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Comorbid anxiety in bipolar spectrum disorders: A neglected research and treatment issue?
Journal of Affective Disorders 137 (2012) 161–164
Contents lists available at SciVerse ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Short communication
Comorbid anxiety in bipolar spectrum disorders: A neglected research and treatment issue? Martin D. Provencher a, b,⁎, Anne-Josée Guimond a, Lisa D. Hawke a a b
École de psychologie, Université Laval, Canada Centre de recherche Université Laval-Robert Giffard, Canada
a r t i c l e
i n f o
Article history: Received 9 November 2011 Received in revised form 15 November 2011 Accepted 1 December 2011 Available online 29 December 2011 Keywords: Anxiety disorders Bipolar disorder Comorbidity Publication trends
a b s t r a c t Background: Anxiety disorders are highly prevalent among patients with bipolar disorder and have a substantial impact on the course of illness and response to treatment. Despite the substantial impact that comorbid anxiety disorders have on the prognosis of individuals with bipolar disorder, many aspects of this comorbidity have received little attention from researchers. This study aims to document the current state of the literature on the comorbidity between anxiety and bipolar disorders by analyzing publication trends on the subject. Method: This study is a quantitative and qualitative review of articles on the comorbidity between anxiety disorders and bipolar disorder published between 1990 and 2010 in the ISI Web of Science, Medline and PsycINFO databases. The number of articles published each year on this comorbidity was calculated and compared to the literature published on bipolar disorder as a whole. Articles were classified into five categories and 13 subcategories to identify the main focuses of the literature and current gaps in the knowledge on the subject. Results: Interest in the comorbidity between anxiety disorders and bipolar disorder grew continually since 1990, but seems to have reached a plateau. The majority of articles addressing this comorbidity are descriptive in nature, with very few concrete studies examining the mechanisms and treatment approaches that might lead to positive advancements in the field. Limitations: Articles written in languages other than English or French were not reviewed. Conclusions: It is time to step up research efforts to better understand and manage this understudied combination of disorders. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Anxiety disorders are highly prevalent among patients with bipolar disorder and represent a considerable risk factor. Epidemiological studies show that as many as 74.9% of individuals with bipolar disorder have at least one anxiety disorder at some point in their lives (Cardoso et al., 2008; Merikangas et al., 2007). Smaller clinical samples suggest that between 27.2% and 55.8% have a comorbid anxiety disorder, while 31.8% to 37% have two or more (Boylan et al., 2004; Simon et al., 2004a,
⁎ Corresponding author at: École de psychologie, Université Laval, 2325 rue des Bibliothèques, Quebec City, Quebec, Canada G1V 0A6. Tel.: + 1 418 656 2131x11089; fax: + 1 418 656 3646. E-mail address: [email protected] (M.D. Provencher). 0165-0327/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2011.12.001
b). The National Comorbidity Survey Replication (NCS-R) found that among the people with bipolar disorder who have a comorbid anxiety disorder, social anxiety, specific phobia and generalized anxiety disorder were the most frequent, at 37.8%, 35.5% and 29.6% respectively. Other anxiety disorders found to be quite prevalent in this population were post-traumatic stress disorder at 24.2%, panic disorder at 20.1% and obsessive-compulsive disorder at 13.6% (Merikangas et al., 2007). Not only highly prevalent, comorbid anxiety disorders also have a substantial impact on the course of illness and response to treatment. Comorbid anxiety disorders or considerable anxiety symptoms are associated with longer and more frequent affective episodes (Azorin et al., 2009; Zutshi et al., 2006), slower time to remission, poorer treatment outcome (Feske et al., 2000; Henry et al., 2003), increased risk of substance
162
M.D. Provencher et al. / Journal of Affective Disorders 137 (2012) 161–164
abuse and psychosis (Kauer-Sant'Anna et al., 2007), suicidal ideation (Simon et al., 2007) and suicide attempt (Simon et al., 2004a, 2004b; Simon et al., 2007). Even subclinical anxiety would appear to have a negative impact on treatment response (El-Mallakh and Hollifield, 2008). Despite the substantial impact that comorbid anxiety disorders have on the prognosis of individuals with bipolar disorder, many aspects of this comorbidity have received little attention from researchers. Several authors point to the importance of studying this comorbidity set in greater detail to better understand the underlying processes and related issues, and particularly to adapt treatments for greater efficacy (e.g. Boylan et al., 2004; Kauer-Sant'Anna et al., 2007, 2009; Simon et al., 2004b). One widely used method of assessing an area of research is the analysis of publication trends (Boschen, 2008; Dugas et al., 2010). Recognized as a valid indicator of the level of interest in a question, publication trends have been used in different fields, such as personality disorders (Blashfield and Intoccia, 2000; Mendlowicz et al., 2006) and anxiety disorders (Boschen, 2008; Cox et al., 1995; Dugas et al., 2010; Norton et al., 1995). This study aims to document the current state of the literature on the comorbidity between anxiety and bipolar disorders. Two questions were examined: 1) Has interest in the anxiety–bipolar comorbidity increased over the past years? 2) What aspects have been most studied? To answer these questions, the literature was examined both from a qualitative and quantitative perspective. 2. Method A search was conducted of literature addressing the comorbidity between anxiety and bipolar disorders in the ISI Web of Science, Medline, and PsycINFO databases. All articles published from the beginning of the period covered by the databases to the end of the year 2010 were included. The search was conducted using the search terms Bipolar Disorder AND Comorbidity AND (individually) Anxiety Disorder, Generalized Anxiety Disorder, Post-traumatic Stress Disorder, Obsessive-Compulsive Disorder, Panic Disorder, Agoraphobia, Social Phobia, Social Anxiety Disorder, and Specific Phobia. For practical reasons, the search was limited to abstracts written in English or French. A database was created including all identified references and abstracts. After deleting duplicates, abstracts were classified into five categories and 13 subcategories inspired by the broader categories used by Dugas (2000) and Dugas et al. (2010). More specific subcategories were developed for a more precise analysis of publication content. Preliminary categories were first applied to approximately one hundred articles, then readjusted and discussed among the research team to achieve a consensus. Once the final categorization was agreed upon, it was applied to all articles. The five main categories are described below. 1 • A) Descriptive articles discussing clinical characteristics, observable impacts, illness onset, diagnostic criteria and epidemiological considerations;
