To review recent findings from positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies that investigate the pathophysiology and treatment of schizophrenia, depression, and dementia.
Methods:
We carried out a review of the literature.
Results:
PET and SPECT studies have provided evidence of dopamine system dysregulation in patients with schizophrenia and variable loss of monoamines in patients with depression. Antipsychotic response has been demonstrated to be associated with blockade of dopamine D2 receptors, and antidepressant response has now been linked to blockade of serotonin transporter receptors. PET and SPECT have been extensively evaluated as diagnostic procedures for dementia. Substantial progress has been made in developing radioligands that bind to amyloid deposits in the brain, which should provide new opportunities for early diagnosis and treatment monitoring in Alzheimer's disease.
Conclusion:
Advances in PET and SPECT imaging have provided new insights into the biology of major psychiatric disorders and their treatment. In the future, we can expect that these imaging techniques will become more central to the management of psychiatric disorders.
FrankleWGLaruelleM.Neuroreceptor imaging in psychiatric disorders. Ann Nucl Med. 2002;16(7):437–446.
2.
SeemanPTallericoT.Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiatry. 1998;3(2):123–134.
3.
SeemanPGuanHCNiznikHB. Endogenous dopamine lowers the dopamine D2 receptor density as measured by [3H]raclopride: Implications for positron emission tomography of the human brain. Synapse. 1989;3(1):96–97.
4.
LaruelleMAbi-DarghamAvan DyckCHSingle photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci U S A. 1996;93(17):9235–9240.
5.
BreierASuTPSaundersRSchizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: Evidence from a novel positron emission tomography method. Proc Natl Acad Sci U S A. 1997;94(6):2569–2574.
6.
Abi-DarghamARodenhiserJPrintzDIncreased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A. 2000;97(14):8104–8109.
7.
LaruelleMAbi-DarghamAGilRIncreased dopamine transmission in schizophrenia: Relationship to illness phases. Biol Psychiatry. 1999;46(1):56–72.
8.
SchlaepferTEPearlsonGDWongDFPET study of competition between intravenous cocaine and [11C]raclopride at dopamine receptors in human subjects. Am J Psychiatry. 1997;154(9):1209–1213.
PruessnerJCChampagneFMeaneyMJDopamine release in response to a psychological stress in humans and its relationship to early life maternal care: A positron emission tomography study using [11C]raclopride. J Neurosci. 2004;24(11):2825–2831.
11.
van KammenDPDochertyJPBunneyWEJr.Prediction of early relapse after pimozide discontinuation by response to d-amphetamine during pimozide treatment. Biol Psychiatry. 1982;17(2):233–242.
12.
LiebermanJAAlvirJGeislerSMethylphenidate response, psychopathology and tardive dyskinesia as predictors of relapse in schizophrenia. Neuropsychopharmacology. 1994;11(2):107–118.
13.
FardeLWieselFAHalldinCCentral D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry. 1988;45(1):71–76.
14.
WolkinABaroucheFWolfAPDopamine blockade and clinical response: Evidence for two biological subgroups of schizophrenia. Am J Psychiatry. 1989;146(7):905–908.
15.
FardeLNordstromALWieselFAPositron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine: Relation to extrapyramidal side effects. Arch Gen Psychiatry. 1992;49:538–544.
16.
Zhang-WongJZipurskyRBBeiserMOptimal haloperidol dosage in first-episode psychosis. Can J Psychiatry. 1999;44(2):164–167.
17.
McEvoyJPHogartyGESteingardS.Optimal dose of neuroleptic in acute schizophrenia. A controlled study of the neuroleptic threshold and higher haloperidol dose. Arch Gen Psychiatry. 1991;48(8):739–745.
18.
KapurSRemingtonGJonesCHigh levels of dopamine D2 receptor occupancy with low dose haloperidol treatment: A PET study. Am J Psychiatry. 1996;153(7):948–950.
19.
KapurSZipurskyRJonesCRelationship between dopamine D(2) occupancy, clinical response, and side effects: A double-blind PET study of first-episode schizophrenia. Am J Psychiatry. 2000;157(4):514–520.
20.
Abi-DarghamALaruelleM.Mechanisms of action of second generation antipsychotic drugs in schizophrenia: Insights from brain imaging studies. Eur Psychiatry. 2005;20(1):15–27.
21.
KapurSRemingtonG.Dopamine D(2) receptors and their role in atypical antipsychotic action: Still necessary and may even be sufficient. Biol Psychiatry. 2001;50(11):873–883.
22.
