Psychotherapies for comorbid anxiety in bipolar spectrum disorders

Journal of Affective Disorders 133 (2011) 371–380

Contents lists available at ScienceDirect

Journal of Affective Disorders j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d

Review

Psychotherapies for comorbid anxiety in bipolar spectrum disorders Martin D. Provencher a,b,⁎, Lisa D. Hawke a, Emmanuelle Thienot 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 8 September 2010 Received in revised form 20 October 2010 Accepted 23 October 2010 Available online 18 November 2010 Keywords: Bipolar disorder Anxiety disorders Comorbidity Psychosocial treatment Psychotherapy

a b s t r a c t Background: Comorbid anxiety disorders are highly prevalent in bipolar disorder and have been shown to have serious negative impacts on the course of illness. The pharmacological treatment of anxiety can interact with the bipolar disorder and has not been proven effective. As such, many have recommended the psychological treatment of anxiety. This paper reviews the literature on psychological treatments for anxiety comorbid to bipolar disorder. Method: The Medline, PsychInfo and Web of Science databases were thoroughly examined for relevant treatment studies. Results: Despite frequent recommendations in the literature, surprisingly few have studied the psychological treatment of comorbid anxiety in bipolar disorders. Nevertheless, preliminary results suggest that comorbid anxiety disorders can be effectively treated in a bipolar clientele using cognitive–behavioral therapy, mindfulness-based cognitive–behavioral therapy or relaxation training. In contrast, interpersonal, family therapy and psychoeducation alone would not seem to be beneficial treatment alternatives for anxiety. Cognitive–behavioral therapy appears to reduce the symptoms of obsessive–compulsive disorder, generalized anxiety disorder, panic disorder, post-traumatic stress disorder and general symptoms of anxiety among patients with bipolar disorder. However, the long-term maintenance of anxiety treatment effects may be somewhat reduced and adaptations may be called for to augment and sustain benefits. Conclusions: There is an urgent need for randomized controlled trials of different forms of psychotherapy for anxiety disorders comorbid to bipolar disorder. Until such trials are available, the most promising approach would appear to be the sequential or modular CBTbased treatment of the anxiety disorder. © 2010 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

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Introduction . . . . . . . . . . . . . Comorbidities in bipolar disorders . . . Comorbid anxiety disorders . . . . . . 3.1. Time spent ill . . . . . . . . . . 3.2. Suicidality . . . . . . . . . . . 3.3. Quality of life and functioning . . Anxiety and pharmacological treatment Anxiety and psychosocial treatments . .

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⁎ Corresponding author. 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 © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2010.10.040

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6. 7.

Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Comorbid bipolar disorder and anxiety disorders . . . . . 7.2. Bipolar disorder with comorbid anxiety symptoms . . . . 7.3. Anxiety disorder with comorbid bipolar spectrum symptoms 8. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . Role of funding source . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Bipolar disorder is a chronic mental health condition characterized by alternating cycles of depression and mania, both of which have potentially devastating impacts on all domains of functioning. Type I bipolar disorder (BP-I), the most severe form of the illness, is characterized by cycles of major depression and mania. Type II bipolar disorder (BP-II) also includes major depressive episodes, but with attenuated hypomanic episodes (APA, 2001). The lifetime prevalence of bipolar disorder is estimated at between 2.2% and 3.9% (Kessler et al., 2005; Schaffer et al., 2006). People living with bipolar disorder experience multiple relapses over the course of their lives. For example, patients with BP-I experience an average of 15.9 depressive episodes and 14.7 manic episodes, for some 30 lifetime relapses (Schaffer et al., 2006). In addition to acute episodes, patients also face substantial residual or inter-episode symptoms (Benazzi, 2004; Paykel et al., 2006), complex comorbidity (Schaffer et al., 2006; Sublette et al., 2009), high suicidality (Judd and Akiskal, 2003), high service utilization (Das Gupta and Guest, 2002; Stensland et al., 2007) and reduced overall quality of life (Brissos et al., 2008). Together, this represents a considerable burden for the healthcare system. Indeed, the average cost incurred per year for a single bipolar patient is $10,402 US in medication, hospitalization and treatment (Stensland et al., 2007).

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(ADs) merit particular attention. The NCS-R population study found that among the 74.9% of people with bipolar disorder who have a comorbid AD, social anxiety, specific phobia and generalized anxiety disorder were the most frequent, at 37.8%, 35.5% and 29.6% respectively. Other ADs 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). Based on epidemiological and genetic studies, bipolar and anxiety disorders appear to be closely linked from a physiological standpoint (Freeman et al., 2002; Wozniak et al., 2002). In fact, the connection between the two categories of disorders is so strong that some have suggested anxious bipolarity might mark a severe subtype of bipolar disorder or a distinct clinical disorder (e.g., Dilsaver et al., 2008; Freeman et al., 2002; Wozniak et al., 2002). Not only highly prevalent to the point of appearing to be an integral part of the bipolar spectrum, comorbid ADs also have a considerable impact on the course of illness and response to treatment. A broad range of studies have demonstrated that the impacts of comorbid ADs include greater symptom chronicity, slower recovery, earlier onset, greater suicidality, lower quality of life and more impaired functioning. 3.1. Time spent ill

In addition to recurrent symptoms of depression and (hypo) mania, people with bipolar disorder face a multitude of psychiatric and physical comorbidities. The National Comorbidity Survey Replication (NCS-R) found that the vast majority of patients with bipolar spectrum disorders have presented another axis I disorder at some point in their lives. In fact, 92.3% of bipolar patients reported having had one or more comorbid disorders. The comorbidities most often observed are anxiety disorders (74.9%), impulse control disorders generally diagnosed during childhood or adolescence (62.8%) and substance abuse disorders (42.3%) (Merikangas et al., 2007). Bipolar patients also present higher levels of physical comorbidities than the general population, including high rates of type II diabetes and cardiovascular disease (McIntyre et al., 2004).

Bipolar patients with comorbid ADs or considerable anxiety symptoms have been shown to spend a greater amount of time in affective episodes and are at higher risk of relapse (Coryell et al., 2009; Otto et al., 2006; Simon et al., 2004; Zutshi et al., 2006). This is also associated with a slower time to remission, whether from manic, mixed or depressed episodes (Feske et al., 2000). One study found that the amount of risk added by comorbid ADs did not differ by BP-I vs. BP-II diagnosis (Otto et al., 2006). Others have suggested that social anxiety disorder or generalized anxiety disorder may have the most negative impact on the course of the bipolar disorder (Boylan et al., 2004; Otto et al., 2006). Patients with comorbid anxiety tend to have an earlier age of onset of the bipolar disorder, perhaps particularly so in the case of panic disorder (Henry et al., 2003; Lee and Dunner, 2008). This means they spend more years living with their illness.

