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Cited by 967Schizophrenia research and treatmentNeurotransmitter Receptor Influence on BehaviorMental Health and Psychiatry

The Nature of Dopamine Dysfunction in Schizophrenia and What This Means for Treatment: Meta-analysis of Imaging Studies

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Howes, Oliver D., Kambeitz, Joseph, Kim, Euitae, Stahl, Daniel, Slifstein, Mark, Abi-Dargham, Anissa, Kapur, Shitij·2012·Archives of General Psychiatry
DOI 10.1001/archgenpsychiatry.2012.169PMC PMC3730746
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Abstract

CONTEXT: Current drug treatments for schizophrenia are inadequate for many patients, and despite 5 decades of drug discovery, all of the treatments rely on the same mechanism: dopamine D(2) receptor blockade. Understanding the pathophysiology of the disorder is thus likely to be critical to the rational development of new treatments for schizophrenia. OBJECTIVE: To investigate the nature of the dopaminergic dysfunction in schizophrenia using meta-analysis of in vivo studies. DATA SOURCES: The MEDLINE, EMBASE, and PsycINFO databases were searched for studies from January 1, 1960, to July 1, 2011. STUDY SELECTION: A total of 44 studies were identified that compared 618 patients with schizophrenia with 606 controls, using positron emission tomography or single-photon emission computed tomography to measure in vivo striatal dopaminergic function. DATA EXTRACTION: Demographic, clinical, and imaging variables were extracted from each study, and effect sizes were determined for the measures of dopaminergic function. Studies were grouped into those of presynaptic function and those of dopamine transporter and receptor availability. Sensitivity analyses were conducted to explore the consistency of effects and the effect of clinical and imaging variables. DATA SYNTHESIS: There was a highly significant elevation (P.<001) in presynaptic dopaminergic function in schizophrenia with a large effect size (Cohen d=0.79). There was no evidence of alterations in dopamine transporter availability. There was a small elevation in D(2/3) receptor availability (Cohen d=0.26), but this was not evident in drug-naive patients and was influenced by the imaging approach used. CONCLUSIONS: The locus of the largest dopaminergic abnormality in schizophrenia is presynaptic, which affects dopamine synthesis capacity, baseline synaptic dopamine levels, and dopamine release. Current drug treatments, which primarily act at D(2/3) receptors, fail to target these abnormalities. Future drug development should focus on the control of presynaptic dopamine synthesis and release capacity.

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  1. [1]1. Rossler W, Salize HJ, van Os J, Riecher-Rossler A. Size of burden of schizophrenia and psychotic disorders. Eur Neuropsychopharmacol. 2005; 15(4):399-409. [PubMed: 15925493]
  2. [2]2. Lewis DA, Gonzalez-Burgos G. Pathophysiologically based treatment interventions in schizophrenia. Nat Med. 2006; 12(9):1016-1022. [PubMed: 16960576]
  3. [3]3. McGuire P, Howes OD, Stone J, Fusar-Poli P. Functional neuroimaging in schizophrenia: diagnosis and drug discovery. Trends Pharmacol Sci. 2008; 29(2):91-98. [PubMed: 18187211]
  4. [4]4. Mackay AV, Iversen LL, Rossor M, Spokes E, Bird E, Arregui A, Creese I, Synder SH. Increased brain dopamine and dopamine receptors in schizophrenia. Arch Gen Psychiatry. 1982; 39(9):991997. [PubMed: 7115016]
  5. [5]5. Lee T, Seeman P. Elevation of brain neuroleptic/dopamine receptors in schizophrenia. Am J Psychiatry. 1980; 137(2):191-197. [PubMed: 6101525]
  6. [6]6. Bird ED, Spokes EG, Iversen LL. Increased dopamine concentration in limbic areas of brain from patients dying with schizophrenia. Brain. 1979; 102(2):347-360. [PubMed: 455044]
  7. [7]7. Zakzanis KK, Hansen KT. Dopamine D2 densities and the schizophrenic brain. Schizophr Res. 1998; 32(3):201-206. [PubMed: 9720125]
  8. [8]8. Widerlov E. A critical appraisal of CSF monoamine metabolite studies in schizophrenia. Ann N Y Acad Sci. 1988; 537:309-323. [PubMed: 2462396]
