Antipsychotic drug mechanisms: Links between therapeutic effects, metabolic side effects and the insulin signaling pathway

Molecular Psychiatry

Volumn 13, Issue 10, 2008, Pages 918-929

  Girgis, R R ^a,b   Javitch, J A ^a,b   Lieberman, J A ^a,b  

^a Columbia University ^*  (United States)

^b NEW YORK STATE PSYCHIATRIC INSTITUTE   (United States)

Author keywords

Antipsychotic; Functional selectivity; Insulin; Mechanism of action; Metabolic side effects; Schizophrenia

Indexed keywords

ARIPIPRAZOLE; CHLORPROMAZINE; CLOZAPINE; DOPAMINE; FLUOXETINE; FLUPHENAZINE; GLYCOGEN SYNTHASE KINASE 3BETA; HALOPERIDOL; IMIPRAMINE; INSULIN; INSULIN RECEPTOR; KETAMINE; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; NEUROLEPTIC AGENT; OLANZAPINE; PHENCYCLIDINE; PHOSPHATIDYLINOSITIDE; PROTEIN KINASE B; PROTEIN KINASE C; QUETIAPINE; RISPERIDONE; SOMATOMEDIN; ZIPRASIDONE;

BRAIN; CHOLESTEROL BLOOD LEVEL; DIABETES MELLITUS; DISORDERS OF CARBOHYDRATE METABOLISM; DRUG EFFECT; DRUG MECHANISM; EXTRAPYRAMIDAL SYMPTOM; GLUCOSE BLOOD LEVEL; HUMAN; HYPERGLYCEMIA; HYPERLIPIDEMIA; INSULIN BLOOD LEVEL; INSULIN METABOLISM; INSULIN RESISTANCE; METABOLIC DISORDER; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; SCHIZOPHRENIA; SIDE EFFECT; SIGNAL TRANSDUCTION; THERAPY EFFECT; TRIACYLGLYCEROL BLOOD LEVEL;

ANIMALS; ANTIPSYCHOTIC AGENTS; HUMANS; INSULIN; SCHIZOPHRENIA; SIGNAL TRANSDUCTION;

EID: 51949118437     PISSN: 13594184     EISSN: 14765578     Source Type: Journal    
DOI: 10.1038/mp.2008.40     Document Type: Review

References (118)