3. Comorbid anxiety disorders

3.2. Suicidality

As one of the most frequent classes of comorbidities observed in bipolar spectrum patients, anxiety disorders

Comorbid ADs are also associated with greater levels of suicidality among bipolar patients. One study showed that a

2. Comorbidities in bipolar disorders

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history of a comorbid AD is associated with double the probability of a past suicide attempt, while a current AD is associated with double the probability and more severe levels of current suicidal ideation (Simon et al., 2007). These findings have been replicated by multiple studies. This increased suicidality appears to hold true when looking at the individual anxiety disorders separately, including comorbid post-traumatic stress disorder (Dell'osso et al., 2009; Quarantini et al., 2010; Simon et al., 2004), panic disorder with or without agoraphobia (Kilbane et al., 2009; Simon et al., 2004), obsessive–compulsive disorder (Simon et al., 2004), social anxiety disorder (Dilsaver et al., 1997; Simon et al., 2004; Simon et al., 2007) and generalized anxiety disorder (Simon et al., 2004). Bipolar patients with a comorbid AD also demonstrate higher levels of impulsivity (Taylor et al., 2008), which is strongly associated with suicidality. 3.3. Quality of life and functioning Given the accumulation of negative impacts on the course of the bipolar disorder, it comes as no surprise that comorbid ADs negatively impact quality of life and functioning. Albert et al. (2008) found that comorbid anxiety disorders reduced health-related quality of life in euthymic bipolar patients, though the effect was most marked in BP-I. Kauer-Sant'Anna, et al. (2007) found that the negative impact was greatest on psychological quality of life. Others have found that not only does the presence of a comorbid AD reduce role functioning and quality of life, but the negative impact is even greater for patients with more than one comorbid AD (Otto et al., 2006). 4. Anxiety and pharmacological treatment Considering the wealth of data demonstrating the deleterious impact that comorbid anxiety has for bipolar patients, a number of authors have agreed that it is time to take a close look at the treatments available for this set of common comorbidities (e.g., El-Mallakh and Hollifield, 2008; Krishnan, 2005; Otto and Reilly-Harrington, 2002; Sasson et al., 2003). The first line of treatmentfor for bipolar disorder is pharmacotherapy, including mood stabilizers, anticonvulsants and antipsychotic medications, among others (Rivas-Vazquez et al., 2002). Pharmacotherapy is also empirically supported for the treatment of anxiety disorders, particularly selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines (Nathan and Gorman, 2007). However, the characteristics of bipolar disorder may reduce the recourse to these medications, since they can interact with the mood stabilizers used to treat bipolar affective symptoms. Notably, SSRIs 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). The presence of a comorbid AD would also appear to reduce the effectiveness of the mood stabilizers used to treat mood symptoms (Keller, 2006) and increase the risk of non-adherence to mood stabilizers (Perlis et al., 2010). Furthermore, bipolar patients

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who are taking anxiety medications spend 16% more time symptomatic (Bauer et al., 2009). Though new research has begun to identify some beneficial pharmacological treatments for comorbid anxiety, results remain preliminary and raise many questions (for a review, see Kauer-Sant'Anna et al., 2009), with the only double-blind published clinical trial on bipolar disorder with comorbid anxiety finding that risperidone was no more effective than a placebo (Sheehan et al., 2009). Since treatment issues are complex and mood stabilization is considered the primary treatment target, 59% of bipolar patients with a comorbid AD do not receive specific pharmacological treatment for their anxiety, despite the negative impacts of anxiety on the course of the disorder (Simon et al., 2004). Given this bleak picture of pharmacological interaction and the absence of robust research evidence showing efficacy, many have suggested that the psychological treatment of the anxiety disorder, using interventions such as cognitive– behavioral therapy, may be an interesting treatment alternative (e.g., Kauer-Sant'Anna et al., 2009; Otto and ReillyHarrington, 2002; Rizvi and Zaretsky, 2007; Sasson et al., 2003). 5. Anxiety and psychosocial treatments Among the psychosocial treatments used to treat anxiety disorders, cognitive–behavioral therapy (CBT) is an interesting option since it has been demonstrated effective both for the symptoms of anxiety disorders and bipolar spectrum disorders (Nathan and Gorman, 2007). CBT for anxiety includes techniques such as exposure, relaxation training and cognitive restructuring. It has been shown to be effective for a wide range of ADs even in the presence of certain comorbidities (e.g., Brown et al., 1995; Craske et al., 2007; Davis et al., 2010; Storch et al., 2010; Tsao et al., 2005). Unfortunately, despite their focus on comorbidities, these studies tend to list bipolar disorders as an exclusion criterion. This exclusion creates a gap in the knowledge when it comes to treating comorbid AD-BP patients — a gap that is of no small concern for a complex bipolar clientele. Given the specific characteristics of bipolarity, research results for other psychological disorders do not always necessarily generalize to bipolar disorder. For example, mood stability, which must remain top of mind with bipolar patients, could in some cases be compromised by potentially stress-inducing strategies such as exposure, a technique commonly used in the treatment of ADs. Despite the promise of psychosocial interventions, it is important to recognize that since comorbid anxiety interacts with the pharmacological treatment of bipolar disorder, it may also interact with psychosocial treatments. Certain interventions for anxiety could either exacerbate bipolar symptoms or be less effective in the presence of bipolar disorder, which could have unfortunate repercussions for patients. To ensure the maximum clinical utility of psychosocial treatments for comorbid anxiety and the absence of any negative effects, it is essential that they be validated among a complex, comorbid bipolar clientele. The psychological treatment of comorbid anxiety in bipolar disorder is a very young area of investigation and, unfortunately, published studies are sparse. Nevertheless, some preliminary studies