  9. [9]9. Howes OD, Egerton A, Allan V, McGuire P, Stokes P, Kapur S. Mechanisms underlying psychosis and antipsychotic treatment response in schizophrenia: insights from PET and SPECT imaging. Curr Pharm Des. 2009; 15(22):2550-2559. [PubMed: 19689327]
  10. [10]10. Lyon GJ, Abi-Dargham A, Moore H, Lieberman JA, Javitch JA, Sulzer D. Presynaptic Regulation of Dopamine Transmission in Schizophrenia. Schizophr Bull. 2011; 37(1):108-17. [PubMed: 19525353]
  11. [11]11. Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry. 1991; 148(11):1474-1486. [PubMed: 1681750]
  12. [13]13. Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III--the final common pathway. Schizophr Bull. 2009; 35(3):549-562. [PubMed: 19325164]
  13. [14]14. Farde L, Wiesel FA, Stone-Elander S, Halldin C, Nordstrom AL, Hall H, Sedvall G. D2 dopamine receptors in neuroleptic-naive schizophrenic patients. A positron emission tomography study with [11C]raclopride. Arch Gen Psychiatry. 1990; 47(3):213-219. [PubMed: 1968328]
  14. [15]15. Wong DF, Wagner HN Jr. Tune LE, Dannals RF, Pearlson GD, Links JM, Tamminga CA, Broussolle EP, Ravert HT, Wilson AA, Toung JK, Malat J, Williams JA, O'Tuama LA, Snyder SH, Kuhar MJ, Gjedde A. Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. Science. 1986; 234(4783):1558-1563. [PubMed: 2878495]
  15. [17]17. Laruelle M, Abi-Dargham A. Dopamine as the wind of the psychotic fire: new evidence from brain imaging studies. J Psychopharmacol. 1999; 13(4):358-371. [PubMed: 10667612] <!-- image --> <!-- image -->
  16. [18]18. Meisenzahl EM, Schmitt GJ, Scheuerecker J, Moller HJ. The role of dopamine for the pathophysiology of schizophrenia. Int Rev Psychiatry. 2007; 19(4):337-345. [PubMed: 17671867]
  17. [19]19. Reith J, Benkelfat C, Sherwin A, Yasuhara Y, Kuwabara H, Andermann F, Bachneff S, Cumming P, Diksic M, Dyve SE, Etienne P, Evans AC, Lal S, Shevell M, Savard G, Wong DF, Chouinard G, Gjedde A. Elevated dopa decarboxylase activity in living brain of patients with psychosis. Proc Natl Acad Sci U.S.A. 1994; 91(24):11651-11654. [PubMed: 7972118]
  18. [20]20. Laruelle M. Imaging dopamine transmission in schizophrenia. A review and meta-analysis. Q J Nucl.Med. 1998; 42(3):211-221. [PubMed: 9796369]
  19. [22]22. Egerton A, Demjaha A, McGuire P, Mehta MA, Howes OD. The test-retest reliability of 18FDOPA PET in assessing striatal and extrastriatal presynaptic dopaminergic function. Neuroimage. 2009; 50(2):524-531. [PubMed: 20034580]
  20. [23]23. Mawlawi O, Martinez D, Slifstein M, Broft A, Chatterjee R, Hwang DR, Huang Y, Simpson N, Ngo K, Van Heertum R, Laruelle M. Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D(2) receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab. 2001; 21(9):1034-1057. [PubMed: 11524609]
  21. [25]25. Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry. 1999; 46(1):56-72. [PubMed: 10394474]
  22. [26]26. Doudet DJ, Holden JE. Raclopride studies of dopamine release: dependence on presynaptic integrity. Biol Psychiatry. 2003; 54(11):1193-1199. [PubMed: 14643086]
  23. [27]27. Cumming P, Boyes BE, Martin WR, Adam M, Grierson J, Ruth T, McGeer EG. The metabolism of [18F]6-fluoro-L-3,4-dihydroxyphenylalanine in the hooded rat. J Neurochem. 1987; 48(2):601608. [PubMed: 3098920]
  24. [28]28. Matsumura K, Bergström M, Onoe H, Takechi H, Westerberg G, Antoni G, Bjurling P, Jacobson GB, Långström B, Watanabe Y. In vitro positron emission tomography (PET): use of positron emission tracers in functional imaging in living brain slices. Neurosci Res. 1995; 22(2):219-229. [PubMed: 7566703]
  25. [29]29. Piccini P, Pavese N, Brooks DJ. Endogenous dopamine release after pharmacological challenges in Parkinson's disease. Ann Neurol. 2003; 53(5):647-653. [PubMed: 12730999]
  26. [30]30. Farde L, Wiesel FA, Halldin C, Sedvall G. Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch.Gen.Psychiatry. 1988; 45(1):71-76. [PubMed: 2892477]
  27. [31]31. Hedges, LV.; Olkin, L. Statistical methods for meta-analysis. Academic Press; San Diego, CA: 1985.
