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Co-morbid anxiety disorders in bipolar disorder and major depression: familial aggregation and clinical characteristics of co-morbid panic disorder, social phobia, specific phobia and obsessive-compulsive disorder

  • F. S. Goes (a1), M. G. McCusker (a1), O. J. Bienvenu (a1), D. F. MacKinnon (a1), F. M. Mondimore (a1), B. Schweizer (a1), National Institute of Mental Health Genetics Initiative Bipolar Disorder Consortium, J. R. DePaulo (a1) and J. B. Potash (a2)...



Co-morbidity of mood and anxiety disorders is common and often associated with greater illness severity. This study investigates clinical correlates and familiality of four anxiety disorders in a large sample of bipolar disorder (BP) and major depressive disorder (MDD) pedigrees.


The sample comprised 566 BP families with 1416 affected subjects and 675 MDD families with 1726 affected subjects. Clinical characteristics and familiality of panic disorder, social phobia, specific phobia and obsessive-compulsive disorder (OCD) were examined in BP and MDD pedigrees with multivariate modeling using generalized estimating equations.


Co-morbidity between mood and anxiety disorders was associated with several markers of clinical severity, including earlier age of onset, greater number of depressive episodes and higher prevalence of attempted suicide, when compared with mood disorder without co-morbid anxiety. Familial aggregation was found with co-morbid panic and OCD in both BP and MDD pedigrees. Specific phobia showed familial aggregation in both MDD and BP families, although the findings in BP were just short of statistical significance after adjusting for other anxiety co-morbidities. We found no evidence for familiality of social phobia.


Our findings suggest that co-morbidity of MDD and BP with specific anxiety disorders (OCD, panic disorder and specific phobia) is at least partly due to familial factors, which may be of relevance to both phenotypic and genetic studies of co-morbidity.


Corresponding author

*Address for correspondence: F. S. Goes, M.D., Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Meyer 4-119, 600 N. Wolfe Street, Baltimore, MD, 21287, USA. (Email:


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Barnett, JH, Huang, J, Perlis, RH, Young, MM, Rosenbaum, JF, Nierenberg, AA, Sachs, G, Nimgaonkar, VL, Miklowitz, DJ, Smoller, JW (2011). Personality and bipolar disorder: dissecting state and trait associations between mood and personality. Psychological Medicine 41, 15931604.
Bienvenu, OJ, Samuels, JF, Costa, PT, Reti, IM, Eaton, WW, Nestadt, G (2004). Anxiety and depressive disorders and the five-factor model of personality: a higher- and lower-order personality trait investigation in a community sample. Depression and Anxiety 20, 9297.
Bienvenu, OJ, Samuels, JF, Wuyek, LA, Liang, KY, Wang, Y, Grados, MA, Cullen, BA, Riddle, MA, Greenberg, BD, Rasmussen, SA, Fyer, AJ, Pinto, A, Rauch, SL, Pauls, DL, McCracken, JT, Piacentini, J, Murphy, DL, Knowles, JA, Nestadt, G (2011). Is obsessive–compulsive disorder an anxiety disorder, and what, if any, are spectrum conditions? A family study perspective. Psychological Medicine. Published online: 13 May 2011. doi:10.1017/S0033291711000742.
Carter, AS, Pollock, RA, Suvak, MK, Pauls, DL (2004). Anxiety and major depression comorbidity in a family study of obsessive-compulsive disorder. Depression and Anxiety 20, 165174.
Coryell, W, Endicott, J, Winokur, G (1992). Anxiety syndromes as epiphenomena of primary major depression: outcome and familial psychopathology. American Journal of Psychiatry 149, 100107.
Coryell, W, Solomon, DA, Fiedorowicz, JG, Endicott, J, Schettler, PJ, Judd, LL (2009). Anxiety and outcome in bipolar disorder. American Journal of Psychiatry 166, 12381243.
Crowe, RR, Noyes, R, Pauls, DL, Slymen, D (1983). A family study of panic disorder. Archives of General Psychiatry 40, 10651069.
Duffy, A, Alda, M, Crawford, L, Milin, R, Grof, P (2007). The early manifestations of bipolar disorder: a longitudinal prospective study of the offspring of bipolar parents. Bipolar Disorders 9, 828838.
Feinstein, AR (1970). The pre-therapeutic classification of co-morbidity in chronic disease. Journal of Chronic Diseases 23, 455468.
Fyer, AJ, Lipsitz, JD, Mannuzza, S, Aronowitz, B, Chapman, TF (2005). A direct interview family study of obsessive-compulsive disorder. I. Psychological Medicine 35, 16111621.
Fyer, AJ, Mannuzza, S, Chapman, TF, Liebowitz, MR, Klein, DF (1993). A direct interview family study of social phobia. Archives of General Psychiatry 50, 286293.
Goldberg, DP, Andrews, G, Hobbs, MJ (2009). Where should bipolar disorder appear in the meta-structure? Psychological Medicine 39, 20712081.
Goldstein, RB, Weissman, MM, Adams, PB, Horwath, E, Lish, JD, Charney, D, Woods, SW, Sobin, C, Wickramaratne, PJ (1994). Psychiatric disorders in relatives of probands with panic disorder and/or major depression. Archives of General Psychiatry 51, 383394.
Hanna, GL, Himle, JA, Hanna, BS, Gold, KJ, Gillespie, BW (2011). Major depressive disorder in a family study of obsessive-compulsive disorder with pediatric probands. Depression and Anxiety 28, 501508.
Hettema, JM, Neale, MC, Kendler, KS (2001). A review and meta-analysis of the genetic epidemiology of anxiety disorders. American Journal of Psychiatry 158, 15681578.
Hettema, JM, Neale, MC, Myers, JM, Prescott, CA, Kendler, KS (2006). A population-based twin study of the relationship between neuroticism and internalizing disorders. American Journal of Psychiatry 163, 857864.
Hettema, JM, Prescott, CA, Myers, JM, Neale, MC, Kendler, KS (2005). The structure of genetic and environmental risk factors for anxiety disorders in men and women. Archives of General Psychiatry 62, 182189.
Jylha, P, Mantere, O, Melartin, T, Suominen, K, Vuorilehto, M, Arvilommi, P, Leppamaki, S, Valtonen, H, Rytsala, H, Isometsa, E (2010). Differences in neuroticism and extraversion between patients with bipolar I or II and general population subjects or major depressive disorder patients. Journal of Affective Disorders 125, 4252.
Kendler, KS, Aggen, SH, Knudsen, GP, Roysamb, E, Neale, MC, Reichborn-Kjennerud, T (2011). The structure of genetic and environmental risk factors for syndromal and subsyndromal common DSM-IV axis I and all axis II disorders. American Journal of Psychiatry 168, 2939.
