The aim of this study was to compare 5-HT1A availability in vivo in individuals with schizophrenia before and during treatment with the atypical antipsychotic ziprasidone. Six individuals with schizophrenia underwent two PET scans with [11C]WAY 100635; the first while medication-free (baseline) and the second while taking the atypical antipsychotic ziprasidone (on-medication). Regional volumes of distribution (VT, mL g−1) were derived using a two-tissue compartment kinetic model. Outcome measures included binding potential relative to the plasma (BPP, mL g−1) and the binding potential relative to the nonspecific distribution volume (BPND, unitless). No significant differences were observed in regional BPP or BPND with ziprasidone treatment. A significant correlation was noted between BPP measured in the orbitofrontal cortex during the on-medication condition and degree of improvement in negative symptoms with treatment (r = 0.96, p = 0.004). Consistent with the published literature of changes in 5-HT1A binding during treatment with 5-HT1A receptor agonists, this study did not detect a significant reduction in 5-HT1A binding with ziprasidone. The finding of a relationship between 5-HT1A binding and the degree of improvement in negative symptoms provides further support for the role of the 5-HT1A receptor in the pathophysiology and treatment of this symptom domain.
Abi-DarghamALaruelleMSeibylJ (1994) SPECT measurement of benzodiazepine receptors in human brain with [123-I]iomazenil: kinetic and equilibrium paradigms. J Nucl Med35: 228–238.
2.
Abi-DarghamAMartinezDMawlawiO (2000) Measurement of striatal and extrastriatal dopamine D1 receptor binding potential with [11C]NNC 112 in humans: validation and reproducibility. J Cereb Blood Flow Metab20: 225–243.
3.
AndreeBHedmanAThorbergSONilssonDHalldinCFardeL (2003) Positron emission tomographic analysis of dose-dependent NAD-299 binding to 5-hydroxytryptamine-1A receptors in the human brain. Psychopharmacology (Berl)167: 37–45.
4.
AndreeBThorbergSOHalldinCFardeL (1999) Pindolol binding to 5-HT1A receptors in the human brain confirmed with positron emission tomography. Psychopharmacology (Berl)144: 303–305.
5.
BantickRADeakinJFGrasbyPM (2001) The 5-HT1A receptor in schizophrenia: a promising target for novel atypical neuroleptics?J Psychopharmacol15: 37–46.
6.
BantickRAMontgomeryAJBenchCJ (2004a) A positron emission tomography study of the 5-HT1A receptor in schizophrenia and during clozapine treatment. J Psychopharmacol18: 346–354.
7.
BantickRARabinerEAHiraniEde VriesMHHumeSPGrasbyPM (2004b) Occupancy of agonist drugs at the 5-HT1A receptor. Neuropsychopharmacology29: 847–859.
8.
BarnesNMSharpT (1999) A review of central 5-HT receptors and their function. Neuropharmacology38: 1083–1152.
9.
BrodyDAdlerLAKimTAngristBRotrosenJ (1990) Effects of buspirone in seven schizophrenic subjects. J Clin Psychopharmacol10: 68–69.
10.
BurnetPWEastwoodSLHarrisonPJ (1996) 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia. Neuropsychopharmacology15: 442–455.
11.
BurnetPWJEastwoodSLHarrisonPJ (1997) [H-3]WAY-100635 for 5-HT1A receptor autoradiography in human brain: A comparison with [H-3]8-OH-DPAT and demonstration of increased binding in the frontal cortex in schizophrenia. Neurochem Int30: 565–574.
12.
DuvernoyH (1991) The Human Brain. Surface, Three-dimensional Sectional Anatomy and MRI. New York: Springer-Verlag.
13.
FardeLAndreeBGinovartNHalldinCThorbergS (2000) PET-Determination of robalzotan (NAD-299) induced 5-HT(1A) receptor occupancy in the monkey brain. Neuropsychopharmacology22: 422–429.
14.
FardeLGinovartNItoH (1997) PET-characterization of [carbonyl-C-11]WAY-100635 binding to 5-HT1A receptors in the primate brain. Psychopharmacology133: 196–202.
15.
FrankleWGLombardoIKegelesLS (2006) Serotonin 1A receptor availability in patients with schizophrenia and schizo-affective disorder: a positron emission tomography imaging study with [(11)C]WAY 100635. Psychopharmacology (Berl)189: 155–164.
