Curr Psychiatry Rep (2015) 17: 3 DOI 10.1007/s11920-014-0540-2

BIPOLAR DISORDERS (W CORYELL, SECTION EDITOR)

The Importance of Anxiety States in Bipolar Disorder Fernando S. Goes

Published online: 24 January 2015 # Springer Science+Business Media New York 2015

Abstract Anxiety symptoms and syndromes are common in bipolar disorders, occurring in over half of all subjects with bipolar disorder type I. Despite methodological and diagnostic inconsistencies, most studies have shown a robust association between the presence of a broadly defined comorbid anxiety disorder and important indices of clinical morbidity in bipolar disorder, including a greater number of depressive episodes, worse treatment outcomes, and elevated risk of attempting suicide. Anxiety symptoms and/or syndromes often precede the onset of bipolar disorder and may represent a clinical phenotype of increased risk in subjects with prodromal symptoms. Although the causal relationship between anxiety and bipolar disorders remains unresolved, the multifactorial nature of most psychiatric phenotypes suggests that even with progress towards more biologically valid phenotypes, the “phenomenon” of comorbidity is likely to remain a clinical reality. Treatment studies of bipolar patients with comorbid anxiety have begun to provide preliminary evidence for the role of specific pharmacological and psychotherapeutic treatments, but these need to be confirmed in more definitive trials. Hence, there is an immediate need for further research to help guide assessment and help identify appropriate treatments for comorbid conditions.

Introduction The frequent co-occurrence of symptoms and syndromes between what are now termed mood and anxiety disorders has been extensively described in the last century since Kraepelin’s seminal observations [1]. In their less severe form, these admixed states were mostly subsumed under the rubric of “neurotic disorders” [2]. With the changes brought forth by the Diagnostic and Statistical Manual of Mental Disorders (DSM)-III, mood and anxiety disorders were separated into different categories, creating what has been termed “a bogus order out of anarchy” [3]. Empirical studies after DSM-III continued to find high levels of admixture between these two disorder categories, which, despite being separated in print, showed no clear point of discontinuity. More recently, the relationship between anxiety symptoms and bipolar disorders has gathered increasing attention, with a recent number of review articles focusing on this subject illness [4, 5, 6•] and the DSM-V addition of “anxious features” as a new specifier of both bipolar and unipolar disorders. While relatively few studies have primarily focused on the relationship between bipolar and anxiety disorders, the literature is rich with secondary analyses, which, despite methodological heterogeneity, provide a relatively uniform picture of the clinical importance of anxiety states in bipolar disorder.

Keywords Bipolar disorder . Comorbidity . Anxiety . Panic . Phobia . OCD . Suicide . Prodromal Comorbidity: Definition of the Term

This article is part of the Topical Collection on Bipolar Disorders F. S. Goes (*) Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Meyer 4-119A, 600 North Wolfe Street, Baltimore, MD 21287, USA e-mail: [email protected]

In his well-known paper, “Problems presented by the ambiguous word ‘anxiety’,” the influential Maudsley psychiatrist Aubrey Lewis provided a “disturbing review of the varied meaning attached to the word ‘anxiety’” [7]. Unfortunately, imprecise and often inconsistent definitions continue to hamper progress in basic psychopathological research. Yet the word “comorbidity” itself also poses a similar challenge.

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Although often used to imply etiological or pathophysiological overlap, the term, as originally described by Feinstein, was broader and more agnostic, referring to any disease or “nondisease” clinical entities that could have implications in the “time to detection,” “prognostic anticipations,” “therapeutic plans,” or “post-therapeutic outcome” [8]. Feinstein considered non-disease entities to be any patient-related characteristics such as “pregnancy…dieting… and certain symptomatic reactions…occur[ing] with various therapeutic maneuvers” that had the potential to affect clinical outcome. For psychiatric research, this could potentially be conceptualized as manifestations of personality dimensions, behaviors, and life experiences that can color, mitigate, or exacerbate psychiatric disorders [9]. While the co-occurrence of anxiety symptoms or disorders and mood disorders seems to fall clearly within this original conception of comorbidity, the substantial vagaries of what is considered comorbid often limit comparisons across studies. In an era where the validity of even “simple” disorders in psychiatry has been called into question [10], it may not be surprising that the high rates of comorbidity are often seen as an “artifact of current diagnostic systems” [11]. However, it is useful to remember that the occurrence and importance of comorbidity was first described for physical disorders, which included many with well-identified etiology and pathophysiology. Hence, it is unlikely that this frequently seen phenomenon in psychiatric illnesses will be “solved” by the promise of a more biologically valid classification system, even though the boundaries themselves might change.