1. Lewis DA, Lieberman JA. Catching up on schizophrenia: natural history and neurobiology. Neuron 2000; 28: 325-334.
2. Lehmann HE, Ban TA. The history of the psychopharmacology of schizophrenia. Can J Psychiatry 1997; 42: 152-162.
3. Miyamoto S, Duncan GE, Marx CE, Lieberman JA. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 2005; 10: 79-104.
4. Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 1976; 192: 481-483.
5. Seeman P, Chau-Wong M, Tedesco J, Wong K. Brain receptors for antipsychotic drugs and dopamine: direct binding assays. Proc Natl Acad Sci USA 1975; 72: 4376-4380.
6. Aghajanian GK, Marek GJ. Serotonin model of schizophrenia: emerging role of glutamate mechanisms. Brain Res Brain Res Rev 2000; 31: 302-312.
7. Tamminga CA, Holcomb HH. Phenotype of schizophrenia: a review and formulation. Mol Psychiatry 2005; 10: 27-39.
8. Remington G. Understanding antipsychotic 'atypicality': a clinical and pharmacological moving target. J Psychiatry Neurosci 2003; 28: 275-284.
9. Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med 2007; 13: 1102-1107.
10. Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP et al. Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006; 63: 1079-1087.
11. Lieberman JA. Comparative effectiveness of antipsychotic drugs. A commentary on: Cost Utility of the latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1) and Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Arch Gen Psychiatry 2006; 63: 1069-1072.
12. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO et al. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353: 1209-1223.
13. Tandon R, Fleischhacker WW. Comparative efficacy of antipsychotics in the treatment of schizophrenia: a critical assessment. Schizophr Res 2005; 79: 145-155.
14. Volavka J, Czobor P, Sheitman B, Lindenmayer JP, Citrome L, McEvoy JP et al. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am J Psychiatry 2002; 159: 255-262.
15. Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H et al. Functional selectivity and classical concepts of quantitative pharmacology. J Pharmacol Exp Ther 2007; 320: 1-13.
16. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45: 789-796.
17. Geddes J, Freemantle N, Harrison P, Bebbington P. Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. BMJ 2000; 321: 1371-1376.
18. Glazer WM. Extrapyramidal side effects, tardive dyskinesia, and the concept of atypicality. J Clin Psychiatry 2000; 61(Suppl 3): 16-21.
19. Caroff SN, Mann SC, Campbell EC, Sullivan KA. Movement disorders associated with atypical antipsychotic drugs. J Clin Psychiatry 2002; 63(Suppl 4): 12-19.
20. Newcomer JW. Abnormalities of glucose metabolism associated with atypical antipsychotic drugs. J Clin Psychiatry 2004; 65(Suppl 18): 36-46.
21. Basu A, Meltzer HY. Differential trends in prevalence of diabetes and unrelated general medical illness for schizophrenia patients before and after the atypical antipsychotic era. Schizophr Res 2006; 86: 99-109.
22. Casey DE. Dyslipidemia and atypical antipsychotic drugs. J Clin Psychiatry 2004; 65(Suppl 18): 27-35.
23. Wirshing DA. Schizophrenia and obesity: impact of antipsychotic medications. J Clin Psychiatry 2004; 65(Suppl 18): 13-26.
24. Patel JK, Pinals DA, Breier A. Schizophrenia and other psychoses. In: Tasman A, Kay J, Lieberman JA (eds). Psychiatry,2nd edn. Wiley: Chichester, 2003,pp 1131-1206.
25. Baptista T, Kin NM, Beaulieu S, de Baptista EA. Obesity and related metabolic abnormalities during antipsychotic drug administration: mechanisms, management and research perspectives. Pharmacopsychiatry 2002; 35: 205-219.