1 A detailed description of subcategories is available from the authors upon request.
• B) Articles on biological, neurological, genetic, cognitive and emotional processes underlying the anxiety–bipolar comorbidity; • C) Articles on treatments for this comorbidity set; • D) General discussions or commentaries; • E) Non-specific: articles mentioning the anxiety–bipolar comorbidity, but not as the main subject matter. Articles were classified based on their abstracts by a master's level research assistant. When ambiguous, the full article was accessed to ensure proper classification. Only abstracts focusing on the anxiety–bipolar comorbidity were considered relevant. Abstracts addressing comorbidity with other disorders were only considered relevant if they placed emphasis on the anxiety–bipolar comorbidity. When an abstract mentioned the comorbidity, but not as a major topic, it was classified in Category E — Non-specific. To ensure an exhaustive review, articles addressing the comorbidity between anxiety disorders and subclinical forms of bipolarity, such as cyclothymia and hypomania, were also considered relevant. Articles not considered relevant were deleted from the database. To ensure the reliability of the classification, 15% of the articles were reclassified by a doctoral level research assistant blind as to the initial classification. The inter-rater reliability was strong for main categories (Kappa = .76, p b .001) and subcategories (Kappa = .74, p b .001), both high at the “substantial agreement” level defined by Landis and Koch (1977). For comparison purposes, the literature on bipolar disorder as a whole was also examined. A search was conducted of articles indexed in the same databases over the same time period. All articles containing the term Bipolar Disorder in the Keywords, Title or Abstract fields were retained. Duplicates were deleted from the database. 3. Results The first step of the analysis was to calculate the number of articles published per year addressing the anxiety–bipolar comorbidity. The first article was published in 1990. As shown in Fig. 1, the rate of publication generally grew from 1990 to 2010, with a particularly strong increase beginning in the early 2000s. The total number of articles addressing this comorbidity increased from 1 in 1990 to 54 articles in 2010. The number of articles specifically addressing anxiety– bipolar comorbidity (excluding Category E — Non-specific) increased from 1 article in 1990 to 17 articles in 2010. However, there appears to be a plateau or even a slight decrease in the number of publications after 2007. The number of articles published each year on the anxiety–bipolar comorbidity was then compared to all literature mentioning bipolar disorder. Articles specifically addressing the anxiety–bipolar comorbidity made up only 0.20% of the entire literature mentioning bipolar disorder in 1990, compared to 0.92% in 2010. The total number of articles addressing this comorbidity made up a slim 3% of the bipolar literature in 2010. The second step of the analysis consisted of categorizing the articles in the 13 subcategories, grouped together into five main categories. The number of articles in each category is presented in Table 1. The majority of articles were Non-
M.D. Provencher et al. / Journal of Affective Disorders 137 (2012) 161–164
80
163 Total number of articles on the anxiety-bipolar comorbidity
70
Frequency
60 50 40
Number of articles specifically addressing the bipolar-anxiety comorbidity
30 20 10
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
0
Year Fig. 1. Annual number of publications addressing the bipolar-anxiety comorbidity, from 1990 to 2010.
specific (Category E), at 65%, meaning they mentioned the anxiety–bipolar comorbidity without making it a major focus. Descriptive issues also received considerable attention, whereas processes, treatment issues and general discussions accounted for few articles. Among the articles specific to the anxiety–bipolar comorbidity (excluding Category E — Non-specific), a full 60.6% were descriptive articles, while 19.2% addressed treatment issues, 10.9% were general discussions, and 9.3% discussed the associated neurological, biological, genetic, cognitive or emotional processes. 4. Discussion The results of the current study suggest that interest in the comorbidity between anxiety and bipolar disorders has continually increased in the literature since the 1990s, as has interest in bipolar disorder as a whole. The total number of published articles peaked in 2007, but then seems to have declined or reached a plateau. The majority of articles addressing this comorbidity are descriptive in nature, with very few Table 1 Number and percentage of articles in each category and subcategory. Category
n
%
A) Descriptive articles 1 — clinical characteristics/observable impacts 2 — illness onset 3 — diagnostic criteria 4 — epidemiology B) Processes 5 — bio-neuro-genetic 6 — cognitive functions 7 — emotional regulation C) Treatments 8 — case studies 9 — meta-analyses 10 — pharmacological treatment studies 11 — psychosocial treatment studies 12 — treatment recommendations 13 — reviews of treatments D) General discussions/commentaries E) Non-specific
117 92 4 4 17 18 16 1 1 37 17 0 12 3 1 4 21 358
21.23 16.70 0.73 0.73 3.09 3.27 2.90 0.18 0.18 6.72 3.09 0.00 2.18 0.54 0.18 0.73 3.81 64.97
Note. Totals and percentages for each main category are in bold.