Etiological Considerations Conceptual models of comorbidity, such as those originally described by Klein and Riso, can be heuristically valuable in determining and weighing the relevance, prognosis, and treatment consideration of comorbid states such as anxiety and mood disorders [12]. Klein and Riso describe a number of etiological modes that can account for comorbid phenomena, which can be broadly simplified into four major categories: (1) sampling bias, (2) diagnostic artifact/bias, (3) phenotypic pleomorphy, and (4) secondary causation. Although there is significant heterogeneity in ascertainment and diagnosis, the phenomena of overlapping mood and anxiety symptoms and disorders have been found across so many types of studies that categories one and two are unlikely to account for a major causal role. The third category, phenotypic pleomorphy, is a phenomenon first described in genetics, which can also be applied more broadly to any form of etiological research [13]. At its simplest level, pleomorphy refers to the causal association of the same genetic variant (or, for that matter, any etiological variant) with a different phenotype. Complexity, however, emerges because single etiological factors (i.e.,

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those that are necessary and sufficient) are extremely rare, and etiological “causes” are often modified by the influence of other competing etiologies, or by the effect of environmental context. Pleomorphy is widely seen in medicine, both with strong etiological factors (such as smoking) and with more modest etiological factors, which are likely be more relevant to the majority of psychiatric disorders. Given the prominent heritability of mood and anxiety disorders, twin studies have been particularly helpful in testing etiological models, particularly those testing pleomorphic models. Unfortunately, the absence of sufficiently powered twin studies in bipolar disorder has so far limited the ability to infer the genetic relationship of comorbid conditions. However, recent genetic studies have used a novel analytical method to estimate the heritability within and across psychiatric disorders using case-control samples, which, unlike twin samples, are widely available for uncommon disorders like bipolar disorder [14]. These studies have shown widespread etiological overlap between the major psychiatric disorders, including between schizophrenia and bipolar disorder, but they have yet to be applied to the anxiety disorders. Yet such studies, which are currently limited by the sparse availability of appropriately phenotyped samples, will be crucial to delineate the phenotypic boundaries of mood and anxiety comorbidity. Finally, comorbidity models assuming that one disorder directly causes the other (fourth category) are also important to consider, since they may have direct treatment implications. However, this direct causation model needs to be viewed with caution, since strong causal assumptions are often difficult to make for disorders that may share a complex interweaving pattern of causal factors. One possible exception may occur when anxiety symptoms are clearly caused by the initiation of medications that may destabilize mood in a vulnerable individual [15].

Epidemiology: Burden and Consequence of Anxiety Comorbidity Numerous surveys of clinical samples have found elevated rates of almost all the anxiety disorders in subjects with bipolar disorder [6•]. These clinical studies have the potential for Berkson’s bias, where ascertainment (for example, in hospitalized populations) is the primary driver of the comorbidity; however, similar rates have also been seen in several population-based studies performed over the last two decades [16–19]. As shown in Fig. 1, the lifetime prevalence rates of most anxiety disorders in these epidemiological samples are substantial and often higher than in clinically ascertained samples. This raises the concern of whether the diagnostic instruments used by population surveys are comparable with the more “standard” clinical interviews employed in clinic-based surveys. Earlier population-based surveys had unacceptably

Curr Psychiatry Rep (2015) 17: 3 100 90 Prevalence of Comorbid Anxiety Disorder (%)

Fig. 1 Overview of the major epidemiological studies showing the prevalence of specific anxiety disorders in subjects with bipolar disorder, type I [16–19]

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80 70 60 50 40 30 20 10 0 Agoraphobia

Panic Disorder

NCS [16]