KapurSZipurskyRBRemingtonG.Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry. 1999;156(2):286–293.
23.
MamoDKapurSShammiCMA PET study of dopamine D2 and serotonin 5-HT2 receptor occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone. Am J Psychiatry. 2004;161(5):818–825.
24.
RemingtonGMamoDLabelleAA PET study evaluating dopamine D2 receptor occupancy for long-acting injectable risperidone. Am J Psychiatry. 2006;163(3):396–401.
25.
GeddesJFreemantleNHarrisonPAtypical antipsychotics in the treatment of schizophrenia: Systematic overview and meta-regression analysis. BMJ. 2000;321(7273):1371–1376.
26.
ZipurskyRBChristensenBKDaskalakisZTreatment response to olanzapine and haloperidol and its association with dopamine D receptor occupancy in first-episode psychosis. Can J Psychiatry. 2005;50(8):462–469.
27.
LiebermanJATollefsonGTohenMComparative efficacy and safety of atypical and conventional antipsychotic drugs in first-episode psychosis: A randomized, double-blind trial of olanzapine versus haloperidol. Am J Psychiatry. 2003;160(8):1396–1404.
28.
KapurSZipurskyRJonesCA positron emission tomography study of quetiapine in schizophrenia: A preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Arch Gen Psychiatry. 2000;57(6):553–559.
29.
KapurSSeemanP.Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics? A new hypothesis. Am J Psychiatry. 2001;158(3):360–369.
30.
NybergSFardeLHalldinC.Delayed normalization of central D2 dopamine receptor availability after discontinuation of haloperidol decanoate. Preliminary findings. Arch Gen Psychiatry. 1997;54(10):953–958.
31.
GitlinMNuechterleinKSubotnikKLClinical outcome following neuroleptic discontinuation in patients with remitted recent-onset schizophrenia. Am J Psychiatry. 2001;158(11):1835–1842.
32.
LaruelleMFrankleWGNarendranRMechanism of action of antipsychotic drugs: From dopamine D(2) receptor antagonism to glutamate NMDA facilitation. Clin Ther. 2005;27(Suppl A):S16–S24.
33.
de HaanLLavalayeJLinszenDSubjective experience and striatal dopamine D(2) receptor occupancy in patients with schizophrenia stabilized by olanzapine or risperidone. Am J Psychiatry. 2000;157(6):1019–1020.
34.
MizrahiRRusjanRAgidOSubjective experience with antipsychotics and its relationship to striatal and extrastriatal D2 receptors—PET study in first episode schizophrenia. Am J Psychiatry. 2007. Forthcoming.
35.
de HaanLBooijJLavalayeJOccupancy of dopamine D2 receptors by antipsychotic drugs is related to nicotine addiction in young patients with schizophrenia. Psychopharmacology (Berl). 2006;183(4):500–505.
36.
MamoDGraffARomeyerFCentral D2 and 5HT2A occupancy of aripiprazole in patients with schizophrenia. Schizophr Res. 2006;82(Suppl):104–105.
37.
BressanRAErlandssonKJonesHMIs regionally selective D2/D3 dopamine occupancy sufficient for atypical antipsychotic effect? an in vivo quantitative [123I]epidepride SPET study of amisulpride-treated patients. Am J Psychiatry. 2003;160(8):1413–1420.
38.
BressanRAErlandssonKJonesHMOptimizing limbic selective D2/D3 receptor occupancy by risperidone: A [123I]-epidepride SPET study. J Clin Psychopharmacol. 2003;23(1):5–14.
39.
AgidOMamoDGinovartNStriatal vs extrastriatal dopamine D(2) receptors in antipsychotic response-a double-blind PET study in schizophrenia. Neuropsychopharmacology. 2006. Nov 1. Epub ahead of print.
40.
EhrinEFardeLde PaulisTPreparation of 11C-labelled Raclopride, a new potent dopamine receptor antagonist: Preliminary PET studies of cerebral dopamine receptors in the monkey. Int J Appl Radiat Isot. 1985;36(4):269–273.
41.
BlinJPappataSKiyosawaM[18F]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;147:73–82.
42.
WilsonASchmidtMGinovartNNovel radiotracers for imaging the serotonin transporter by positron emission tomography: Synthesis, radiosynthesis, in vitro and ex vivo evaluation of [11C]-labelled 2-(phenylthio) araalkylamines. J Med Chem. 2000;43(16):3103–3110.
43.
BergstromMWesterbergGKihlbergTSynthesis of some 11C-labelled MAO-A inhibitors and their in vivo uptake kinetics in rhesus monkey brain. Nucl Med Biol. 1997;24(5):381–388.