26. Gardner DM, Baldessarini RJ, Waraich P. Modern antipsychotic drugs: a critical overview. CMAJ 2005; 172: 1703-1711.
27. Holt RI, Bushe C, Citrome L. Diabetes and schizophrenia 2005: are we any closer to understanding the link? J Psychopharmacol 2005; 19(6 Suppl): 56-65.
28. Spelman LM, Walsh PI, Sharifi N, Collins P, Thakore JH. Impaired glucose tolerance in first-episode drug-naïve patients with schizophrenia. Diabet Med 2007; 24: 481-485.
29. Newcomer JW. Metabolic considerations in the use of antipsychotic medications: a review of recent evidence. J Clin Psychiatry 2007; 68(Suppl 1): 20-27.
30. Newcomer JW, Haupt DW. The metabolic effects of antipsychotic medications. Can J Psychiatry 2006; 51: 480-491.
31. Reaven GM. The metabolic syndrome: is this diagnosis necessary? Am J Clin Nutr 2006; 83: 1237-1247.
32. Ferraioli A, Shirley KL, David P. The role of atypical antipsychotics in glucose/insulin dysregulation and the evolving role of the psychiatrist in a new era of drug treatment options. CNS Spectr 2004; 9: 849-861.
33. Dwyer DS, Donohoe D, Lu XH, Aamodt EJ. Mechanistic connections between glucose/lipid disturbances and weight gain induced by antipsychotic drugs. Int Rev Neurobiol 2005; 65: 211-247.
34. Houseknecht KL, Robertson AS, Zavadoski W, Gibbs EM, Johnson DE, Rollema H. Acute effects of atypical antipsychotics on whole-body insulin resistance in rats: implications for adverse metabolic effects. Neuropsychopharmacology 2007; 32: 289-297.
35. Sasaki N, Iwase M, Uchizono Y, Nakamura U, Imoto H, Abe S et al. The atypical antipsychotic clozapine impairs insulin secretion by inhibiting glucose metabolism and distal steps in rat pancreatic islets. Diabetologia 2006; 49: 2930-2938.
36. Haupt DW, Newcomer JW. Abnormalities in glucose regulation associated with mental illness and treatment. J Psychosom Res 2002; 53: 925-933.
37. Kim SF, Huang AS, Snowman AM, Teuscher C, Snyder SH. From the cover: antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMPkinase. Proc Natl Acad Sci USA 2007; 104: 3456-3459.
38. Dwyer DS, Bradley RJ, Kablinger AS, Freeman III AM. Glucose metabolism in relation to schizophrenia and antipsychotic drug treatment. Ann Clin Psychiatry 2001; 13: 103-113.
39. Dwyer DS, Ardizzone TD, Bradley RJ. Psychoactive drugs affect glucose transport and the regulation of glucose metabolism. Int Rev Neurobiol 2002; 51: 503-530.
40. Dwyer DS, Donohoe D. Induction of hyperglycemia in mice with atypical antipsychotic drugs that inhibit glucose uptake. Pharmacol Biochem Behav 2003; 75: 255-260.
41. Bondy CA, Cheng CM. Insulin-like growth factor-1 promotes neuronal glucose utilization during brain development and repair processes. Int Rev Neurobiol 2002; 51: 189-217.
42. Gunnell D, Holly JM. Do insulin-like growth factors underlie associations of birth complications, fetal and pre-adult growth with schizophrenia? Schizophr Res 2004; 67: 309-311.
43. Kalkman HO. The role of the phosphatidylinositide 3-kinaseprotein kinase B pathway in schizophrenia. Pharmacol Ther 2006; 110: 117-134.
44. Bjornholm M, Zierath JR. Insulin signal transduction in human skeletal muscle: identifying the defects in type II diabetes. Biochem Soc Trans 2005; 33: 354-357.
45. Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL et al. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia 2003; 17: 590-603.
