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Imaging genomics and response to treatment with antipsychotics in schizophrenia

NeuroRX volume 3, pages 117–130 (2006)Cite this article

Abstract

Recent important advancements in genomic research have opened the way to new strategies for public health management. One of these questions pertains to how individual genetic variation may be associated with individual variability in response to drug treatment. The field of pharmacogenetics may have a profound impact on treatment of complex psychiatric disorders like schizophrenia. However, pharmacogenetic studies in schizophrenia have produced conflicting results. The first studies examined potential associations between clinical response and drug receptor genes. Subsequent studies have tried to use more objective phenotypes still in association with drug receptor genes. More recently, other studies have sought the association between putative causative or modifier genes and intermediate phenotypes. Thus, conflicting results may be at least in part explained by variability and choice of the phenotype, by choice of candidate genes, or by the relatively little knowledge about the neurobiology of this disorder. We propose that choosing intermediate phenotypes that allow in vivo measurement of specific neuronal functions may be of great help in reducing several of the potential confounds intrinsic to clinical measurements. Functional neuroimaging is ideally suited to address several of these potential confounds, and it may represent a powerful strategy to investigate the relationship between behavior, brain function, genes, and individual variability in the response to treatment with antipsychotic drugs in schizophrenia. Preliminary evidence with potential susceptilibity genes such as COMT, DISC1, and GRM3 support these assumptions.

References

  1. McGuffin P, Riley B, Plomin R. Genomics and behavior. Toward behavioral genomics. Science 5507: 1232–1249, 2001.

    Article  Google Scholar 

  2. Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 1: 40–68, 2005.

    Article  CAS  Google Scholar 

  3. Lewis CM, Levinson DF, Wise LH, Delisi LE, Straub RE, Hovatta I, et al. Genome scan meta-analysis of schizophrenia and bipolar disorder. Part II: schizophrenia. Am J Hum Genet 1: 34–48, 2003.

    Article  Google Scholar 

  4. Badner JA, Gershon ES. Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 4: 405–411, 2002.

    Article  Google Scholar 

  5. Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 7: 660–669, 1987.

    Article  Google Scholar 

  6. Sesack SR, Hawrylak VA, Matus C, Guido MA, Levey AI. Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter. J Neurosci 7: 2697–2708, 1998.

    Google Scholar 

  7. Moron JA, Brockington A, Wise RA, Rocha BA, Hope BT. Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines. J Neurosci 2: 389–395, 2002.

    Google Scholar 

  8. Shen HW, Hagino Y, Kobayashi H, Shinohara-Tanaka K, Ikeda K, Yamamoto H, et al. Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters. Neuropsychopharmacology 10: 1790–1799, 2004.

    Article  CAS  Google Scholar 

  9. Tunbridge EM, Bannerman DM, Sharp T, Harrison PJ. Catecholo-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J Neurosci 23: 5331–5335, 2004.

    Article  CAS  Google Scholar 

  10. Liljequist R, Haapalinna A, Ahlander M, Li YH, Mannisto PT. Catechol O-methyltransferase inhibitor tolcapone has minor influence on performance in experimental memory models in rats. Behav Brain Res 2: 195–202, 1997.

    Article  Google Scholar 

  11. Gogos JA, Morgan M, Luine V, Santha M, Ogawa S, Pfaff D, et al. Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci USA 17: 9991–9996, 1998.

    Article  Google Scholar 

  12. Mannisto PT, Kaakkola S. Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev 4: 593–628, 1999.

    Google Scholar 

  13. Seamans JK, Yang CR. The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol 1: 1–58, 2004.

    Article  CAS  Google Scholar 

  14. Goldman-Rakic PS. The cortical dopamine system: role in memory and cognition. Adv Pharmacol 707–711, 1998.

  15. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 12: 6917–6922, 2001.

    Article  Google Scholar 

  16. Goldberg TE, Egan MF, Gscheidle T, Coppola R, Weickert T, Kolachana BS, et al. Executive subprocesses in working memory: relationship to catechol-O-methyltransferase Vall58Met genotype and schizophrenia. Arch Gen Psychiatry 9: 889–896, 2003.

    Article  Google Scholar 

  17. Blasi G, Mattay VS, Bertolino A, Elvevag B, Callicott JH, Das S, et al. Effect of catechol-O-methyltransferase val158met genotype on attentional control. J Neurosci 20: 5038–5045, 2005.