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are available and their combined results may provide valuable information for orienting treatment. This paper provides an overview of the studies available to date addressing the efficacy of psychosocial treatments for comorbid anxiety and bipolar spectrum disorders. 6. Method A documentation search was conducted among articles indexed in the PsychInfo, Medline and Web of Science databases. Search terms, queried in the title, keywords and abstract fields, included Bipolar Disorder, Anxiety Disorder, Comorbidity, Psychotherapy, Generalized Anxiety Disorder, GAD, Post-traumatic Stress Disorder, PTSD, Obsessive– Compulsive Disorder, OCD, Panic Disorder, Agoraphobia, Social Phobia, Social Anxiety Disorder, Hypomania, Cyclothymia and Severe Mental Illness. Reference lists of relevant articles were also closely examined for additional studies. Treatment studies written in either English or French and presenting data on the impact of psychosocial treatments on anxiety or the impact of anxiety on psychosocial treatments among people with bipolar disorder or bipolar spectrum symptoms were retained. To be included, studies had to either focus on a diagnosed AD or present data attesting to the presence of anxiety symptoms at pre- and/or post-treatment assessments. Given the dearth of results available, all applicable studies were considered regardless of sample size or design. 7. Results Despite the abundance of articles discussing the prevalence of anxiety disorders comorbid to bipolar disorder and their effects on the course of illness, surprisingly few have studied their psychosocial treatment. The few studies that have addressed the issue are generally small-scale and exploratory in nature, using case study or single-case designs. In all, seven studies were identified studying psychosocial treatments in patients with bipolar disorder and a comorbid anxiety disorder. Since so few studies were available, we also considered those studies addressing diagnosed bipolar disorder combined with the symptoms of anxiety, rather than diagnosed comorbid ADs. This revealed five additional studies. Likewise, studies examining treatments for anxiety disorders in the presence of certain symptoms characteristic of the bipolar spectrum were also included, providing one additional study. The studies reviewed are summarized in Table 1. 7.1. Comorbid bipolar disorder and anxiety disorders Gaudiano and Miller (2005) compared three types of treatment for bipolar patients with or without a comorbid anxiety disorder in a randomized controlled trial. Out of a total of 92 patients, 29 received pharmacotherapy alone, 30 received pharmacotherapy plus family psychoeducation and 33 received pharmacotherapy plus family therapy. Twenty eight percent of the sample met criteria for at least one current or past anxiety disorder, while 11% met criteria for more than one. Results showed that comorbid anxiety negatively affected the course of the disorder in terms of depressive episodes, current affective symptoms and time

spent symptomatic. Patients with comorbid ADs experienced depressive symptoms 40.8% of the time, compared to only 12.9% of the time for non-comorbid participants. The percentage of time spent manic was similar in the two groups (8% vs. 6% respectively). There was no significant difference in the impact of an AD on outcome by treatment group. Though the study confirmed the negative impact of ADs on the course of illness, it was unable to demonstrate that family therapy reduces the negative impact of anxiety any more than pharmacotherapy alone or pharmacotherapy plus psychoeducation. However, anxiety was considered only in terms of the presence or absence of an AD rather than as a measure of symptoms, limiting the conclusions that can be drawn from the study. One brief case report describes the use of behavioral therapy to treat obsessive–compulsive disorder in two patients with bipolar disorder (Baer et al., 1985). In both cases, the patients had gained some benefit from a previous round of behavioral therapy, but the gains were insufficient and symptoms had since worsened. The patients therefore embarked on a full behavioral intervention emphasizing in vivo exposure and response prevention. After 51 sessions of treatment, the first patient had made considerable gains in his symptoms, though his obsessions and compulsions tended to reemerge when he experienced an increase in affective symptoms. The patient was continuing with biweekly sessions. The second patient had received 30 sessions at the time of the report. Her obsessions and compulsions had also diminished, though treatment also remained ongoing. This preliminary, descriptive report of two cases suggests that patients with bipolar disorder may benefit from fairly extensive behavioral therapy targeting obsessive–compulsive disorder, particularly when mood symptoms are stabilized. A recent study specifically addressed the treatment of comorbid generalized anxiety disorder (GAD) in patients with bipolar disorders. Provencher et al. (2010) tested the efficacy of manualized CBT for generalized anxiety disorder among four bipolar patients. Participants in this single-case design received 12 sessions of individualized cognitive– behavioral therapy (CBT) after multiple baseline assessments of anxiety and affective symptoms. The treatment produced clinically significant change in the cognitive (i.e., the tendency to worry) and somatic symptoms of generalized anxiety disorder for three of four patients. Improvements in somatic symptoms were maintained at the four-month follow-up assessment, though cognitive symptoms had reemerged to some extent. In all, the therapeutic response was not as strong as hoped and the fourth patient retained little benefit from the treatment. This preliminary study suggests that CBT may be useful for patients with GAD comorbid to a bipolar disorder, though its effects may be somewhat diluted and some of its benefits may not be maintained as well as in a non-comorbid clientele. One team conducted a randomized controlled trial comparing interpersonal and social rhythm therapy (IPSRT) to intensive clinical management (ICM), which consisted primarily of psychoeducation combined with general clinical management and support (Feske et al., 2000; Frank et al., 2002; Frank et al., 2005). A total of 175 participants with bipolar disorder were randomized to four conditions, including each of the four possible combinations of IPSRT and ICM

Table 1 Summary of treatment studies. Study

Design

Bipolar disorder with comorbid AD Gaudiano and RCT with TAU Miller (2005) (med.) and active tx controls Baer et al. (1985) Case study Provencher et al. Single-case (2010)

Participants (controls)

Anxiety

Main results

Additional information

Med: N = 29 Current or Med + FPsyed: N = 30 Med + FT: N = 33 past AD, 28%

FT (6–10 sess., 50 min) vs. F-PE (6 sess., 90 min) vs. medication

- Ø outcome difference by tx group - Lifetime AD ↓ outcome (N = 20)

N=2 N=4

OCD GAD

BT (51 and 30 sessions) Individual CBT for GAD (12 sess.) Individual CBT for PTSD (12-16 sess.) Individual CBT for PTSD (12 sess.)

-

BP+AD : N depressive episodes N % time symptomatic N current affective sx - Treatment ongoing

↓ obsessions and compulsions ↓ ANX for 3 participants (cognitive and somatic) Somatic ANX maintained at 4 months Some loss of cognitive ANX gains ↓ PTSD criteria - Mixed sample including 3 BP

-

PTSD recovery ↓ psychiatric symptoms Maintained at 3 months ↓ PTSD cognitions, symptoms

- Participant from Rosenberg et al. (2004)

↓ PTSD symptoms ↓ depression Maintained at 3 months Better outcome if ICM in acute tx phase

- All participants with comorbid mental illness - Results not presented separately for BP

Rosenberg et al. (2004) Hamblen et al. (2004)

Open trial

N = 22, including 3 BP

PTSD

Case study

N = 3, including 1 BP

PTSD

Mueser et al. (2008) Mueser et al. (2007)

RCT with TAU Controls Open trial

N = 54 (N = 54) including 25 BP

PTSD

N = 80, including 7 BP

PTSD

Frank et al. (2005) RCT with active tx controls

ICM/ICM: N = 7 AD (N = 36) ICM/IP N = 2 History of AD (N = 42) IP/ICM N = 2 AD (N = 46) IP/ AD IP N = 9 AD (N = 30)

Bipolar disorder with anxiety symptoms Williams et al. RCT with wait- N = 7 (N = 7) (2008) list controls Miklowitz et al. (2009) Dusser et al. (2009) Van Gent and Zwart (1993) and Van Gent (2000) Van Gent and Zwart (1991)

Symptoms

Individual CBT for PTSD (12-16 sess.) Group CBT for PTSD (21 sess.)

IP vs ICM with PE in Acute vs Maintenance tx phases

Group MBCT for mood disorders (8 sess., 120 min + 1 day) Group MBCT for BP (8 sess, 120 min) Group PE with relaxation practice (6 sess., 120 min) Group PE (5 sess. vs. 10 sess.)

