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Norio Ozaki MD, PhDProfessor, Department of Psychiatry, Nagoya University Graduate School of Medicine


Specialized field

Psychiatry

Career Summary

March 1982:
Graduated from Nagoya University School of Medicine.
March 1990:
Got the Degree of Medical Science at Nagoya University School of Medicine.
July 1990:
Visiting Fellow, Clinical Psychobiology Branch, National Institute of Mental Health.
September 1995:
Assistant Professor, at department of Psychiatry, Fujita Health University School of Medicine.
March 1998:
Professor and Chairman, at department of Psychiatry, Fujita Health University School of Medicine.
October 2003:
Professor and Chairman, at department of Psychiatry, Nagoya University Graduate School of Medicine

Research Theme

Elucidation of Pathophysiology of Mental Disorders

Research Summary

Comprehensive follow-up of the Japanese genome wide association study of schizophrenia

Objective

Numerous genome-wide association studies (GWAS) of schizophrenia have been published in the past 6 years, with a number of key reports published in the last year. We conducted a Japanese genome-wide association study of schizophrenia (SZ) comprising 575 cases and 564 controls. We followed 97 markers, representing a nonredundant panel of markers derived mainly from the top 150 findings, in up to three data sets totaling 1990 cases and 5389 controls. Single-locus analysis did not reveal genome-wide support for any locus in the genome-wide association study sample (best p = 6.2 × 10-6) or in the complete data set in which the best supported locus was SULT6B1 (rs11895771: p = 3.7 × 10-5) in the meta-analysis)1. Of loci previously supported by genome-wide association studies, we obtained in the Japanese support for NOTCH4 (rs2071287: pmeta = 5.1 × 10-5).
Considering our sample size and lack of power to detect association on genome wide level (p<10-8), we selected VAV3 for follow up based on our genetic findings and prior biological studies. We performed voxel-based morphometry (VBM) and mutation screening of VAV3. Four independent samples were used in the present study: (1) for VBM analysis, we used case-control sample comprising 100 patients with schizophrenia and 264 healthy controls, (2) mutation analysis was performed on a total of 321 patients suffering from schizophrenia, and 2 case-control samples (3) 729 unrelated patients with schizophrenia and 564 healthy comparison subjects, and (4) sample comprising 1511 cases and 1517 healthy comparison subjects and were used for genetic association analysis of novel coding variants with schizophrenia.
In addition weak association signal (p<0.05) was detected within the PTPRA gene. Solid evidence links SZ susceptibility to neurodevelopmental processes involving tyrosine phosphorylation-mediated signaling. Moreover, PTPRA maps to a chromosomal region (20p13) associated with susceptibility to psychotic illness. We characterized neurobehavioral parameters, as well as gene expression in the central nervous system, of mice with a null mutation in the Ptpra gene. We searched for genetic association between polymorphisms in PTPRA and schizophrenia risk (two independent cohorts, 1420 cases and 1377 controls), and we monitored PTPRA expression in prefrontal dorsolateral cortex of SZ patients (35 cases, 2 control groups of 35 cases).

Results

The first part of the project was focused on VAV3 gene. The VBM analysis suggests that rs1410403 might affect the volume of the left superior and middle temporal gyri (p= .011 and P = .013, respectively), which were reduced in patients with schizophrenia compared with healthy subjects (figure 1). Moreover, 4 rare novel missense variants were detected. The mutations were followed-up in large independent sample, and one of the novel variants (Glu741Gly) was associated with schizophrenia (P = .02) (figure 2). Our genetic association results suggested that the rare variant, which is predicted to alter function of the VAV3, would decrease the risk of schizophrenia, whereas normal function is associated with schizophrenia. Same protective allelic effect was observed for common variant identified by JPN_GWAS.In case of VAV3, our results showed that in schizophrenia, the “rare high-risk variant” vs the “common variant with low effect” hypotheses should not be viewed as 2 mutually exclusive hypotheses. Therefore, direct resequencing of candidate genes and copy number variants on the one side and GWAS analyses on the other side could be viewed as complementary approaches to analyze the genetic susceptibilities to schizophrenia.
In the second part of our project we evaluated PTPRA gene. We found that Ptpra-/- mice reproduce neurobehavioral endophenotypes of human SZ: sensitization to methamphetamine-induced hyperactivity, defective sensorimotor gating, and defective habituation to a startle response. Ptpra loss of function also leads to reduced expression of multiple myelination genes, mimicking the hypomyelination-associated changes in gene expression observed in postmortem patient brains. We further report that a polymorphism at the PTPRA locus is genetically associated with SZ (figure 3), and that PTPRA mRNA levels are reduced in postmortem dorsolateral prefrontal cortex of subjects with SZ. This study was prompted by implications of Ptpra in developmental processes linked to schizophrenia (neuronal migration, myelination); by RPTPα acting as a signaling subunit for cell adhesion molecules (NCAM and CHL1) with genes that have been related to SZ risk; and by the mapping of a SZ locus close to PTPRA. The avenues we explored provide independent lines of convergent evidence linking RPTPα to SZ: typical changes in neuropsychological parameters in RPTPα-deficient mice, association of the human gene with disease risk, and reduced cortical PTPRA expression in SZ patients.

