研究目的：本研究主要探討第二型雙極症是否合併焦慮症，在多巴胺系統中乙醛脱氢酶(aldehyde dehydrogenase 2, ALDH2)與第二型多巴胺受體(dopamine D2 receptor, DRD2)基因型之差異與影響。為減少不同亞型雙極症之間病因的高異質性，本研究進一步分類雙極症亞型，僅收集第二型雙極症之案例。從基因的角度切入，探討第二型雙極症合併與不合併焦慮症，其合併焦慮症為一種症狀，亦或者為一特殊亞型。
研究背景：當雙極症患者合併其他疾病時，往往造成病情更加不穩定、藥物治療效果差、預後不佳等負面影響，其中雙極症最常見的合併疾患為，物質依賴/濫用與焦慮症(包括廣泛性焦慮症、社交恐懼症、恐慌發作、強迫症以及創傷後壓力症候群等)。然而，有關雙極症合併焦慮症之研究，至今仍未被學界所重視，僅有少部分研究著重在雙極症合併創傷後壓力症候群或強迫症。目前已有許多研究證實多巴胺系統與雙極症和焦慮症有關，其中多巴胺系統中ALDH2與DRD2為較多研究且具影響的基因。然而，在有關DRD2基因與雙極症或焦慮症的研究，並未得到一致的發現。此外，台灣漢族之雙極症合併焦慮症的比例遠較歐美人種低，因此較易收集第二型雙極症未合併焦慮症之患者，進一步比較DRD2與ALDH2基因及其交互作用在第二型雙極症合併/不合併焦慮症之間的相關。
研究方法：本研究共收集462名第二型雙極症的案例，其中335名為第二型雙極症未合併焦慮症，127名為第二型雙極症合併焦慮症，以及348名之健康受試者做為控制組。此外，在第二型雙極症之診斷標準，以較具研究基礎之輕躁狂發作持續2天做為本研究之收案標準。每一名參與研究的第二型雙極症案例，均經過精神科專科醫師診斷為第二型雙極症後，再由受過完整訓練的專業心理人員以中文版結構性診斷晤談(Chinese Version of the Modified Schedule of Affective Disorder and Schizophrenia- Lifetime, SADS-L)確認其診斷。確定符合研究納入條件後，將收取受試者血樣進行聚合酶鏈鎖反應(Polymerase chain reaction, PCR)以檢測其DRD2及ALDH2之基因型。
研究結果：邏輯氏迴歸分析結果發現，僅DRD2 Taq-I A1/A2基因型與第二型雙極症合併焦慮症有關，而在DRD2 Taq-I A1/A1 與ALDH2*1*1兩種基因型的交互作用下，則與第二型雙極症不合併焦慮症有關。
研究討論：本研究結果支持第二型雙極症合併與不合併焦慮症，分別具有不同的遺傳機制，可能為兩種不同亞型，且DRD2 Taq-I A1/A2此基因型可能為第二型雙極症合併焦慮症之主要致病基因，而同時具有DRD2 Taq-I A1/A1與ALDH2*1*1此兩種基因型的案例，較容易罹患第二型雙極症不合併焦慮症。

Aim: The aim of this study was to clarify aldehyde dehydrogenase 2 (ALDH2) and dopamine D2 receptor (DRD2) genes for predisposition to Bipolar II disorder (BP-II) comorbid with and without anxiety disorders (AD). To specify phenotype of BP-II and to reduce heterogeneity in the etiology of BP-II might support that comorbid AD is a subtype of BP-II.
Background: The presence of comorbidity compounds disability, complicates treatment, and appears to worse the prognosis of bipolar disorders (BP). The frequently comorbid conditions include substance use disorders and anxiety disorders (AD) (generalized anxiety disorder, social phobia, panic disorder, obsessive compulsive disorder, and post-traumatic stress disorder), but comorbid AD has been underrecognized and understudies. The dopaminergic system has been implicated in the pathogenesis of BP and AD. The genes involved in metabolizing dopamine and encoding dopamine receptors, such as the aldehyde dehydrogenase 2 (ALDH2) and dopamine D2 receptor (DRD2) genes may be important. In the past few decades, a number of studies have investigated the association of DRD2 gene with BP as well as AD, but the findings are controversial. However, the comorbidity rate of AD and BP was relatively lower in the Han Chinese population than in the Western population. It may be easier for us to clarify the association of the DRD2 and ALDH2 polymorphisms and the possible interactions in BP-II with and without AD.
