研究背景：躁鬱症第一型(Bipolar-I Disorder) 與焦慮疾患(Anxiety Disorders) 和物質使用疾患 (Substance Use Disorders) 具有很高的共病比例。共病不只增加公共衛生研究和臨床治療的挑戰，並會表現更為複雜和難以釐清的疾病成因。本研究試圖以實徵取向研究方法，探討第一型躁鬱症病人之焦慮疾患和物質使用疾患的共病型態差異。
研究方法：本研究共招募306位臨床診斷為躁鬱症第一型的台灣籍病人。使用複合性國際診斷問卷進行結構式訪談，收集包含人口學變項、臨床特徵、功能損害等資訊。以潛在類別分析 (Latent Class Analysis) 將五種焦慮疾患 (恐慌症、懼曠症、廣泛性焦慮症、特定對象畏懼症和社交畏懼症) 和三種物質使用疾患 (尼古丁依賴、酒精使用疾患和非醫療藥物使用疾患) ，共八項共病指標放入模式之中，分類找出最適躁鬱症第一型病人之亞型模式，並以一系列臨床變項檢驗不同亞型間之差異。
研究結果：潛在類別分析結果顯示三種類型的分類模式為最佳。第一類低共病型（BPI-LOW，83.99％）與任一焦慮和物質使用疾患的共病比例最低，然過去一年有較多次的躁症發作，以及較低的自殺比例和輕微的功能損傷。第二類焦慮型（BPI-ANX，3.06％）與多重焦慮疾患共病，但未和任一物質使用疾患共病，此類型的主要臨床特徵為女性和早發疾病年齡。第三類物質使用型（BPI-SUD，12.42％）臨床特徵則以男性為主、較高的物質使用疾患之終身盛行率，以及過去一年頻繁的情緒症狀發作。而在焦慮型和物質使用型的躁鬱症第一型之亞型，皆有較高的自殺比例和嚴重的功能損傷。
結論：本研究發現最適合躁鬱症第一型的亞型模式為三類，尤以自殺行為、頻繁的情緒症狀發作、功能損害最能有效區辨此三種亞型。本研究對於幫助躁鬱症第一型病人之介入和治療策略發展具有臨床貢獻，並期盼能增進未來研究了解致病機制的基礎。

Objective: Bipolar-I disorder (BPI) often co-occurred with anxiety (ANX) and substance use disorders (SUD), which poses challenges in public health and clinical treatment, and adds complexity in searching for relevant etiologic factors. The present study sought to identify subgroups of BPI patients using comorbidity patterns with ANX and SUD.
Methods: Clinical patients (N=306) diagnosed with BPI were recruited and interviewed using the Composite International Diagnostic Interview to collect data on demographics and clinical features, including episodic information, impairments, and lifetime diagnoses of ANX (panic, agoraphobia, generalized anxiety disorder, specific and social phobia) and SUD (nicotine dependence, alcohol use and drug use disorder). We applied latent class analysis to empirically derive classes of BPI. A number of exogenous variables were examined for each class.
Results: A three-class model provides excellent discriminability for subgrouping BPI patients with different comorbidity patterns. The BPI-LOW class (83.99%) had more pure mania without most lifetime comorbidity, higher numbers of last year mania episodes, and less suicidality and impairments. The BPI-ANX class (3.60%) was female predominant, tended to comorbid with multiple anxiety disorders but no SUD, and had early onset age. The BPI-SUD class (12.42%) was male predominant, had high prevalence of lifetime SUD and frequent mood episodes in the last year. Both the BPI-ANX and BPI-SUD classes had severe functional impairments and suicidal behaviors.
Conclusion: The three empirically identified subgroups of BPI patients exhibited distinguished comorbidity patterns and clinical features, including suicidal behaviors, frequent mood episodes and functional impairments. Our findings have clinical implication in intervention and treatment as well as to explore their different underlying mechanisms.

1.Akiskal, H. S., Bourgeois, M. L., Angst, J., Post, R., Moller, H., & Hirschfeld, R. (2000). Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. Journal of affective disorders, 59(Suppl 1), S5-S30.
2.Altindag, A., Yanik, M., & Nebioglu, M. (2006). The comorbidity of anxiety disorders in bipolar I patients: prevalence and clinical correlates. Israel Journal of Psychiatry & Related Sciences, 43(1), 10-15.
3.American Psychiatry Association. (2000). Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision). Washington, DC: American Psychiatry Association.