Principal Research Achievement

  1. Furumura K, Koide T, Okada T, Murase S, Aleksic B, Hayakawa N, Shiino T, Nakamura Y, Tamaji A, Ishikawa N, Ohoka H, Usui H, Banno N, Morita T, Goto S, Kanai A, Masuda T, Ozaki N: Prospective Study on the Association between Harm Avoidance and Postpartum Depressive State in a Maternal Cohort of Japanese Women. PLoS One, in press (2012)
  2. Aleksic B, Kushima I, Hashimoto R, Ohi K, Ikeda M, Yoshimi A, Nakamura Y, Ito Y, Okochi T, Fukuo Y, Yasuda Y, Fukumoto M, Yamamori H, Ujike H, Suzuki M, Inada T, Takeda M, Kaibuchi K, Iwata N, Ozaki N: Analysis of the VAV3 as Candidate Gene for Schizophrenia: Evidences From Voxel-Based Morphometry and Mutation Screening. Schizophr Bull, in press (2012)
  3. Tamaji A, Iwamoto K, Kawamura Y, Takahashi M, Ebe K, Kawano N, Kunimoto S, Aleksic B, Noda Y, Ozaki N: Differential effects of diazepam, tandospirone, and paroxetine on plasma brain-derived neurotrophic factor level under mental stress. Hum Psychopharmacol, in press (2012)
  4. Kushima I, Okada T, Ozaki N: Developmental disorders. Brain Nerve, 64, 139-147 (2012)
  5. Torii Y, Iritani S, Sekiguchi H, Habuchi C, Hagikura M, Arai T, Ikeda K, Akiyama H, Ozaki N: Effects of aging on the morphologies of Heschl's gyrus and the superior temporal gyrus in schizophrenia: a postmortem study. Schizophr Res, 134, 137-142 (2012)
  6. Banno M, Koide T, Aleksic B, Yamada K, Kikuchi T, Kohmura K, Adachi Y, Kawano N, Kushima I, Ikeda M, Inada T, Yoshikawa T, Iwata N, Ozaki N: A case control association study and cognitive function analysis of neuropilin and tolloid-like 1 gene and schizophrenia in the Japanese population. PLoS One, 6, e28929 (2011)
  7. Fuchikami M, Morinobu S, Segawa M, Okamoto Y, Yamawaki S, Ozaki N, Inoue T, Kusumi I, Koyama T, Tsuchiyama K, Terao T: DNA methylation profiles of the brain-derived neurotrophic factor (BDNF) gene as a potent diagnostic biomarker in major depression. PLoS One, 6, e23881 (2011)
  8. Ikeda M, Aleksic B, Kinoshita Y, Okochi T, Kawashima K, Kushima I, Ito Y, Nakamura Y, Kishi T, Okumura T, Fukuo Y, Williams HJ, Hamshere ML, Ivanov D, Inada T, Suzuki M, Hashimoto R, Ujike H, Takeda M, Craddock N, Kaibuchi K, Owen MJ, Ozaki N, O'Donovan MC, Iwata N: Genome-wide association study of schizophrenia in a Japanese population. Biol Psychiatry, 69, 472-478 (2011)
  9. Ishikawa N, Goto S, Murase S, Kanai A, Masuda T, Aleksic B, Usui H, Ozaki N: Prospective study of maternal depressive symptomatology among Japanese women. J Psychosom Res, 71, 264-269 (2011)
  10. Kishi T, Yoshimura R, Fukuo Y, Kitajima T, Okochi T, Matsunaga S, Inada T, Kunugi H, Kato T, Yoshikawa T, Ujike H, Umene-Nakano W, Nakamura J, Ozaki N, Serretti A, Correll CU, Iwata N: The CLOCK gene and mood disorders: a case-control study and meta-analysis. Chronobiol Int, 28, 825-833 (2011)
  11. Niwa M, Matsumoto Y, Mouri A, Ozaki N, Nabeshima T: Vulnerability in early life to changes in the rearing environment plays a crucial role in the aetiopathology of psychiatric disorders. Int J Neuropsychopharmacol, 14, 459-477 (2011)