44.
MeyerJGinovartNBoovariwalaAElevated brain monoamine oxidase-a: An explanation for the monoamine imbalance of major depression. Arch Gen Psychiatry. 2006;63(11):1209–1216.
45.
MeyerJHWilsonAAGinovartNOccupancy of serotonin transporters by paroxetine and citalopram during treatment of depression: A [(11)C]DASB PET imaging study. Am J Psychiatry. 2001;158(11):1843–1849.
46.
MeyerJHWilsonAASagratiSSerotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: An [11C]DASB positron emission tomography study. Am J Psychiatry. 2004;161(5):826–835.
47.
MeyerJHMcNeelyHESagratiSElevated putamen D(2) receptor binding potential in major depression with motor retardation: An [11C]raclopride positron emission tomography study. Am J Psychiatry. 2006;163(9):1594–1602.
48.
SchildkrautJJKetySS. Biogenic amines and emotion. Science. 1967;156(771):21–37.
49.
MeltzerCPriceJMathisCPET Imaging of serotonin type 2a receptors in late-life neuropsychiatric disorders. Am J Psychiatry. 1999;156(12):1871–1878.
50.
MeyerJKapurSHouleSPrefrontal cortex 5-HT2 receptors in depression: A [18F]setoperone PET imaging study. Am J Psychiatry. 1999;156(7):1029–1034.
51.
MeyerJHMcMainSKennedySHDysfunctional attitudes and 5-HT(2) receptors during depression and self-harm. Am J Psychiatry. 2003;160(1):90–99.
52.
BhagwagarZHinzRTaylorMIncreased 5-HT(2A) receptor binding in euthymic, medication-free patients recovered from depression: A positron emission study with [(11)C]MDL 100,907. Am J Psychiatry. 2006;163(9):1580–1587.
53.
LaruelleM.Imaging synaptic neurotransmission with in vivo binding competition techniques: A critical review. J Cereb Blood Flow Metab. 2000;20(3):423–451.
54.
KorfJPraagHMV. Retarded depression and the dopamine metabolism. Psychopharmacologia. 1971;19(2):199–203.
55.
PostRMKotinJGoodwinFKPsychomotor activity and cerebrospinal fluid amine metabolites in affective illness. Am J Psychiatry. 1973;130(1):67–72.
56.
KishSJShannakKUneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease. Pathophysiologic and clinical implications. N Engl J Med. 1988;318(14):876–880.
57.
MeyerJHKrugerSWilsonAALower dopamine transporter binding potential in striatum during depression. Neuroreport. 2001;12(18):4121–4125.
58.
MeyerJHHouleSSagratiSBrain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: Effects of major depressive episodes and severity of dysfunctional attitudes. Arch Gen Psychiatry. 2004;61(12):1271–1279.
59.
BelNArtigasF.Fluvoxamine preferentially increases extracellular 5-hydroxytryptamine in the raphe nuclei: An in vivo microdialysis study. Eur J Pharmacol. 1992;229(1):101–103. Erratum. Eur J Pharmacol. 1993;232(2–3):326.
60.
AscherJAColeJOColinJNBupropion: A review of its mechanism of antidepressant activity. J Clin Psychiatry. 1995;56(9):395–401.
61.
MeyerJ.Imaging the Serotonin transporter during major depressive disorder and antidepressant treatment: CCNP Young Investigator Award paper. J Psychiatry Neurosci. 2007. Forthcoming.
62.
LeschKPWolozinBLEstlerHCIsolation of a cDNA encoding the human brain serotonin transporter. J Neural Transm Gen Sect. 1993;91(1):67–72.
63.
LeschKPWolozinBLMurphyDLPrimary structure of the human platelet serotonin uptake site: Identity with the brain serotonin transporter. J Neurochem. 1993;60(6):2319–2322.
64.
ZhouFCTao-ChengJHSeguLSerotonin transporters are located on the axons beyond the synaptic junctions: Anatomical and functional evidence. Brain Res. 1998;805(1–2):241–254.
65.
CortesRSorianoEPazosAAutoradiography of antidepressant binding sites in the human brain: Localization using [3h]imipramine and [3H]paroxetine. Neuroscience. 1988;27(2):473–496.
66.
KishSJFurukawaYChangLJRegional distribution of serotonin transporter protein in postmortem human brain: Is the cerebellum a SERT-free brain region?Nucl Med Biol. 2005;32(2):123–128.
67.
