A gene expression and systems pathway analysis of the effects of clozapine compared to haloperidol in the mouse brain implicates susceptibility genes for schizophrenia
Restricted accessResearch articleFirst published online September, 2012
A gene expression and systems pathway analysis of the effects of clozapine compared to haloperidol in the mouse brain implicates susceptibility genes for schizophrenia
Clozapine has markedly superior clinical properties compared to other antipsychotic drugs but the side effects of agranulocytosis, weight gain and diabetes limit its use. The reason why clozapine is more effective is not well understood. We studied messenger RNA (mRNA) gene expression in the mouse brain to identify pathways changed by clozapine compared to those changed by haloperidol so that we could identify which changes were specific to clozapine. Data interpretation was performed using an over-representation analysis (ORA) of gene ontology (GO), pathways and gene-by-gene differences. Clozapine significantly changed gene expression in pathways related to neuronal growth and differentiation to a greater extent than haloperidol; including the microtubule-associated protein kinase (MAPK) signalling and GO terms related to axonogenesis and neuroblast proliferation. Several genes implicated genetically or functionally in schizophrenia such as frizzled homolog 3 (FZD3), U2AF homology motif kinase 1 (UHMK1), pericentriolar material 1 (PCM1) and brain-derived neurotrophic factor (BDNF) were changed by clozapine but not by haloperidol. Furthermore, when compared to untreated controls clozapine specifically regulated transcripts related to the glutamate system, microtubule function, presynaptic proteins and pathways associated with synaptic transmission such as clathrin cage assembly. Compared to untreated controls haloperidol modulated expression of neurotoxic and apoptotic responses such as NF-kappa B and caspase pathways, whilst clozapine did not. Pathways involving lipid and carbohydrate metabolism and appetite regulation were also more affected by clozapine than by haloperidol.
AdvokatCDBertmanLJComatyJEJr (1999) Clinical outcome to clozapine treatment in chronic psychiatric inpatients. Prog Neuropsychopharmacol Biol Psychiatry23: 1–14.
2.
AlaoAOMalhotraKDewanMJ (2002) Comparing the side effect profile of the atypical antipsychotics. West Afr J Med21: 313–315.
3.
AlimohamadHRajakumarNSeahYH. (2005) Antipsychotics alter the protein expression levels of beta-catenin and GSK-3 in the rat medial prefrontal cortex and striatum. Biol Psychiatry57: 533–542.
4.
AllisonDMentoreJHeoM. (1999) Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry156: 1686–1696.
AndrieuxASalinPSchweitzerA. (2006) Microtubule stabilizer ameliorates synaptic function and behavior in a mouse model for schizophrenia. Biol Psychiatry60: 1224–1230.
7.
AndrieuxASalinPAJobD (2004) (A role for microtubules in mental diseases?). Pathol Biol (Paris)52: 89–92.
8.
AndrieuxASalinPAVernetM. (2002) The suppression of brain cold-stable microtubules in mice induces synaptic defects associated with neuroleptic-sensitive behavioral disorders. Genes Dev16: 2350–2364.
9.
AngelucciFBreneSMatheAA (2005) BDNF in schizophrenia, depression and corresponding animal models. Mol Psychiatry10: 345–352.
10.
AnguloJACadetJLMcEwenBS (1990) Effect of typical and atypical neuroleptic treatment on protachykinin mRNA levels in the striatum of the rat. Neurosci Lett113: 217–221.
11.
ArguelloPAJentschJD (2004) Cannabinoid CB1 receptor-mediated impairment of visuospatial attention in the rat. Psychopharmacology (Berl)177: 141-150.
12.
BaptistaTKinNMBeaulieuS. (2002) Obesity and related metabolic abnormalities during antipsychotic drug administration: mechanisms, management and research perspectives. Pharmacopsychiatry35: 205–219.
13.
BishnoiMChopraKKulkarniSK (2008) Activation of striatal inflammatory mediators and caspase-3 is central to haloperidol-induced orofacial dyskinesia. Eur J Pharmacol590: 241–245.
14.