Kendler, KS, Neale, MC, Kessler, RC, Heath, AC, Eaves, LJ (1993). Major depression and phobias: the genetic and environmental sources of comorbidity. Psychological Medicine 23, 361371.
Kendler, KS, Walters, EE, Neale, MC, Kessler, RC, Heath, AC, Eaves, LJ (1995). The structure of the genetic and environmental risk factors for six major psychiatric disorders in women. Phobia, generalized anxiety disorder, panic disorder, bulimia, major depression, and alcoholism. Archives of General Psychiatry 52, 374383.
Kessler, RC, Berglund, P, Demler, O, Jin, R, Koretz, D, Merikangas, KR, Rush, AJ, Walters, EE, Wang, PS, National Comorbidity Survey Replication (2003). The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). Journal of the American Medical Association 289, 30953105.
Kessler, RC, Berglund, P, Demler, O, Jin, R, Merikangas, KR, Walters, EE (2005). Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry 62, 593602.
Kessler, RC, Merikangas, KR, Wang, PS (2007). Prevalence, comorbidity, and service utilization for mood disorders in the United States at the beginning of the twenty-first century. Annual Review of Clinical Psychology 3, 137158.
Klein, D, Riso, L (1994). Psychiatric disorders: problems of boundaries and comorbidity. In Basic Issues in Psychopathology (ed. Costello, C. G.), pp. 1966. Guilford Press: New York.
Krueger, RF (1999). The structure of common mental disorders. Archives of General Psychiatry 56, 921926.
Lamers, F, van Oppen, P, Comijs, HC, Smit, JH, Spinhoven, P, van Balkom, AJ, Nolen, WA, Zitman, FG, Beekman, AT, Penninx, BW (2011). Comorbidity patterns of anxiety and depressive disorders in a large cohort study: the Netherlands Study of Depression and Anxiety (NESDA). Journal of Clinical Psychiatry 72, 341348.
Leckman, JF, Weissman, MM, Merikangas, KR, Pauls, DL, Prusoff, BA (1983). Panic disorder and major depression. Increased risk of depression, alcoholism, panic, and phobic disorders in families of depressed probands with panic disorder. Archives of General Psychiatry 40, 10551060.
Levinson, DF, Zubenko, GS, Crowe, RR, DePaulo, RJ, Scheftner, WS, Weissman, MM, Holmans, P, Zubenko, WN, Boutelle, S, Murphy-Eberenz, K, MacKinnon, D, McInnis, MG, Marta, DH, Adams, P, Sassoon, S, Knowles, JA, Thomas, J, Chellis, J (2003). Genetics of Recurrent Early-onset Depression (GenRED): design and preliminary clinical characteristics of a repository sample for genetic linkage studies. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 119, 118130.
MacKinnon, DF, McMahon, FJ, Simpson, SG, McInnis, MG, DePaulo, JR (1997). Panic disorder with familial bipolar disorder. Biological Psychiatry 42, 9095.
MacKinnon, DF, Zandi, PP, Cooper, J, Potash, JB, Simpson, SG, Gershon, E, Nurnberger, J, Reich, T, DePaulo, JR (2002). Comorbid bipolar disorder and panic disorder in families with a high prevalence of bipolar disorder. American Journal of Psychiatry 159, 3035.
Maier, W, Minges, J, Lichtermann, D (1995). The familial relationship between panic disorder and unipolar depression. Journal of Psychiatric Research 29, 375388.
Maj, M (2005). “Psychiatric comorbidity”: an artefact of current diagnostic systems? British Journal of Psychiatry 186, 182184.
Mantere, O, Isometsa, E, Ketokivi, M, Kiviruusu, O, Suominen, K, Valtonen, HM, Arvilommi, P, Leppamaki, S (2010). A prospective latent analyses study of psychiatric comorbidity of DSM-IV bipolar I and II disorders. Bipolar Disorders 12, 271284.
McElroy, SL, Altshuler, LL, Suppes, T, Keck, PE Jr., Frye, MA, Denicoff, KD, Nolen, WA, Kupka, RW, Leverich, GS, Rochussen, JR, Rush, AJ, Post, RM (2001). Axis I psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder. American Journal of Psychiatry 158, 420426.
Merikangas, KR, Akiskal, HS, Angst, J, Greenberg, PE, Hirschfeld, RM, Petukhova, M, Kessler, RC (2007). Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Archives of General Psychiatry 64, 543552.
Mosing, MA, Gordon, SD, Medland, SE, Statham, DJ, Nelson, EC, Heath, AC, Martin, NG, Wray, NR (2009). Genetic and environmental influences on the co-morbidity between depression, panic disorder, agoraphobia, and social phobia: a twin study. Depression and Anxiety 26, 10041011.