  12. Sekiguchi H, Iritani S, Habuchi C, Torii Y, Kuroda K, Kaibuchi K, Ozaki N: Impairment of the tyrosine hydroxylase neuronal network in the orbitofrontal cortex of a genetically modified mouse model of schizophrenia. Brain Res, 1392, 47-53 (2011)
  13. Takahashi N, Nielsen KS, Aleksic B, Petersen S, Ikeda M, Kushima I, Vacaresse N, Ujike H, Iwata N, Dubreuil V, Mirza N, Sakurai T, Ozaki N, Buxbaum JD, Sap J: Loss of function studies in mice and genetic association link receptor protein tyrosine phosphatase alpha to schizophrenia. Biol Psychiatry, 70, 626-635 (2011)
  14. Takata A, Kim SH, Ozaki N, Iwata N, Kunugi H, Inada T, Ujike H, Nakamura K, Mori N, Ahn YM, Joo EJ, Song JY, Kanba S, Yoshikawa T, Kim YS, Kato T: Association of ANK3 with bipolar disorder confirmed in East Asia. Am J Med Genet B Neuropsychiatr Genet, 156B, 312-315 (2011)
  15. Yoshimura T, Usui H, Takahashi N, Yoshimi A, Saito S, Aleksic B, Ujike H, Inada T, Yamada M, Uchimura N, Iwata N, Sora I, Iyo M, Ozaki N: Association analysis of the GDNF gene with methamphetamine use disorder in a Japanese population. Prog Neuropsychopharmacol Biol Psychiatry, 35, 1268-1272 (2011)
  16. Kushima I, Nakamura Y, Aleksic B, Ikeda M, Ito Y, Shiino T, Okochi T, Fukuo Y, Ujike H, Suzuki M, Inada T, Hashimoto R, Takeda M, Kaibuchi K, Iwata N, Ozaki N: Resequencing and Association Analysis of the KALRN and EPHB1 Genes And Their Contribution to Schizophrenia Susceptibility. Schizophr Bull, in press (2011)
  17. Ikeda M, Aleksic B, Kinoshita Y, Okochi T, Kawashima K, Kushima I, Ito Y, Nakamura Y, Kishi T, Okumura T, Fukuo Y, Williams HJ, Hamshere ML, Ivanov D, Inada T, Suzuki M, Hashimoto R, Ujike H, Takeda M, Craddock N, Kaibuchi K, Owen MJ, Ozaki N, O'Donovan MC, Iwata N: Genome-Wide Association Study of Schizophrenia in a Japanese Population. Biol Psychiatry, 69, 472-478 (2011)
  18. Syu A, Ishiguro H, Inada T, Horiuchi Y, Tanaka S, Ishikawa M, Arai M, Itokawa M, Niizato K, Iritani S, Ozaki N, Takahashi M, Kakita A, Takahashi H, Nawa H, Keino-Masu K, Arikawa-Hirasawa E, Arinami T: Association of the HSPG2 Gene with Neuroleptic-Induced Tardive Dyskinesia. Neuropsychopharmacology, 35, 1155-1164 (2010)
  19. Hashimoto R, Noguchi H, Hori H, Nakabayashi T, Suzuki T, Iwata N, Ozaki N, Kosuga A, Tatsumi M, Kamijima K, Harada S, Takeda M, Saitoh O, Kunugi H: A genetic variation in the dysbindin gene (DTNBP1) is associated with memory performance in healthy controls. World J Biol Psychiatry, 11, 431-438 (2010)
  20. Ishiguro H, Koga M, Horiuchi Y, Noguchi E, Morikawa M, Suzuki Y, Arai M, Niizato K, Iritani S, Itokawa M, Inada T, Iwata N, Ozaki N, Ujike H, Kunugi H, Sasaki T, Takahashi M, Watanabe Y, Someya T, Kakita A, Takahashi H, Nawa H, Arinami T: Supportive evidence for reduced expression of GNB1L in schizophrenia, Schizophr Bull, in press (2011)
  21. Takahashi M, Hayashi H, Watanabe Y, Sawamura K, Fukui N, Watanabe J, Kitajima T, Yamanouchi Y, Iwata N, Mizukami K, Hori T, Shimoda K, Ujike H, Ozaki N, Iijima K, Takemura K, Aoshima H, Someya T: Diagnostic classification of schizophrenia by neural network analysis of blood-based gene expression signatures. Schizophr Res, 119, 210-218 (2010)