BrandonNJHandfordEJSchurovI. (2004) Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders. Mol Cell Neurosci25: 42–55.
15.
BrazmaAHingampPQuackenbushJ. (2001) Minimum information about a microarray experiment (MIAME)-toward standards for microarray data. Nat Genet29: 365–371.
16.
BrowningJLPatelTBrandtPC. (2005) Clozapine and the mitogen-activated protein kinase signal transduction pathway: implications for antipsychotic actions. Biol Psychiatry57: 617–623.
17.
CaberlottoLHurdYL (2001) Neuropeptide Y Y(1) and Y(2) receptor mRNA expression in the prefrontal cortex of psychiatric subjects. Relationship of Y(2) subtype to suicidal behavior. Neuropsychopharmacology25: 91–97.
18.
CapuanoBCrosbyITLloydEJ (2002) Schizophrenia: genesis, receptorology and current therapeutics. Curr Med Chem9: 521–548.
19.
CastilloMAGhoseSTammingaCA. (2010) Deficits in syntaxin 1 phosphorylation in schizophrenia prefrontal cortex. Biol Psychiatry67: 208–216.
20.
ChakosMLiebermanJHoffmanE. (2001) Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry158: 518–526.
21.
ChenCMLaneHYWuYR. (2005) Expanded trinucleotide repeats in the TBP/SCA17 gene mapped to chromosome 6q27 are associated with schizophrenia. Schizophr Res78: 131–136.
22.
ChertkowYWeinrebOYoudimMB. (2006) The effect of chronic co-administration of fluvoxamine and haloperidol compared to clozapine on the GABA system in the rat frontal cortex. Int J Neuropsychopharmacol9: 287–296.
23.
ChongVZYoungLTMishraRK (2002) cDNA array reveals differential gene expression following chronic neuroleptic administration: implications of synapsin II in haloperidol treatment. J Neurochem82: 1533–1539.
24.
ClaingAPerrySJAchiriloaieM. (2000) Multiple endocytic pathways of G protein-coupled receptors delineated by GIT1 sensitivity. Proc Natl Acad Sci U S A97: 1119–1124.
25.
CouegnasASchweitzerAAndrieuxA. (2007) Expression pattern of STOP lacZ reporter gene in adult and developing mouse brain. J Neurosci Res85: 1515–1527.
26.
CussacDDuqueyroixDNewman-TancrediA. (2002) Stimulation by antipsychotic agents of mitogen-activated protein kinase (MAPK) coupled to cloned, human (h)serotonin (5-HT)(1A) receptors. Psychopharmacology (Berl)162: 168–177.
27.
DattaSRMcQuillinARizigM. (2010) A threonine to isoleucine missense mutation in the pericentriolar material 1 gene is strongly associated with schizophrenia. Mol Psychiatry15: 615–628.
28.
De ErausquinGA (2003) Mechanism of molecular action of neuroleptics. Vertex14: 36-44.
29.
De FerrariGVMoonRT (2006) The ups and downs of Wnt signaling in prevalent neurological disorders. Oncogene25: 7545–7553.
30.
De OliveiraIRDe SenaEPPereiraEL. (1996) Haloperidol blood levels and clinical outcome: a meta-analysis of studies relevant to testing the therapeutic window hypothesis. J Clin Pharm Ther21: 229–236.
31.
DeanCE (2006) Antipsychotic-associated neuronal changes in the brain: toxic, therapeutic, or irrelevant to the long-term outcome of schizophrenia?Prog Neuropsychopharmacol Biol Psychiatry30: 174–189.
32.
DeutchAY (1994) Identification of the neural systems subserving the actions of clozapine: clues from immediate-early gene expression. J Clin Psychiatry55: B37–B42.
33.
DrorVShamirEGhanshaniS. (1999) hKCa3/KCNN3 potassium channel gene: association of longer CAG repeats with schizophrenia in Israeli Ashkenazi Jews, expression in human tissues and localization to chromosome 1q21. Mol Psychiatry4: 254–260.
34.
DuncanCEChetcutiAFSchofieldPR (2008) Coregulation of genes in the mouse brain following treatment with clozapine, haloperidol, or olanzapine implicates altered potassium channel subunit expression in the mechanism of antipsychotic drug action. Psychiatr Genet18: 226–239.