16.
GoffDCMidhaKKBrotmanAWMcCormickSWaitesMAmicoET (1991) An open trial of buspirone added to neuroleptics in schizophrenic patients. J Clin Psychopharmacol11: 193–197.
17.
GozlanHThibaultSLaporteAMLimaLHamonM (1995) The selective 5-HT1A antagonist radioligand [3H]WAY 100635 labels both G-protein-coupled and free 5-HT1A receptors in rat brain membranes. Eur J Pharmacol288: 173–186.
18.
GurevichEVJoyceJN (1997) Alterations in the cortical serotonergic system in schizophrenia: A postmortem study. Biol Psychiatry42: 529–545.
19.
HallHLundkvistCHalldinC (1997) Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [3H]WAY-100635 and [11C]WAY-100635. Brain Res745: 96–108.
20.
HamiltonM (1960) A rating scale for depression. J Neurol Neurosurg Psych23: 56–62.
21.
HashimotoTNishinoNNakaiHTanakaC (1991) Increase in serotonin 5-HT1A receptors in prefrontal and temporal cortices of brains from patients with chronic schizophrenia. Life Sci48: 355–363.
22.
HoyerDPazosAProbstAPalaciosJM (1986) Serotonin receptors in the human brain. I. Characterization and autoradiographic localization of 5-HT1A recognition sites. Apparent absence of 5-HT1B recognition sites. Brain Res376: 85–96.
23.
HwangDRSimpsonNMontoyaJMannJJLaruelleM (1999) An improved one-pot procedure for the preparation of [11C-carbonyl]WAY 100635. Nucl Med Biol26: 815–819.
24.
InnisRCunninghamVJDelforgeJ (2007) Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cerebral Blood Flow Metab27: 1533–1539.
25.
JordanSKoprivicaVChenRTottoriKKikuchiTAltarCA (2002) The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT(1A) receptor. Eur J Pharmacol441: 137–140.
26.
JoyceJNShaneALexowNWinokurACasanovaMFKleinmanJE (1993) Serotonin uptake sites and serotonin receptors are altered in the limbic system of schizophrenics. Neuropsychopharmacology8: 315–336.
27.
KatesWRAbramsMTKaufmannWEBreiterSNReissAL (1997) Reliability and validity of MRI measurement of the amygdala and hippocampus in children with fragile X syndrome. Psychiat Res Neuroimag75: 31–48.
28.
KaySRFiszbeinAOplerLA (1987) The Positive and Negative Syndrome scale (PANSS) for schizophrenia. Schizophrenia Bull13: 261–276.
29.
KillianyRJMossMBNicholsonTJolezFSandorT (1997) An interactive procedure for extracting features of the brain from magnetic resonance images: the lobes. Human Brain Mapping5: 355–363.
30.
KumarJSPrabhakaranJMajoVJ (2007) Synthesis and in vivo evaluation of a novel 5-HT1A receptor agonist radioligand [O-methyl- 11C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine -3,5(2H,4H)dione in nonhuman primates. Eur J Nucl Med Mol Imaging34: 1050–1060.
31.
LacerdaALHardanAYYorbikOVemulapalliMPrasadKMKeshavanMS (2007) Morphology of the orbitofrontal cortex in first-episode schizophrenia: relationship with negative symptomatology. Prog Neuropsychopharmacol Biol Psychiatry31: 510–516.
32.
MahLArnoldMCGrafmanJ (2004) Impairment of social perception associated with lesions of the prefrontal cortex. Am J Psychiatry161: 1247–1255.
33.
MamoDGraffAMizrahiRShammiCMRomeyerFKapurS (2007) Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A) receptor occupancy in patients with schizophrenia: a triple tracer PET study. Am J Psychiatry164: 1411–1417.
34.
MamoDKapurSShammiCM (2004) A PET study of dopamine D2 and serotonin 5-HT2 receptor occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone. Am J Psychiatry161: 818–825.
35.
MartinezDHwangDMawlawiO (2001a) Differential occupancy of somatodendritic and postsynaptic 5HT(1A) receptors by pindolol. A dose-occupancy study with [11C]WAY 100635 and positron emission tomography in humans. Neuropsychopharmacology24: 209–229.