LaruelleMVanisbergM-AMaloteauxJ-M.Regional and subcellular localization in human brain of [3H]paroxetine binding, a marker of serotonin uptake sites. Biol Psychiatry. 1988;24(3):299–309.
68.
BlierPDe MontignyC.Electrophysiological investigations on the effect of repeated zimelidine administration on serotonergic neurotransmission in the rat. J Neurosci. 1983;3(6):1270–1278.
69.
BelNArtigasF.Chronic treatment with fluvoxamine increases extracellular serotonin in frontal cortex but not in raphe nuclei. Synapse. 1993;15(3):243–245.
70.
SuharaTTakanoASudoYHigh levels of serotonin transporter occupancy with low-dose clomipramine in comparative occupancy study with fluvoxamine using positron emission tomography. Arch Gen Psychiatry. 2003;60(4):386–391.
71.
FinebergNAGaleTM. Evidence-based pharmacotherapy of obsessive-compulsive disorder. Int J Neuropsychopharmacol. 2005;8(1):107–129.
72.
MeyerJHGouldingVSWilsonAABupropion occupancy of the dopamine transporter is low during clinical treatment. Psychopharmacology (Berl). 2002;163(1):102–105.
73.
Learned-CoughlinSMBergstromMSavitchevaIIn vivo activity of bupropion at the human dopamine transporter as measured by positron emission tomography. Biol Psychiatry. 2003;54(8):800–805.
74.
KugayaASenecaNMSnyderPJChanges in human in vivo serotonin and dopamine transporter availabilities during chronic antidepressant administration. Neuropsychopharmacology. 2003;28(2):413–420.
75.
BrannanTPrikhojanAMartinez-TicaJIn vivo comparison of the effects of inhibition of MAO-A versus MAO-B on striatal L-DOPA and dopamine metabolism. J Neural Transm Park Dis Dement Sect. 1995;10(2–3):79–89.
76.
ColziAd'AgostiniFKettlerREffect of selective and reversible MAO inhibitors on dopamine outflow in rat striatum: A microdialysis study. J Neural Transm Suppl. 1990;32:79–84.
77.
Canadian Study of Health and Aging: Study methods and prevalence of dementia. CMAJ. 1994;150(6):899–913.
78.
McKhannGDrachmanDFolsteinMClinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984;34(7):939–944.
79.
StevensTLivingstonGKitchenGIslington study of dementia subtypes in the community. Br J Psychiatry. 2002;180:270–276.
80.
RomanGCTatemichiTKErkinjunttiTVascular dementia: Diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology. 1993;43(2):250–260.
81.
RogersSLFriedhoffLT. Long-term efficacy and safety of donepezil in the treatment of Alzheimer's disease: An interim analysis of the results of a US multicentre open label extension study. Eur Neuropsychopharmacol. 1998;8(1):67–75.
82.
ImbimboBPVerdelliGMartelliPTwo-year treatment of Alzheimer's disease with eptastigmine. The Eptastigmine Study Group. Dement Geriatr Cogn Disord. 1999;10(2):139–147.
83.
CoyleJKershawP.Galantamine, a cholinesterase inhibitor that allosterically modulates nicotinic receptors: Effects on the course of Alzheimer's disease. Biol Psychiatry. 2001;49(3):289–299.
GeldmacherDSProvenzanoGMcRaeTDonepezil is associated with delayed nursing home placement in patients with Alzheimer's disease. J Am Geriatr Soc. 2003;51(7):937–944.
86.
Corey-BloomJAnandRVeachJA randomized trial evaluating the efficacy and safety of the ENA 713 rivastigmine tartrate, a new acetylcholineesterase inhibitor, in patients with mild to moderately severe AD. Int J Psychopharmacol. 1998;1:55–65.
87.
RaskindMAPeskindERWesselTGalantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology. 2000;54(12):2261–2268.
88.
DoodyRSGeldmacherDSGordonBOpen-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease. Arch Neurol. 2001;58(3):427–433.
89.
SilvermanDH. Brain 18F-FDG PET in the diagnosis of neurodegenerative dementias: Comparison with perfusion SPECT and with clinical evaluations lacking nuclear imaging. J Nucl Med. 2004;45(4):594–607.
90.
GambhirSSCzerninJSchwimmerJA tabulated summary of the FDG PET literature. J Nucl Med. 2001;42(5 Suppl):1S–93S.
91.
KnopmanDSDeKoskySTCummingsJLPractice parameter: Diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001;56(9):1143–1153.
92.