concrete studies examining the mechanisms and treatment approaches that might lead to positive advancements in the field. Though the number of publications increased from 1990 to 2010, anxiety–bipolar comorbidity remains understudied and the proportion addressing the issue directly is negligible. Furthermore, the trend observed since 2007 suggests that interest in the issue may have stagnated. Descriptive issues are well documented, particularly the clinical characteristics and observable impacts of anxiety disorders comorbid to bipolar disorder. However, gaps remain in the study of descriptive aspects, such as diagnostic and onset-related issues. Biological, neurological, genetic, cognitive and emotional aspects, as well as treatment alternatives, remain relatively unstudied. The impact of this comorbidity on cognitive and emotional processes is particularly understudied, each subcategory accounting for a single article. This leaves the factors that contribute to the development and maintenance of comorbidity unknown. The treatments for anxiety disorders comorbid to bipolar disorder are also under-studied, despite the fact that a number of studies have shown that anxiety comorbidity has a negative impact on treatment response (El-Mallakh and Hollifield, 2008). The majority of treatment studies are case studies, with few large-scale trials. Most address pharmacological treatments, with very few examining psychosocial interventions. In comparison, an article examining anxiety disorder literature reported that 30.8% of articles addressed treatment issues (Cox, et al., 1995). For generalized anxiety disorder, 19.2% of articles examined processes, while a full 43.9% addressed possible treatments (Dugas et al., 2010) — more than double the proportion for anxiety–bipolar comorbidity. Though a relatively detailed descriptive portrait of anxiety– bipolar comorbidity is available, little is known about the underlying processes and management. More large-scale studies are needed to better understand the underlying mechanisms and develop effective treatments. Particular attention should be paid to psychosocial treatments that hold a great deal of potential, (for a review, see Provencher et al., 2011) such as Cognitive Behavioral Therapy (CBT; e.g., Mueser et al., 2007; Rosenberg et al., 2004) and Mindfulness-Based Cognitive Therapy (MBCT; Miklowitz et al., 2007, 2009). Psychotherapy is a promising alternative since pharmacological treatment of
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comorbid anxiety can interact with bipolar disorder. Indeed, antidepressants – a major pharmacological treatment choice in anxiety – may aggravate the side effects of mood stabilizers for many patients and can even worsen or trigger mania (El-Mallakh and Hollifield, 2008; Freeman et al., 2002; Sasson et al., 2003). Benzodiazepines can induce dependence (Chouinard, 2004), which may make them contraindicated since bipolar patients are at particularly high risk of developing substance dependencies (Brunette et al., 2003; Goodwin and Jamison, 2007). Fortunately, the pending publication of the DSM-5 might stimulate this essential growth in research on anxiety–bipolar comorbidity. During the 1980s, research on anxiety disorders saw a remarkable increase (Boschen, 2008; Cox et al., 1995; Norton et al., 1995). This growth was due, in part, to the release of the DSM-III and DSM-III-R, which were the first to propose distinct subtypes of anxiety disorders (Boschen, 2008; Cox et al., 1995; Norton et al., 1995). In the preliminary DSM-5, anxiety has been introduced as a specifier to describe mood episodes in bipolar disorder (see www. dsm5.org). With this new approach, it will be possible to pose a diagnosis of “bipolar disorder with anxiety, mild to severe.” Although this specifier will not be a distinct DSM category, it does acknowledge that anxiety is an important feature of bipolar disorder and that anxiety symptoms frequently reach the threshold of a comorbid anxiety disorder. When the anxious–bipolar disorder diagnosis becomes an official entity and the specifier is used with new patients, the need for effective treatment and management will likely become all that much more apparent. It is hoped that the release of a new DSM and the current study will, together, spur interest in research and open the door to considerable advances in the largely under-studied area of anxiety–bipolar comorbidity. Role of funding source This study was made possible in part by a summer research studentship to the second author from the Fonds de la recherche en santé du Québec (FRSQ). Conflict of interest None to report.
References Azorin, J.-M., Kaladjian, A., Adida, M., Hantouche, E.G., Hameg, A., Lancrenon, S., Akiskal, H.S., 2009. Psychopathological correlates of lifetime anxiety comorbidity in bipolar I patients: findings from a French national cohort. Psychopathology 42, 380–386. Blashfield, R.K., Intoccia, V., 2000. Growth of the literature on the topic of personality disorders. The American Journal of Psychiatry 157, 472–473. Boschen, M.J., 2008. Publication trends in individual anxiety disorders: 1980–2015. Journal of Anxiety Disorders 22, 570–575. 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. The Journal of Clinical Psychiatry 65, 1106–1113. Brunette, M.F., Noordsy, D.L., Xie, H., Drake, R.E., 2003. Benzodiazepine use and abuse among patients with severe mental illness and co-occurring substance use disorders. Psychiatric Services 54, 1395–1401. Cardoso, B.M., Kauer Sant'Anna, M., Dias, V.V., Andreazza, A.C., Cereser, K.M., Kapczinski, F., 2008. The impact of co-morbid alcohol use disorder in bipolar patients. Alcohol 42, 451–457. Chouinard, G., 2004. Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. The Journal of Clinical Psychiatry 65, 7–21. Cox, B.J., Wessel, I., Norton, G.R., Swinson, R.P., Direnfeld, D.M., 1995. Publication trends in anxiety disorders research: 1990–1992. Journal of Anxiety Disorders 9, 531–538.