36.
MartinezDHwangDMawlawiO (2001b) Differential occupancy of somatodendritic and postsynaptic 5HT(1A) receptors by pindolol: a dose-occupancy study with [11C]WAY 100635 and positron emission tomography in humans. Neuropsychopharmacology24(3): 209–229.
37.
MawlawiOMWeissRShinnAPidcockJSlifstienMLaruelleM (1999) Performance characteristics of a head immobilization device for PET imaging. J Nucl Med40: 281P–281P.
38.
MeltzerHYSumiyoshiT (2008) Does stimulation of 5-HT(1A) receptors improve cognition in schizophrenia?Behav Brain Res195: 98–102.
39.
MintunMARaichleMEKilbournMRWootenGFWelchMJ (1984) A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann Neurol15: 217–227.
40.
MongeauRWelnerSAQuirionRSuranyi-CadotteBE (1992) Further evidence for differential affinity states of the serotonin1A receptor in rat hippocampus. Brain Res590: 229–238.
41.
NakayamaTSuharaTOkuboY (2002) In vivo drug action of tandospirone at 5-HT1A receptor examined using positron emission tomography and neuroendocrine response. Psychopharmacology (Berl)165: 37–42.
42.
Newman-TancrediAAssieMBLeducNOrmiereAMDantyNCosiC (2005) Novel antipsychotics activate recombinant human and native rat serotonin 5-HT1A receptors: affinity, efficacy and potential implications for treatment of schizophrenia. Int J Neuropsychopharmacol8: 341–356.
43.
Newman-TancrediAGavaudanSConteC (1998) Agonist and antagonist actions of antipsychotic agents at 5-HT1A receptors: a [35S]GTPgammaS binding study. Eur J Pharmacol355: 245–256.
44.
OsmanSLundkvistCPikeVW (1996) Characterization of the radioactive metabolites of the 5-HT1A receptor radioligand, [O-methyl-11C]WAY-100635, in monkey and human plasma by HPLC: comparison of the behavior of an identified radioactive metabolite with parent radioligand in monkey using PET. Nucl Med Biol23: 627–634.
45.
PaniLGessaGLCarboniSPortasCMRossettiZL (1990) Brain dialysis and dopamine: does the extracellular concentration of dopamine reflect synaptic release?Eur J Pharmacol180: 85–90.
46.
ParseyRVSlifsteinMHwangDR (2000) Validation and reproducibility of measurement of 5-HT1A receptor parameters with [carbonyl-11C]WAY-100635 in humans: comparison of arterial and reference tisssue input functions. J Cereb Blood Flow Metab20: 1111–1133.
47.
PriceJL (1999) Prefrontal cortical networks related to visceral function and mood. Ann N Y Acad Sci877: 383–396.
48.
RabinerEAGunnRNWilkinsMR (2000) Drug action at the 5-HT(1A) receptor in vivo: autoreceptor and postsynaptic receptor occupancy examined with PET and [carbonyl-(11)C]WAY-100635. Nucl Med Biol27: 509–513.
49.
RabinerEAGunnRNWilkinsMRSedmanEGrasbyPM (2002a) Evaluation of EMD 128 130 occupancy of the 5-HT1A and the D2 receptor: a human PET study with [11C]WAY-100635 and [11C]raclopride. J Psychopharmacol16: 195–199.
50.
RabinerEAMessaCSargentPA (2002b) A database of [(11)C]WAY-100635 binding to 5-HT(1A) receptors in normal male volunteers: normative data and relationship to methodological, demographic, physiological, and behavioral variables. Neuroimage15: 620–632.
51.
RabinerEAWilkinsMRTurkheimerF (2002c) 5-Hydroxytryptamine1A receptor occupancy by novel full antagonist 2-[4-[4-(7-chloro-2,3-dihydro-1,4-benzdioxyn-5-yl)-1-piperazinyl]butyl]-1, 2-benzisothiazol-3-(2H)-one-1,1-dioxide: a[11C][O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-py ridinyl)cyclohexanecarboxamide trihydrochloride (WAY-100635) positron emission tomography study in humans. J Pharmacol Exp Ther301: 1144–1150.
52.