    Article  CAS  Google Scholar 

  18. Bearden CE, Jawad AF, Lynch DR, Sokol S, Kanes SJ, McDonald-McGinn DM, et al. Effects of a functional COMT polymorphism on prefrontal cognitive function in patients with 22ql 1.2 deletion syndrome. Am J Psychiatry 9: 1700–1702, 2004.

    Article  Google Scholar 

  19. Diamond A, Briand L, Fossella J, Gehlbach L. Genetic and neurochemical modulation of prefrontal cognitive functions in children. Am J Psychiatry 1: 125–132, 2004.

    Article  Google Scholar 

  20. Callicott JH, Bertolino A, Mattay VS, Langheim FJ, Duyn J, Coppola R, et al. Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. Cereb Cortex 11: 1078–1092, 2000.

    Article  Google Scholar 

  21. Manoach DS, Gollub RL, Benson ES, Searl MM, Goff DC, Halpern E, et al. Schizophrenic subjects show aberrant fMRI activation of dorsolateral prefrontal cortex and basal ganglia during working memory performance. Biol Psychiatry 2: 99–109, 2000.

    Article  Google Scholar 

  22. Bertolino A, Caforio G, Blasi G, De Candia M, Latorre V, Petruzzella V, et al. Interaction of COMT Vall08/158 Met genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. Am J Psychiatry 10: 1798–1805, 2004.

    Article  Google Scholar 

  23. Ho BC, Wassink TH, O’Leary DS, Sheffield VC, Andreasen NC. Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow. Mol Psychiatry 3: 229: 287–298, 2005.

    Article  CAS  Google Scholar 

  24. St Clair D, Blackwood D, Muir W, Carothers A, Walker M, Spowart G, et al. Association within a family of a balanced autosomal translocation with major mental illness. Lancet 8706: 13–16, 1990.

    Article  Google Scholar 

  25. Devon RS, Anderson S, Teague PW, Burgess P, Kipari TM, Semple CA, et al. Identification of polymorphisms within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2, and an investigation of their association with schizophrenia and bipolar affective disorder. Psychiatr Genet 2: 71–78, 2001.

    Article  Google Scholar 

  26. Hennah W, Varilo T, Kestila M, Paunio T, Arajarvi R, Haukka J, et al. Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. Hum Mol Genet 23: 3151–3159, 2003.

    Article  CAS  Google Scholar 

  27. Ekelund J, Hennah W, Hiekkalinna T, Parker A, Meyer J, Lonnqvist J, et al. Replication of 1q42 linkage in Finnish schizophrenia pedigrees. Mol Psychiatry 11: 1037–1041, 2004.

    Article  CAS  Google Scholar 

  28. Hodgkinson CA, Goldman D, Jaeger J, Persaud S, Kane JM, Lipsky RH, et al. Disrupted in Schizophrenia 1 (DISC1): association with schizophrenia, schizoaffective disorder, and bipolar disorder. Am J Hum Genet 5: 862–872, 2004.

    Article  Google Scholar 

  29. Sachs NA, Sawa A, Holmes SE, Ross CA, Delisi LE, Margolis RL. A frameshift mutation in disrupted in schizophrenia 1 in an American family with schizophrenia and schizo affective disorder. Mol Psychiatry 10: 758–764, 2005.

    PubMed  CAS  Article  Google Scholar 

  30. Thomson PA, Wray NR, Millar JK, Evans KL, Hellard SL, Condie A, et al. Association between the TRAX/DISC locus and both bipolar disorder and schizophrenia in the Scottish population. Mol Psychiatry 7: 616, 657–668, 2005.

    Article  CAS  Google Scholar 

  31. Morris JA, Kandpal G, Ma L, Austin CP. DISC1 (Disrupted-In-Schizophrenia 1) is a centra some-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. Hum Mol Genet 13: 1591–1608, 2003.

    Article  Google Scholar 

  32. Austin CP, Ky B, Ma L, Morris JA, Shughrue PJ. Expression of Disrupted-In-Schizophrenia-1, a schizophrenia-associated gene, is prominent in the mouse hippocampus throughout brain development. Neuroscience 1: 3–10, 2004.