46. Munafo MR, Thiselton DL, Clark TG, Flint J. Association of the NRG1 gene and schizophrenia: a meta-analysis. Mol Psychiatry 2006; 11: 539-546.
47. Li BS, MaW, Jaffe H, Zheng Y, Takahashi S, Zhang L et al. Cyclindependent kinase-5 is involved in neuregulin-dependent activation of phosphatidylinositol 3-kinase and Akt activity mediating neuronal survival. J Biol Chem 2003; 278: 35702-35709.
48. Lai WS, Xu B, Westphal KG, Paterlini M, Olivier B, Pavlidis P et al. Akt1 deficiency affects neuronal morphology and predisposes to abnormalities in prefrontal cortex functioning. Proc Natl Acad Sci USA 2006; 103: 16906-16911.
49. Gould TD, Manji HK. Glycogen synthase kinase-3: a putative molecular target for lithium mimetic drugs. Neuropsychopharmacology 2005; 30: 1223-1237.
50. Jope RS, Roh MS. Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions. Curr Drug Targets 2006; 7: 1421-1434.
51. Lovestone S, Killick R, Di Forti M, Murray R. Schizophrenia as a GSK-3 dysregulation disorder. Trends Neurosci 2007; 30: 142-149.
52. Kozlovsky N, Belmaker RH, Agam G. GSK-3 and the neurodevelopmental hypothesis of schizophrenia. Eur Neuropsychopharmacol 2002; 12: 13-25.
53. Doble BW, Woodgett JR. GSK-3: tricks of the trade for a multitasking kinase. J Cell Sci 2003; 116: 1175-1186.
54. Beaulieu JM, Gainetdinov RR, Caron MG. The Akt-GSK-3 signaling cascade in the actions of dopamine. Trends Pharmacol Sci 2007; 28: 166-172.
55. Beaulieu JM, Sotnikova TD, Yao WD, Kockeritz L, Woodgett JR, Gainetdinov RR et al. Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc Natl Acad Sci USA 2004; 101: 5099-5104.
56. Beaulieu JM, Sotnikova TD, Marion S, Lefkowitz RJ, Gainetdinov RR, Caron MG. An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 2005; 122: 261-273.
57. Lei G, Xia Y, Johnson KM. The role of Akt-GSK-3beta signaling and synaptic strength in phencyclidine-induced neurodegeneration. Neuropsychopharmacology 2007 [e-pub ahead of print].
58. Coyle JT. Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 2006; 26: 365-384.
59. Ide M, Ohnishi T, Murayama M, Matsumoto I, Yamada K, Iwayama Y et al. Failure to support a genetic contribution of AKT1 polymorphisms and altered AKT signaling in schizophrenia. J Neurochem 2006; 99: 277-287.
60. Stopkova P, Saito T, Papolos DF, Vevera J, Paclt I, Zukov I et al. Identification of PIK3C3 promoter variant associated with bipolar disorder and schizophrenia. Biol Psychiatry 2004; 55: 981-988.
61. Duan S, Gao R, Xing Q, Du J, Liu Z, Chen Q et al. A family-based association study of schizophrenia with polymorphisms at three candidate genes. Neurosci Lett 2005; 379: 32-36.
62. Saito T, Aghalar MR, Lachman HM. Analysis of PIK3C3 promoter variant in African-Americans with schizophrenia. Schizophr Res 2005; 76: 361-362.
63. Jamra RA, Klein K, Villela AW, Becker T, Schulze TG, Schmael C et al. Association study between genetic variants at the PIP5K2A gene locus and schizophrenia and bipolar affective disorder. Am J Med Genet B Neuropsychiatr Genet 2006; 141: 663-665.
64. Schwab SG, Knapp M, Sklar P, Eckstein GN, Sewekow C, Borrmann-Hassenbach M et al. Evidence for association of DNA sequence variants in the phosphatidylinositol-4-phosphate 5-kinase IIalpha gene (PIP5K2A) with schizophrenia. Mol Psychiatry 2006; 11: 837-846.
65. Gunnell D, Lewis S, Wilkinson J, Georgieva L, Davey GS, Day IN et al. IGF1, growth pathway polymorphisms and schizophrenia: a pooling study. Am J Med Genet B Neuropsychiatr Genet 2007; 144: 117-120.