RajeSPatatAAParksV (2008) A positron emission tomography study to assess binding of lecozotan, a novel 5-hydroxytryptamine-1A silent antagonist, to brain 5-HT1A receptors in healthy young and elderly subjects, and in patients with Alzheimer's disease. Clin Pharmacol Ther83: 86–96.
53.
RollemaHLuYSchmidtAWSprouseJSZornSH (2000) 5-HT(1A) receptor activation contributes to ziprasidone-induced dopamine release in the rat prefrontal cortex. Biol Psychiatry48: 229–237.
54.
RollemaHLuYSchmidtAWZornSH (1997) Clozapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation. Eur J Pharmacol338: R3–R5.
55.
SimpsonMDLubmanDISlaterPDeakinJF (1996) Autoradiography with [3H]8-OH-DPAT reveals increases in 5-HT(1A) receptors in ventral prefrontal cortex in schizophrenia. Biol Psychiatry39: 919–928.
56.
SirotaPEpsteinBBenatovRSousnostzkyMKindlerS (2001) An open study of buspirone augmentation of neuroleptics in patients with schizophrenia. J Clin Psychopharmacol21: 454–455.
57.
SlaterPDoyleCADeakinJF (1998) Abnormal persistence of cerebellar serotonin-1A receptors in schizophrenia suggests failure to regress in neonates. J Neural Transm105: 305–315.
58.
SovnerRParnell-SovnerN (1989) Use of buspirone in the treatment of schizophrenia. J Clin Psychopharmacol9: 61–62.
59.
SpitzerRWilliamsJGibbonMFirstM (1992) The Structured Clinical interview for DSM-III-R: 1. History, rationale and description. Arch Gen Psychiatry49: 624–629.
60.
SumiyoshiTHiguchiYMatsuiM (2007a) Effective adjunctive use of tandospirone with perospirone for enhancing verbal memory and quality of life in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry31: 965–967.
61.
SumiyoshiTMatsuiMNoharaS (2001a) Enhancement of cognitive performance in schizophrenia by addition of tandospirone to neuroleptic treatment. Am J Psychiatry158: 1722–1725.
62.
SumiyoshiTMatsuiMYamashitaI (2001b) The effect of tandospirone, a serotonin(1A) agonist, on memory function in schizophrenia. Biol Psychiatry49: 861–868.
63.
SumiyoshiTMatsuiMYamashitaI (2000) Effect of adjunctive treatment with serotonin-1A agonist tandospirone on memory functions in schizophrenia. J Clin Psychopharmacol20: 386–388.
64.
SumiyoshiTParkSJayathilakeKRoyAErtugrulAMeltzerHY (2007b) Effect of buspirone, a serotonin1A partial agonist, on cognitive function in schizophrenia: a randomized, double-blind, placebo‐controlled study. Schizophr Res95: 158–168.
65.
SumiyoshiTStockmeierCAOverholserJCDilleyGEMeltzerHY (1996) Serotonin1A receptors are increased in postmortem prefrontal cortex in schizophrenia. Brain Res708: 209–214.
66.
TalairachJTournouxP (1988) Co-planar Stereotactic Atlas of the Human Brain. Three-dimensional Proportional System: An Approach of Cerebral Imaging. New York: Theime Medical Publisher.
67.
TauscherJKapurSVerhoeffNP (2002) Brain serotonin 5-HT1A receptor binding in schizophrenia measured by positron emission tomography and [11C]WAY-100635. Arch Gen Psychiatry59: 514–520.
68.
VernalekenIFellowsCJanouschekH (2008) Striatal and extrastriatal D2/D3-receptor-binding properties of ziprasidone: a positron emission tomography study with [18F]Fallypride and [11C]raclopride (D2/D3-receptor occupancy of ziprasidone). J Clin Psychopharmacol28: 608–617.
69.
WadenbergML (1996) Serotonergic mechanisms in neuroleptic-induced catalepsy in the rat. Neurosci Biobehav Rev20: 325–339.
70.
WoodsRPCherrySRMazziottaJC (1992) Rapid automated algorithm for aligning and reslicing PET images. J Comp Assist Tomogr16: 620–633.
71.
YasunoFSuharaTIchimiyaTTakanoAAndoTOkuboY (2004) Decreased 5-HT1A receptor binding in amygdala of schizophrenia. Biol Psychiatry55: 439–444.