    Article  CAS  Google Scholar 

  33. Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR, et al. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci USA 24: 8627–8632, 2005.

    Article  CAS  Google Scholar 

  34. Bunney BS, Chiodo LA, Grace AA. Midbrain dopamine system electro physiological functioning: a review and new hypothesis. Synapse 2: 79–94, 1991.

    Article  Google Scholar 

  35. Deakin JF, Slater P, Simpson MD, Gilchrist AC, Skan WJ, Royston MC, et al. Frontal cortical and left temporal glutamatergic dysfunction in schizophrenia. J Neurochem 6: 1781–1786, 1989.

    Article  Google Scholar 

  36. Nishikawa T, Takashima M, Toru M. Increased [3H]kainic acid binding in the prefrontal cortex in schizophrenia. Neurosci Lett 3: 245–250, 1983.

    Article  Google Scholar 

  37. Tsai G, Passani LA, Slusher BS, Carter R, Baer L, Kleinman JE, et al. Abnormal excitatory neurotransmitter metabolism in schizophrenic brains. Arch Gen Psychiatry 10: 829–836, 1995.

    Article  Google Scholar 

  38. Cartmell J, Schoepp DD. Regulation of neurotransmitter release by metabotropic glutamate receptors. J Neurochem 3: 889–907, 2000.

    Google Scholar 

  39. Aronica E, Goiter JA, Ijlst-Keizers H, Rozemuller AJ, Yankaya B, Leenstra S, et al. Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins. Eur J Neurosci 10: 2106–2118, 2003.

    Article  Google Scholar 

  40. Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 3: 675–686, 1996.

    Article  Google Scholar 

  41. Moghaddam B, Adams BW. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 5381: 1349–1352, 1998.

    Article  Google Scholar 

  42. Ohnuma T, Tessler S, Arai H, Faull RL, McKenna PJ, Emson PC. Gene expression of metabotropic glutamate receptor 5 and excitatory amino acid transporter 2 in the schizophrenic hippocampus. Brain Res Mol Brain Res 1–2: 24–31, 2000.

    Article  Google Scholar 

  43. Egan MF, Straub RE, Goldberg TE, Yakub I, Callicott JH, Hariri AR, et al. Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia. Proc Natl Acad Sci USA 34: 12604–12609, 2004.

    Article  Google Scholar 

  44. Fujii Y, Shibata H, Kikuta R, Makino C, Tani A, Hirata N, et al. Positive associations of polymorphisms in the metabotropic glutamate receptor type 3 gene (GRM3) with schizophrenia. Psychiatr Genet 2: 71–16, 2003.

    Google Scholar 

  45. Chen Q, He G, Wu S, Xu Y, Feng G, Li Y, et al. A case-control study of the relationship between the metabotropic glutamate receptor 3 gene and schizophrenia in the Chinese population. Schizophr Res 1: 21–26, 2005.

    Article  Google Scholar 

  46. Bertolino A, Nawroz S, Mattay VS, Barnett AS, Duyn JH, Moonen CT, et al. Regionally specific pattern of neurochemical pathology in schizophrenia as assessed by multislice proton magnetic resonance spectroscopic imaging. Am J Psychiatry 12: 1554–1563, 1996.

    Google Scholar 

  47. Marti SB, Cichon S, Propping P, Nothen M. Metabotropic glutamate receptor 3 (GRM3) gene variation is not associated with schizophrenia or bipolar affective disorder in the German population. Am J Med Genet 1: 46–50, 2002.

    Article  Google Scholar 

  48. Norton N, Williams HJ, Dwyer S, Ivanov D, Preece AC, Gerrish A, et al. No evidence for association between polymorphisms in GRM3 and schizophrenia. BMC Psychiatry 1: 23, 2005.

    Article  CAS  Google Scholar 

  49. Lu B, Gottschalk W. Modulation of hippocampal synaptic transmission and plasticity by neurotrophins. Prog Brain Res 128: 231–241, 2000.

    PubMed  CAS  Article  Google Scholar 

  50. Poo MM. Neurotrophins as synaptic modulators. Nat Rev Neurosci 1: 24–32, 2001.

    Article  CAS  Google Scholar 

  51. Gottschalk W, Pozzo-Miller LD, Figurov A, Lu B. Presynaptic modulation of synaptic transmission and plasticity by brain-derived neurotrophic factor in the developing hippocampus. J Neurosci 17: 6830–6839, 1998.