  28. [36]36. Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, Weiss R, Cooper TB, Mann JJ, Van Heertum RL, Gorman JM, Laruelle M. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A. 2000; 97(14):8104-8109. [PubMed: 10884434] <!-- image --> <!-- image -->
  29. [37]37. Shotbolt P, Stokes PR, Owens SF, Toulopoulou T, Picchioni MM, Bose SK, Murray RM, Howes OD. Striatal dopamine synthesis capacity in twins discordant for schizophrenia. Psychol Med. 2011; 41(11):2331-2338. [PubMed: 21426628]
  30. [38]38. Tune LE, Wong DF, Pearlson G, Strauss M, Young T, Shaya EK, Dannals RF, Wilson AA, Ravert HT, Sapp J, Cooper T, Chase GA, Wagner HN. Dopamine D2 receptor density estimates in schizophrenia: a positron emission tomography study with 11C-N-methylspiperone. Psychiatry Res. 1993; 49(3):219-237. [PubMed: 7909948]
  31. [39]39. Knable MB, Egan MF, Heinz A, Gorey J, Lee KS, Coppola R, Weinberger DR. Altered dopaminergic function and negative symptoms in drug-free patients with schizophrenia. [123I]iodobenzamide SPECT study. Br J Psychiatry. 1997; 171:574-577. [PubMed: 9519100]
  32. [40]40. Abi-Dargham A, Mawlawi O, Lombardo I, Gil R, Martinez D, Huang Y, Hwang DR, Keilp J, Kochan L, Van Heertum R, Gorman JM, Laruelle M. Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci. 2002; 22(9):3708-3719. [PubMed: 11978847]
  33. [41]41. Karlsson P, Farde L, Halldin C, Sedvall G. PET study of D(1) dopamine receptor binding in neuroleptic-naive patients with schizophrenia. Am J Psychiatry. 2002; 159(5):761-767. [PubMed: 11986129]
  34. [42]42. Okubo Y, Suhara T, Suzuki K, Kobayashi K, Inoue O, Terasaki O, Someya Y, Sassa T, Sudo Y, Matsushima E, Iyo M, Tateno Y, Toru M. Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature. 1997; 385(6617):634-636. [PubMed: 9024661]
  35. [43]43. Abi-Dargham A, Xu X, Thompson JL, Gil R, Kegeles LS, Urban NB, Narendran R, Hwang DR, Laruelle M, Slifstein M. Increased prefrontal cortical D1 receptors in drug naive patients with schizophrenia: a PET study with [11C]NNC112. J Psychopharmacology. Jul 18.2011 [Epub ahead of print] PMID: 21768159.