Nestadt, G, Samuels, J, Riddle, MA, Liang, KY, Bienvenu, OJ, Hoehn-Saric, R, Grados, M, Cullen, B (2001). The relationship between obsessive-compulsive disorder and anxiety and affective disorders: results from the Johns Hopkins OCD Family Study. Psychological Medicine 31, 481487.
Nierenberg, AA, Trivedi, MH, Fava, M, Biggs, MM, Shores-Wilson, K, Wisniewski, SR, Balasubramani, GK, Rush, AJ (2007). Family history of mood disorder and characteristics of major depressive disorder: a STAR*D (sequenced treatment alternatives to relieve depression) study. Journal of Psychiatric Research 41, 214221.
Nurnberger, JI Jr, Blehar, MC, Kaufmann, CA, York-Cooler, C, Simpson, SG, Harkavy-Friedman, J, Severe, JB, Malaspina, D, Reich, T (1994). Diagnostic Interview for Genetic Studies. Rationale, unique features, and training. NIMH Genetics Initiative. Archives of General Psychiatry 51, 849859.
Post, RM, Denicoff, KD, Leverich, GS, Altshuler, LL, Frye, MA, Suppes, TM, Rush, AJ, Keck, PE Jr., McElroy, SL, Luckenbaugh, DA, Pollio, C, Kupka, R, Nolen, WA (2003). Morbidity in 258 bipolar outpatients followed for 1 year with daily prospective ratings on the NIMH life chart method. Journal of Clinical Psychiatry 64, 680690.
Potash, JB, Toolan, J, Steele, J, Miller, EB, Pearl, J, Zandi, PP, Schulze, TG, Kassem, L, Simpson, SG, Lopez, V, NIMH Genetics Initiative Bipolar Disorder Consortium, MacKinnon, DF, McMahon, FJ (2007). The bipolar disorder phenome database: a resource for genetic studies. American Journal of Psychiatry 164, 12291237.
Regier, DA, Rae, DS, Narrow, WE, Kaelber, CT, Schatzberg, AF (1998). Prevalence of anxiety disorders and their comorbidity with mood and addictive disorders. British Journal of Psychiatry Supplement 34, 2428.
Sala, R, Axelson, DA, Castro-Fornieles, J, Goldstein, TR, Ha, W, Liao, F, Gill, MK, Iyengar, S, Strober, MA, Goldstein, BI, Yen, S, Hower, H, Hunt, J, Ryan, ND, Dickstein, D, Keller, MB, Birmaher, B (2010). Comorbid anxiety in children and adolescents with bipolar spectrum disorders: prevalence and clinical correlates. Journal of Clinical Psychiatry 71, 13441350.
Sareen, J, Cox, BJ, Afifi, TO, de Graaf, R, Asmundson, GJ, ten Have, M, Stein, MB (2005). Anxiety disorders and risk for suicidal ideation and suicide attempts: a population-based longitudinal study of adults. Archives of General Psychiatry 62, 12491257.
Stein, MB, Chartier, MJ, Hazen, AL, Kozak, MV, Tancer, ME, Lander, S, Furer, P, Chubaty, D, Walker, JR (1998). A direct-interview family study of generalized social phobia. American Journal of Psychiatry 155, 9097.
Sullivan, PF, Neale, MC, Kendler, KS (2000). Genetic epidemiology of major depression: review and meta-analysis. American Journal of Psychiatry 157, 15521562.
Verhagen, M, van der Meij, A, Franke, B, Vollebergh, WA, de Graaf, R, Buitelaar, JK, Janzing, JG (2008). Familiality of major depressive disorder and patterns of lifetime comorbidity. The NEMESIS and GenMood studies. A comparison of three samples. European Archives of Psychiatry and Clinical Neuroscience 258, 505512.
Wehr, TA, Goodwin, FK (1979). Rapid cycling in manic-depressives induced by tricyclic antidepressants. Archives of General Psychiatry 36, 555559.
Weissman, MM, Wickramaratne, P, Adams, PB, Lish, JD, Horwath, E, Charney, D, Woods, SW, Leeman, E, Frosch, E (1993). The relationship between panic disorder and major depression. A new family study. Archives of General Psychiatry 50, 767780.
Wickramaratne, PJ, Weissman, MM (1993). Using family studies to understand comorbidity. European Archives of Psychiatry and Clinical Neuroscience 243, 150157.
Zeger, SL, Liang, KY, Albert, PS (1988). Models for longitudinal data: a generalized estimating equation approach. Biometrics 44, 10491060.
Zimmerman, M, Chelminski, I, McDermut, W (2002). Major depressive disorder and axis I diagnostic comorbidity. Journal of Clinical Psychiatry 63, 187193.


Type Description Title
Supplementary Table 1

Goes Supplementary Table 1
Supplementary Table S1. Familial aggregation of comorbid anxiety disorders in all available relatives in the bipolar disorder sample

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