4.Andrade, L., Eaton, W. W., & Chilcoat, H. (1994). Lifetime comorbidity of panic attacks and major depression in a population-based study. Symptom profiles. British Journal of Psychiatry, 165(3), 363-369.
5.Angst, J., Gerber-Werder, R., Zuberbuhler, H. U., & Gamma, A. (2004). Is bipolar I disorder heterogeneous? European Archives of Psychiatry and Clinical Neuroscience, 254(2), 82-91.
6.Bauer, M. S., Altshuler, L., Evans, D. R., Beresford, T., Williford, W. O., & Hauger, R. (2005). 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(3), 301-315.
7.Bijl, R. V., & Ravelli, A. (2000a). Current and residual functional disability associated with psychopathology: findings from the Netherlands Mental Health Survey and Incidence Study (NEMESIS). Psychological Medicine, 30(3), 657-668.
8.Bijl, R. V., & Ravelli, A. (2000b). Psychiatric morbidity, service use, and need for care in the general population: results of The Netherlands Mental Health Survey and Incidence Study. American Journal of Public Health, 90(4), 602-607.
9.Bizzarri, J. V., Sbrana, A., Rucci, P., Ravani, L., Massei, G. J., Gonnelli, C., Spagnolli, S., Doria, M. R., Raimondi, F., Endicott, J., Dell'Osso, L., & Cassano, G. B. (2007). The spectrum of substance abuse in bipolar disorder: reasons for use, sensation seeking and substance sensitivity. Bipolar Disorders, 9(3), 213-220.
10.Bolton, J. M., Robinson, J., & Sareen, J. (2009). Self-medication of mood disorders with alcohol and drugs in the National Epidemiologic Survey on Alcohol and Related Conditions. Journal of affective disorders, 115(3), 367-375.
11.Bourdon, K. H., Rae, D. S., Locke, B. Z., & Regier, D. A. (1992). Estimating the prevalence of mental disorders in US adults from the Epidemiologic Catchment Area Survey. Public Health Reports, 107(6), 663-668.
12.Boylan, K. R., Bieling, P. J., Marriott, M., Begin, H., Young, L. T., & MacQueen, G. M. (2004). Impact of comorbid anxiety disorders on outcome in a cohort of patients with bipolar disorder. Journal of Clinical Psychiatry, 65(8), 1106-1113.
13.Caley, C. F. (2009). Bipolar disorder patient care opportunities: let's answer the call. The Annals of pharmacotherapy, 43(11), 1890-1892.
14.Cassano, G. B., Pini, S., Saettoni, M., & Dell'Osso, L. (1999). Multiple anxiety disorder comorbidity in patients with mood spectrum disorders with psychotic features. The American journal of psychiatry, 156(3), 474-476.
15.Cerda, M., Sagdeo, A., & Galea, S. (2008). Comorbid forms of psychopathology: key patterns and future research directions. Epidemiologic reviews, 30, 155-177.
16.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., Huang, S. Y., Chou, K. R., Yang, Y. K., Ko, H. C., Lu, R. B., & Angst, J. (2011a). Low anxiety disorder comorbidity rate in bipolar disorders in Han Chinese in Taiwan. (submitted).
17.Chang, Y. H., Lee, S. Y., Chen, S. L., Chen, S. H., Chu, C. H., Yang, H. F., Tzeng, N. S., Lee, I. H., Chen, P. S., Yeh, T. L., Huang, S. Y., Choug, K. R., Yang, Y. K., Ko, H. C., & Lu, R. B. (2011b). The impact of alcohol metabolism genotypes and comorbidity rate in bipolar disorders among Han Chinese in Taiwan. (submitted).
18.Chen, C. N., Wong, J., Lee, N., Chan-Ho, M. W., Lau, J. T., & Fung, M. (1993). The Shatin community mental health survey in Hong Kong. II. Major findings. Archives of general psychiatry, 50(2), 125-133.
19.Dalton, E. J., Cate-Carter, T. D., Mundo, E., Parikh, S. V., & Kennedy, J. L. (2003). Suicide risk in bipolar patients: the role of co-morbid substance use disorders. Bipolar Disorders, 5(1), 58-61.
20.Fagiolini, A., Frank, E., Rucci, P., Cassano, G. B., Turkin, S., & Kupfer, D. J. (2007). Mood and anxiety spectrum as a means to identify clinically relevant subtypes of bipolar I disorder. Bipolar Disorders, 9(5), 462-467.