EastwoodSLBurnetPWHarrisonPJ (1995) Altered synaptophysin expression as a marker of synaptic pathology in schizophrenia. Neuroscience66: 309–319.
37.
EastwoodSLHarrisonPJ (1995) Decreased synaptophysin in the medial temporal lobe in schizophrenia demonstrated using immunoautoradiography. Neuroscience69: 339–343.
38.
EscamillaMLeeBDOntiverosA. (2008) The epsin 4 gene is associated with psychotic disorders in families of Latin American origin. Schizophr Res106: 253–257.
39.
EssockSMHargreavesWACovellNH. (1996) Clozapine’s effectiveness for patients in state hospitals: results from a randomized trial. Psychopharmacol Bull32: 683–697.
40.
FeherLZKalmanJPuskasLG. (2005) Impact of haloperidol and risperidone on gene expression profile in the rat cortex. Neurochem Int47: 271–280.
41.
FernoJRaederMBVik-MoAO. (2005) Antipsychotic drugs activate SREBP-regulated expression of lipid biosynthetic genes in cultured human glioma cells: a novel mechanism of action?Pharmacogenomics J5: 298–304.
42.
FibigerHC (1994) Neuroanatomical targets of neuroleptic drugs as revealed by Fos immunochemistry. J Clin Psychiatry55: B33–B36.
43.
FleischhackerWW (1999) Clozapine: a comparison with other novel antipsychotics. J Clin Psychiatry60 Suppl12: 30–34.
GoghariVMSponheimSRMacDonaldAW3rd (2010) The functional neuroanatomy of symptom dimensions in schizophrenia: a qualitative and quantitative review of a persistent question. Neurosci Biobehav Rev34: 468–486.
GurlingHPimmJMcQuillinA (2007) Replication of genetic association studies between markers at the Epsin 4 gene locus and schizophrenia in two Han Chinese samples. Schizophr Res89: 357–359.
50.
GurlingHMCritchleyHDattaSR. (2006) Genetic association and brain morphology studies and the chromosome 8p22 pericentriolar material 1 (PCM1) gene in susceptibility to schizophrenia. Arch Gen Psychiatry63: 844–854.
51.
HaggSSpigsetOBateA. (2001) Myocarditis related to clozapine treatment. J Clin Psychopharmacol21: 382–388.
52.
HalimNDWeickertCSMcClintockBW. (2003) Presynaptic proteins in the prefrontal cortex of patients with schizophrenia and rats with abnormal prefrontal development. Mol Psychiatry8: 797–810.
53.
HamnerM (2002) The effects of atypical antipsychotics on serum prolactin levels. Ann Clin Psychiatry14: 163–173.
54.
HashimotoRSuzukiTIwataN. (2005) Association study of the frizzled-3 (FZD3) gene with schizophrenia and mood disorders. J Neural Transm112: 303–307.
55.
HennahWThomsonPMcQuillinA. (2009) DISC1 association, heterogeneity and interplay in schizophrenia and bipolar disorder. Mol Psychiatry14: 865–873.
56.
HennahWVariloTKestilaM. (2003) Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. Hum Mol Genet12: 3151–3159.
57.
HilgerEBarnasC (2002) (Atypical antipsychotics in the treatment of bipolar affective disorders). Fortschr Neurol Psychiatr70: 234–242.
58.
HodgkinsonCAGoldmanDJaegerJ. (2004) Disrupted in schizophrenia 1 (DISC1): association with schizophrenia, schizoaffective disorder, and bipolar disorder. Am J Hum Genet75: 862–872.
59.
HoferMPagliusiSRHohnA. (1990) Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain. Embo J9: 2459-2464.
60.
HummerMKemmlerGKurzM. (1995) Weight gain induced by clozapine. Eur Neuropsychopharmacol5: 437–440.
61.
HuntleyGWVickersJCMorrisonJH (1994) Cellular and synaptic localization of NMDA and non-NMDA receptor subunits in neocortex: organizational features related to cortical circuitry, function and disease. Trends Neurosci17: 536–543.