Method: The sample consisted of total 462 BP-II patients with Research Diagnostic Criteria for 2-day hypomania cutoff based on DSM-IV-TR. 335 subjects were BP-II without AD, 127 subjects were of BP-II with AD and 348 were healthy subjects as normal control. The diagnosis for each patient was made by an attending psychiatrist and confirmed by a clinical psychologist using the Chinese Version of the Modified Schedule of Affective Disorder and Schizophrenia-Lifetime (SADS-L) to screen their psychiatric conditions. The genotypes of the ALDH2 and DRD2 TaqIA polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis.
Results: Logistic regression analysis showed a statistically significant association between DRD2 Taq-I A1/A2 genotype and BP-II with AD (OR=2.231, P=0.021). Moreover, a significant interaction of the DRD2 Taq-I A1/A1 and the ALDH2*1*1 genotypes in BP-II without AD was revealed. (OR=5.623, P= 0.001) to compare with normal control.
Conclusion: Our findings support the hypothesis that a unique genetic distinction between BP-II with and without AD, and suggest a novel association between DRD2 Taq-I A1/A2 genotype and BP-II with AD. Our study also provides further evidence that the ALDH2 and DRD2 genes interact in BP-II, particularly BP-II without AD.

Agarwal, D.P., and Goedde, H.W. Pharmacogenetics of alcohol metabolism and alcoholism. Pharmacogenetics 2, 48-62, 1992.
Akiskal, H.S., Djenderedjian, A.M., Rosenthal, R.H., and Khani, M.K. Cyclothymic disorder: validating criteria for inclusion in the bipolar affective group. The American journal of psychiatry 134, 1227-1233, 1977.
Akiskal, H.S., Rosenthal, R.H., Rosenthal, T.L., Kashgarian, M., Khani, M.K., and Puzantian, V.R. Differentiation of primary affective illness from situational, symptomatic, and secondary depressions. Arch Gen Psychiatry 36, 635-643, 1979.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorder-TR, 5th edn. American Psychiatric Association:Washington, 2000.
Angst, J. Panic disorder: History and epidemiology. European psychiatry : the journal of the Association of European Psychiatrists 13 Suppl 2, 51s-55s, 1998.
Angst, J. The bipolar spectrum. The British journal of psychiatry : the journal of mental science 190, 189-191, 2007.
Angst, J., Gamma, A., Benazzi, F., Ajdacic, V., Eich, D., and Rossler, W. Toward a re-definition of subthreshold bipolarity: epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania. Journal of affective disorders 73, 133-146, 2003.
Bauer, M.S., Altshuler, L., Evans, D.R., Beresford, T., Williford, W.O., and Hauger, R. Prevalence and distinct correlates of anxiety, substance, and combined comorbidity in a multi-site public sector sample with bipolar disorder. Journal of affective disorders 85, 301-315, 2005.
Benazzi, F. Is 4 days the minimum duration of hypomania in bipolar II disorder? European archives of psychiatry and clinical neuroscience 251, 32-34, 2001.
Boylan, K.R., Bieling, P.J., Marriott, M., Begin, H., Young, L.T., and MacQueen, G.M. Impact of comorbid anxiety disorders on outcome in a cohort of patients with bipolar disorder. The Journal of clinical psychiatry 65, 1106-1113, 2004.
Brugue, E., and Vieta, E. Atypical antipsychotics in bipolar depression: neurobiological basis and clinical implications. Prog Neuropsychopharmacol Biol Psychiatry 31, 275-282, 2007.
Carlson, C.S., Eberle, M.A., Kruglyak, L., and Nickerson, D.A. Mapping complex disease loci in whole-genome association studies. Nature 429, 446-452, 2004.
Chang, Y.H., Chen, S.L., Chen, S.H., Chu, C.H., Lee, S.Y., Yang, H.F., Tzeng, N.S., Lee, I.H., Chen, P.S., Yeh, T.L., et al. Low anxiety disorder comorbidity rate in bipolar disorders in Han Chinese in Taiwan. Prog Neuropsychopharmacol Biol Psychiatry 36, 194-197, 2012.