- Tx prevents increase in anxiety

Group PE (5 sess.) (vs. no treatment)

- ↑ patient ANX at post-tx - Return to pre-tx ANX at 6 months

- Administered to partners of bipolar patients

- Equal improvement in ANX and DEP - Less maintenance at 12 months (ANX)

- Post-hoc analysis of patients with past subsyndromal hypomania (vs. no hypomania)

Open trial

N = 22

Symptoms

Open trial

N=8

Symptoms

Controlled trial comparing 2 forms of PE RCT with TAU controls

N = 15 (N = 20)

Symptoms

N = 14 partners (N = 12 partners)

Symptoms

N = 18 (N = 38)

Group CBT for PD (openPD with ended, 120 min) history of hypomania

Soft bipolar spectrum + AD Bowen and Open trial D'Arcy (2003)

-

↓ self-reported anxiety ↓ depression, mania, hopelessness ↓ clinician-assessed anxiety Ø self-report state-trait anxiety Ø on anxiety at 3 months, 15 months, 3 years

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Treatment

Note: ↓ = decrease; ↑ = increase; Ø = no impact; AD = Anxiety Disorder; ANX = anxiety; DEP = depression; BP = Bipolar Disorder; CBT = Cognitive–Behavioral Therapy; BT = Behavior Therapy; FT = Family Therapy; F-PE = Family psychoeducation; GAD = Generalized Anxiety Disorder; ICM = Intensive Clinical Management; IP = Interpersonal and Social Rhythm Therapy; PD = Panic Disorder; PE = Psychoeducation; PTSD = Post-traumatic stress disorder; RCT = Randomized controlled trial. 375

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administered during 1) the acute treatment phase, and 2) the maintenance phase. As a whole, IPSRT helped regularize social rhythms and extend survival time until relapse, in accordance with the original hypotheses (Frank et al., 2005). However, secondary analyses revealed that the presence of a comorbid AD interacted with the treatment effect. Specifically, participants with a comorbid anxiety disorder relapsed sooner if they received IPSRT (N = 9) during the acute treatment phase, compared to longer survival times for those with acute ICM treatment (N = 11). It was concluded that the ICM approach better addressed anxiety-related somatic concerns and was therefore more useful for patients managing comorbid anxiety in addition to a bipolar disorder. As such, this study points to the importance of directly addressing somatic concerns among patients with anxiety, possibly through a psychoeducational approach. The comorbid AD that has received the most attention is post-traumatic stress disorder (PTSD), examined in multiple studies by a single research team. First, Rosenberg et al. (2004) conducted a pilot study of a CBT-based intervention for PTSD among patients with severe mental illnesses (axis I only). A sample of 22 patients in this open trial included three patients with bipolar disorder. Participants received 12 to 16 sessions of an individual intervention that included psychoeducation, cognitive restructuring of the traumatic experience and relaxation training. Global results of the pilot study were modest but positive, with an 86% completion rate. Of the patients available at the three-month follow-up assessment, 50% no longer met the diagnostic criteria for PTSD. Though results were not broken down by primary diagnosis, Hamblen et al. (2004) presented a case illustration of three of the patients who participated in the pilot study. Of the cases presented, one had a comorbid bipolar disorder combined with substance abuse and two had schizoaffective disorder, depressive type. The patient with bipolar disorder attended 12 sessions of the PTSD intervention and engaged well in the treatment process. Breathing exercises were well integrated, though the patient had some difficulty using cognitive restructuring techniques. In all, the treatment was considered a success, the patient no longer meeting the criteria for PTSD at the post-treatment assessment or three-month follow-up. General psychiatric symptoms declined dramatically and no negative effects were observed. Together, this pilot study and case illustration suggest that patients with comorbid PTSD and bipolar disorder may benefit from CBT specifically targeting the anxiety disorder. Based on these positive preliminary results, Mueser et al., (2008) then tested the PTSD intervention in a randomized controlled trial. A total of 108 participants with a severe mental illness and PTSD were randomized to individual CBT or treatment as usual (TAU). Among them, 25 had a bipolar disorder (N = 14 in CBT vs. N = 11 in TAU). Although results showed no difference between CBT and TAU in terms of the percentage of participants who no longer met the diagnostic criteria for PTSD at post-treatment, treatment completers did have significantly greater improvements in post-traumatic stress symptoms and cognitions than TAU. These differences were maintained at 6 month follow-up. However, after accounting for dropouts and participants lost to follow-up, only 59% of CBT participants were assessed at post-treatment. Since only 26% of the original sample had a diagnosis of a

bipolar disorder and results were not broken down by comorbidity, it is impossible to determine how the bipolar participants fared, or even if they tended to complete the treatment. Nevertheless, results do suggest that this type of individual CBT may be feasible and effective for PTSD-type anxiety comorbid to a severe mental illness, possibly including bipolar disorder. Lastly, Mueser et al. (2007) adapted their PTSD intervention for administration in a group format and tested its effects in an open trial. A total of 80 participants (6–8 per group) diagnosed with PTSD and a comorbid severe mental illness took part in the study. Seven of the participants had bipolar disorder. The 21 session PTSD group was similar to the individual intervention, combining relaxation training, psychoeducation, cognitive restructuring, coping skills and the development of a recovery plan. Results show that participants who completed the treatment demonstrated significant reductions in the symptoms and cognitions associated with PTSD. Twenty-seven percent of participants no longer met diagnostic criteria for PTSD at post-treatment. However, the retention rate for the group intervention was also 59%. Once again, given that only 9% of the sample had bipolar disorder and results were not broken down by comorbidity, it is impossible to determine how the bipolar participants fared. Nevertheless, these results support the use of CBT in group format for PTSD comorbid to a severe mental illness such as bipolar disorder. Though preliminary in nature, the results from these studies do provide important information to guide clinicians and researchers working with a comorbid bipolar clientele. As a whole, they tend to suggest that CBT may be useful in treating an AD comorbid to bipolar disorder, but that IPSRT may not be the best treatment option. However, the scope of the studies was limited and further exploration is therefore necessary. The following studies, examining the treatment of anxiety symptoms in bipolar disorder rather than full comorbid ADs, are presented in an attempt to glean additional knowledge from the literature. 7.2. Bipolar disorder with comorbid anxiety symptoms A randomized controlled trial examined the effect of mindfulness-based cognitive therapy (MBCT) for patients with either unipolar depression or bipolar disorder (Williams et al., 2008). Although patients were not specifically diagnosed with a comorbid anxiety disorder, anxiety symptoms were among the targets of the treatment. A total of 48 participants took part in the study. Among them, 14 had a diagnosis of bipolar disorder, of whom seven were randomized to each of the treatment and wait-list control groups. The MCBT treatment group received weekly two-hour sessions for eight weeks, along with daily homework assignments in the form of mindfulness practice. They also participated in a full day of intensive meditation practice near the end of the treatment period. Pre- and post-treatment assessments revealed a significant group by time interaction: bipolar participants who received MBCT had significantly lower levels of self-reported anxiety after treatment than bipolar controls. Though the mean reduction in anxiety levels did not reach statistical significance in the bipolar MCBT group, possibly due to a lack of statistical power, the treatment