Dugas, M.J., 2000. Generalized anxiety disorder publications: so where do we stand? Journal of Anxiety Disorders 14, 31–40. Dugas, M.J., Anderson, K.G., Deschenes, S.S., Donegan, E., 2010. Generalized anxiety disorder publications: where do we stand a decade later? Journal of Anxiety Disorders 24, 780–784. El-Mallakh, R.S., Hollifield, M., 2008. Comorbid anxiety in bipolar disorder alters treatment and prognosis. Psychiatric Quarterly 79, 139–150. Feske, U., Frank, E., Mallinger, A.G., Houck, P.R., Fagiolini, A., Shear, M.K., Grochocinski, V.J., Kupfer, D.J., 2000. Anxiety as a correlate of response to the acute treatment of bipolar I disorder. The American Journal of Psychiatry 157, 956–962. Freeman, M.P., Freeman, S.A., McElroy, S.L., 2002. The comorbidity of bipolar and anxiety disorders: prevalence, psychobiology, and treatment issues. Journal of Affective Disorders 68, 1–23. Goodwin, F.K., Jamison, K.R., 2007. Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression, 2nd ed. . (Oxford, New York, NY). Henry, C., Van den Bulke, D., Bellivier, F., Etain, B., Rouillon, F., Leboyer, M., 2003. Anxiety disorders in 318 bipolar patients: prevalence and impact on illness severity and response to mood stabilizer. The Journal of Clinical Psychiatry 64, 331–335. Kauer-Sant'Anna, M., Frey, B.N., Andreazza, A.C., Cereser, K.M., Gazalle, F.K., Tramontina, J., Correa da Costa, S., Santin, A., Kapczinski, F., 2007. Anxiety comorbidity and quality of life in bipolar disorder patients. Canadian Journal of Psychiatry 52, 175–181. Kauer-Sant'Anna, M., Kapczinski, F., Vieta, E., 2009. Epidemiology and management of anxiety in patients with bipolar disorder. CNS Drugs 23 (11), 953–964. Landis, J.R., Koch, G.G., 1977. The measurement of observer agreement for categorical data. Biometrics 33 (1), 159–174. Mendlowicz, M.V., Braga, R.J., Cabizuca, M., Land, M.G., Figueira, I.L., 2006. A comparison of publication trends on avoidant personality disorder and social phobia. Psychiatry Research 144, 205–209. Merikangas, K.R., Akiskal, H.S., Angst, J., Greenberg, P.E., Hirschfeld, R.M.A., 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, 543–552. Miklowitz, D.J., Otto, M.W., Frank, E., Reilly-Harrington, N.A., Wisniewski, S.R., Kogan, J.N., Nierenberg, A.A., Calabrese, J.R., Marangell, L.B., Gyulai, L., Araga, M., Gonzalez, J.M., Shirley, E.R., Thase, M.E., Sachs, G.S., 2007. Psychosocial treatments for bipolar depression: a 1-year randomized trial from the Systematic Treatment Enhancement Program. Archives of General Psychiatry 64, 419–427. Miklowitz, D.J., Alatiq, Y., Goodwin, G.M., Geddes, J.R., Fennell, M.J.V., Dimidjian, S., Hauser, M., Williams, J.M.G., 2009. A pilot study of mindfulness-based cognitive therapy for bipolar disorder. International Journal of Cognitive Therapy 2, 373–382. Mueser, K.T., Bolton, E., Carty, P.C., Bradley, M.J., Ahlgren, K.F., DiStaso, D.R., Gilbride, A., Liddell, C., 2007. The trauma recovery group: a cognitive-behavioral program for post-traumatic stress disorder in persons with severe mental illness. Community Mental Health Journal 43, 281–304. Norton, G.R., Cox, B.J., Asmundson, G.J.G., Maser, J.D., 1995. The growth of research on anxiety disorders during the 1980s. Journal of Anxiety Disorders 9, 75–85. Provencher, M.D., Hawke, L.D., Thienot, E., 2011. Psychotherapies for comorbid anxiety in bipolar spectrum disorders. Journal of Affective Disorders 133, 371–380. Rosenberg, S.D., Mueser, K.T., Jankowski, M.K., Salyers, M.P., Acker, K., 2004. Cognitive-behavioral treatment of PTSD in severe mental illness: results of a pilot study. American Journal of Psychiatric Rehabilitation 7, 171–186. Sasson, Y., Chopra, M., Harrari, E., Amitai, K., Zohar, J., 2003. Bipolar comorbidity: from diagnostic dilemmas to therapeutic challenge. International Journal of Neuropsychopharmacology 6, 139–144. Simon, N.M., Fischmann, D., Otto, M.W., Ostacher, M.J., Demopulos, C.M., Nierenberg, A.A., Pollack, M.H., 2004a. Exploring the association of anxiety comorbidity with suicidality in bipolar disorder. Neuropsychopharmacology 29, S208–S209. 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., 2004b. 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. Simon, N.M., Zalta, A.K., Otto, M.W., Ostacher, M.J., Fischmann, D., Chow, C.W., Thompson, E.H., Stevens, J.C., Demopulos, C.M., Nierenberg, A.A., Pollack, M.H., 2007. The association of comorbid anxiety disorders with suicide attempts and suicidal ideation in outpatients with bipolar disorder. Journal of Psychiatric Research 41, 255–264. Zutshi, A., Reddy, Y.C.J., Thennarasu, K., Chandrashekhar, C.R., 2006. Comorbidity of anxiety disorders in patients with remitted bipolar disorder. European Archives of Psychiatry and Clinical Neuroscience 256, 428–436.