Chen, C.C., Lu, R.B., Chen, Y.C., Wang, M.F., Chang, Y.C., Li, T.K., and Yin, S.J. Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism. American journal of human genetics 65, 795-807, 1999.
Comings, D.E. Molecular heterosis as the explanation for the controversy about the effect of the DRD2 gene on dopamine D2 receptor density. Molecular psychiatry 4, 213-215, 1999.
Comings, D.E., and MacMurray, J.P. Molecular heterosis: a review. Mol Genet Metab 71, 19-31, 2000.
Coryell, W., Endicott, J., Maser, J.D., Keller, M.B., Leon, A.C., and Akiskal, H.S. Long-term stability of polarity distinctions in the affective disorders. The American journal of psychiatry 152, 385-390, 1995.
Crabb, D.W., Edenberg, H.J., Bosron, W.F., and Li, T.K. Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity. The inactive ALDH2(2) allele is dominant. J Clin Invest 83, 314-316, 1989.
Craddock, N., and Sklar, P. Genetics of bipolar disorder: successful start to a long journey. Trends Genet 25, 99-105, 2009.
Dandre, F., Cassaigne, A., and Iron, A. The frequency of the mitochondrial aldehyde dehydrogenase I2 (atypical) allele in Caucasian, Oriental and African black populations determined by the restriction profile of PCR-amplified DNA. Mol Cell Probes 9, 189-193, 1995.
Doughty, C.J., Wells, J.E., Joyce, P.R., Olds, R.J., and Walsh, A.E. Bipolar-panic disorder comorbidity within bipolar disorder families: a study of siblings. Bipolar disorders 6, 245-252, 2004.
Dunlop, B.W., and Nemeroff, C.B. The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry 64, 327-337, 2007.
Endicott, J., and Spitzer, R.L. A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiatry 35, 837-844, 1978.
Fan, J., Ionita-Laza, I., McQueen, M.B., Devlin, B., Purcell, S., Faraone, S.V., Allen, M.H., Bowden, C.L., Calabrese, J.R., Fossey, M.D., et al. Linkage disequilibrium mapping of the chromosome 6q21-22.31 bipolar I disorder susceptibility locus. Am J Med Genet B Neuropsychiatr Genet 153B, 29-37, 2010.
Freeman, M.P., Freeman, S.A., and McElroy, S.L. The comorbidity of bipolar and anxiety disorders: prevalence, psychobiology, and treatment issues. Journal of affective disorders 68, 1-23, 2002.
Furlong, R.A., Coleman, T.A., Ho, L., Rubinsztein, J.S., Walsh, C., Paykel, E.S., and Rubinsztein, D.C. No association of a functional polymorphism in the dopamine D2 receptor promoter region with bipolar or unipolar affective disorders. Am J Med Genet 81, 385-387, 1998.
Gerner, R.H., Post, R.M., and Bunney, W.E., Jr. A dopaminergic mechanism in mania. The American journal of psychiatry 133, 1177-1180, 1976.
Gershon, A.A., Vishne, T., and Grunhaus, L. Dopamine D2-like receptors and the antidepressant response. Biol Psychiatry 61, 145-153, 2007.
Golimbet, V.E., Aksenova, M.G., Abramova, L.I., Kaleda, V.G., Orlova, V.A., Braga, E.A., Nosikov, V.V., and Trubnikov, V.I. [Association of allele polymorphism of dopamine d2 receptors with schizophrenic and affective disorders]. Zh Nevrol Psikhiatr Im S S Korsakova 98, 32-35, 1998.
Grandy, D.K., Zhang, Y., and Civelli, O. Pcr Detection of the Taqa Rflp at the Drd2 Locus. Human molecular genetics 2, 2197-2197, 1993.
Hayden, E.P., Klein, D.N., Dougherty, L.R., Olino, T.M., Laptook, R.S., Dyson, M.W., Bufferd, S.J., Durbin, C.E., Sheikh, H.I., and Singh, S.M. The dopamine D2 receptor gene and depressive and anxious symptoms in childhood: associations and evidence for gene-environment correlation and gene-environment interaction. Psychiatr Genet 20, 304-310, 2010.
Huang, S.Y., Lin, W.W., Ko, H.C., Lee, J.F., Wang, T.J., Chou, Y.H., Yin, S.J., and Lu, R.B. Possible interaction of alcohol dehydrogenase and aldehyde dehydrogenase genes with the dopamine D2 receptor gene in anxiety-depressive alcohol dependence. Alcohol Clin Exp Res 28, 374-384, 2004.