  22. Ohnuma T, Shibata N, Baba H, Ohi K, Yasuda Y, Nakamura Y, Okochi T, Naitoh H, Hashimoto R, Iwata N, Ozaki N, Takeda M, Arai H: No association between DAO and schizophrenia in a Japanese patient population: a multicenter replication study. Schizophr Res, 118, 300-302 (2010)
  23. Ohi K, Hashimoto R, Yasuda Y, Yoshida T, Takahashi H, Iike N, Iwase M, Kamino K, Ishii R, Kazui H, Fukumoto M, Takamura H, Yamamori H, Azechi M, Ikezawa K, Tanimukai H, Tagami S, Morihara T, Okochi M, Yamada K, Numata S, Ikeda M, Tanaka T, Kudo T, Ueno S, Yoshikawa T, Ohmori T, Iwata N, Ozaki N, Takeda M: The chitinase 3-like 1 gene and schizophrenia: Evidence from a multi-center case-control study and meta-analysis. Schizophr Res, 116, 126-132 (2010)
  24. Kushima I, Aleksic B, Ito Y, Nakamura Y, Nakamura K, Mori N, Kikuchi M, Inada T, Kunugi H, Nanko S, Kato T, Yoshikawa T, Ujike H, Suzuki M, Iwata N, Ozaki N: Association study of ubiquitin-specific peptidase 46 (USP46) with bipolar disorder and schizophrenia in a Japanese population. J Hum Genet, 55, 133-136 (2010)
  25. Kushima I, Aleksic B, Ikeda M, Yamanouchi Y, Kinoshita Y, Ito Y, Nakamura Y, Inada T, Iwata N, Ozaki N: Association study of bromodomain-containing 1 gene with schizophrenia in Japanese population. Am J Med Genet B Neuropsychiatr Genet, 153B, 786-791 (2010)
  26. Ishiguro H, Horiuchi Y, Ishikawa M, Koga M, Imai K, Suzuki Y, Morikawa M, Inada T, Watanabe Y, Takahashi M, Someya T, Ujike H, Iwata N, Ozaki N, Onaivi ES, Kunugi H, Sasaki T, Itokawa M, Arai M, Niizato K, Iritani S, Naka I, Ohashi J, Kakita A, Takahashi H, Nawa H, Arinami T: Brain Cannabinoid CB2 Receptor in Schizophrenia. Biol Psychiatry, 67, 974-982 (2010)
  27. Ikeda M, Tomita Y, Mouri A, Koga M, Okochi T, Yoshimura R, Yamanouchi Y, Kinoshita Y, Hashimoto R, Williams H.J, Takeda M, Nakamura J, Nabeshima T, Owen M.J, O'Donovan M.C, H. Honda, Arinami T, Ozaki N, Iwata N: Identification of Novel Candidate Genes for Treatment Response to Risperidone and Susceptibility for Schizophrenia: Integrated Analysis Among Pharmacogenomics, Mouse Expression, and Genetic Case-Control Association Approaches. Biol Psychiatry, 1, 67, 263-269 (2010)
  28. Ikeda M, Aleksic B, Kirov G, Kinoshita Y, Yamanouchi Y, Kitajima T, Kawashima K, Okochi T, Kishi T, Zaharieva I, Owen MJ, O'Donovan MC, Ozaki N, Iwata N: Copy number variation in schizophrenia in the Japanese population. Biol Psychiatry, 67, 283-286 (2010)
  29. Iidaka T, Saito DN, Komeda H, Mano Y, Kanayama N, Osumi T, Ozaki N, Sadato N: Transient Neural Activation in Human Amygdala Involved in Aversive Conditioning of Face and Voice. J Cogn Neurosci, 22, 2074-2085 (2010)
  30. Aleksic B, Kushima I, Ito Y, Nakamura Y, Ujike H, Suzuki M, Inada T, Hashimoto R, Takeda M, Iwata N, and Ozaki N: Genetic association study of KREMEN1 and DKK1 and schizophrenia in a Japanese population. Schizophr Res, 118, 113-117 (2010)