66. Dean B, Opeskin K, Pavey G, Hill C, Keks N. Changes in protein kinase C and adenylate cyclase in the temporal lobe from subjects with schizophrenia. J Neural Transm 1997; 104: 1371-1381.
67. Opeskin K, Dean B, Pavey G, Hill C, Keks N, Copolov D. Neither protein kinase C nor adenylate cyclase are altered in the striatum from subjects with schizophrenia. Schizophr Res 1996; 22: 159-164.
68. Hahn CG, Umapathy, Wang HY, Koneru R, Levinson DF, Friedman E. Lithium and valproic acid treatments reduce PKC activation and receptor-G protein coupling in platelets of bipolar manic patients. J Psychiatr Res 2005; 39: 355-363.
69. Borda T, Genaro AM, Cremaschi G. Haloperidol effect on intracellular signals system coupled to alpha1-adrenergic receptor in rat cerebral frontal cortex. Cell Signal 1999; 11: 293-300.
70. Wan DC, Dean B, Pavey G, Copolov DL. Treatment with haloperidol or clozapine causes changes in dopamine receptors but not adenylate cyclase or protein kinase C in the rat forebrain. Life Sci 1996; 59: 2001-2008.
71. Jardemark KE, Ninan I, Liang X, Wang RY. Protein kinase C is involved in clozapine's facilitation of N-methyl-D-aspartate- and electrically evoked responses in pyramidal cells of the medial prefrontal cortex. Neuroscience 2003; 118: 501-512.
72. Engl J, Laimer M, Niederwanger A, Kranebitter M, Starzinger M, Pedrini MT et al. Olanzapine impairs glycogen synthesis and insulin signaling in L6 skeletal muscle cells. Mol Psychiatry 2005; 10: 1089-1096.
73. Fatemi SH, Reutiman TJ, Folsom TD, Bell C, Nos L, Fried P et al. Chronic olanzapine treatment causes differential expression of genes in frontal cortex of rats as revealed by DNA microarray technique. Neuropsychopharmacology 2006; 31: 1888-1899.
74. Zhao Z, Ksiezak-Reding H, Riggio S, Haroutunian V, Pasinetti GM. Insulin receptor deficits in schizophrenia and in cellular and animal models of insulin receptor dysfunction. Schizophr Res 2006; 84: 1-14.
75. Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA. Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet 2004; 36: 131-137.
76. Schwab SG, Hoefgen B, Hanses C, Hassenbach MB, Albus M, Lerer B et al. Further evidence for association of variants in the AKT1 gene with schizophrenia in a sample of European sib-pair families. Biol Psychiatry 2005; 58: 446-450.
77. Bajestan SN, Sabouri AH, Nakamura M, Takashima H, Keikhaee MR, Behdani F et al. Association of AKT1 haplotype with the risk of schizophrenia in Iranian population. Am J Med Genet B Neuropsychiatr Genet 2006; 141: 383-386.
78. IkedaM, Iwata N, Suzuki T, Kitajima T, Yamanouchi Y, Kinoshita Y et al. Association of AKT1 with schizophrenia confirmed in a Japanese population. Biol Psychiatry 2004; 56: 698-700.
79. Xu MQ, Xing QH, Zheng YL, Li S, Gao JJ, He G et al. Association of AKT1 gene polymorphisms with risk of schizophrenia and with response to antipsychotics in the Chinese population. J Clin Psychiatry 2007; 68: 1358-1367.
80. Ohtsuki T, Inada T, Arinami T. Failure to confirm association between AKT1 haplotype and schizophrenia in a Japanese case-control population. Mol Psychiatry 2004; 9: 981-983.
81. Liu YL, Fann CS, Liu CM, Wu JY, Hung SI, Chan HY et al. Absence of significant associations between four AKT1 SNP markers and schizophrenia in the Taiwanese population. Psychiatr Genet 2006; 16: 39-41.
82. Norton N, Williams HJ, Dwyer S, Carroll L, Peirce T, Moskvina V et al. Association analysis of AKT1 and schizophrenia in a UK case control sample. Schizophr Res 2007; 93: 58-65.