Joe, K.H., Kim, D.J., Park, B.L., Yoon, S., Lee, H.K., Kim, T.S., Cheon, Y.H., Gwon, D.H., Cho, S.N., Lee, H.W., et al. Genetic association of DRD2 polymorphisms with anxiety scores among alcohol-dependent patients. Biochemical and biophysical research communications 371, 591-595, 2008.
Jonsson, E.G., Nothen, M.M., Grunhage, F., Farde, L., Nakashima, Y., Propping, P., and Sedvall, G.C. Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Molecular psychiatry 4, 290-296, 1999.
Joshi, G., and Wilens, T. Comorbidity in pediatric bipolar disorder. Child Adolesc Psychiatr Clin N Am 18, 291-319, vii-viii, 2009.
Judd, L.L., Akiskal, H.S., Schettler, P.J., Coryell, W., Maser, J., Rice, J.A., Solomon, D.A., and Keller, M.B. The comparative clinical phenotype and long term longitudinal episode course of bipolar I and II: a clinical spectrum or distinct disorders? Journal of affective disorders 73, 19-32, 2003.
Keck, P.E., Jr., McElroy, S.L., and Arnold, L.M. Bipolar disorder. Med Clin North Am 85, 645-661, ix, 2001.
Kelsoe, J.R. Arguments for the genetic basis of the bipolar spectrum. Journal of affective disorders 73, 183-197, 2003.
Kessler, D., Lloyd, K., Lewis, G., and Gray, D.P. Cross sectional study of symptom attribution and recognition of depression and anxiety in primary care. BMJ 318, 436-439, 1999.
Keung, W.M., and Vallee, B.L. Daidzin: a potent, selective inhibitor of human mitochondrial aldehyde dehydrogenase. Proceedings of the National Academy of Sciences of the United States of America 90, 1247-1251, 1993.
Keung, W.M., and Vallee, B.L. Daidzin and its antidipsotropic analogs inhibit serotonin and dopamine metabolism in isolated mitochondria. Proceedings of the National Academy of Sciences of the United States of America 95, 2198-2203, 1998.
Kirov, G., Jones, I., McCandless, F., Craddock, N., and Owen, M.J. Family-based association studies of bipolar disorder with candidate genes involved in dopamine neurotransmission: DBH, DAT1, COMT, DRD2, DRD3 and DRD5. Molecular psychiatry 4, 558-565, 1999.
Klein, D.N., and Riso, L.P. Psychiatric Disorders: Problems of Boundaries and Comorbidity. In Basic Issues in Psychopathology C.G. Costello, ed. Guilford Press: New York, pp. 19-66, 1993.
Lamensdorf, I., Eisenhofer, G., Harvey-White, J., Nechustan, A., Kirk, K., and Kopin, I.J. 3,4-Dihydroxyphenylacetaldehyde potentiates the toxic effects of metabolic stress in PC12 cells. Brain research 868, 191-201, 2000.
Lee, H.C., Lee, H.S., Jung, S.H., Yi, S.Y., Jung, H.K., Yoon, J.H., and Kim, C.Y. Association between polymorphisms of ethanol-metabolizing enzymes and susceptibility to alcoholic cirrhosis in a Korean male population. J Korean Med Sci 16, 745-750, 2001.
Lee, S.Y., Chen, S.L., Chang, Y.H., Chen, S.H., Chu, C.H., Huang, S.Y., Tzeng, N.S., Wang, C.L., Lee, I.H., Yeh, T.L., et al. The ALDH2 and DRD2/ANKK1 genes interacted in bipolar II but not bipolar I disorder. Pharmacogenet Genomics 20, 500-506, 2010a.
Lee, S.Y., Hahn, C.Y., Lee, J.F., Huang, S.Y., Chen, S.L., Kuo, P.H., Lee, I.H., Yeh, T.L., Yang, Y.K., Chen, S.H., et al. MAOA interacts with the ALDH2 gene in anxiety-depression alcohol dependence. Alcohol Clin Exp Res 34, 1212-1218, 2010b.