62.
IdeMMuratakeTYamadaK. (2004) Genetic and expression analyses of FZD3 in schizophrenia. Biol Psychiatry56: 462–465.
63.
IrvingAJWallaceLDurakoglugilD. (2006) Leptin enhances NR2B-mediated N-methyl-D-aspartate responses via a mitogen-activated protein kinase-dependent process in cerebellar granule cells. Neuroscience138: 1137–1148.
64.
International Schizophrenia Consortium (ISC) (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature460: 748–752.
65.
JamesRAdamsRRChristieS. (2004) Disrupted in Schizophrenia 1 (DISC1) is a multicompartmentalized protein that predominantly localizes to mitochondria. Mol Cell Neurosci26: 112–122.
66.
JanssensNJanicotMPereraT (2006) The Wnt-dependent signaling pathways as target in oncology drug discovery. Invest New Drugs24: 263–280.
67.
JonesCTMorrisSYatesCM. (1992) Mutation in codon 713 of the beta amyloid precursor protein gene presenting with schizophrenia. Nat Genet1: 306–309.
68.
KaneJHonigfeldGSingerJ. (1988) Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry45: 789–796.
69.
KarlTBurneTHHerzogH (2006) Effect of Y1 receptor deficiency on motor activity, exploration, and anxiety. Behav Brain Res167: 87–93.
70.
KatsuTUjikeHNakanoT. (2003) The human frizzled-3 (FZD3) gene on chromosome 8p21, a receptor gene for Wnt ligands, is associated with the susceptibility to schizophrenia. Neurosci Lett353: 53–56.
71.
KishimotoMUjikeHOkahisaY. (2008) The frizzled 3 gene is associated with methamphetamine psychosis in the Japanese population. Behav Brain Funct4: 37–42.
72.
KoFTallericoTSeemanP (2006) Antipsychotic pathway genes with expression altered in opposite direction by antipsychotics and amphetamine. Synapse60: 141–151.
73.
KontkanenOToronenPLaksoM. (2002) Antipsychotic drug treatment induces differential gene expression in the rat cortex. J Neurochem83: 1043–1053.
74.
KorosEDorner-CiossekC (2007) The role of glycogen synthase kinase-3beta in schizophrenia. Drug News Perspect20: 437–445.
75.
KozlovskyNBelmakerRHAgamG (2002) GSK-3 and the neurodevelopmental hypothesis of schizophrenia. Eur Neuropsychopharmacol12: 13–25.
76.
KozlovskyNShanon-WeickertCTomaskovic-CrookE. (2004) Reduced GSK-3beta mRNA levels in postmortem dorsolateral prefrontal cortex of schizophrenic patients. J Neural Transm111: 1583–1592.
77.
KrebsMOGuillinOBourdellMC. (2000) Brain derived neurotrophic factor (BDNF) gene variants association with age at onset and therapeutic response in schizophrenia. Mol Psychiatry5: 558–562.
78.
KrishnanMNNgASukumaranB. (2008) RNA interference screen for human genes associated with West Nile virus infection. Nature455: 242–245.
79.
Le-NiculescuHBalaramanYPatelS. (2007) Towards understanding the schizophrenia code: an expanded convergent functional genomics approach. Am J Med Genet B Neuropsychiatr Genet144B: 129–158.
80.
LeroySGriffonNBourdelMC. (2001) Schizophrenia and the cannabinoid receptor type 1 (CB1): association study using a single-base polymorphism in coding exon 1. Am J Med Genet105: 749–752.
81.
LewisSWBarnesTRDaviesL. (2006) Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull
82.
LiebermanJJohnsCCooperT. (1989) Clozapine pharmacology and tardive dyskinesia. Psychopharmacology (Berl)99: S54–S59.
83.
LiouYJLaiICWangYC. (2006) Genetic analysis of the human ENTH (Epsin 4) gene and schizophrenia. Schizophr Res84: 236–243.
84.
LovestoneSKillickRDi FortiM. (2007) Schizophrenia as a GSK-3 dysregulation disorder. Trends Neurosci30: 142–149.