DougallNJBrugginkSEbmeierKP. Systematic review of the diagnostic accuracy of 99mTc-HMPAO-SPECT in dementia. Am J Geriatr Psychiatry. 2004;12(6):554–570.
93.
JagustWThistedRDevousMDSrSPECT perfusion imaging in the diagnosis of Alzheimer's disease: A clinical-pathologic study. Neurology. 2001;56(7):950–956.
94.
MessaCPeraniDLucignaniGHigh-resolution technetium-99m-HMPAO SPECT in patients with probable Alzheimer's disease: Comparison with fluorine-18-FDG PET. J Nucl Med. 1994;35(2):210–216.
95.
MielkeRPietrzykUJacobsAHMPAO SPET and FDG PET in Alzheimer's disease and vascular dementia: Comparison of perfusion and metabolic pattern. Eur J Nucl Med. 1994;21(10):1052–1060.
96.
MielkeRHeissWD. Positron emission tomography for diagnosis of Alzheimer's disease and vascular dementia. J Neural Transm Suppl. 1998;53:237–250.
97.
HerholzKSchopphoffHSchmidtMDirect comparison of spatially normalized PET and SPECT scans in Alzheimer's disease. J Nucl Med. 2002;43(1):21–26.
98.
VisvikisDRestC Cheze-LeJarrittP.PET technology: Current trends and future developments. Br J Radiol. 2004;77(923):906–910.
99.
BraakHBraakE.Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl). 1991;82(4):239–259.
100.
DelacourteADavidJPSergeantNThe biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease. Neurology. 1999;52(6):1158–1165.
101.
IqbalKAdelC AlonsoChenSTau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta. 2005;1739(2–3):198–210.
102.
HardyJSelkoeDJ. The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics. Science. 2002;297(5580):353–356.
103.
ThalDRRubUOrantesMPhases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002;58(12):1791–1800.
104.
TerryRDMasliahESalmonDPPhysical basis of cognitive alterations in Alzheimer's disease: Synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30(4):572–580.
105.
MasliahEMalloryMAlfordMAltered expression of synaptic proteins occurs early during progression of Alzheimer's disease. Neurology. 2001;56(1):127–129.
106.
Shoghi-JadidKSmallGWAgdeppaEDLocalization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry. 2002;10(1):24–35.
107.
ArnoldSEHymanBTFloryJThe topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cereb Cortex. 1991;1(1):103–116.
108.
SmallGWAgdeppaEDKepeVIn vivo brain imaging of tangle burden in humans. J Mol Neurosci. 2002;19(3):323–327.
109.
KlunkWEEnglerHNordbergAImaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol. 2004;55(3):306–319.
110.
EnglerHForsbergAAlmkvistOTwo-year follow-up of amyloid deposition in patients with Alzheimer's disease. Brain. 2006;129(Pt 11):2856–2866.
111.
MarkRJPangZGeddesJWAmyloid beta-peptide impairs glucose transport in hippocampal and cortical neurons: Involvement of membrane lipid peroxidation. J Neurosci. 1997;17(3):1046–1054.
112.
CopaniAKohJYCotmanCW. Beta-amyloid increases neuronal susceptibility to injury by glucose deprivation. Neuroreport. 1991;2(12):763–765.
113.
VerhoeffNPWilsonAATakeshitaSIn-vivo imaging of Alzheimer disease beta-amyloid with [11C]SB-13 PET. Am J Geriatr Psychiatry. 2004;12(6):584–595.
114.
MorrisJCStorandtMMcKeelDWJrCerebral amyloid deposition and diffuse plaques in “normal” aging: Evidence for presymptomatic and very mild Alzheimer's disease. Neurology. 1996;46(3):707–719.
115.
PetersenRC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004;256(3):183–194.
116.
SmallGKepeVHuangSPlaque and tangle brain imaging using [18F]FDDNP-PET differentiates Alzheimer's disease, mild cognitive impairment, and older controls. Neurobiol Aging. 2004;25(S2):S58.
117.
PriceJCKlunkWELoprestiBJKinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh compound-B. J Cereb Blood Flow Metab. 2005;25(11):1528–1547.
118.
SoricelliAPostiglioneAGrivet-FojajaMRReduced cortical distribution volume of iodine-123 iomazenil in Alzheimer's disease as a measure of loss of synapses. Eur J Nucl Med. 1996;23(10):1323–1328.
119.
NearyDSnowdenJSGustafsonLFrontotemporal lobar degeneration: A consensus on clinical diagnostic criteria. Neurology. 1998;51(6):1546–1554.