    Google Scholar 

  52. Gottschalk WA, Jiang H, Tartaglia N, Feng L, Figurov A, Lu B. Signaling mechanisms mediating BDNF modulation of synaptic plasticity in the hippocampus. Learn Mem 3: 243–256, 1999.

    Google Scholar 

  53. Jovanovic JN, Czernik AJ, Fienberg AA, Greengard P, Sihra TS. Synapsins as mediators of BDNF-enhanced neurotransmitter release. Nat Neurosci 4: 323–329, 2000.

    Google Scholar 

  54. Pozzo-Miller LD, Gottschalk W, Zhang L, McDermott K, Du J, Gopalakrishnan R, et al. Impairments in high-frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. J Neurosci 12: 4972–4983, 1999.

    Google Scholar 

  55. Xu B, Gottschalk W, Chow A, Wilson RI, Schnell E, Zang K, et al. The role of brain-derived neurotrophic factor receptors in the mature hippocampus: modulation of long-term potentiation through a presynaptic mechanism involving TrkB. J Neurosci 18: 6888–6897, 2000.

    Google Scholar 

  56. Linnarsson S, Bjorklund A, Ernfors P. Learning deficit in BDNF mutant mice. Eur J Neurosci 12: 2581–2587, 1997.

    Article  Google Scholar 

  57. Minichiello L, Korte M, Wolfer D, Kuhn R, Unsicker K, Cestari V, et al. Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 2: 401–414, 1999.

    Article  Google Scholar 

  58. Mizuno M, Yamada K, Olariu A, Nawa H, Nabeshima T. Involvement of brain-derived neurotrophic factorin spatial memory formation and maintenance in a radial arm maze test in rats. J Neurosci 18: 7116–7121, 2000.

    Google Scholar 

  59. Angelucci F, Brene S, Mathe AA. BDNF in schizophrenia, depression and corresponding animal models. Mol Psychiatry 4: 345–352, 2005.

    Article  CAS  Google Scholar 

  60. Callicott JH, Egan MF, Bertolino A, Mattay VS, Langheim FJ, Frank JA, et al. Hippocampal N-acetyl aspartate in unaffected siblings of patients with schizophrenia: a possible intermediate neurobiological phenotype. Biol Psychiatry 10: 941–950, 1998.

    Article  Google Scholar 

  61. Hattori M, Kunugi H, Akahane A, Tanaka H, Ishida S, Hirose T, et al. Novel polymorphisms in the promoter region of the neurotrophin-3 gene and their associations with schizophrenia. Am J Med Genet 3: 304–309, 2002.

    Article  Google Scholar 

  62. Jonsson E, Brene S, Zhang XR, Nimgaonkar VL, Tylec A, Schalling M, et al. Schizophrenia and neurotrophin-3 alleles. Acta Psychiatr Scand 5: 414–419, 1997.

    Article  Google Scholar 

  63. Szekeres G, Juhasz A, Rimanoczy A, Keri S, Janka Z. The C270T polymorphism of the brain-derived neurotrophic factor gene is associated with schizophrenia. Schizophr Res 1: 15–18, 2003.

    Article  Google Scholar 

  64. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2: 257–269, 2003.

    Article  Google Scholar 

  65. Neves-Pereira M, Cheung JK, Pasdar A, Zhang F, Breen G, Yates P, et al. BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol Psychiatry 2: 208–212, 2005.

    Article  CAS  Google Scholar 

  66. Szczepankiewicz A, Skibinska M, Czerski PM, Kapelski P, Leszczynska-Rodziewicz A, Slopien A, et al. No association of the brain-derived neurotrophic factor (BDNF) gene C-270T polymorphism with schizophrenia. Schizophr Res 2–3: 187–193, 2005.

    Article  Google Scholar 

  67. de Krom M, Bakker SC, Hendriks J, van Elburg A, Hoogendoorn M, Verduijn W, et al. Polymorphisms in the brain-derived neurotrophic factor gene are not associated with either anorexia nervosa or schizophrenia in Dutch patients. Psychiatr Genet 2: 81, 2005.

    Article  Google Scholar 

  68. Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF, et al. Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci 17: 6690–6694, 2003.