  36. [44]44. Kumakura Y, Cumming P. PET studies of cerebral levodopa metabolism: a review of clinical findings and modeling approaches. Neuroscientist. 2009; 15(6):635-650. [PubMed: 19793723]
  37. [45]45. Elkashef AM, Doudet D, Bryant T, Cohen RM, Li SH, Wyatt RJ. 6-(18)F-DOPA PET study in patients with schizophrenia. Positron emission tomography. Psychiatry Res. 2000; 100(1):1-11. [PubMed: 11090720]
  38. [46]46. Taylor SF, Koeppe RA, Tandon R, Zubieta JK, Frey KA. In vivo measurement of the vesicular monoamine transporter in schizophrenia. Neuropsychopharmacology. 2000; 23(6):667-675. [PubMed: 11063922]
  39. [47]47. Zubieta JK, Taylor SF, Huguelet P, Koeppe RA, Kilbourn MR, Frey KA. Vesicular monoamine transporter concentrations in bipolar disorder type I, schizophrenia, and healthy subjects. Biol Psychiatry. 2001; 49(2):110-116. [PubMed: 11164757]
  40. [48]48. Bogerts B, Hantsch J, Herzer M. A morphometric study of the dopamine-containing cell groups in the mesencephalon of normals, Parkinson patients, and schizophrenics. Biol Psychiatry. 1983; 18(9):951-969. [PubMed: 6640008]
  41. [49]49. Kumakura Y, Cumming P, Vernaleken I, Buchholz HG, Siessmeier T, Heinz A, Kienast T, Bartenstein P, Gründer G. Elevated [18F]fluorodopamine turnover in brain of patients with schizophrenia: an [18F]fluorodopa/positron emission tomography study. J Neurosci. 2007; 27(30): 8080-8087. [PubMed: 17652599]
  42. [50]50. Wong DF, Gjedde A, Wagner HN Jr. Quantification of neuroreceptors in the living human brain. I. Irreversible binding of ligands. J Cereb Blood Flow Metab. 1986; 6(2):137-146. [PubMed: 2937794]
  43. [51]51. Ishiwata K, Ogi N, Hayakawa N, Umegaki H, Nagaoka T, Oda K, Toyama H, Endo K, Tanaka A, Senda M. Positron emission tomography and ex vivo and in vitro autoradiography studies on dopamine D2-like receptor degeneration in the quinolinic acid-lesioned rat striatum: comparison of [11C]raclopride, [11C]nemonapride and [11C]N-methylspiperone. Nucl Med Biol. 2002; 29(3): 307-316. [PubMed: 11929700]
  44. [52]52. Ishiwata K, Hayakawa N, Ogi N, Oda K, Toyama H, Endo K, Tanaka A, Senda M. Comparison of three PET dopamine D2-like receptor ligands, [11C]raclopride, [11C]nemonapride and [11C]Nmethylspiperone, in rats. Ann Nucl Med. 1999; 13(3):161-167. [PubMed: 10435376] <!-- image --> <!-- image -->
  45. [53]53. Bischoff S, Gunst F. Distinct binding patterns of [3H]raclopride and [3H]spiperone at dopamine D2 receptors in vivo in rat brain. Implications for pet studies. J Recept Signal Transduct Res. 1997; 17(1-3):419-431. [PubMed: 9029505]
  46. [54]54. Chugani DC, Ackermann RF, Phelps ME. In vivo [3H]spiperone binding: evidence for accumulation in corpus striatum by agonist-mediated receptor internalization. J Cereb Blood Flow Metab. 1988; 8(3):291-303. [PubMed: 2966803]
  47. [56]56. Guo N, Guo W, Kralikova M, Jiang M, Schieren I, Narendran R, Slifstein M, Abi-Dargham A, Laruelle M, Javitch JA, Rayport S. Impact of D2 receptor internalization on binding affinity of neuroimaging radiotracers. Neuropsychopharmacology. 2010; 35(3):806-817. [PubMed: 19956086]
  48. [57]57. Hartvig P, Torstenson R, Tedroff J, Watanabe Y, Fasth KJ, Bjurling P, Långström B. Amphetamine effects on dopamine release and synthesis rate studied in the Rhesus monkey brain by positron emission tomography. J Neural Transm. 1997; 104(4-5):329-339. [PubMed: 9295169]
  49. [58]58. Snyder SH. The dopamine hypothesis of schizophrenia: focus on the dopamine receptor. Am J Psychiatry. 1976; 133(2):197-202. [PubMed: 1251927]
  50. [61]61. Fusar-Poli P, Howes OD, Allen P, Broome M, Valli I, Asselin MC, Grasby PM, McGuire PK. Abnormal frontostriatal interactions in people with prodromal signs of psychosis: a multimodal imaging study. Arch Gen Psychiatry. 2010; 67(7):683-691. [PubMed: 20603449]
  51. [63]63. Kegeles LS, Abi-Dargham A, Zea-Ponce Y, Rodenhiser-Hill J, Mann JJ, Van Heertum RL, Cooper TB, Carlsson A, Laruelle M. Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia. Biol Psychiatry. 2000; 48(7):627-640. [PubMed: 11032974]