85.
MacDonaldMLEatonMEDudmanJT. (2005) Antipsychotic drugs elevate mRNA levels of presynaptic proteins in the frontal cortex of the rat. Biol Psychiatry57: 1041–1051.
86.
MarsdenCDJennerP (1980) The pathophysiology of extrapyramidal side-effects of neuroleptic drugs. Psychol Med10: 55–72.
87.
McElroySLKeckPEJr (2000) Pharmacologic agents for the treatment of acute bipolar mania. Biol Psychiatry48: 539–557.
88.
McEvoyJPLiebermanJAStroupTS. (2006) Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry163: 600–610.
89.
Mehler-WexCGrunblattEZeiskeS. (2006) Microarray analysis reveals distinct gene expression patterns in the mouse cortex following chronic neuroleptic and stimulant treatment: implications for body weight changes. J Neural Transm. 113: 1383–1393.
90.
MelkerssonK (2005) Differences in prolactin elevation and related symptoms of atypical antipsychotics in schizophrenic patients. J Clin Psychiatry66: 761–767.
MillarJKChristieSPorteousDJ (2003) Yeast two-hybrid screens implicate DISC1 in brain development and function. Biochem Biophys Res Commun311: 1019–1025.
93.
MillarJKJamesRBrandonNJ. (2004) DISC1 and DISC2: discovering and dissecting molecular mechanisms underlying psychiatric illness. Ann Med36: 367–378.
94.
MillarJKWilson-AnnanJCAndersonS. (2000) Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet9: 1415–1423.
95.
MiyoshiKHondaABabaK. (2003) Disrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth. Mol Psychiatry8: 685–694.
96.
MoensLNCeulemansSAlaertsM. (2010) PCM1 and schizophrenia: A replication study in the Northern Swedish population. Am J Med Genet Part B153B: 1240–1243.
97.
MoriceEBillardJMDenisC. (2007) Parallel loss of hippocampal LTD and cognitive flexibility in a genetic model of hyperdopaminergia. Neuropsychopharmacology32: 2108–2116.
98.
MugliaPVicenteAMVergaM. (2003) Association between the BDNF gene and schizophrenia. Mol Psychiatry8: 146–147.
99.
NadriCDeanBScarrE. (2004) GSK-3 parameters in postmortem frontal cortex and hippocampus of schizophrenic patients. Schizophr Res71: 377–382.
100.
NankoSKunugiHHirasawaH. (2003) Brain-derived neurotrophic factor gene and schizophrenia: polymorphism screening and association analysis. Schizophr Res62: 281–283.
101.
NeedACGeDWealeME. (2009) A genome-wide investigation of SNPs and CNVs in schizophrenia. PLoS Genet5: e1000373.
102.
NordMFardeL (2011) Antipsychotic occupancy of dopamine receptors in schizophrenia. CNS Neurosci Ther17: 97–103.
103.
O’DonnellPGraceAA (1998) Dysfunctions in multiple interrelated systems as the neurobiological bases of schizophrenic symptom clusters. Schizophr Bull24: 267–283.
104.
PhonphokYRosenthalKS (1991) Stabilization of clathrin coated vesicles by amantadine, tromantadine and other hydrophobic amines. FEBS Lett281: 188–190.
105.
PimmJMcQuillinAThirumalaiS. (2005) The Epsin 4 gene on chromosome 5q, which encodes the clathrin-associated protein enthoprotin, is involved in the genetic susceptibility to schizophrenia. Am J Hum Genet76: 902–907.
106.
PostAHolsboerFBehlC (1998) Induction of NF-kappaB activity during haloperidol-induced oxidative toxicity in clonal hippocampal cells: suppression of NF-kappaB and neuroprotection by antioxidants. J Neurosci18: 8236–8246.
107.
PreskornSH (2010) CNS drug development: part II: advances from the 1960s to the 1990s. J Psychiatr Pract16: 413–415.
108.
PuriVMcQuillinAChoudhuryK. (2007) Fine mapping by genetic association implicates the chromosome 1q23.3 gene UHMK1, encoding a serine/threonine protein kinase, as a novel schizophrenia susceptibility gene. Biol Psychiatry61: 873–879.