21.Fazel, S., Lichtenstein, P., Grann, M., Goodwin, G. M., & Langstrom, N. (2010). Bipolar disorder and violent crime: new evidence from population-based longitudinal studies and systematic review. Archives of general psychiatry, 67(9), 931-938.
22.Feinstein, A. R. (1970). The pre-therapeutic classification of co-morbidity in chronic disease. Journal of Chronic Diseases, 23(7), 455-468.
23.Frye, M. A., & Salloum, I. M. (2006). Bipolar disorder and comorbid alcoholism: prevalence rate and treatment considerations. Bipolar Disorders, 8(6), 677-685.
24.Goldstein, B. I., & Levitt, A. J. (2008). The specific burden of comorbid anxiety disorders and of substance use disorders in bipolar I disorder. Bipolar Disorders, 10(1), 67-78.
25.Goodwin, R. D., Lieb, R., Hoefler, M., Pfister, H., Bittner, A., Beesdo, K., & Wittchen, H. U. (2004). Panic attack as a risk factor for severe psychopathology. The American journal of psychiatry, 161(12), 2207-2214.
26.Gravel, R., & Beland, Y. (2005). The Canadian Community Health Survey: mental health and well-being. The Canadian Journal of Psychiatry, 50(10), 573-579.
27.Haro, J. M., van Os, J., Vieta, E., Reed, C., Lorenzo, M., & Goetz, I. (2006). Evidence for three distinct classes of 'typical', 'psychotic' and 'dual' mania: results from the EMBLEM study. Acta Psychiatrica Scandinavica, 113(2), 112-120.
28.Johnson, C., Drgon, T., McMahon, F. J., & Uhl, G. R. (2009). Convergent genome wide association results for bipolar disorder and substance dependence. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 150B(2), 182-190.
29.Judd, L. L., Akiskal, H. S., Schettler, P. J., Coryell, W., Maser, J., Rice, J. A., Solomon, D. A., & Keller, M. B. (2003). 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(1-2), 19-32.
30.Kawakami, N., Shimizu, H., Haratani, T., Iwata, N., & Kitamura, T. (2004). Lifetime and 6-month prevalence of DSM-III-R psychiatric disorders in an urban community in Japan. Psychiatry research, 121(3), 293-301.
31.Kessler, R. C., Berglund, P., Demler, O., Jin, R., Merikangas, K. R., & Walters, E. E. (2005). Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Archives of general psychiatry, 62(6), 593-602.
32.Kessler, R. C., McGonagle, K. A., Zhao, S., Nelson, C. B., Hughes, M., Eshleman, S., Wittchen, H. U., & Kendler, K. S. (1994). Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Archives of general psychiatry, 51(1), 8-19.
33.Kessler, R. C., & Ustun, T. B. (2004). The World Mental Health (WMH) Survey Initiative Version of the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI). International Journal of Methods in Psychiatric Research, 13(2), 93-121.
34.Kilbane, E. J., Gokbayrak, N. S., Galynker, I., Cohen, L., & Tross, S. (2009). A review of panic and suicide in bipolar disorder: does comorbidity increase risk? Journal of affective disorders, 115(1-2), 1-10.
35.Krueger, R. F., & Markon, K. E. (2006). Reinterpreting comorbidity: a model-based approach to understanding and classifying psychopathology. Annual Review of Clinical Psychology, 2, 111-133.
36.Kuo, P. H., Aggen, S. H., Prescott, C. A., Kendler, K. S., & Neale, M. C. (2008). Using a factor mixture modeling approach in alcohol dependence in a general population sample. Drug and Alcohol Dependence, 98(1-2), 105-114.
37.Kupfer, D. J. (2005). The increasing medical burden in bipolar disorder. [Journal Article]. Journal of the American Medical Association, 293(20), 2528-2530.
38.Kupka, R. W., Luckenbaugh, D. A., Post, R. M., Leverich, G. S., & Nolen, W. A. (2003). Rapid and non-rapid cycling bipolar disorder: a meta-analysis of clinical studies. Journal of Clinical Psychiatry, 64(12), 1483-1494.
39.Lai, Y. C., Lu, M. K., Young, Y. K., Lin, J. J., Tan, H. P., Chen, W. J., Lu, R. B., & Kuo, P. H. (2010). Clinical Features and Familial Aggregation of Social Relationships in Major Depressive and Bipolar Disorders in Southern Taiwan. Taiwan Journal of Public Health, 29(2), 169-182.