Contents lists available at SciVerse ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Short communication
Comorbid anxiety in bipolar spectrum disorders: A neglected research and treatment issue? Martin D. Provencher a, b,⁎, Anne-Josée Guimond a, Lisa D. Hawke a a b
École de psychologie, Université Laval, Canada Centre de recherche Université Laval-Robert Giffard, Canada
a r t i c l e
i n f o
Article history: Received 9 November 2011 Received in revised form 15 November 2011 Accepted 1 December 2011 Available online 29 December 2011 Keywords: Anxiety disorders Bipolar disorder Comorbidity Publication trends
a b s t r a c t Background: Anxiety disorders are highly prevalent among patients with bipolar disorder and have a substantial impact on the course of illness and response to treatment. Despite the substantial impact that comorbid anxiety disorders have on the prognosis of individuals with bipolar disorder, many aspects of this comorbidity have received little attention from researchers. This study aims to document the current state of the literature on the comorbidity between anxiety and bipolar disorders by analyzing publication trends on the subject. Method: This study is a quantitative and qualitative review of articles on the comorbidity between anxiety disorders and bipolar disorder published between 1990 and 2010 in the ISI Web of Science, Medline and PsycINFO databases. The number of articles published each year on this comorbidity was calculated and compared to the literature published on bipolar disorder as a whole. Articles were classified into five categories and 13 subcategories to identify the main focuses of the literature and current gaps in the knowledge on the subject. Results: Interest in the comorbidity between anxiety disorders and bipolar disorder grew continually since 1990, but seems to have reached a plateau. The majority of articles addressing this comorbidity are descriptive in nature, with very few concrete studies examining the mechanisms and treatment approaches that might lead to positive advancements in the field. Limitations: Articles written in languages other than English or French were not reviewed. Conclusions: It is time to step up research efforts to better understand and manage this understudied combination of disorders. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Anxiety disorders are highly prevalent among patients with bipolar disorder and represent a considerable risk factor. Epidemiological studies show that as many as 74.9% of individuals with bipolar disorder have at least one anxiety disorder at some point in their lives (Cardoso et al., 2008; Merikangas et al., 2007). Smaller clinical samples suggest that between 27.2% and 55.8% have a comorbid anxiety disorder, while 31.8% to 37% have two or more (Boylan et al., 2004; Simon et al., 2004a,
⁎ Corresponding author at: École de psychologie, Université Laval, 2325 rue des Bibliothèques, Quebec City, Quebec, Canada G1V 0A6. Tel.: + 1 418 656 2131x11089; fax: + 1 418 656 3646. E-mail address: [email protected] (M.D. Provencher). 0165-0327/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2011.12.001
b). The National Comorbidity Survey Replication (NCS-R) found that among the people with bipolar disorder who have a comorbid anxiety disorder, social anxiety, specific phobia and generalized anxiety disorder were the most frequent, at 37.8%, 35.5% and 29.6% respectively. Other anxiety disorders found to be quite prevalent in this population were post-traumatic stress disorder at 24.2%, panic disorder at 20.1% and obsessive-compulsive disorder at 13.6% (Merikangas et al., 2007). Not only highly prevalent, comorbid anxiety disorders also have a substantial impact on the course of illness and response to treatment. Comorbid anxiety disorders or considerable anxiety symptoms are associated with longer and more frequent affective episodes (Azorin et al., 2009; Zutshi et al., 2006), slower time to remission, poorer treatment outcome (Feske et al., 2000; Henry et al., 2003), increased risk of substance
162
M.D. Provencher et al. / Journal of Affective Disorders 137 (2012) 161–164
abuse and psychosis (Kauer-Sant'Anna et al., 2007), suicidal ideation (Simon et al., 2007) and suicide attempt (Simon et al., 2004a, 2004b; Simon et al., 2007). Even subclinical anxiety would appear to have a negative impact on treatment response (El-Mallakh and Hollifield, 2008). Despite the substantial impact that comorbid anxiety disorders have on the prognosis of individuals with bipolar disorder, many aspects of this comorbidity have received little attention from researchers. Several authors point to the importance of studying this comorbidity set in greater detail to better understand the underlying processes and related issues, and particularly to adapt treatments for greater efficacy (e.g. Boylan et al., 2004; Kauer-Sant'Anna et al., 2007, 2009; Simon et al., 2004b). One widely used method of assessing an area of research is the analysis of publication trends (Boschen, 2008; Dugas et al., 2010). Recognized as a valid indicator of the level of interest in a question, publication trends have been used in different fields, such as personality disorders (Blashfield and Intoccia, 2000; Mendlowicz et al., 2006) and anxiety disorders (Boschen, 2008; Cox et al., 1995; Dugas et al., 2010; Norton et al., 1995). This study aims to document the current state of the literature on the comorbidity between anxiety and bipolar disorders. Two questions were examined: 1) Has interest in the anxiety–bipolar comorbidity increased over the past years? 2) What aspects have been most studied? To answer these questions, the literature was examined both from a qualitative and quantitative perspective. 2. Method A search was conducted of literature addressing the comorbidity between anxiety and bipolar disorders in the ISI Web of Science, Medline, and PsycINFO databases. All articles published from the beginning of the period covered by the databases to the end of the year 2010 were included. The search was conducted using the search terms Bipolar Disorder AND Comorbidity AND (individually) Anxiety Disorder, Generalized Anxiety Disorder, Post-traumatic Stress Disorder, Obsessive-Compulsive Disorder, Panic Disorder, Agoraphobia, Social Phobia, Social Anxiety Disorder, and Specific Phobia. For practical reasons, the search was limited to abstracts written in English or French. A database was created including all identified references and abstracts. After deleting duplicates, abstracts were classified into five categories and 13 subcategories inspired by the broader categories used by Dugas (2000) and Dugas et al. (2010). More specific subcategories were developed for a more precise analysis of publication content. Preliminary categories were first applied to approximately one hundred articles, then readjusted and discussed among the research team to achieve a consensus. Once the final categorization was agreed upon, it was applied to all articles. The five main categories are described below. 1 • A) Descriptive articles discussing clinical characteristics, observable impacts, illness onset, diagnostic criteria and epidemiological considerations;