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appeared to have prevented the significant increase in anxiety seen in the control group. The result was specific to the bipolar participants, unipolar depressed patients demonstrating no group effect for anxiety symptoms. Depression scores were also reduced at post-treatment among all MCBT patients compared to controls. Manic symptoms were not assessed. The promising results of this study suggest that MCBT may be an interesting non-pharmacological treatment option to reduce anxiety levels among bipolar patients, while also helping to improve their depressive symptoms. Subsequent to the promising results of the previous study, the team went on to adapt the MBCT treatment specifically for patients with bipolar disorder (Miklowitz et al., 2009). The new treatment adds a psychoeducation component specific to bipolar disorder and applies the concepts of mindfulness to the mood fluctuations characteristic of bipolar disorder. In a preliminary open trial, 22 bipolar patients (N = 14 BP-I; N = 8 BP-II) participated in the eightweek treatment program. In addition to improvements in the symptoms of depression and mania and in suicidal ideation, self-reported anxiety diminished from pre- to post-treatment among the 16 treatment completers (d = .23). This reduction was not statistically significant, but the sample size was small in this pilot study and a greater number of participants would be required to obtain adequate power. Miklowitz et al. then go on to report the subjective experience of one study participant in a case illustration. This patient had learned to successfully apply the mindfulness techniques outside of structured meditation. She reported that these techniques helped her slow her racing thoughts, calm intense emotions and recognize her prodromal symptoms. As such, the MCBT approach would appear to be a good means of meeting the needs of at least some bipolar patients. These mindfulnessbased treatments did not specifically target a comorbid anxiety disorder, but rather took a more holistic approach to symptom management. Nevertheless, their positive impact on anxiety suggests that MBCT may be a valuable part of the treatment arsenal for bipolar anxiety. Dusser et al. (2009) assessed a stress-management treatment inspired by a psychoeducational intervention for bipolar disorder developed by Bauer and McBride (1996). The six-session group treatment included many of the psychoeducational, cognitive and behavioral components typical of the original structured intervention, but added a relaxation practice period to each session. Study participants were not diagnosed with comorbid anxiety disorders, but presented anxiety symptoms. Though only preliminary analyses from small open trial (N = 8) with no control group, this study demonstrated a significant post-treatment reduction in clinician-assessed anxiety symptoms and selfreported perceived stress. However, no change was observed on a self-report measure of state-trait anxiety. Clinicianassessed symptoms of depression and mania remained stable from pre- to post-treatment assessments. Though mixed, these results do suggest that it is feasible and may be clinically useful to integrate relaxation practice into treatments for bipolar patients. Enhancing existing, validated interventions for bipolar patients by adding anxiety-focused techniques is an interesting avenue that should be further explored. Van Gent and colleagues conducted a series of studies assessing a psychoeducational group intervention for patients

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with bipolar disorder or their partners. Among the studies, they compared a five-session and a ten-session psychoeducational intervention administered to bipolar patients (Van Gent and Zwart, 1993). The group consisted of providing information about bipolar disorder, its symptoms, its treatments and related issues. Fifteen bipolar participants took part in the program. Results showed that neither format had any effect on trait anxiety at three-month or 15 month follow-up. In a three-year follow-up study, Van Gent (2000) again found that neither the five-session nor ten-session psychoeducational program specifically targeting patients with bipolar disorder had any effect on anxiety. However, Van Gent and Zwart (1991) also tested a five-session psychoeducational program administered not to the patients themselves, but rather to the partners of patients with bipolar disorder. This treatment was similar to the program for patients, but added discussions of the partner's role and the effect of the illness on the partner, friends and family. While the effects of the intervention were globally positive, patients who had a partner in the group (N = 14) actually experienced increases in anxiety not observed in the control group. Patients' anxiety level returned to pre-treatment levels at six-month follow-up. These studies suggest that psychoeducation for patients does not reduce anxiety levels, and that when the intervention targets family members, it may actually be anxiety-inducing for patients. 7.3. Anxiety disorder with comorbid bipolar spectrum symptoms Given the limited number of studies found directly examining psychosocial treatments for comorbid anxiety disorders in the bipolar spectrum, a broader net must be cast. A number of studies have considered the impact of comorbid depression on psychotherapy for anxiety disorders, and have done so with globally positive results. Multiple studies have shown that, though patients with comorbid unipolar depression present more severe symptoms, the comorbidity does not hamper their improvement in CBT (e.g., Allen et al., 2010; Davis et al., 2010; Joormann et al., 2005; Storch et al., 2010). Comorbid participants improved at the same rate as those without comorbidity, demonstrating the clinical utility of the sequential treatment of the anxiety disorder. However, results have not been unanimous. One study found that comorbid depression reduced the response to CBT for panic disorder with agoraphobia (Chambless et al., 2000). Nevertheless, patients with unipolar depression appear to benefit from CBT for anxiety disorders. Though there are considerable differences in the evolution of patients who have experienced an episode of unipolar depression and those diagnosed with a chronic bipolar disorder, it is possible that these results can be extended to some degree to the depressive phase of bipolar disorder. Bowen and D'Arcy (2003) examined the effect of cognitive–behavioral group therapy for panic disorder. In a sample of 56 patients receiving treatment for panic, they identified 18 patients who also had a history of hypomanic symptoms. These patients met the symptom criteria for hypomania, without meeting the duration or severity criteria necessary to receive a bipolar diagnosis. As such, their symptoms are considered to lie on the bipolar spectrum, despite the absence of a formal diagnosis. Patients diagnosed