40.Lin, C. C., Bai, Y. M., Hu, P. G., & Yeh, H. S. (1998). Substance use disorders among inpatients with bipolar disorder and major depressive disorder in a general hospital. General Hospital Psychiatry, 20(2), 98-101.
41.Lopez, A. D., & Murray, C. C. (1998). The global burden of disease, 1990-2020. Nature Medicine, 4(11), 1241-1243.
42.MacKinnon, D. F., & Zamoiski, R. (2006). Panic comorbidity with bipolar disorder: what is the manic-panic connection? Bipolar Disorders, 8(6), 648-664.
43.McElroy, S. L., Altshuler, L. L., Suppes, T., Keck, P. E., Jr., Frye, M. A., Denicoff, K. D., Nolen, W. A., Kupka, R. W., Leverich, G. S., Rochussen, J. R., Rush, A. J., & Post, R. M. (2001). Axis I psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder. The American journal of psychiatry, 158(3), 420-426.
44.McIntyre, R. S., & Keck, P. E., Jr. (2006a). Comorbidity in bipolar disorder: clinical and research opportunities. Bipolar Disorders, 8(6), 645-647.
45.McIntyre, R. S., Soczynska, J. K., Bottas, A., Bordbar, K., Konarski, J. Z., & Kennedy, S. H. (2006b). Anxiety disorders and bipolar disorder: a review. Bipolar Disorders, 8(6), 665-676.
46.Meehl, P. (2001). Comorbidity and taxometrics. Clinical Psychology Science and Practice, 8(4), 507-519.
47.Merikangas, K. R., Akiskal, H. S., Angst, J., Greenberg, P. E., Hirschfeld, R. M., Petukhova, M., & Kessler, R. C. (2007). Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Archives of general psychiatry, 64(5), 543-552.
48.Monga, N., Rehm, J., Fischer, B., Brissette, S., Bruneau, J., El-Guebaly, N., Noel, L., Tyndall, M., Wild, C., Leri, F., Fallu, J. S., & Bahl, S. (2007). Using latent class analysis (LCA) to analyze patterns of drug use in a population of illegal opioid users. Drug and Alcohol Dependence, 88(1), 1-8.
49.Moreno, D. H., & Andrade, L. H. (2010). Latent class analysis of manic and depressive symptoms in a population-based sample in Sao Paulo, Brazil. Journal of affective disorders, 123(1-3), 208-215.
50.Moss, H. B., Chen, C. M., & Yi, H. Y. (2007). Subtypes of alcohol dependence in a nationally representative sample. Drug and Alcohol Dependence, 91(2-3), 149-158.
51.Muthén, L. K., & Muthén, B. (2006). M-Plus: The Comprehensive Modeling Program for Applied Researchers (Version 4.1). Los Angeles, CA: Muthén & Muthén.
52.Nestadt, G., Addington, A., Samuels, J., Liang, K. Y., Bienvenu, O. J., Riddle, M., Grados, M., Hoehn-Saric, R., & Cullen, B. (2003). The identification of OCD-related subgroups based on comorbidity. Biological Psychiatry, 53(10), 914-920.
53.Neves, F. S., Malloy-Diniz, L. F., & Correa, H. (2009). Suicidal behavior in bipolar disorder: what is the influence of psychiatric comorbidities? Journal of Clinical Psychiatry, 70(1), 13-18.
54.Nierenberg, A. A., Akiskal, H. S., Angst, J., Hirschfeld, R. M., Merikangas, K. R., Petukhova, M., & Kessler, R. C. (2010). Bipolar disorder with frequent mood episodes in the national comorbidity survey replication (NCS-R). Molecular psychiatry, 15(11), 1075-1087.
55.Nylund, K. L., Asparouhov, T., & Muthén, B. O. (2007). Deciding on the number of classes in latent class analysis and growth mixture modeling: A Monte Carlo simulation study. Structural Equation Modeling: A Multidisciplinary Journal, 14(4), 535-569.
56.Ormel, J., Petukhova, M., Chatterji, S., Aguilar-Gaxiola, S., Alonso, J., Angermeyer, M. C., Bromet, E. J., Burger, H., Demyttenaere, K., de Girolamo, G., Haro, J. M., Hwang, I., Karam, E., Kawakami, N., Lepine, J. P., Medina-Mora, M. E., Posada-Villa, J., Sampson, N., Scott, K., Ustun, T. B., Von Korff, M., Williams, D. R., Zhang, M., & Kessler, R. C. (2008). Disability and treatment of specific mental and physical disorders across the world. British Journal of Psychiatry, 192(5), 368-375.