1 A detailed description of subcategories is available from the authors upon request.
• B) Articles on biological, neurological, genetic, cognitive and emotional processes underlying the anxiety–bipolar comorbidity; • C) Articles on treatments for this comorbidity set; • D) General discussions or commentaries; • E) Non-specific: articles mentioning the anxiety–bipolar comorbidity, but not as the main subject matter. Articles were classified based on their abstracts by a master's level research assistant. When ambiguous, the full article was accessed to ensure proper classification. Only abstracts focusing on the anxiety–bipolar comorbidity were considered relevant. Abstracts addressing comorbidity with other disorders were only considered relevant if they placed emphasis on the anxiety–bipolar comorbidity. When an abstract mentioned the comorbidity, but not as a major topic, it was classified in Category E — Non-specific. To ensure an exhaustive review, articles addressing the comorbidity between anxiety disorders and subclinical forms of bipolarity, such as cyclothymia and hypomania, were also considered relevant. Articles not considered relevant were deleted from the database. To ensure the reliability of the classification, 15% of the articles were reclassified by a doctoral level research assistant blind as to the initial classification. The inter-rater reliability was strong for main categories (Kappa = .76, p b .001) and subcategories (Kappa = .74, p b .001), both high at the “substantial agreement” level defined by Landis and Koch (1977). For comparison purposes, the literature on bipolar disorder as a whole was also examined. A search was conducted of articles indexed in the same databases over the same time period. All articles containing the term Bipolar Disorder in the Keywords, Title or Abstract fields were retained. Duplicates were deleted from the database. 3. Results The first step of the analysis was to calculate the number of articles published per year addressing the anxiety–bipolar comorbidity. The first article was published in 1990. As shown in Fig. 1, the rate of publication generally grew from 1990 to 2010, with a particularly strong increase beginning in the early 2000s. The total number of articles addressing this comorbidity increased from 1 in 1990 to 54 articles in 2010. The number of articles specifically addressing anxiety– bipolar comorbidity (excluding Category E — Non-specific) increased from 1 article in 1990 to 17 articles in 2010. However, there appears to be a plateau or even a slight decrease in the number of publications after 2007. The number of articles published each year on the anxiety–bipolar comorbidity was then compared to all literature mentioning bipolar disorder. Articles specifically addressing the anxiety–bipolar comorbidity made up only 0.20% of the entire literature mentioning bipolar disorder in 1990, compared to 0.92% in 2010. The total number of articles addressing this comorbidity made up a slim 3% of the bipolar literature in 2010. The second step of the analysis consisted of categorizing the articles in the 13 subcategories, grouped together into five main categories. The number of articles in each category is presented in Table 1. The majority of articles were Non-
M.D. Provencher et al. / Journal of Affective Disorders 137 (2012) 161–164
80
163 Total number of articles on the anxiety-bipolar comorbidity
70
Frequency
60 50 40
Number of articles specifically addressing the bipolar-anxiety comorbidity
30 20 10
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
0
Year Fig. 1. Annual number of publications addressing the bipolar-anxiety comorbidity, from 1990 to 2010.
specific (Category E), at 65%, meaning they mentioned the anxiety–bipolar comorbidity without making it a major focus. Descriptive issues also received considerable attention, whereas processes, treatment issues and general discussions accounted for few articles. Among the articles specific to the anxiety–bipolar comorbidity (excluding Category E — Non-specific), a full 60.6% were descriptive articles, while 19.2% addressed treatment issues, 10.9% were general discussions, and 9.3% discussed the associated neurological, biological, genetic, cognitive or emotional processes. 4. Discussion The results of the current study suggest that interest in the comorbidity between anxiety and bipolar disorders has continually increased in the literature since the 1990s, as has interest in bipolar disorder as a whole. The total number of published articles peaked in 2007, but then seems to have declined or reached a plateau. The majority of articles addressing this comorbidity are descriptive in nature, with very few Table 1 Number and percentage of articles in each category and subcategory. Category
n
%
A) Descriptive articles 1 — clinical characteristics/observable impacts 2 — illness onset 3 — diagnostic criteria 4 — epidemiology B) Processes 5 — bio-neuro-genetic 6 — cognitive functions 7 — emotional regulation C) Treatments 8 — case studies 9 — meta-analyses 10 — pharmacological treatment studies 11 — psychosocial treatment studies 12 — treatment recommendations 13 — reviews of treatments D) General discussions/commentaries E) Non-specific
117 92 4 4 17 18 16 1 1 37 17 0 12 3 1 4 21 358
21.23 16.70 0.73 0.73 3.09 3.27 2.90 0.18 0.18 6.72 3.09 0.00 2.18 0.54 0.18 0.73 3.81 64.97
Note. Totals and percentages for each main category are in bold.