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with full-blown bipolar disorder were excluded from the study. All participants attended an open-ended CBT group, supplemented with individual sessions as needed with one of the psychiatric nurses conducting the group. The CBT treatment consisted of cognitive restructuring, exposure and relaxation training. Results showed that patients with a history of hypomanic symptoms gained just as much benefit from the treatment as those without such a history at the 6 month follow-up assessment, including significant reductions in somatic and phobic anxiety, as well as improvements in depression and perceived stress. Most gains were maintained over the 12 month follow-up period. However, there was a non-significant trend toward worsening on the phobic anxiety and somatization scales at 12 months in the hypomanic group. Surprisingly, the hypomanic group also demonstrated a trend toward greater improvements on measures of depression and of the sense of control over their lives compared to patients without a history of hypomanic symptoms. It was suggested that the deterioration on anxiety may be due to the effects of medication for bipolar spectrum symptoms or greater numbers of other comorbidities in this group, while the greater improvements on depression and control might be due to more easy access to positive feelings to assist in these improvements in the hypomania group. As a whole, the study suggested that CBT for panic disorder is a beneficial treatment option for people with comorbid bipolar spectrum symptoms, but that the comorbidity may be associated with some differences in treatment response. 8. Discussion Given the extremely high prevalence rates and clear impact on outcome, comorbid anxiety must be attended to in patients with bipolar disorder. This paper examined the literature addressing the effect of psychosocial treatments for anxiety disorders comorbid to bipolar disorder. Due to the paucity of trials, studies addressing anxiety symptoms or bipolar spectrum symptoms were also reviewed. Results suggest that comorbid anxiety disorders can be effectively treated in a bipolar clientele using psychological interventions. Results to date are limited, but promising. In sum, cognitive–behavioral therapy would appear to be a feasible and useful treatment for anxiety comorbid to bipolar disorder (Baer et al., 1985; Bowen and D'Arcy, 2003; Hamblen et al., 2004; Mueser et al., 2007; Mueser et al., 2008; Provencher et al., 2010; Rosenberg et al., 2004), as would mindfulnessbased cognitive therapy (Miklowitz et al., 2009; Williams et al., 2008). In contrast, interpersonal therapy would not seem to be a beneficial treatment alternative for anxiety (Frank et al., 2005), nor would family therapy (Gaudiano and Miller, 2005). The effects of psychoeducational interventions are mixed, one study suggesting its superiority over interpersonal therapy (Frank et al., 2005), two showing no impact on anxiety (Van Gent, 2000; Van Gent and Zwart, 1993) and one showing a worsening effect on anxiety when the intervention is administered to family members (Van Gent and Zwart, 1991). However, when relaxation training is integrated into psychoeducation, the intervention may become effective against anxiety (Dusser et al., 2009). Some form of cognitive–behavioral therapy (CBT or MBCT) would appear to be the most promising treatment

option to date, since it reduces comorbid anxiety symptoms without exacerbating affective symptoms. Preliminary evidence suggests its positive impact for bipolar patients presenting a broad range of comorbid anxiety symptoms, including obsessive–compulsive disorder (Baer et al., 1985), generalized anxiety disorder (Provencher et al., 2010), panic disorder (Bowen and D'Arcy, 2003), post-traumatic stress disorder (Hamblen et al., 2004; Mueser et al., 2007; Mueser et al., 2008; Rosenberg et al., 2004) and the general symptoms of anxiety (Dusser et al., 2009; Miklowitz et al., 2009; Williams et al., 2008). However, despite the initial benefits, the long-term maintenance of anxiety treatment effects may be somewhat compromised in patients with bipolar disorder (Baer et al., 1985; Bowen and D'Arcy, 2003; Provencher et al., 2010). Nevertheless, even moderate gains are of great value for patients with complex clinical profiles and these results should therefore be considered positive, though some adjustments may be called for with a view to augmenting and prolonging treatment benefits. Among the studies reviewed, two broad approaches to treatment were observed. Some studies took an integrated treatment approach, building anxiety-focused techniques into a treatment centered on bipolarity. This approach seems to have produced moderate results (Dusser et al., 2009; Williams et al., 2008). A second approach reviewed was the sequential treatment, i.e., targeting the AD in a specific intervention separately from the treatment of the principal bipolar disorder. This approach has also produced moderate results (Baer et al., 1985; Hamblen et al., 2004; Mueser et al., 2007; Mueser et al., 2008; Provencher et al., 2010; Rosenberg et al., 2004). A third approach can also be considered, though it was not reviewed since no studies have been conducted to date to assess its impact on anxiety. This third possibility, which is a compromise between the first two, is the modular approach to the treatment of comorbidities. In a treatment manual for bipolar disorder, Otto et al. (2009) suggest adapting the standard CBT protocol by adding a series of modules selected based on the individual patient's clinical profile. For example, a patient with a comorbid AD could receive a number of sessions focusing on anxiety within the framework of a broader treatment for bipolar disorder. The manual does not propose a specific treatment approach for anxiety, but rather refers clinicians to manuals for the specific ADs. Preliminary assessment of the treatment of bipolar depression using this approach shows significant improvements in mood (Miklowitz et al., 2007), but the impact of the modular approach on comorbid ADs remains unknown. It must be recognized that the research results available to date are largely preliminary in nature, consisting primarily of case studies, open trials and secondary analyses. Though these studies are valuable tools in the initial exploration of different treatment alternatives, they are no longer sufficient given the enormity of the impact of comorbid anxiety in a bipolar clientele. Based on these preliminary findings, it is now time for large, randomized controlled trials comparing treatment options for specific comorbid anxiety disorders. Only by testing the various treatment options will it be possible to identify the optimal approach and hone treatments to best meet the needs of these patients and improve the long-term course of the bipolar disorder. Pending the

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results of these critical trials, clinicians are encouraged to address their patients' comorbid anxiety using a CBT-based sequential or modular treatment approach. This may take the form of an individual treatment or group format, employing the best evidence-based interventions available to date for anxiety. Even then, clinicians are encouraged to be modest in their expectations, closely monitor mood fluctuations during the anxiety treatment and be willing to adapt to the needs of the individual patient with a view to optimizing and prolonging therapeutic gains. 9. Conclusion Considering the limited number of treatment studies and the potential interactions between treatments, there is an urgent need for randomized controlled trials of different forms of psychotherapy for anxiety disorders specifically among patients with bipolar disorder. Among the approaches to be tested are the sequential, integrated and modular treatments of comorbid anxiety using evidence-based interventions for the anxiety disorders. Until such time as large randomized controlled trials point to the optimal treatment approach, the most promising avenue would appear to be the sequential CBT-based treatment of the comorbid anxiety disorder. Role of funding source Nothing declared. Conflict of interest No conflict declared.