    Google Scholar 

  69. Pezawas L, Verchinski BA, Mattay VS, Callicott JH, Kolachana BS, Straub RE, et al. The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci 45: 10099–10102, 2004.

    Article  CAS  Google Scholar 

  70. Szeszko PR, Lipsky R, Mentschel C, Robinson D, Gunduz-Bruce H, Sevy S, et al. Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation. Mol Psychiatry 7: 631–636, 2005.

    Article  CAS  Google Scholar 

  71. Malhotra AK, Murphy GM Jr, Kennedy JL. Pharmacogenetics of psychotropic drug response. Am J Psychiatry 5: 780–796, 2004.

    Article  Google Scholar 

  72. Schafer M, Rujescu D, Giegling I, Guntermann A, Erfurth A, Bondy B, et al. Association of short-term response to haloperidol treatment with a polymorphism in the dopamine D(2) receptor gene. Am J Psychiatry 5: 802–804, 2001.

    Article  Google Scholar 

  73. Suzuki A, Mihara K, Kondo T, Tanaka O, Nagashima U, Otani K, et al. The relationship between dopamine D2 receptor polymorphism at the Taq1 A locus and therapeutic response to nemonapride, a selective dopamine antagonist, in schizophrenic patients. Pharmacogenetics 4: 335–341, 2000.

    Article  Google Scholar 

  74. Suzuki A, Kondo T, Mihara K, Yasui-Furukori N, Ishida M, Furukori H, et al. The −141C Ins/Del polymorphism in the dopamine D2 receptor gene promoter region is associated with anxiolytic and antidepressive effects during treatment with dopamine antagonists in schizophrenic patients. Pharmacogenetics 6: 545–550, 2001.

    Article  Google Scholar 

  75. Arranz MJ, Li T, Munro J, Liu X, Murray R, Collier DA, et al. Lack of association between a polymorphism in the promoter region of the dopamine-2 receptor gene and clozapine response. Pharmacogenetics 6: 481–484, 1998.

    Article  Google Scholar 

  76. Kapur S, Agid O, Mizrahi R, Li M. How anitpsychotics work-from receptors to reality. NeuroRx 3: 10–21, 2006.

    PubMed  Article  Google Scholar 

  77. Gessa GL, Devoto P, Diana M, Flore G, Melis M, Pistis M. Dissociation of haloperidol, clozapine, and olanzapine effects on electrical activity of mesocortical dopamine neurons and dopamine release in the prefrontal cortex. Neuropsychopharmacology 6: 642–649, 2000.

    Article  Google Scholar 

  78. Diaz-Asper C, Goldberg T. COMT polymorphism and prefrontal cognitive function. NeuroRx 3: 97–105, 2006.

    PubMed  CAS  Article  Google Scholar 

  79. Weickert TW, Goldberg TE, Mishara A, Apud JA, Kolachana BS, Egan MF, et al. Catechol-O-methyltransferase val108/158met genotype predicts working memory response to antipsychotic medications. Biol Psychiatry 9: 677–682, 2004.

    Article  CAS  Google Scholar 

  80. Bishop JR, Ellingrod VL, Moline J, Miller D. Association between the polymorphic GRM3 gene and negative symptom improvement during olanzapine treatment. Schizophr Res 77: 253–60, 2005.

    PubMed  Article  Google Scholar 

  81. Krebs MO, Guillin O, Bourdell MC, Schwartz JC, Olie JP, Poirier MF, et al. Brain derived neurotrophic factor (BDNF) gene variants association with age at onset and therapeutic response in schizophrenia. Mol Psychiatry 5: 558–562, 2000.

    PubMed  CAS  Article  Google Scholar 

  82. Hong CJ, Yu YW, Lin CH, Tsai SJ. An association study of a brain-derived neurotrophic factor Val66Met polymorphism and clozapine response of schizophrenic patients. Neurosci Lett 3: 206–208, 2003.

    Article  CAS  Google Scholar 

  83. Anttila S, Illi A, Kampman O, Mattila KM, Lehtimaki T, Leinonen E. Lack of association between two polymorphisms of brain-derived neurotrophic factor and response to typical neuroleptics. J Neural Transm 7: 885–890, 2005.