  31. Koga M, Ishiguro H, Yazaki S, Horiuchi Y, Arai M, Niizato K, Iritani S, Itokawa M, Inada T, Iwata N, Ozaki N, Ujike H, Kunugi H, Sasaki T, Takahashi M, Watanabe Y, Someya T, Kakita A, Takahashi H, Nawa H, Muchardt C, Yaniv M, Arinami T. Involvement of SMARCA2/BRM in the SWI/SNF chromatin-remodeling complex in schizophrenia. Hum Mol Genet, 18, 2483-2494 (2009)
  32. Yoshimi A, Takahashi N, Saito S, Ito Y, Aleksic B, Usui H, Kawamura Y, Waki Y, Yoshikawa T, Kato T, Iwata N, Inada T, Noda Y, Ozaki N. Genetic analysis of the gene coding for DARPP-32 (PPP1R1B) in Japanese patients with schizophrenia or bipolar disorder. Schizophr Res, 100, 334-341 (2008)
  33. Yamasaki N, Maekawa M, Kobayashi K, Kajii Y, Maeda J, Soma M, Takao K, Tanda K, Ohira K, Toyama K, Kanzaki K, Fukunaga K, Sudo Y, Ichinose H, Ikeda M, Iwata N, Ozaki N, Suzuki H, Higuchi M, Suhara T, Yuasa S, Miyakawa T. Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders. Mol Brain, 1, 6 (2008)
  34. Uhl GR, Drgon T, Liu QR, Johnson C, Walther D, Komiyama T, Harano M, Sekine Y, Inada T, Ozaki N, Iyo M, Iwata N, Yamada M, Sora I, Chen CK, Liu HC, Ujike H, Lin SK. Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry, 65, 345-355 (2008)
  35. Kuratomi G, Iwamoto K, Bundo M, Kusumi I, Kato N, Iwata N, Ozaki N, Kato T. Aberrant DNA methylation associated with bipolar disorder identified from discordant monozygotic twins. Mol Psychiatry, 13, 429-441 (2008)
  36. Kishimoto M, Ujike H, Motohashi Y, Tanaka Y, Okahisa Y, Kotaka T, Harano M, Inada T, Yamada M, Komiyama T, Hori T, Sekine Y, Iwata N, Sora I, Iyo M, Ozaki N, Kuroda S. The Dysbindin Gene (DTNBP1) Is Associated with Methamphetamine Psychosis. Biol Psychiatry, 63, 191-196 (2008)
  37. Inada T, Koga M, Ishiguro H, Horiuchi Y, Syu A, Yoshio T, Takahashi N, Ozaki N, Arinami T. Pathway-based association analysis of genome-wide screening data suggest that genes associated with the gamma-aminobutyric acid receptor signaling pathway are involved in neuroleptic-induced, treatment-resistant tardive dyskinesia. Pharmacogenet Genomics, 18, 317-323 (2008)
  38. Ikeda M, Yamanouchi Y, Kinoshita Y, Kitajima T, Yoshimura R, Hashimoto S, O'Donovan MC, Nakamura J, Ozaki N, Iwata N. Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first-episode schizophrenia. Pharmacogenomics, 9, 1437-1443 (2008)
  39. Ikeda M, Takahashi N, Saito S, Aleksic B, Watanabe Y, Nunokawa A, Yamanouchi Y, Kitajima T, Kinoshita Y, Kishi T, Kawashima K, Hashimoto R, Ujike H, Inada T, Someya T, Takeda M, Ozaki N, Iwata N. Failure to replicate the association between NRG1 and schizophrenia using Japanese large sample. Schizophr Res, 101, 1-8 (2008)
  40. Ikeda M, Hikita T, Taya S, Uraguchi-Asaki J, Toyo-oka K, Wynshaw-Boris A, Ujike H, Inada T, Takao K, Miyakawa T, Ozaki N, Kaibuchi K, Iwata N. Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia. Hum Mol Genet, 17, 3212-3222 (2008)
  41. Ohnishi T et al. A Promoter Haplotype of the Inositol Monophosphatase 2 Gene (IMPA2) at 18p11.2 Confers a Possible Risk for Bipolar Disorder by Enhancing Transcription. Neuropsychopharmacology 32: 1727-1737 (2007)