109.
PuriVMcQuillinADattaS. (2008) Confirmation of the genetic association between the U2AF homology motif (UHM) kinase 1 (UHMK1) gene and schizophrenia on chromosome 1q23.3. Eur J Hum Genet16: 1275–1282.
110.
ReimersMWeinsteinJN (2005) Quality assessment of microarrays: visualization of spatial artifacts and quantitation of regional biases. BMC Bioinformatics6: 166–174.
111.
RichelsonE (2010) New antipsychotic drugs: how do their receptor-binding profiles compare?J Clin Psychiatry71: 1243–1244.
112.
RohSAhnDHNamJH. (2006) Cardiomyopathy associated with clozapine. Exp Clin Psychopharmacol14: 94–98.
113.
RosenheckRCramerJXuW. (1997) A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. N Engl J Med337: 809–815.
114.
RosenheckREvansDHerzL. (1999) How long to wait for a response to clozapine: a comparison of time course of response to clozapine and conventional antipsychotic medication in refractory schizophrenia. Schizophr Bull25: 709–719.
115.
RottnekMRiggioSByneW. (2008) Schizophrenia in a patient with spinocerebellar ataxia 2: coincidence of two disorders or a neurodegenerative disease presenting with psychosis?Am J Psychiatry165: 964–967.
SakaeNYamasakiNKitaichiK. (2008) Mice lacking the schizophrenia-associated protein FEZ1 manifest hyperactivity and enhanced responsiveness to psychostimulants. Hum Mol Genet17: 3191–3203.
118.
SarhanSHitchcockJMGrauffelCA. (1997) Comparative antipsychotic profiles of neurotensin and a related systemically active peptide agonist. Peptides18: 1223–1227.
119.
SawamuraNSawamura-YamamotoTOzekiY. (2005) A form of DISC1 enriched in nucleus: altered subcellular distribution in orbitofrontal cortex in psychosis and substance/alcohol abuse. Proc Natl Acad Sci U S A102: 1187–1192.
120.
SchurovILHandfordEJBrandonNJ. (2004) Expression of disrupted in schizophrenia 1 (DISC1) protein in the adult and developing mouse brain indicates its role in neurodevelopment. Mol Psychiatry9: 1100–1110.
121.
SedvallGC (1996) Neurobiological correlates of acute neuroleptic treatment. Int Clin Psychopharmacol11: S41–S46.
122.
SerrettiADe RonchiDLorenziC. (2004) New antipsychotics and schizophrenia: a review on efficacy and side effects. Curr Med Chem11: 343–358.
123.
SommerJUSchmittAHeckM. (2010) Differential expression of presynaptic genes in a rat model of postnatal hypoxia: relevance to schizophrenia. Eur Arch Psychiatry Clin Neurosci260: S81–S89.
124.
SondhiSCastellanoJMChongVZ. (2006) cDNA array reveals increased expression of glucose-dependent insulinotropic polypeptide following chronic clozapine treatment: role in atypical antipsychotic drug-induced adverse metabolic effects. Pharmacogenomics J6: 131–140.
125.
SpinaEAvenosoAFacciolàG. (2000) Relationship between plasma concentrations of clozapine and norclozapine and therapeutic response in patients with schizophrenia resistant to conventional neuroleptics. Psychopharmacology (Berl)148: 83–89.
126.
StefanssonHOphoffRASteinbergS. (2009) Common variants conferring risk of schizophrenia. Nature460: 744–747.
127.
StoreyJ (2002) A direct approach to false discovery rates. A direct approach to false discovery rates. Series B: 479–498.
128.
StoreyJDTibshiraniR (2003) Statistical significance for genomewide studies. Proc Natl Acad Sci U S A100: 9440–9445.
129.
StoweZNBissetteGNemeroffCB (1991) Neurotensin-dopamine interactions: relevance to schizophrenia and the action of antipsychotic drugs. Yakubutsu Seishin Kodo11: 49–59.
130.