    Article  CAS  Google Scholar 

  84. Corson PW, Nopoulos P, Miller DD, Arndt S, Andreasen NC. Change in basal ganglia volume over 2 years in patients with schizophrenia: typical versus atypical neuroleptics. Am J Psychiatry 8: 1200–1204, 1999.

    Google Scholar 

  85. Scheepers FE, de Wied CC, Hulshoff Pol HE, van de Flier W, van der Linden JA, Kahn RS. The effect of clozapine on caudate nucleus volume in schizophrenic patients previously treated with typical anti psychotics. Neuropsychopharmacology 1: 47–54, 2001.

    Article  Google Scholar 

  86. Scheepers FE, Gispen de Wied CC, Hulshoff Pol HE, Kahn RS. Effect of clozapine on caudate nucleus volume in relation to symptoms of schizophrenia. Am J Psychiatry 4: 644–646, 2001.

    Article  Google Scholar 

  87. Lang DJ, Kopala LC, Vandorpe RA, Rui Q, Smith GN, Goghari VM, et al. AnMRI study of basal ganglia volumes in first-episode schizophrenia patients treated with risperidone. Am J Psychiatry 4: 625–631, 2001.

    Article  Google Scholar 

  88. Lang DJ, Kopala LC, Vandorpe RA, Rui Q, Smith GN, Goghari VM, et al. Reduced basal ganglia volumes after switching to olanzapine in chronically treated patients with schizophrenia. Am J Psychiatry 10: 1829–1836, 2004.

    Article  Google Scholar 

  89. Lieberman JA, Tollefson GD, Charles C, Zipursky R, Sharma T, Kahn RS, et al. Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry 4: 361–370, 2005.

    Article  Google Scholar 

  90. Dorph-Petersen KA, Pierri JN, Perel JM, Sun Z, Sampson AR, Lewis DA. The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of Haloperidol and Olanzapine in Macaque monkeys. Neuropsychopharmacology 9: 1649–1661, 2005.

    Article  CAS  Google Scholar 

  91. Fukuzako H, Fukuzako T, Kodama S, Hashiguchi T, Takigawa M, Fujimoto T. Haloperidol improves membrane phospholipid abnormalities in temporal lobes of schizophrenic patients. Neuropsychopharmacology 4: 542–549, 1999.

    Article  Google Scholar 

  92. Bertolino A, Callicott JH, Mattay VS, Weidenhammer KM, Rakow R, Egan MF, et al. The effect of treatment with antipsychotic drugs on brain N-acetylaspartate measures in patients with schizophrenia. Biol Psychiatry 1: 39–46, 2001.

    Article  Google Scholar 

  93. Liddle PF, Lane CJ, Ngan ET. Immediate effects of risperidone on cortico-striato-thalamic loops and the hippocampus. Br J Psychiatry 402–407, 2000

  94. Bartlett EJ, Brodie JD, Simkowitz P, Schlosser R, Dewey SL, Lindenmayer JP, et al. Effect of a haloperidol challenge on regional brain metabolism in neuroleptic-responsive and nonresponsive schizophrenic patients. Am J Psychiatry 3: 337–343, 1998.

    Google Scholar 

  95. Molina V, Gispert JD, Reig S, Sanz J, Pascau J, Santos A, et al. Cerebral metabolism and risperidone treatment in schizophrenia. Schizophr Res 1: 1–7, 2003.

    Article  Google Scholar 

  96. Molina V, Gispert JD, Reig S, Sanz J, Pascau J, Santos A, et al. Cerebral metabolic changes induced by clozapine in schizophrenia and related to clinical improvement. Psychopharmacology (Berl) 1: 17–26, 2005.

    Article  CAS  Google Scholar 

  97. Rodriguez VM, Andrée RM, Castejon MJ, Zamora ML, Alvaro PC, Delgado JL, et al. Fronto-striato-thalamic perfusion and clozapine response in treatment-refractory schizophrenic patients. A 99mTc-HMPAO study. Psychiatry Res 1: 51–61, 1997.

    Google Scholar 

  98. Lahti AC, Holcomb HH, Weiler MA, Medoff DR, Frey KN, Hardin M, et al. Clozapine but not haloperidol re-establishes normal task-activated rCBF patterns in schizophrenia within the anterior cingulate cortex. Neuropsychopharmacology 1: 171–178, 2004.