Leszczynska-Rodziewicz, A., Hauser, J., Dmitrzak-Weglarz, M., Skibinska, M., Czerski, P., Zakrzewska, M., Kosmowska, M., and Rybakowski, J. Lack of association between polymorphisms of dopamine receptors, type D2, and bipolar affective illness in a Polish population. Medical Science Monitor 11, Cr289-Cr295, 2005.
Li, T., Liu, X.H., Sham, P.C., Aitchison, K.J., Cai, G.Q., Arranz, M.J., Deng, H., Liu, J., Kirov, G., Murray, R.M., et al. Association analysis between dopamine receptor genes and bipolar affective disorder. Psychiatry research 86, 193-201, 1999.
Li, X., Zhang, J., Wang, Y., Ji, J., Yang, F., Wan, C., Wang, P., Feng, G., Lindpaintner, K., He, L., et al. Association study on the NAPG gene and bipolar disorder in the Chinese Han population. Neuroscience letters 457, 159-162, 2009.
Lin, C.H., Lin, S.H., and Jang, F.L. Adjunctive low-dose aripiprazole with standard-dose sertraline in treating fresh major depressive disorder: a randomized, double-blind, controlled study. Journal of clinical psychopharmacology 31, 563-568, 2011.
Mann, J.J., and Kapur, S. A Dopaminergic Hypothesis of Major Depression. Clinical Neuropharmacology 18, S57-S65, 1995.
Mardh, G., and Vallee, B.L. Human class I alcohol dehydrogenases catalyze the interconversion of alcohols and aldehydes in the metabolism of dopamine. Biochemistry 25, 7279-7282, 1986.
McElroy, S.L. Diagnosing and treating comorbid (complicated) bipolar disorder. The Journal of clinical psychiatry 65 Suppl 15, 35-44, 2004.
McGuffin, P., Rijsdijk, F., Andrew, M., Sham, P., Katz, R., and Cardno, A. The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry 60, 497-502, 2003.
McIntyre, R.S., Soczynska, J.K., Bottas, A., Bordbar, K., Konarski, J.Z., and Kennedy, S.H. Anxiety disorders and bipolar disorder: a review. Bipolar disorders 8, 665-676, 2006.
McMahon, F.J., Simpson, S.G., McInnis, M.G., Badner, J.A., MacKinnon, D.F., and DePaulo, J.R. Linkage of bipolar disorder to chromosome 18q and the validity of bipolar II disorder. Arch Gen Psychiatry 58, 1025-1031, 2001.
Nakamura, K., Iwahashi, K., Matsuo, Y., Miyatake, R., Ichikawa, Y., and Suwaki, H. Characteristics of Japanese alcoholics with the atypical aldehyde dehydrogenase 2*2. I. A comparison of the genotypes of ALDH2, ADH2, ADH3, and cytochrome P-4502E1 between alcoholics and nonalcoholics. Alcohol Clin Exp Res 20, 52-55, 1996.
Nierenberg, A.A., Dougherty, D., and Rosenbaum, J.F. Dopaminergic agents and stimulants as antidepressant augmentation strategies. The Journal of clinical psychiatry 59 Suppl 5, 60-63; discussion 64, 1998.
Noble, E.P., Blum, K., Ritchie, T., Montgomery, A., and Sheridan, P.J. Allelic association of the D2 dopamine receptor gene with receptor-binding characteristics in alcoholism. Arch Gen Psychiatry 48, 648-654, 1991.
Noble, E.P., Gottschalk, L.A., Fallon, J.H., Ritchie, T.L., and Wu, J.C. D-2 dopamine receptor polymorphism and brain regional glucose metabolism. American Journal of Medical Genetics 74, 162-166, 1997.
Nothen, M.M., Erdmann, J., Korner, J., Lanczik, M., Fritze, J., Fimmers, R., Grandy, D.K., O'Dowd, B., and Propping, P. Lack of association between dopamine D1 and D2 receptor genes and bipolar affective disorder. The American journal of psychiatry 149, 199-201, 1992.
Osby, U., Brandt, L., Correia, N., Ekbom, A., and Sparen, P. Excess mortality in bipolar and unipolar disorder in Sweden. Arch Gen Psychiatry 58, 844-850, 2001.
Pallanti, S., Quercioli, L., Pazzagli, A., Rossi, A., Dell'Osso, L., Pini, S., and Cassano, G.B. Awareness of illness and subjective experience of cognitive complaints in patients with bipolar I and bipolar II disorder. The American journal of psychiatry 156, 1094-1096, 1999.