concrete studies examining the mechanisms and treatment approaches that might lead to positive advancements in the field. Though the number of publications increased from 1990 to 2010, anxiety–bipolar comorbidity remains understudied and the proportion addressing the issue directly is negligible. Furthermore, the trend observed since 2007 suggests that interest in the issue may have stagnated. Descriptive issues are well documented, particularly the clinical characteristics and observable impacts of anxiety disorders comorbid to bipolar disorder. However, gaps remain in the study of descriptive aspects, such as diagnostic and onset-related issues. Biological, neurological, genetic, cognitive and emotional aspects, as well as treatment alternatives, remain relatively unstudied. The impact of this comorbidity on cognitive and emotional processes is particularly understudied, each subcategory accounting for a single article. This leaves the factors that contribute to the development and maintenance of comorbidity unknown. The treatments for anxiety disorders comorbid to bipolar disorder are also under-studied, despite the fact that a number of studies have shown that anxiety comorbidity has a negative impact on treatment response (El-Mallakh and Hollifield, 2008). The majority of treatment studies are case studies, with few large-scale trials. Most address pharmacological treatments, with very few examining psychosocial interventions. In comparison, an article examining anxiety disorder literature reported that 30.8% of articles addressed treatment issues (Cox, et al., 1995). For generalized anxiety disorder, 19.2% of articles examined processes, while a full 43.9% addressed possible treatments (Dugas et al., 2010) — more than double the proportion for anxiety–bipolar comorbidity. Though a relatively detailed descriptive portrait of anxiety– bipolar comorbidity is available, little is known about the underlying processes and management. More large-scale studies are needed to better understand the underlying mechanisms and develop effective treatments. Particular attention should be paid to psychosocial treatments that hold a great deal of potential, (for a review, see Provencher et al., 2011) such as Cognitive Behavioral Therapy (CBT; e.g., Mueser et al., 2007; Rosenberg et al., 2004) and Mindfulness-Based Cognitive Therapy (MBCT; Miklowitz et al., 2007, 2009). Psychotherapy is a promising alternative since pharmacological treatment of
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comorbid anxiety can interact with bipolar disorder. Indeed, antidepressants – a major pharmacological treatment choice in anxiety – may aggravate the side effects of mood stabilizers for many patients and can even worsen or trigger mania (El-Mallakh and Hollifield, 2008; Freeman et al., 2002; Sasson et al., 2003). Benzodiazepines can induce dependence (Chouinard, 2004), which may make them contraindicated since bipolar patients are at particularly high risk of developing substance dependencies (Brunette et al., 2003; Goodwin and Jamison, 2007). Fortunately, the pending publication of the DSM-5 might stimulate this essential growth in research on anxiety–bipolar comorbidity. During the 1980s, research on anxiety disorders saw a remarkable increase (Boschen, 2008; Cox et al., 1995; Norton et al., 1995). This growth was due, in part, to the release of the DSM-III and DSM-III-R, which were the first to propose distinct subtypes of anxiety disorders (Boschen, 2008; Cox et al., 1995; Norton et al., 1995). In the preliminary DSM-5, anxiety has been introduced as a specifier to describe mood episodes in bipolar disorder (see www. dsm5.org). With this new approach, it will be possible to pose a diagnosis of “bipolar disorder with anxiety, mild to severe.” Although this specifier will not be a distinct DSM category, it does acknowledge that anxiety is an important feature of bipolar disorder and that anxiety symptoms frequently reach the threshold of a comorbid anxiety disorder. When the anxious–bipolar disorder diagnosis becomes an official entity and the specifier is used with new patients, the need for effective treatment and management will likely become all that much more apparent. It is hoped that the release of a new DSM and the current study will, together, spur interest in research and open the door to considerable advances in the largely under-studied area of anxiety–bipolar comorbidity. Role of funding source This study was made possible in part by a summer research studentship to the second author from the Fonds de la recherche en santé du Québec (FRSQ). Conflict of interest None to report.
References Azorin, J.-M., Kaladjian, A., Adida, M., Hantouche, E.G., Hameg, A., Lancrenon, S., Akiskal, H.S., 2009. Psychopathological correlates of lifetime anxiety comorbidity in bipolar I patients: findings from a French national cohort. Psychopathology 42, 380–386. Blashfield, R.K., Intoccia, V., 2000. Growth of the literature on the topic of personality disorders. The American Journal of Psychiatry 157, 472–473. Boschen, M.J., 2008. Publication trends in individual anxiety disorders: 1980–2015. Journal of Anxiety Disorders 22, 570–575. 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. The Journal of Clinical Psychiatry 65, 1106–1113. Brunette, M.F., Noordsy, D.L., Xie, H., Drake, R.E., 2003. Benzodiazepine use and abuse among patients with severe mental illness and co-occurring substance use disorders. Psychiatric Services 54, 1395–1401. Cardoso, B.M., Kauer Sant'Anna, M., Dias, V.V., Andreazza, A.C., Cereser, K.M., Kapczinski, F., 2008. The impact of co-morbid alcohol use disorder in bipolar patients. Alcohol 42, 451–457. Chouinard, G., 2004. Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. The Journal of Clinical Psychiatry 65, 7–21. Cox, B.J., Wessel, I., Norton, G.R., Swinson, R.P., Direnfeld, D.M., 1995. Publication trends in anxiety disorders research: 1990–1992. Journal of Anxiety Disorders 9, 531–538.