    Article  CAS  Google Scholar 

  99. Molina V, Gispert JD, Reig S, Pascau J, Martinez R, Sanz J, et al. Olanzapine-induced cerebral metabolic changes related to symptom improvement in schizophrenia. Int Clin Psychopharmacol 1: 13–18, 2005.

    Article  Google Scholar 

  100. Honey GD, Bullmore ET, Soni W, Varatheesan M, Williams SC, Sharma T. Differences in frontal cortical activation by a working memory task after substitution of risperidone for typical antipsychotic drugs in patients with schizophrenia. Proc Natl Acad Sci USA 23: 13432–13437, 1999.

    Article  Google Scholar 

  101. Mattay VS, Callicott JH, Bertolino A, Santha AK, Tallent KA, Goldberg TE, et al. Abnormal functional lateralization of the sensorimotor cortex in patients with schizophrenia. Neuroreport 13: 2977–2984, 1997.

    Article  Google Scholar 

  102. Stephan KE, Magnotta VA, White T, Arndt S, Flaum M, O’Leary DS, et al. Effects of olanzapine on cerebellar functional connectivity in schizophrenia measured by fMRI during a simple motor task. Psychol Med 6: 1065–1078, 2001.

    Google Scholar 

  103. Bertolino A, Blasi G, Caforio G, Latorre V, DeCandia M, Rubino V, et al. Functional lateralization of the sensorimotor cortex in patients with schizophrenia: effects of treatment with olanzapine. Biol Psychiatry 3: 190–197, 2004.

    Article  CAS  Google Scholar 

  104. Stip E, Fahim C, Mancini-Marie A, Bentaleb LA, Mensour B, Mendrek A, et al. Restoration of frontal activation during a treatment with quetiapine: an fMRI study of blunted affect in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 1: 21–26, 2005.

    Article  CAS  Google Scholar 

  105. Potkin SG, Basile VS, Jin Y, Masellis M, Badri F, Keator D, et al. D1 receptor alleles predict PET metabolic correlates of clinical response to clozapine. Mol Psychiatry 1: 109–113, 2003.

    Article  CAS  Google Scholar 

  106. Bertolino A, Caforio G, Petruzzella V, Latorre V, Rubino V, Dimalta S, et al. GRM3 genotype and olanzapine treatment: Differential effects on prefrontal cortical function during working memory in patients with schizophrenia. Biol Psychiatry 8: S293, 2005.

    Google Scholar 

  107. Abi-Dargham A, Mawlawi O, Lombardo I, Gil R, Martinez D, Huang Y, et al. Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 9: 3708–3719, 2002.

    Google Scholar 

  108. Bilder RM, Volavka J, Lachman HM, Grace AA. The catechol-O-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatrie phenotypes. Neuropsychopharmacology 11: 1943–1961, 2004.

    Article  CAS  Google Scholar 

  109. Stahl S. Finding what you are not looking for: strategies for developing novel treatments in psychiatry. NeuroRx 3: 3–9, 2006.

    PubMed  CAS  Article  Google Scholar 

  110. Goldberg TE, Weinberger DR. Genes and the parsing of cognitive processes. Trends Cogn Sci 7: 325–335, 2004.

    Article  Google Scholar 

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Affiliations

  1. Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University of Bari, 70125, Bari, Italy

    Giuseppe Blasi & Alessandro Bertolino

  2. Clinical Brain Disorders Branch, Gene, Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, 20892, Bethesda, MD

    Giuseppe Blasi & Alessandro Bertolino

  3. Department of Neuroradiology, IRCCSS “Casa Sollievo della Sofferenza,”, 71013, San Giovanni Rotondo, Italy

    Alessandro Bertolino

Authors
  1. Giuseppe Blasi
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  2. Alessandro Bertolino
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Correspondence to Alessandro Bertolino.

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Blasi, G., Bertolino, A. Imaging genomics and response to treatment with antipsychotics in schizophrenia. NeuroRX 3, 117–130 (2006). https://doi.org/10.1016/j.nurx.2005.12.001

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  • DOI: https://doi.org/10.1016/j.nurx.2005.12.001

Key Words

  • Imaging genomics
  • antipsychotics
  • schizophrenia
  • fMRI
  • PET
  • COMT
  • DISC1
  • GRM3