PTSD

Specific

Phobia

NCS-R[17]

high (70.8 %) false positive rates for diagnosing bipolar disorder compared with clinical interviews [16]; however, more recent surveys have reported improved psychometric properties [20, 21]. While there is variability in the rates across the different epidemiological studies, the overall pattern is one of elevated rates of almost all anxiety disorder comorbidities for all the major adult mood disorders, including bipolar disorder. Both epidemiological and clinical studies have found higher indices of illness severity, such as increased number and length of mood episodes, greater prevalence of lifetime suicide attempts, and higher rates of lifetime hospitalization, in patients with bipolar disorder and a comorbid anxiety disorder [17, 22–24]. Strict comparison across these studies is challenging due to the variable ascertainment and diagnostic methods, but, again, the pattern is consistent and clearly shows the increased burden imparted by the presence of comorbid anxiety. Longitudinal studies have similarly shown worse clinical outcomes among those with both bipolar disorder and anxiety, whether testing the presence of comorbid symptoms during a mood episode or the lifetime presence of anxiety disorders. For example, in the Collaborative Depression Study (CDS), Coryell et al. found an association between psychic and somatic anxiety symptoms during the index mood episode and increased time spent in depressive episodes in 427 patients with bipolar disorder [25]. A subsequent analysis of this sample, which focused on subjects with bipolar disorders I and II in an index depressive episode (N=335), again found an association between anxiety symptoms at intake and overall time spent in depression [26]. A “dose effect” was seen, with higher numbers of anxiety symptoms (measured by SADS

GAD

Social Phobia

World Mental Health Survey [18]

OCD

Any Anxiety Disorder

NESARC [19]

ratings of somatic and psychic anxiety) correlating with a longer depressive morbidity. Notably, the lifetime presence of anxiety disorders, with the exception of obsessivecompulsive disorder, was not associated with time spent in depression. However, more recent longitudinal studies, such as the effectiveness treatment trial Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), did find an association between anxiety disorders and more persistent depressive symptoms, as well as evidence for a similar dose-response pattern, with greater morbidity occurring in patients with bipolar disorder and more than one anxiety disorder [27]. One important difference between CDS and STEPBD was the use of diagnostic instruments based on the Research Diagnostic Criteria (CDS) versus DSM-IV (STEPBD), which differed in their use of a diagnostic hierarchy. Hence, under the RDC, anxiety disorders could only be diagnosed if the syndrome was clearly present outside the confines of a mood episode [28], whereas DSM-IV took a more permissive approach, allowing the diagnosis of the two disorders as long as both diagnostic criteria were met [29]. Not unexpectedly, the prevalence of concurrent anxiety disorders is much higher in STEP-BD compared with the CDS, and it is not unreasonable to presume that some of the subjects in the CDS with anxiety symptoms but no anxiety disorder would have likely been diagnosed with a comorbid anxiety disorder under DSM-IV. Findings similar to those in STEP-BD were also seen in the Bipolar Comprehensive Outcomes Study, where a lifetime history of any one of five anxiety disorders (based on DSMIV criteria) was associated with failure to remit from depression in a naturalistic 2-year study [30]. These findings in adult

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studies were similarly seen in the Course and Outcome of Bipolar Youth Study (COBY), a longitudinal study following children (ages 7–17) diagnosed with bipolar disorder for an average of 5 years [31]. Over half (62 %) of all participants had at least one lifetime anxiety disorder, which was also associated with a longer time to recovery and a greater likelihood of recurrence.

Anxiety and the Risk of Suicide Attempts Anxiety disorders by themselves have been associated with increased risk of suicidal ideation and suicide attempt in a number of epidemiological [32] and clinical studies [33]. Studies have also found that comorbid anxiety disorders in patients with mood disorders, including bipolar disorder, are also associated with an increased risk for suicidal behavior compared with subjects with bipolar disorder and no anxiety comorbidity [34, 35]. Whether specific anxiety disorders are more likely to be associated with suicidal behaviors remains unclear, since most studies, even those based on large registry data, have not systematically investigated the specific anxiety disorders separately. It is also difficult from the current literature to discern if the association of anxiety disorders with suicidality is confounded or mediated by other phenomena, such as co-occurring substance abuse [36] or personality disorders [37], which could be partial or main drivers of suicidal behavior [34]. The presence of anxiety symptoms during a mood episode has also been associated with increased suicidal ideations [38]. Surprisingly, however, the relationship between anxiety symptoms and anxiety disorders has been generally unstudied in bipolar disorder, even though the relevance of anxiety symptoms during an affective episode figured prominently in Kraepelin’s early descriptions of what he then described as mixed states, marked by “inward anxiety…trembling… painful tension…uneasy restlessness” and frequent “attempts at suicide” [39].

