet,et al.  Serotonin 5HT2 Receptor Imaging in the Human Brain Using Positron Emission Tomography and a New Radioligand, [18F]Altanserin: Results in Young Normal Controls , 1995, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[25]  G. Aghajanian,et al.  Excitation of interneurons in piriform cortex by 5-hydroxytryptamine: blockade by MDL 100,907, a highly selective 5-HT2A receptor antagonist. , 1994, European journal of pharmacology.

[26]  L. Iversen,et al.  Preliminary studies of human cortical 5-HT2 receptors and their involvement in schizophrenia and neuroleptic drug action. , 1983, Journal of neural transmission. Supplementum.

[27]  J. Hietala,et al.  Differential Regulation of Rat 5-HT2A and 5-HT2C Receptors after Chronic Treatment with Clozapine, Chlorpromazine and Three Putative Atypical Antipsychotic Drugs , 1995, Neuropsychopharmacology.

[28]  R. Mattson,et al.  Effects of Vigabatrin on the GABAergic System as Determined by [123I]Iomazenil SPECT and GABA MRS , 1999, Epilepsia.

[29]  H. Meltzer,et al.  Effect of typical and atypical antipsychotic drugs on 5-HT2 receptor density in rat cerebral cortex. , 1989, Life sciences.

[30]  Philip D. Harvey,et al.  Empirical assessment of the factorial structure of clinical symptoms in schizophrenia. A multisite, multimodel evaluation of the factorial structure of the Positive and Negative Syndrome Scale. The PANSS Study Group. , 1997, Psychopathology.

[31]  J. Marcusson,et al.  Effect of aging in human cortical pre- and postsynaptic serotonin binding sites , 1993, Brain Research.

[32]  T. Woo,et al.  Schizophrenia and the parvalbumin-containing class of cortical local circuit neurons. , 1997, The American journal of psychiatry.

[33]  G. Aghajanian,et al.  Excitatory responses to serotonin (5‐HT) in neurons of the rat piriform cortex: Evidence for mediation by 5‐HT1C receptors in pyramidal cells and 5‐HT2 receptors in interneurons , 1991, Synapse.

[34]  P A Sargent,et al.  Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. , 2000, Archives of general psychiatry.

[35]  B. Landeau,et al.  Parametric PET imaging of 5HT2A receptor distribution with 18F-setoperone in the normal human neocortex. , 1999, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[36]  V J Cunningham,et al.  Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study. , 1998, Archives of general psychiatry.

[37]  Karl J. Friston,et al.  453 Mapping of gray matter changes in schizophrenia , 1997, Schizophrenia Research.

[38]  Anat Biegon,et al.  Autoradiographic analysis of [3H]ketanserin binding in the human brain postmortem: effect of suicide , 1990, Brain Research.

[39]  Patrick Dupont,et al.  Visualisation of loss of 5-HT2A receptors with age in healthy volunteers using [18F]altanserin and positron emission tomographic imaging , 1996, Psychiatry Research: Neuroimaging.

[40]  J D Watson,et al.  Nonparametric Analysis of Statistic Images from Functional Mapping Experiments , 1996, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[41]  H. Meltzer,et al.  Differential Effect of Subchronic Treatment with Various Neuroleptic Agents on Serotonin2 Receptors in Rat Cerebral Cortex , 1986, Journal of neurochemistry.

[42]  Karl J. Friston,et al.  Statistical parametric maps in functional imaging: A general linear approach , 1994 .

[43]  S. Woods,et al.  Changes of benzodiazepine receptors during chronic benzodiazepine administration in humans. , 1999, European journal of pharmacology.

[44]  S. Snyder,et al.  Neurotransmitter receptors in frontal cortex of schizophrenics. , 1979, Archives of general psychiatry.

[45]  C Crouzel,et al.  Ligands and tracers for PET studies of the 5-HT system--current status. , 1992, International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology.

[46]  David Silbersweig,et al.  SPECT [I-123]iomazenil measurement of the benzodiazepine receptor in panic disorder , 2000, Biological Psychiatry.

[47]  Karl J. Friston,et al.  Patterns of Cerebral Blood Flow in Schizophrenia , 1992, British Journal of Psychiatry.

[48]  Y. Samson,et al.  Post-stroke changes in cortical 5-HT2 serotonergic receptors. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[49]  S. Tang,et al.  Loxapine and clozapine decrease serotonin (S2) but do not elevate dopamine (D2) receptor numbers in the rat brain , 1984, Psychiatry Research.

[50]  V J Cunningham,et al.  11C-Diprenorphine Binding in Huntington's Disease: A Comparison of Region of Interest Analysis with Statistical Parametric Mapping , 1997, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[51]  P. Somogyi,et al.  Neurons Expressing 5-HT2 Receptors in the Rat Brain: Neurochemical Identification of Cell Types by Immunocytochemistry , 1994, Neuropsychopharmacology.

[52]  C. Beasley,et al.  Parvalbumin-immunoreactive neurons are reduced in the prefrontal cortex of schizophrenics , 1997, Schizophrenia Research.

[53]  P F Liddle,et al.  Decreased serotonin 2A receptor densities in neuroleptic-naive patients with schizophrenia: A PET study using [(18)F]setoperone. , 2000, The American journal of psychiatry.

[54]  R. Andrade,et al.  5-Hydroxytryptamine2 and 5-hydroxytryptamine1A receptors mediate opposing responses on membrane excitability in rat association cortex , 1991, Neuroscience.

[55]  G. Aghajanian,et al.  The role of serotonin in the pathophysiology and treatment of schizophrenia. , 1997, The Journal of neuropsychiatry and clinical neurosciences.

[56]  P. Liddle,et al.  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. , 1999, Archives of general psychiatry.

[57]  S. Kapur,et al.  Prefrontal cortex 5-HT2 receptors in depression: an [18F]setoperone PET imaging study. , 1999, The American journal of psychiatry.

[58]  John Seibyl,et al.  No Evidence of Altered In Vivo Benzodiazepine Receptor Binding in Schizophrenia , 1999, Neuropsychopharmacology.

[59]  R. North,et al.  Actions of 5-hydroxytryptamine on neurons of the rat cingulate cortex. , 1993, Journal of neurophysiology.