References Albert, U., Rosso, G., Maina, G., Bogetto, F., 2008. Impact of anxiety disorder comorbidity on quality of life in euthymic bipolar disorder patients: differences between bipolar I and II subtypes. J. Affect. Disord. 105, 297–303. Allen, L.B., White, K.S., Barlow, D.H., Shear, M.K., Gorman, J.M., Woods, S.W., 2010. Cognitive-behavior therapy (CBT) for panic disorder: relationship of anxiety and depression comorbidity with treatment outcome. J. Psychopathol. Behav. Assess. 32, 185–192. American Psychiatric Association, 2001. Diagnostic and Statistical Manual of Mental Disorders, Text Revision (DSM-IV-TR)4th Edition. Author, Washington, DC. Baer, L., Minichiello, W.E., Jenike, M.A., 1985. Behavioral treatment in two cases of obsessive–compulsive disorder with concomitant bipolar affective disorder. Am. J. Psychiat. 142, 358–360. Bauer, M.S., McBride, L., 1996. The Life Goals Program: Structured Group Psychotherapy for Bipolar Disorder. Springer, New York, NY. Bauer, M., Glenn, T., Grof, P., Rasgon, N.L., Marsh, W., Sagduyu, K., Alda, M., Lewitzka, U., Schmid, R., Whybrow, P.C., 2009. Relationship between adjunctive medications for anxiety and time spent ill in patients with bipolar disorder. Int. J. Psychiatry Clin. Pract. 13, 70–77. Benazzi, F., 2004. Inter-episode mood lability in mood disorders: residual symptom or natural course of illness? Psychiatry Clin. Neurosci. 58, 480–486. Bowen, R.C., D'Arcy, C., 2003. Response of patients with panic disorder and symptoms of hypomania to cognitive behavior therapy for panic. Bipolar Disord. 5, 144–149. 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. J. Clin. Psychiat. 65, 1106–1113. Brissos, S., Dias, V.V., Carita, A.I., Martinez-Arán, A., 2008. Quality of life in bipolar type I disorder and schizophrenia in remission: clinical and neurocognitive correlates. Psychiatry Res. 160, 55–62. Brown, T.A., Antony, M.M., Barlow, D.H., 1995. Diagnostic comorbidity in panic disorder: effect on treatment outcome and course of comorbid diagnoses following treatment. J. Consult. Clin. Psychol. 63, 408–418.

379

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. Psychiatr. Serv. 54, 1395–1401. Chambless, D.L., Renneberg, B., Gracely, E.J., Goldstein, A.J., Fydrich, T., 2000. Axis I and II comorbidity in agoraphobia: prediction of psychotherapy outcome in a clinical setting. Psychother. Res. 10, 279–295. Chouinard, G., 2004. Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. J. Clin. Psychiat. 65, 7–21. Coryell, W., Solomon, D.A., Fiedorowicz, J.G., Endicott, J., Schettler, P.J., Judd, L.L., 2009. Anxiety and outcome in bipolar disorder. Am. J. Psychiat. 166, 1238–1243. Craske, M.G., Farchione, T.J., Allen, L.B., Barrios, V., Stoyanova, M., Rose, R., 2007. Cognitive behavioral therapy for panic disorder and comorbidity: more of the same or less of more? Behav. Res. Ther. 45, 1095–1109. Das Gupta, R., Guest, J.F., 2002. Annual cost of bipolar disorder to UK society. Br. J. Psychiat. 180, 227–233. Davis, L., Barlow, D.H., Smith, L., 2010. Comorbidity and the treatment of principal anxiety disorders in a naturalistic sample. Behav. Ther. 41, 296–305. Dell'osso, L., Carmassi, C., Rucci, P., Ciapparelli, A., Paggini, R., Ramacciotti, C.E., Conversano, C., Balestrieri, M., Marazziti, D., 2009. Lifetime subthreshold mania is related to suicidality in posttraumatic stress disorder. CNS Spectr. 14, 262–266. Dilsaver, S.C., Chen, Y.W., Swann, A.C., Shoaib, A.M., Tsai-Dilsaver, Y., Krajewski, K.J., 1997. Suicidality, panic disorder and psychosis in bipolar depression, depressive-mania and pure-mania. Psychiatry Res. 73, 47–56. Dilsaver, S.C., Benazzi, F., Akiskal, K.K., Akiskal, H.S., 2008. Differential patterns of lifetime multiple anxiety disorder comorbidity between Latino adults with bipolar I and major depressive disorders. Bull. Menninger Clin. 72, 130–148. Dusser, I., Romo, L., Leboyer, M., 2009. Élaboration et évaluation d'un programme de gestion du stress pour patients souffrant de troubles bipolaires (Construction and evaluation of a stress management group for patients with bipolar disorder). J. Thér. Comportementale Cogn. 19, 56–60. El-Mallakh, R.S., Hollifield, M., 2008. Comorbid anxiety in bipolar disorder alters treatment and prognosis. Psychiatr. Q. 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. Am. J. Psychiat. 157, 956–962. Frank, E., Cyranowski, J.M., Rucci, P., Shear, M.K., Fagiolini, A., Thase, M.E., Cassano, G.B., Grochocinski, V.J., Kostelnik, B., Kupfer, D.J., 2002. Clinical significance of lifetime panic spectrum symptoms in the treatment of patients with bipolar I disorder. Arch. Gen. Psychiat. 59, 905–911. Frank, E., Kupfer, D.J., Thase, M.E., Mallinger, A.G., Swartz, H.A., Fagiolini, A.M., Grochocinski, V., Houck, P., Scott, J., Thompson, W., Monk, T., 2005. Twoyear outcomes for interpersonal and social rhythm therapy in individuals with bipolar I disorder. Arch. Gen. Psychiat. 62, 996–1004. Freeman, M.P., Freeman, S.A., McElroy, S.L., 2002. The comorbidity of bipolar and anxiety disorders: prevalence, psychobiology, and treatment issues. J. Affect. Disord. 68, 1–23. Gaudiano, B.A., Miller, I.W., 2005. Anxiety disorder comorbidity in bipolar I disorder: relationship to depression severity and treatment outcome. Depress. Anxiety 21, 71–77. Goodwin, F.K., Jamison, K.R., 2007. Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression. Oxford, New York, NY. Hamblen, J.L., Jankowski, M.K., Rosenberg, S.D., Mueser, K.T., 2004. Cognitive–behavioral treatment for PTSD in people with severe mental illness: three case studies. Am. J. Psychiatr. Rehabil. 7, 147–170. 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. J. Clin. Psychiat. 64, 331–335. Joormann, J., Kosfelder, J., Schulte, D., 2005. The impact of comorbidity of depression on the course of anxiety treatments. Cognit. Ther. Res. 29, 569–591. Judd, L.L., Akiskal, H.S., 2003. The prevalence and disability of bipolar spectrum disorders in the US population: re-analysis of the ECA database taking into account subthreshold cases. J. Affect. Disorders 73, 123–131. Kauer-Sant'Anna, M., Frey, B.N., Andreazza, A.C., Ceresér, K.M., Gazalle, F.K., Tramontina, J., da Costa, S.C., Santin, A., Kapczinski, F., 2007. Anxiety comorbidity and quality of life in bipolar disorder patients. Can. J. Psychiat. 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, 953–964. Keller, M.B., 2006. Prevalence and impact of comorbid anxiety and bipolar disorder. J. Clin. Psychiat. 67 (Suppl 1), 5–7. 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