Anxiety Disorders as Precursors to Bipolar Disorder A number of prospective bipolar high-risk studies have been conducted in the last decade to help understand the prodromal and early course of illness. Although they differ in diagnostic methodology, follow-up duration, and ascertainment strategy, these studies have all found elevated rates of anxiety disorders predating the onset of bipolar disorder [31, 40, 41, 42•, 43]. As summarized in Table 1, the prevalence rates of anxiety disorders in high-risk bipolar offspring range from 23.4 to 42.5 % and typically represent twice the rates seen in offspring of control subjects. At least two of these studies have controlled for anxiety disorder in the parent [41, 42•], suggesting that

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anxiety disorder may be a direct early manifestation of the elevated risk of bipolar disorder rather than just the transmission of an independent anxiety disorder. Moreover, the studies by Duffy et al. and Nurnberger et al. found that high-risk offsprings who manifested early-onset anxiety disorders were more likely to develop a bipolar spectrum disorder (the primary manifestation of bipolar disorder in this early age group), suggesting the possibility that prodromal childhood anxiety disorder could potentially be used in future screening and prevention studies.

Treatment First-line treatment for any of the anxiety disorders involves a targeted form of cognitive behavioral therapy or a selective serotonin reuptake inhibitor (SSRI)-based antidepressant [44]. However, the uncertain role of antidepressants in the treatment of bipolar disorders, along with their potential to destabilize mood and precipitate manic symptoms, often complicates the pharmacological treatment of comorbid anxiety symptoms and syndromes in bipolar patients [45]. Mixed symptoms during mania have historically been associated with worse response to conventional mood stabilizers [46], although how much of this can be “attributed” to the presence of anxiety symptoms rather than a broader constellation of mixed symptoms is unclear. Most of the early trials of mood stabilizers for bipolar disorder did not evaluate the role of anxiety symptoms in treatment response. More recent trials of atypical antipsychotics have examined the role of anxiety symptoms as measured by clinical rating scales in secondary analyses of randomized controlled trials for bipolar disorder. Initial reports of efficacy in reducing anxiety symptoms have been reported for the combination of olanzapine and fluoxetine in [47], as well as for quetiapine [48], but not for with ziprasidone [49]. A number of small trials have also evaluated the impact of a comorbid anxiety disorder (primarily generalized anxiety disorder and panic disorder) on treatment response in patients with bipolar disorder. An initial study found no effect of risperidone on anxiety symptoms in patients with comorbid panic or generalized anxiety disorder [50]. In contrast, quetiapine was shown to alleviate anxiety symptoms in a study of quetiapine XR versus divalproex monotherapy. However, this effect was not replicated in a second similarly sized but placebo-controlled study of quetiapine XR [51]. The limited evidence base for pharmacological treatment of comorbid anxiety disorders has led to recommendations that psychotherapeutic approaches be tried as first-line treatments [52•]. This is supported by a recent secondary analysis of the STEP-BD trial, which found modestly improved rates of recovery among subjects with bipolar disorder and comorbid anxiety disorders who were treated with adjunctive psychotherapy [53] compared with similarly treated subjects with

Curr Psychiatry Rep (2015) 17: 3 Table 1

Overview of the prevalence of anxiety disorders in recent longitudinal studies of offspring at high risk for bipolar disorder

Study (author, year)

Birmaher, 2009 [31] Nurnberger, 2011 [40] Vandeleur, 2012 [41] Duffy, 2013 [42•] Mesman, 2013 [43] a

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Age (mean)

11.9 16.7 11.8 22.6 16.5

OR (95 % CI)a

2.3 (1.3–4.0) 2.1 (1.0–4.7) 2.1 (1.2–3.8) 2.6 (1.2–6.4)

Prevalence of anxiety disorders (N) High-risk offspring

Control offspring

25.8 % (100/388) 26.2 % (37/141) 42.5 % (59/139) 23.4 % (53/229) 25 % (27/108)

10.8 % (27/251) 14.3 % (13/91) 22.8 % (29/127) 10.42 % (9/86)

Odds ratios were obtained directly from the cited paper or calculated unadjusted from the raw numbers

bipolar disorder and no anxiety comorbidity. Whether this represents a direct effect on the symptoms themselves rather than a moderating role (for example, in improving overall adherence) is an important question for further research. However, trials of psychotherapies for comorbid anxiety disorders in bipolar or unipolar disorder have been few and limited in scope [54], raising additional research questions about how to best implement and adapt structured psychotherapy to this challenging set of patients.