Pearlson, G.D., Wong, D.F., Tune, L.E., Ross, C.A., Chase, G.A., Links, J.M., Dannals, R.F., Wilson, A.A., Ravert, H.T., Wagner, H.N., Jr., et al. In vivo D2 dopamine receptor density in psychotic and nonpsychotic patients with bipolar disorder. Arch Gen Psychiatry 52, 471-477, 1995.
Pohjalainen, T., Rinne, J.O., Nagren, K., Lehikoinen, P., Anttila, K., Syvalahti, E.K., and Hietala, J. The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers. Molecular psychiatry 3, 256-260, 1998.
Rakofsky, J.J., Ressler, K.J., and Dunlop, B.W. BDNF function as a potential mediator of bipolar disorder and post-traumatic stress disorder comorbidity. Molecular psychiatry 17, 22-35, 2012.
Rihmer, Z., Szadoczky, E., Furedi, J., Kiss, K., and Papp, Z. Anxiety disorders comorbidity in bipolar I, bipolar II and unipolar major depression: results from a population-based study in Hungary. Journal of affective disorders 67, 175-179, 2001.
Ritchie, T., and Noble, E.P. Association of seven polymorphisms of the D2 dopamine receptor gene with brain receptor-binding characteristics. Neurochem Res 28, 73-82, 2003.
Rooke, N., Li, D.J., Li, J., and Keung, W.M. The mitochondrial monoamine oxidase-aldehyde dehydrogenase pathway: a potential site of action of daidzin. J Med Chem 43, 4169-4179, 2000.
Rotondo, A., Mazzanti, C., Dell'Osso, L., Rucci, P., Sullivan, P., Bouanani, S., Gonnelli, C., Goldman, D., and Cassano, G.B. Catechol o-methyltransferase, serotonin transporter, and tryptophan hydroxylase gene polymorphisms in bipolar disorder patients with and without comorbid panic disorder. The American journal of psychiatry 159, 23-29, 2002.
Saint-Cyr, J.A., Taylor, A.E., and Lang, A.E. Neuropsychological and psychiatric side effects in the treatment of Parkinson's disease. Neurology 43, S47-52, 1993.
Savoye, C., Laurent, C., Amadeo, S., Gheysen, F., Leboyer, M., Lejeune, J., Zarifian, E., and Mallet, J. No association between dopamine D1, D2, and D3 receptor genes and manic-depressive illness. Biol Psychiatry 44, 644-647, 1998.
Silverstone, T., and Romans-Clarkson, S. Bipolar affective disorder: causes and prevention of relapse. The British journal of psychiatry : the journal of mental science 154, 321-335, 1989.
Simon, G.E. Social and economic burden of mood disorders. Biol Psychiatry 54, 208-215, 2003.
Simon, N.M., Otto, M.W., Wisniewski, S.R., Fossey, M., Sagduyu, K., Frank, E., Sachs, G.S., Nierenberg, A.A., Thase, M.E., and Pollack, M.H. Anxiety disorder comorbidity in bipolar disorder patients: data from the first 500 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). The American journal of psychiatry 161, 2222-2229, 2004.
Sipila, T., Kananen, L., Greco, D., Donner, J., Silander, K., Terwilliger, J.D., Auvinen, P., Peltonen, L., Lonnqvist, J., Pirkola, S., et al. An association analysis of circadian genes in anxiety disorders. Biol Psychiatry 67, 1163-1170, 2010.
Smith, E.N., Bloss, C.S., Badner, J.A., Barrett, T., Belmonte, P.L., Berrettini, W., Byerley, W., Coryell, W., Craig, D., Edenberg, H.J., et al. Genome-wide association study of bipolar disorder in European American and African American individuals. Molecular psychiatry 14, 755-763, 2009.
Sokoloff, P., Giros, B., Martres, M.P., Bouthenet, M.L., and Schwartz, J.C. Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347, 146-151, 1990.
Souery, D., Lipp, O., Mahieu, B., Mendelbaum, K., De Martelaer, V., Van Broeckhoven, C., and Mendlewicz, J. Association study of bipolar disorder with candidate genes involved in catecholamine neurotransmission: DRD2, DRD3, DAT1, and TH genes. American Journal of Medical Genetics 67, 551-555, 1996.