  52. [64]64. Lodge DJ, Grace AA. Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia. J Neurosci. 2007; 27(42):11424-11430. [PubMed: 17942737]
  53. [65]65. Stone JM, Howes OD, Egerton A, Kambeitz J, Allen P, Lythgoe DJ, O'Gorman RL, McLean MA, Barker GJ, McGuire P. Relationship between glutamate and dopamine in individuals with prodromal symptoms of schizophrenia. Biol Psychiatry. 2010; 68(7):599-602. [PubMed: 20638047]
  54. [66]66. Staley JK, Krishnan-Sarin S, Zoghbi S, Tamagnan G, Fujita M, Seibyl JP, Maciejewski PK, O'Malley S, Innis RB. Sex differences in [123I]beta-CIT SPECT measures of dopamine and serotonin transporter availability in healthy smokers and nonsmokers. Synapse. 2001; 41(4):275284. [PubMed: 11494398]
  55. [67]67. Howes OD, Montgomery AJ, Asselin MC, Murray RM, Valli I, Tabraham P, Bramon-Bosch E, Valmaggia L, Johns L, Broome M, McGuire PK, Grasby PM. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry. 2009; 66(1):13-20. [PubMed: 19124684]
  56. [69]69. Seeman P, Lee T, Chau-Wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature. 1976; 261(5562):717-719. [PubMed: 945467] <!-- image --> <!-- image -->
  57. [70]70. Ginovart N, Wilson AA, Hussey D, Houle S, Kapur S. D2-receptor upregulation is dependent upon temporal course of D2-occupancy: a longitudinal [11C]-raclopride PET study in cats. Neuropsychopharmacology. 2009; 34(3):662-671. [PubMed: 18688210]
  58. [71]71. Silvestri S, Seeman MV, Negrete JC, Houle S, Shammi CM, Remington GJ, Kapur S, Zipursky RB, Wilson AA, Christensen BK, Seeman P. Increased dopamine D2 receptor binding after longterm treatment with antipsychotics in humans: a clinical PET study. Psychopharmacology. 2000; 152(2):174-180. [PubMed: 11057521]
  59. [72]72. Hollister LE, Krieger GE, Kringel A, Roberts RH. Treatment of chronic schizophrenic reactions with reserpine. Ann N Y Acad Sci. 1955; 61(1):92-100. [PubMed: 14377276]
  60. [75]75. Tamminga CA, Schaffer MH, Smith RC, Davis JM. Schizophrenic symptoms improve with apomorphine. Science. 1978; 200(4341):567-568. [PubMed: 347574]
  61. [76]76. Graff-Guerrero A, Mizrahi R, Agid O, Marcon H, Barsoum P, Rusjan P, Wilson AA, Zipursky R, Kapur S. The dopamine D2 receptors in high-affinity state and D3 receptors in schizophrenia: a clinical [11C]-(+)-PHNO PET study. Neuropsychopharmacology. 2009; 34(4):1078-1086. [PubMed: 18987627]
  62. [77]77. Heinz A, Saunders RC, Kolachana BS, Jones DW, Gorey JG, Bachevalier J, Weinberger DR. Striatal dopamine receptors and transporters in monkeys with neonatal temporal limbic damage. Synapse. 1999; 32(2):71-79. [PubMed: 10231127] <!-- image --> <!-- image -->

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Authors
Howes, O. D., Kambeitz, J., Kim, E., Stahl, D., Slifstein, M., Abi-Dargham, A., & Kapur, S.
Affiliations
  • King's College London (GB)
  • New York Psychoanalytic Society and Institute (US)
ORCID
Venue
Archives of General Psychiatry
Publisher
American Medical Association (AMA)
Published
2012-08-01
Volume
69
Issue
8
Pages
776-86
ISSN
0003-990X (ISSN-L)
DOI
10.1001/archgenpsychiatry.2012.169
PMC
PMC3730746
OpenAlex
W1518890501
Cited by
967
References
11
Citations by year
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FWCI
53.91
Type
journal article
Language
en
Open access
Locations
  • Archives of General Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Research Portal (King's College London) (submittedVersion, other-oa)
Funders
  • Medical Research Council
  • Biomedical Research Council
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Social Sciences › Arts and Humanities › Philosophy › Mental Health and Psychiatry
Keywords
schizophrenia, dopaminergic dysfunction, dopamine transporter availability, striatal dopamine synthesis, dopamine release, dopamine synthesis capacity
MeSH terms
Biological Availability, Brain, Dopamine, Humans, Neuropharmacology, Receptors, Dopamine, Schizophrenia, Drug Design, Tomography, Emission-Computed, Single-Photon, Presynaptic Terminals, Neurotransmitter Agents, Dopamine Antagonists, Dopamine Plasma Membrane Transport Proteins

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