SullivanPFLinDTzengJY. (2008) Genomewide association for schizophrenia in the CATIE study: results of stage 1. Mol Psychiatry13: 570–584.
131.
SuttonLPHonardoustDMouyalJ. (2007) Activation of the canonical Wnt pathway by the antipsychotics haloperidol and clozapine involves dishevelled-3. J Neurochem102: 153–169.
132.
Tabares-SeisdedosRRubensteinJL (2009) Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer. Mol Psychiatry14: 563–589.
133.
TakahashiYKumanishiTHayashiS (2004) Using a DNA microarray method to examine gene expression in brain from clozapine-injected mice. Ann N Y Acad Sci1025: 561–569.
134.
TanakaTSJaradatSALimMK. (2000) Genome-wide expression profiling of mid-gestation placenta and embryo using a 15,000 mouse developmental cDNA microarray. Proc Natl Acad Sci U S A97: 9127–9132.
135.
TandonR (2002) Safety and tolerability: how do newer generation ‘atypical’ antipsychotics compare?Psychiatr Q73: 297–311.
136.
TangRQZhaoXZShiYY. (2006) Family-based association study of Epsin 4 and Schizophrenia. Mol Psychiatry11: 395–399.
137.
TarriconeICasoriaMGozziBF. (2006) Metabolic risk factor profile associated with use of second generation antipsychotics: a cross sectional study in a Community Mental Health Centre. BMC Psychiatry6: 11–19.
ThomasEAGeorgeRCDanielsonPE. (2003) Antipsychotic drug treatment alters expression of mRNAs encoding lipid metabolism-related proteins. Mol Psychiatry8: 983–993.
140.
ThuileJEvenCGuelfiJD (2005) (Mixed states in bipolar disorders: a review of current therapeutic strategies). Encephale31: 617–623.
141.
UjikeHTakakiMNakataK. (2002) CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia. Mol Psychiatry7: 515–518.
142.
VawterMPFerranEGalkeB. (2004) Microarray screening of lymphocyte gene expression differences in a multiplex schizophrenia pedigree. Schizophr Res67: 41–52.
143.
VolavkaJCzoborPCooperTB. (2004) Prolactin levels in schizophrenia and schizoaffective disorder patients treated with clozapine, olanzapine, risperidone, or haloperidol. J Clin Psychiatry65: 57–61.
144.
WisdenWHerbAWielandH. (1991) Cloning, pharmacological characteristics and expression pattern of the rat GABAA receptor alpha 4 subunit. FEBS Lett289: 227–230.
145.
WoodMMorrisM (2002) Simultaneous quantification of psychotherapeutic drugs in human plasma by tandem mass spectrometry. Paper presented at American Society of Mass Spectrometry conference, Orlando, Florida, USA3–6 June 2002.
146.
WudarskyMNicolsonRHamburgerSD. (1999) Elevated prolactin in pediatric patients on typical and atypical antipsychotics. J Child Adolesc Psychopharmacol9: 239–245.
147.
XiangYQZhangZJWengYZ. (2006) Serum concentrations of clozapine and norclozapine in the prediction of relapse of patients with schizophrenia. Schizophr Res83: 201–210.
148.
YamadaKNakamuraKMinabeY. (2004) Association analysis of FEZ1 variants with schizophrenia in Japanese cohorts. Biol Psychiatry56: 683–690.
149.
YangJSiTLingY. (2003) Association study of the human FZD3 locus with schizophrenia. Biol Psychiatry54: 1298–1301.
150.
YangYHDudoitSLuuP. (2001) Normalization for cDNA Microarray Data. SPIE BiOS 2001, San Jose, California, 30: e15.
151.
ZachrissonONomikosGGMarcusMM. (2000) Effects of antipsychotic drugs on cholecystokinin and preprotachykinin (substance P) mRNA expression in the rat hippocampal formation. Eur Neuropsychopharmacol10: 355–363.
152.
ZhangYYuXYuanY. (2004) Positive association of the human frizzled 3 (FZD3) gene haplotype with schizophrenia in Chinese Han population. Am J Med Genet B Neuropsychiatr Genet129B: 16–19.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