  42. Matsuzawa D et al. Identification of Functional Polymorphisms in the Promoter Region of the Human PICK1 Gene and Their Association With Methamphetamine Psychosis. Am. J. Psychiatry 164: 1105-1114 (2007)
  43. Horiuchi Y et al. Support for association of the PPP3CC gene with schizophrenia. Mol. Psychiatry 12: 891-893 (2007)
  44. Hashimoto R et al. Pituitary adenylate cyclase-activating polypeptide is associated with schizophrenia. Mol. Psychiatry 12: 1026-1032 (2007)
  45. Ikeda M et al. Positive association of the serotonin 5-HT7 receptor gene with schizophrenia in a Japanese population. Neuropsychopharmacology 31: 866-871 (2006)
  46. Hashimoto R et al. Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling. Hum. Mol. Genet. 15: 3024-3033 (2006)
  47. Ikeda M et al. Association Analysis of Chromosome 5 GABA(A) Receptor Cluster in Japanese Schizophrenia Patients. Biol. Psychiatry 58: 440-445 (2005)
  48. Arinami T et al. Genomewide high-density SNP linkage analysis of 236 Japanese families supports the existence of schizophrenia susceptibility Loci on chromosomes 1p, 14q, and 20p. Am. J. Hum. Genet. 77: 937-944 (2005)
  49. Iidaka T et al. A variant C178T in the regulatory region of the serotonin receptor gene HTR3A modulates neural activation in the human amygdala. J. Neurosci. 25: 6460-6466 (2005)
  50. Okada M et al. Modification of Human 5-HT2C Receptor Function by Cys23Ser, an Abundant, Naturally Occurring Amino Acid Substitution. Mol. Psychiatry 9: 55-64 (2004)
  51. Numakawa T et al. Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. Hum. Mol. Genet. 13: 2699-2708 (2004)
  52. Iwata N et al. No Association With the Neuregulin 1 Haplotype to Japanese Schizophrenia. Mol. Psychiatry 9: 126-127 (2004)
  53. Ikeda M et al. Association of AKT1 with schizophrenia confirmed in a Japanese population. Biol. Psychiatry 56: 698-700 (2004)
  54. Ozaki N et al. Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype. Mol. Psychiatry 8: 933-936 (2003)
  55. Iwata N et al. Association of a 5-HT(5A) receptor polymorphism, Pro15Ser, to schizophrenia. Mol. Psychiatry 6: 217-219 (2001)
  56. Lappalainen J et al. Linkage of antisocial alcoholism to the serotonin 5-HT1B receptor gene in 2 populations. Arch. Gen. Psychiatry 55: 989-994 (1998)
  57. Schwartz PJ et al. Effects of meta-chlorophenylpiperazine infusions in patients with seasonal affective disorder and healthy control subjects. Diurnal responses and nocturnal regulatory mechanisms. Arch. Gen. Psychiatry 54: 375-385 (1997)
  58. Ozaki N. et al. Two naturally occurring amino acid substitutions of the 5-HT2A receptor, similar prevalence in patients with seasonal affective disorder and controls. Biol. Psychiatry 40: 1267-1272 (1996)
  59. Malhotra AK et al. Lack of association between polymorphisms in the 5-HT2A receptor gene and the antipsychotic response to clozapine. Am. J. Psychiatry 153: 1092-1094 (1996)
  60. Ozaki N et al. Prevalence of seasonal difficulties in mood and behavior among Japanese civil servants. Am. J. Psychiatry 152: 1225-1227 (1995)

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