Spitzer, R.L., Endicott, J., and Williams, J.B. Research diagnostic criteria. Arch Gen Psychiatry 36, 1381-1383, 1979.
Squassina, A., Manchia, M., Costa, M., Chillotti, C., Ardau, R., Del Zompo, M., and Severino, G. Age at onset in bipolar disorder: Investigation of the role of TaqIA polymorphism of DRD2 gene in a Sardinian sample. European psychiatry : the journal of the Association of European Psychiatrists 26, 141-143, 2011.
Stober, G., Jatzke, S., Heils, A., Jungkunz, G., Knapp, M., Mossner, R., Riederer, P., and Lesch, K.P. Insertion/deletion variant (-141C Ins/Del) in the 5' regulatory region of the dopamine D2 receptor gene: lack of association with schizophrenia and bipolar affective disorder. Short communication. J Neural Transm 105, 101-109, 1998.
Tamam, L. [Comorbid anxiety disorders in bipolar disorder patients: a review]. Turk Psikiyatri Derg 18, 59-71, 2007.
Taylor, A.E., and Saint-Cyr, J.A. Depression in Parkinson's disease: reconciling physiological and psychological perspectives. J Neuropsychiatry Clin Neurosci 2, 92-98, 1990.
Thomasson, H.R., Edenberg, H.J., Crabb, D.W., Mai, X.L., Jerome, R.E., Li, T.K., Wang, S.P., Lin, Y.T., Lu, R.B., and Yin, S.J. Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. American journal of human genetics 48, 677-681, 1991.
Thompson, J., Thomas, N., Singleton, A., Piggott, M., Lloyd, S., Perry, E.K., Morris, C.M., Perry, R.H., Ferrier, I.N., and Court, J.A. D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. Pharmacogenetics 7, 479-484, 1997.
Urata, T., Takahashi, N., Hakamata, Y., Iijima, Y., Kuwahara, N., Ozaki, N., Ono, Y., Amano, M., and Inada, T. Gene-gene interaction analysis of personality traits in a Japanese population using an electrochemical DNA array chip analysis. Neuroscience letters 414, 209-212, 2007.
Vieta, E., Gasto, C., Otero, A., Nieto, E., and Vallejo, J. Differential features between bipolar I and bipolar II disorder. Comprehensive psychiatry 38, 98-101, 1997.
Vieta, E., and Suppes, T. Bipolar II disorder: arguments for and against a distinct diagnostic entity. Bipolar disorders 10, 163-178, 2008.
Wozniak, J., Biederman, J., Monuteaux, M., Richards, J., and Faraone, S.V. Parsing hte comorbidity between bipolar disorder and anxiety disorders: A familial risk analysis. J Child Adolescent Psychopharmacology 12, 101-111, 2002.
Wu, H.I., Chang, Y.H., Lai, C.C., Wu, J.Y., Chen, S.L., Chu, C.H., Lee, I.H., Yeh, T.L., Tzeng, N.S., Huang, S.Y., et al. The effect of comorbid anxiety disorder on neuropsychological function in bipolar II disorder. Prog Neuropsychopharmacol Biol Psychiatry 35, 1841-1845, 2011.
Wurst, F.M., Tabakoff, B., Alling, C., Aradottir, S., Wiesbeck, G.A., Muller-Spahn, F., Pragst, F., Johnson, B., Javors, M., Ait-Daoud, N., et al. World Health Organization/International Society for Biomedical Research on Alcoholism study on state and trait markers of alcohol use and dependence: back to the future. Alcohol Clin Exp Res 29, 1268-1275, 2005.
Yoshida, A., Hsu, L.C., and Yasunami, M. Genetics of human alcohol-metabolizing enzymes. Prog Nucleic Acid Res Mol Biol 40, 255-287, 1991.
Zou, Y.F., Wang, F., Feng, X.L., Li, W.F., Tian, Y.H., Tao, J.H., Pan, F.M., and Huang, F. Association of DRD2 gene polymorphisms with mood disorders: a meta-analysis. Journal of affective disorders 136, 229-237, 2012.
Zutshi, A., Reddy, Y.C., Thennarasu, K., and Chandrashekhar, C.R. Comorbidity of anxiety disorders in patients with remitted bipolar disorder. European archives of psychiatry and clinical neuroscience 256, 428-436, 2006.