Conclusions Anxiety symptoms and disorders are highly prevalent in patients with bipolar disorder; they occur throughout the illness course and have important effects on prognosis and treatment. Yet despite the existence of a vast literature on the topic of anxiety comorbidity, a synthesis of the evidence is hindered by limitations noted in review written almost a decade ago, which highlighted “small sample sizes, a scarcity of consistent standards for making assessment across multiple studies, and study groups that are too heterogeneous confound the interpretation of data that do exist” [55]. Nevertheless, the general convergence of findings described in this article reflects the prominent additional burden that anxiety imparts on patients with bipolar disorder and highlights the important need to tailor appropriate clinical interventions to patients with bipolar disorder and comorbid anxiety. Further etiological and treatment insights will require more fine-grained studies on a larger scale, with more harmonized phenotypes and, preferably, longitudinal follow-up. The many unresolved questions that need to be addressed in future studies include: 1. What is the relationship between lifetime anxiety disorders and the more time-limited anxiety symptoms during an affective episode? Etiological studies have almost exclusively focused on lifetime diagnoses, while treatment studies more often rely on anxiety symptom rating scales during a mood episode. There appears to be at least a partial correlation between these two facets of anxiety

[38], but their relationship has otherwise remained unstudied. 2. How do specific anxiety disorders (and symptoms) affect the course and treatment of bipolar disorder? For understandable reasons, studies clump the anxiety disorders into one category, even though there is clear evidence for some degree of differing etiologies among the anxiety disorders [56] as well as differing response to treatment [44]. 3. How do different anxiety disorders relate etiologically to bipolar disorder? Recent successes in psychiatric genetics have revealed a prominent degree of etiological overlap among the major psychiatric phenotypes. As samples with anxiety phenotypes become more available, these genetic “bottom-up” analyses will provide important insights about the etiological relationship of the mood and anxiety overlap. The relative lack of anxiety-related phenotypes has so far limited such analyses. 4. How should clinicians tailor pharmacological and/or psychotherapeutic treatments to patients with bipolar disorder with comorbid anxiety? The secondary analyses suggest initial evidence for improved response with a limited number of atypical antipsychotics and structured psychotherapies. Although fully powered trials focusing on a comorbid patient population may or may not be feasible, it is imperative that future trials of bipolar disorder include large numbers of adequately phenotyped subjects with comorbid anxiety disorder to allow more reliable secondary analyses of treatment response in the comorbid subgroup. Implementation of such “next-generation” phenotype studies will likely require the infrastructure of ongoing regional or national cohort studies with “enriched” or targeted electronic medical record-based diagnoses [57, 58]. These studies will be crucial for identifying specific etiological factors (genetic and environmental) that will inform nosology and provide targets for novel treatments. The beginnings of such progress are emerging, for example, with large-scale genetic studies being carried out by the Psychiatric Genetics Consortium

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[14], where initial results are consistent with many modest etiological factors, suggesting that psychiatric phenotypes are likely to be formed by a diverse and probabilistic causal framework, with porous boundaries and few points of phenotypic discontinuity. A corollary is that even as progress is made towards a more biologically valid diagnostic classification, phenotypic admixture and comorbidity may be inevitable manifestations of the multifactorial and “dappled” nature of psychiatric disorders [59]. Hence, in an illness associated with as much lifelong morbidity as bipolar disorder, there is a pressing need to adequately measure, study, and treat comorbid anxiety. Compliance with Ethics Guidelines Conflict of Interest Fernando S. Goes has received consultancy fees from Teva Pharmaceuticals (Advisory Board 29 September 2012). Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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The importance of anxiety states in bipolar disorder.

Anxiety symptoms and syndromes are common in bipolar disorders, occurring in over half of all subjects with bipolar disorder type I. Despite methodolo...
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