83. Thiselton DL, Vladimirov VI, Kuo PH, McClay J, Wormley B, Fanous A et al. AKT1 is associated with schizophrenia across multiple symptom dimensions in the Irish study of high density schizophrenia families. Biol Psychiatry 2007; 63: 449-457.
84. Amar S, Shaltiel G, Mann L, Shamir A, Dean B, Scarr E et al. Possible involvement of post-dopamine D2 receptor signalling components in the pathophysiology of schizophrenia. Int J Neuropsychopharmacol 2007; 11: 197-205.
85. Hashimoto R, Numakawa T, Ohnishi T, Kumamaru E, Yagasaki Y, Ishimoto T et al. Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling. Hum Mol Genet 2006; 15: 3024-3033.
86. Kang UG, Seo MS, Roh MS, Kim Y, Yoon SC, Kim YS. The effects of clozapine on the GSK-3-mediated signaling pathway. FEBS Lett 2004; 560: 115-119.
87. Basta-Kaim A, Budziszewska B, Jaworska-Feil L, Tetich M, Kubera M, Leskiewicz M et al. Antipsychotic drugs inhibit the human corticotropin-releasing-hormone gene promoter activity in neuro-2A cells-an involvement of protein kinases. Neuropsychopharmacology 2006; 31: 853-865.
88. Lu XH, Bradley RJ, Dwyer DS. Olanzapine produces trophic effects in vitro and stimulates phosphorylation of Akt/PKB, ERK1/2, and the mitogen-activated protein kinase p38. Brain Res 2004; 1011: 58-68.
89. Lu XH, Dwyer DS. Second-generation antipsychotic drugs, olanzapine, quetiapine, and clozapine enhance neurite outgrowth in PC12 cells via PI3K/AKT, ERK, and pertussis toxin-sensitive pathways. J Mol Neurosci 2005; 27: 43-64.
90. Ukai W, Ozawa H, Tateno M, Hashimoto E, Saito T. Neurotoxic potential of haloperidol in comparison with risperidone: implication of Akt-mediated signal changes by haloperidol. J Neural Transm 2004; 111: 667-681.
91. Dwyer DS, Lu XH, Bradley RJ. Cytotoxicity of conventional and atypical antipsychotic drugs in relation to glucose metabolism. Brain Res 2003; 971: 31-39.
92. Shin SY, Choi BH, Ko J, Kim SH, Kim YS, Lee YH. Clozapine, a neuroleptic agent, inhibits Akt by counteracting Ca(2p)/ calmodulin in PTEN-negative U-87MG human glioblastoma cells. Cell Signal 2006; 18: 1876-1886.
93. Scassellati C, Bonvicini C, Perez J, Bocchio-Chiavetto L, Tura GB, Rossi G et al. Association study of 1727 A/T, 50 C/T and (CAA)n repeat GSK-3beta gene polymorphisms with schizophrenia. Neuropsychobiology 2004; 50: 16-20.
94. Meng J, Shi Y, Zhao X, Zhou J, Zheng Y, Tang R et al. No significant association between the genetic polymorphisms in the GSK-3beta gene and schizophrenia in the Chinese population. J Psychiatr Res 2007; 42: 365-370.
95. Turunen JA, Peltonen JO, Pietilaïnen OP, Hennah W, Loukola A, Paunio T et al. The role of DTNBP1, NRG1, and AKT1 in the genetics of schizophrenia in Finland. Schizophr Res 2007; 91: 27-36.
96. Ikeda M, Iwata N, Suzuki T, Kitajima T, Yamanouchi Y, Kinoshita Y et al. No association of GSK3beta gene (GSK3B) with Japanese schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2005; 134: 90-92.
97. Lee KY, Ahn YM, Joo EJ, Jeong SH, Chang JS, Kim SC et al. No association of two common SNPs at position 1727 A/T, 50 C/T of GSK-3 beta polymorphisms with schizophrenia and bipolar disorder of Korean population. Neurosci Lett 2006; 395: 175-178.
98. Kozlovsky N, Belmaker RH, Agam G. Low GSK-3beta immunoreactivity in postmortem frontal cortex of schizophrenic patients. Am J Psychiatry 2000; 157: 831-833.
99. Kozlovsky N, Belmaker RH, Agam G. Low GSK-3 activity in frontal cortex of schizophrenic patients. Schizophr Res 2001; 52: 101-105.
100. Kozlovsky N, Shanon-Weickert C, Tomaskovic-Crook E, Kleinman JE, Belmaker RH, Agam G. Reduced GSK-3beta mRNA levels in postmortem dorsolateral prefrontal cortex of schizophrenic patients. J Neural Transm 2004; 111: 1583-1592.