380

M.D. Provencher et al. / Journal of Affective Disorders 133 (2011) 371–380

disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiat. 62, 593–602. 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? J. Affect. Disord. 115, 1–10. Krishnan, K.R.R., 2005. Psychiatric and medical comorbidities of bipolar disorder. Psychosom. Med. 67, 1–8. Lee, J.H., Dunner, D.L., 2008. The effect of anxiety disorder comorbidity on treatment resistant bipolar disorders. Depress. Anxiety 25, 91–97. McIntyre, R.S., Konarski, J.Z., Yatham, L.N., 2004. Comorbidity in bipolar disorder: a framework for rational treatment selection. Hum. Psychopharm. 19, 369–386. 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. Arch. Gen. Psychiat. 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. Arch. Gen. Psychiat. 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. Int. J. Cog. Ther. 2, 373–382. Mueser, K.T., Bolton, E., Carty, P., Bradley, M., Ahlgren, K., DiStaso, D., 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 Ment. Health J. 43, 281–304. Mueser, K.T., Rosenberg, S.D., Xie, H., Jankowski, M.K., Bolton, E.E., Lu, W., Hamblen, J.L., Rosenberg, H.J., McHugo, G.J., Wolfe, R., 2008. A randomized controlled trial of cognitive–behavioral treatment for posttraumatic stress disorder in severe mental illness. J. Consult. Clin. Psychol. 76, 259–271. Nathan, P.E., Gorman, J.M., 2007. A Guide to Treatments that Work3rd ed. Oxford University Press, New York, NY, US. Otto, M.W., Reilly-Harrington, N., 2002. Cognitive–behavioral therapy for the management of bipolar disorder. In: Hofmann, S.G., Tompson, M.C. (Eds.), Treating Chronic and Severe Mental Disorders: A Handbook of Empirically Supported Interventions. Guilford, New York, pp. 116–130. Otto, M.W., Simon, N.M., Wisniewski, S.R., Miklowitz, D.J., Kogan, J.N., ReillyHarrington, N.A., et al., 2006. Prospective 12-month course of bipolar disorder in out-patients with and without comorbid anxiety disorders. Br. J. Psychiat. 189, 20–25. Paykel, E.S., Abbott, R., Morriss, R., Hayhurst, H., Scott, J., 2006. Subsyndromal and syndromal symptoms in the longitudinal course of bipolar disorder. Br. J. Psychiat. 189, 118–123. Perlis, R.H., Ostacher, M.J., Miklowitz, D.J., Hay, A., Nierenberg, A.A., Thase, M.E., Sachs, G.S., 2010. Clinical features associated with poor pharmacologic adherence in bipolar disorder: results from the STEP-BD study. J. Clin. Psychiat. 71, 296–303. Provencher, M.D., Thienot, E., St-Amand, J., 2010. Treatment of generalized anxiety disorder for patients with bipolar disorder: a single case experimental design. Poster presented at the World Congress of Behavioral and Cognitive Therapies, Boston, MA, June 2010. Quarantini, L.C., Miranda-Scippa, A., Nery-Fernandes, F., Andrade-Nascimento, M., Galvao-de-Almeida, A., Guimaraes, J.L., Teles, C.A., Netto, L.R., Lira, S.B., de Oliveira, I.R., Post, R.M., Kapczinski, F., Koenen, K.C., 2010. The impact of comorbid posttraumatic stress disorder on bipolar disorder patients. J. Affect. Disord. 123, 71–76.

Rivas-Vazquez, R.A., Johnson, S.L., Rey, G.J., Blais, M.A., Rivas-Vazquez, A., 2002. Current treatments for bipolar disorder: a review and update for psychologists. Prof. Psychol. Res Pr 33, 212–223. Rizvi, S., Zaretsky, A.E., 2007. Psychotherapy through the phases of bipolar disorder: evidence for general efficacy and differential effects. J. Clin. Psychol. 63, 491–506. 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. Am. J. Psychiatr. Rehabil. 7, 171–186. Sasson, Y., Chopra, M., Harrari, E., Amitai, K., Zohar, J., 2003. Bipolar comorbidity: from diagnostic dilemmas to therapeutic challenge. Int. J. Neuropsychopharmacol. 6, 139–144. Schaffer, A., Cairney, J., Cheung, A., Veldhuizen, S., Levitt, A., 2006. Community survey of bipolar disorder in Canada: lifetime prevalence and illness characteristics. Can. J. Psychiat. 51, 9–16. Sheehan, D.V., McElroy, S.L., Harnett-Sheehan, K., Keck Jr., P.E., Janavs, J., Rogers, J., Gonzalez, R., Shivakumar, G., Suppes, T., 2009. Randomized, placebo-controlled trial of risperidone for acute treatment of bipolar anxiety. J. Affect. Disord. 115, 376–385. 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). Am. J. Psychiat. 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. J. Psychiatr. Res. 41, 255–264. Stensland, M.D., Jacobson, J.G., Nyhuis, A., 2007. Service utilization and associated direct costs for bipolar disorder in 2004: an analysis in managed care. J. Affect. Disorders 101, 187–193. Storch, E.A., Lewin, A.B., Farrell, L., Aldea, M.A., Reid, J., Geffken, G.R., Murphy, T.K., 2010. Does cognitive–behavioral therapy response among adults with obsessive–compulsive disorder differ as a function of certain comorbidities? J. Anxiety Disord. 24, 547–552. Sublette, E.M., 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. J. Psychiatr. Res. 43, 230–238. Taylor, C.T., Hirshfeld-Becker, D.R., Ostacher, M.J., Chow, C.W., LeBeau, R.T., Pollack, M.H., Nierenberg, A.A., Simon, N.M., 2008. Anxiety is associated with impulsivity in bipolar disorder. J. Anxiety Disord. 22, 868–876. Tsao, J.C.I., Mystkowski, J.L., Zucker, B.G., Craske, M.G., 2005. Impact of cognitive–behavioral therapy for panic disorder on comorbidity: a controlled investigation. Behav. Res. Ther. 43, 959–970. Van Gent, E.M., 2000. Une étude suivie de 3 ans de thérapies de groupe additives au traitement au lithium. Encephale 26, 76–79. Van Gent, E.M., Zwart, F.M., 1991. Psychoeducation of partners of bipolarmanic patients. J. Affect. Disorders 21, 15–18. Van Gent, E.M., Zwart, F.M., 1993. Ultra-short versus short group therapy in addition to lithium. Patient Educ. Couns. 21, 135–141. Williams, J.M., Alatiq, Y., Crane, C., Barnhofer, T., Fennell, M.J., Duggan, D.S., Hepburn, S., Goodwin, G.M., 2008. Mindfulness-based Cognitive Therapy (MBCT) in bipolar disorder: preliminary evaluation of immediate effects on between-episode functioning. J. Affect. Disord. 107, 275–279. Wozniak, J., Biederman, J., Monuteaux, M.C., Richards, J., Faraone, S.V., 2002. Parsing the comorbidity between bipolar disorder and anxiety disorders: a familial risk analysis. J. Child Adolesc. Psychopharmacol. 12, 101–111. Zutshi, A., Reddy, Y.C., Thennarasu, K., Chandrashekhar, C.R., 2006. Comorbidity of anxiety disorders in patients with remitted bipolar disorder. Eur. Arch. Psychiatry Clin. Neurosci. 256, 428–436.