57.Peh, A. L., & Tay, L. K. (2008). Demographical profile and clinical features of patients with bipolar disorder in an outpatient setting in Singapore. Singapore Medical Journal, 49(5), 380-383.
58.Rihmer, Z., Szadoczky, E., Furedi, J., Kiss, K., & Papp, Z. (2001). 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(1-3), 175-179.
59.Roy-Byrne, P. P., Stang, P., Wittchen, H. U., Ustun, B., Walters, E. E., & Kessler, R. C. (2000). Lifetime panic-depression comorbidity in the National Comorbidity Survey. Association with symptoms, impairment, course and help-seeking. British Journal of Psychiatry, 176, 229-235.
60.Schaffer, A., Cairney, J., Veldhuizen, S., Kurdyak, P., Cheung, A., & Levitt, A. (2010). A population-based analysis of distinguishers of bipolar disorder from major depressive disorder. Journal of affective disorders, 125(1-3), 103-110.
61.Simon, N. M., Otto, M. W., Wisniewski, S. R., Fossey, M., Sagduyu, K., Frank, E., Sachs, G. S., Nierenberg, A. A., Thase, M. E., & Pollack, M. H. (2004). 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(12), 2222-2229.
62.Strakowski, S. M., Tsai, S. Y., Delbello, M. P., Chen, C. C., Fleck, D. E., Adler, C. M., Arndt, S., & Amicone, J. (2007). Outcome following a first manic episode: cross-national US and Taiwan comparison. Bipolar Disorders, 9(8), 820-827.
63.Sublette, M. E., Carballo, J. J., Moreno, C., Galfalvy, H. C., Brent, D. A., Birmaher, B., John Mann, J., & Oquendo, M. A. (2009). Substance use disorders and suicide attempts in bipolar subtypes. Journal of psychiatric research, 43(3), 230-238.
64.Sullivan, P. F., Kessler, R. C., & Kendler, K. S. (1998). Latent class analysis of lifetime depressive symptoms in the national comorbidity survey. The American journal of psychiatry, 155(10), 1398-1406.
65.Teesson, M., Slade, T., & Mills, K. (2009). Comorbidity in Australia: findings of the 2007 National Survey of Mental Health and Wellbeing. The Australian and New Zealand journal of psychiatry, 43(7), 606-614.
66.Tsai, S. M., Chen, C., Kuo, C., Lee, J., Lee, H., & Strakowski, S. M. (2001). 15-year outcome of treated bipolar disorder. Journal of affective disorders, 63(1-3), 215-220.
67.Vella, G., Aragona, M., & Alliani, D. (2000). The complexity of psychiatric comorbidity: a conceptual and methodological discussion. Psychopathology, 33(1), 25-30.
68.Vieta, E., Colom, F., Corbella, B., Martinez-Aran, A., Reinares, M., Benabarre, A., & Gasto, C. (2001). Clinical correlates of psychiatric comorbidity in bipolar I patients. Bipolar Disorders, 3(5), 253-258.
69.Waxmonsky, J. A., Thomas, M. R., Miklowitz, D. J., Allen, M. H., Wisniewski, S. R., Zhang, H., Ostacher, M. J., & Fossey, M. D. (2005). Prevalence and correlates of tobacco use in bipolar disorder: data from the first 2000 participants in the Systematic Treatment Enhancement Program. General Hospital Psychiatry, 27(5), 321-328.
70.Weiss, R. D., Ostacher, M. J., Otto, M. W., Calabrese, J. R., Fossey, M., Wisniewski, S. R., Bowden, C. L., Nierenberg, A. A., Pollack, M. H., Salloum, I. M., Simon, N. M., Thase, M. E., & Sachs, G. S. (2005). Does recovery from substance use disorder matter in patients with bipolar disorder? Journal of Clinical Psychiatry, 66(6), 730-735.
71.Wilens, T. E., Biederman, J., Adamson, J. J., Henin, A., Sgambati, S., Gignac, M., Sawtelle, R., Santry, A., & Monuteaux, M. C. (2008). Further evidence of an association between adolescent bipolar disorder with smoking and substance use disorders: a controlled study. Drug and Alcohol Dependence, 95(3), 188-198.