101. Beasley C, Cotter D, Khan N, Pollard C, Sheppard P, Varndell I et al. Glycogen synthase kinase-3beta immunoreactivity is reduced in the prefrontal cortex in schizophrenia. Neurosci Lett 2001; 302: 117-120.
102. Kozlovsky N, Regenold WT, Levine J, Rapoport A, Belmaker RH, Agam G. GSK-3beta in cerebrospinal fluid of schizophrenia patients. J Neural Transm 2004; 111: 1093-1098.
103. Nadri C, Lipska BK, Kozlovsky N, Weinberger DR, Belmaker RH, Agam G. Glycogen synthase kinase (GSK)-3beta levels and activity in a neurodevelopmental rat model of schizophrenia. Brain Res Dev Brain Res 2003; 141: 33-37.
104. Harrison PJ. The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology (Berl) 2004; 174: 151-162.
105. Kozlovsky N, Belmaker RH, Agam G. Lack of effect of acute, subchronic, or chronic stress on glycogen synthase kinase-3beta protein levels in rat frontal cortex. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 1309-1312.
106. Kozlovsky N, Nadri C, Belmaker RH, Agam G. Lack of effect of mood stabilizers or neuroleptics on GSK-3 protein levels and GSK-3 activity. Int J Neuropsychopharmacol 2003; 6: 117-120.
107. Beasley C, Cotter D, Everall I. An investigation of the Wntsignalling pathway in the prefrontal cortex in schizophrenia, bipolar disorder and major depressive disorder. Schizophr Res 2002; 58: 63-67.
108. Swatton JE, Sellers LA, Faull RL, Holland A, Iritani S, Bahn S. Increased MAP kinase activity in Alzheimer's and Down syndrome but not in schizophrenia human brain. Eur J Neurosci 2004; 19: 2711-2719.
109. Nadri C, Dean B, Scarr E, Agam G. GSK-3 parameters in postmortem frontal cortex and hippocampus of schizophrenic patients. Schizophr Res 2004; 71: 377-382.
110. Nadri C, Kozlovsky N, Agam G, Bersudsky Y. GSK-3 parameters in lymphocytes of schizophrenic patients. Psychiatry Res 2002; 112: 51-57.
111. Alimohamad H, Rajakumar N, Seah YH, Rushlow W. Antipsychotics alter the protein expression levels of beta-catenin and GSK-3 in the rat medial prefrontal cortex and striatum. Biol Psychiatry 2005; 57: 533-542.
112. Alimohamad H, Sutton L, Mouyal J, Rajakumar N, Rushlow WJ. The effects of antipsychotics on beta-catenin, glycogen synthase kinase-3 and dishevelled in the ventral midbrain of rats. J Neurochem 2005; 95: 513-525.
113. Kozlovsky N, Amar S, Belmaker RH, Agam G. Psychotropic drugs affect Ser9-phosphorylated GSK-3 beta protein levels in rodent frontal cortex. Int J Neuropsychopharmacol 2006; 9: 337-342.
114. Li X, Rosborough KM, Friedman AB, Zhu W, Roth KA. Regulation of mouse brain glycogen synthase kinase-3 by atypical antipsychotics. Int J Neuropsychopharmacol 2007; 10: 7-19.
115. González-Maeso J, Weisstaub NV, Zhou M, Chan P, Ivic L, Ang R et al. Hallucinogens recruit specific cortical 5-HT(2A) receptormediated signaling pathways to affect behavior. Neuron 2007; 53: 439-452.
116. Kenakin T. Ligand-selective receptor conformations revisited: the promise and the problem. Trends Pharmacol Sci 2003; 24: 346-354.
117. Schmid CL, Raehal KM, Bohn LM. Agonist-directed signaling of the serotonin 2A receptor depends on beta-arrestin-2 interactions in vivo. Proc Natl Acad Sci USA 2008; 105: 1079-1084.
118. Gay EA, Urban JD, Nichols DE, Oxford GS, Mailman RB. Functional selectivity of D2 receptor ligands in a Chinese hamster ovary hD2L cell line: evidence for induction of ligandspecific receptor states. Mol Pharmacol 2004; 66: 97-105.