Dugas, M.J., 2000. Generalized anxiety disorder publications: so where do we stand? Journal of Anxiety Disorders 14, 31–40. Dugas, M.J., Anderson, K.G., Deschenes, S.S., Donegan, E., 2010. Generalized anxiety disorder publications: where do we stand a decade later? Journal of Anxiety Disorders 24, 780–784. El-Mallakh, R.S., Hollifield, M., 2008. Comorbid anxiety in bipolar disorder alters treatment and prognosis. Psychiatric Quarterly 79, 139–150. Feske, U., Frank, E., Mallinger, A.G., Houck, P.R., Fagiolini, A., Shear, M.K., Grochocinski, V.J., Kupfer, D.J., 2000. Anxiety as a correlate of response to the acute treatment of bipolar I disorder. The American Journal of Psychiatry 157, 956–962. Freeman, M.P., Freeman, S.A., McElroy, S.L., 2002. The comorbidity of bipolar and anxiety disorders: prevalence, psychobiology, and treatment issues. Journal of Affective Disorders 68, 1–23. Goodwin, F.K., Jamison, K.R., 2007. Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression, 2nd ed. . (Oxford, New York, NY). Henry, C., Van den Bulke, D., Bellivier, F., Etain, B., Rouillon, F., Leboyer, M., 2003. Anxiety disorders in 318 bipolar patients: prevalence and impact on illness severity and response to mood stabilizer. The Journal of Clinical Psychiatry 64, 331–335. Kauer-Sant'Anna, M., Frey, B.N., Andreazza, A.C., Cereser, K.M., Gazalle, F.K., Tramontina, J., Correa da Costa, S., Santin, A., Kapczinski, F., 2007. Anxiety comorbidity and quality of life in bipolar disorder patients. Canadian Journal of Psychiatry 52, 175–181. Kauer-Sant'Anna, M., Kapczinski, F., Vieta, E., 2009. Epidemiology and management of anxiety in patients with bipolar disorder. CNS Drugs 23 (11), 953–964. Landis, J.R., Koch, G.G., 1977. The measurement of observer agreement for categorical data. Biometrics 33 (1), 159–174. Mendlowicz, M.V., Braga, R.J., Cabizuca, M., Land, M.G., Figueira, I.L., 2006. A comparison of publication trends on avoidant personality disorder and social phobia. Psychiatry Research 144, 205–209. Merikangas, K.R., Akiskal, H.S., Angst, J., Greenberg, P.E., Hirschfeld, R.M.A., 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, 543–552. Miklowitz, D.J., Otto, M.W., Frank, E., Reilly-Harrington, N.A., Wisniewski, S.R., Kogan, J.N., Nierenberg, A.A., Calabrese, J.R., Marangell, L.B., Gyulai, L., Araga, M., Gonzalez, J.M., Shirley, E.R., Thase, M.E., Sachs, G.S., 2007. Psychosocial treatments for bipolar depression: a 1-year randomized trial from the Systematic Treatment Enhancement Program. Archives of General Psychiatry 64, 419–427. Miklowitz, D.J., Alatiq, Y., Goodwin, G.M., Geddes, J.R., Fennell, M.J.V., Dimidjian, S., Hauser, M., Williams, J.M.G., 2009. A pilot study of mindfulness-based cognitive therapy for bipolar disorder. International Journal of Cognitive Therapy 2, 373–382. Mueser, K.T., Bolton, E., Carty, P.C., Bradley, M.J., Ahlgren, K.F., DiStaso, D.R., Gilbride, A., Liddell, C., 2007. The trauma recovery group: a cognitive-behavioral program for post-traumatic stress disorder in persons with severe mental illness. Community Mental Health Journal 43, 281–304. Norton, G.R., Cox, B.J., Asmundson, G.J.G., Maser, J.D., 1995. The growth of research on anxiety disorders during the 1980s. Journal of Anxiety Disorders 9, 75–85. Provencher, M.D., Hawke, L.D., Thienot, E., 2011. Psychotherapies for comorbid anxiety in bipolar spectrum disorders. Journal of Affective Disorders 133, 371–380. Rosenberg, S.D., Mueser, K.T., Jankowski, M.K., Salyers, M.P., Acker, K., 2004. Cognitive-behavioral treatment of PTSD in severe mental illness: results of a pilot study. American Journal of Psychiatric Rehabilitation 7, 171–186. Sasson, Y., Chopra, M., Harrari, E., Amitai, K., Zohar, J., 2003. Bipolar comorbidity: from diagnostic dilemmas to therapeutic challenge. International Journal of Neuropsychopharmacology 6, 139–144. Simon, N.M., Fischmann, D., Otto, M.W., Ostacher, M.J., Demopulos, C.M., Nierenberg, A.A., Pollack, M.H., 2004a. Exploring the association of anxiety comorbidity with suicidality in bipolar disorder. Neuropsychopharmacology 29, S208–S209. 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., 2004b. 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. Simon, N.M., Zalta, A.K., Otto, M.W., Ostacher, M.J., Fischmann, D., Chow, C.W., Thompson, E.H., Stevens, J.C., Demopulos, C.M., Nierenberg, A.A., Pollack, M.H., 2007. The association of comorbid anxiety disorders with suicide attempts and suicidal ideation in outpatients with bipolar disorder. Journal of Psychiatric Research 41, 255–264. Zutshi, A., Reddy, Y.C.J., Thennarasu, K., Chandrashekhar, C.R., 2006. Comorbidity of anxiety disorders in patients with remitted bipolar disorder. European Archives of Psychiatry and Clinical Neuroscience 256, 428–436.