Anxiety symptoms in depression: clinical and conceptual considerations






Dan J. STEIN,FRCPC, PhD
Dept of Psychiatry & Mental Health
University of Cape Town – SOUTH AFRICA

Anxiety symptoms in depression: clinical and conceptual considerations


by D. J . Stein, South Africa



It is increasingly accepted that anxiety in depression is associated with increased morbidity, that anxiety disorders typically precede the development of major depression, and that patients with major depression and anxiety respond to efficacious treatments and so deserve early and robust intervention. However, the occurrence of anxiety in depression raises many complex questions: Should the co-occurrence of depression and anxiety be conceptualized as a comorbidity or as a separate diagnostic construct? Does anxiety in depression have particular psychobiological correlates and deserve distinctive treatments? What are the implications of co-occurring anxiety for understanding the nature of depression? This review emphasizes that both categorical and dimensional approaches to co-occurring depression and anxiety are needed, that anxiety in depression is a heterogeneous construct, and that variants of anxious depression, such as stressor-related depression and agitated depression, likely require quite different approaches.

Medicographia. 2013;35:299-303 (see French abstract on page 303)

The topic of anxiety in depression is, on the one hand, a reasonably straightforward one. The literature emphasizes a number of clinically important lessons: anxiety is a potentially important symptom of major depression that is associated with increased morbidity; anxiety disorders typically precede the development of major depression; and patients with major depression and anxiety respond to efficacious treatments and, therefore, deserve early and robust intervention.

On the other hand, the occurrence of anxiety in depression raises many complex questions: Should the co-occurrence of depression and anxiety be conceptualized as a comorbidity or as a separate diagnostic construct? Does anxiety in depression have particular psychobiological correlates and, therefore, deserve distinctive treatments? Is anxiety in depression merely a clinical observation, or can this co-occurrence shed light on some deeper questions about our understanding of the nature and experience of depression?

Here, I will briefly review some of the clinically important lessons that the literature has provided on anxiety in major depression, but also address some of the more complex conceptual issues in this area in an attempt to outline some clinically relevant approaches to these debates. I will briefly address in turn the phenomenology, psychobiology, and management of anxiety in major depression.

Phenomenology of depression-anxiety comorbidity

It has long been recognized that anxiety is a central clinical feature of major depression.1 Anxiety is a prevalent symptom in depression, and patients with anxious depression have greater morbidity, as assessed by a number of indices, including symptom severity, illness chronicity, functional impairment, and suicide risk.2,3 Indeed, participants in the revision of the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) have proposed that severity of anxiety symptoms should be specified in patients with major depression.3 Conversely, patients with anxiety disorders often have significant levels of depressive symptoms.

It is important to also consider the overlap between anxiety disorders and major depression. Several symptoms of generalized anxiety disorder (GAD), eg, anxiety and insomnia, are core features both of major depression and GAD (Table I), and psychological models indicate that major depression and GAD share negative affect.4 Panic attacks are found in both depression and several anxiety disorders. Furthermore, many individuals with depression have obsessive-compulsive and related disorder symptomatology, and many individuals either with depression or trauma and stress-related disorders have been exposed to stressors.

Given such overlaps, an immediate nosological question is whether co-occurrence of depression and anxiety represents an artifact of the diagnostic system?5,6 Indeed, it has been suggested that mixed anxiety-depressive disorder, characterized by subthreshold depressive and anxiety symptoms, is highly prevalent and disabling, and therefore deserves recognition as an independent diagnostic entity.7,8 This disorder is listed in the appendix of the DSM, Fourth Edition (DSM-IV), and is widely employed when International Classification of Diseases, Tenth Revision (ICD-10) diagnoses are used.

Such a view may be supported by many who work in primary care settings. Mixed presentations of depressive and anxiety symptoms are common in these settings, and practitioners who have relatively little time to undertake detailed assessments may argue that an encompassing entity (ie, mixed anxiety- depressive disorder) facilitates efficient diagnosis and treatment planning.9 Certainly, a number of antidepressants are currently considered first-line agents for the treatment both of major depression and anxiety disorders.10



Table I
Table I. Overlap in symptoms of depression and anxiety.

After reference 2: Stein and Hollander. Anxiety Disorders Comorbid with Depression:
Social Anxiety Disorder, Post-Traumatic Stress Disorder, Generalized
Anxiety Disorder and Obsessive-Compulsive Disorder. London: Martin Dunitz;
2002. © 2002, Martin Dunitz Ltd, a member of the Taylor & Francis group.

On the other hand, it is also important to recognize that anxiety disorders are the most prevalent psychiatric disorders, and that they are underdiagnosed and undertreated. Thus, a contrary view is that epidemiological data on mixed anxiety depressive disorder have significant methodological limitations, and that in patients with both depressive and anxiety symptoms, it is crucial to determine if a particular anxiety disorder is currently present or will develop over time.11 There are important differences in the management of different anxiety disorders, so these need carefully tailored assessment and intervention.

A potential compromise here is to recognize the importance of both categorical and dimensional approaches to psychiatric disorders in general, and to depression and anxiety in particular.12,13 Separate diagnostic categories for different mood and anxiety disorders have been useful in ensuring efficient clinical communication, and also in preliminary neurobiological research. At the same time, the use of dimensional assessments of anxiety in major depression may be useful in emphasizing the spectrum of anxiety symptoms seen in depression, and in encouraging researchers and clinicians to evaluate this set of symptoms more rigorously.

Psychobiology of depression-anxiety comorbidity

It has long been recognized that anxiety in major depression is associated with significantly worse treatment outcome.14,15 The recent STAR*D trial (Sequenced Treatment Alternatives to Relieve Depression) similarly found that anxious depression is associated with lower response and remission rates, as well as slower response, than non-anxious depression, with a poorer response not only to first-line antidepressant treatment, but also after second-line switching and augmentation pharmacotherapy or psychotherapy.16,17 Furthermore, patients with anxious depression had increased side-effect frequency, intensity, and burden.

It is also important to emphasize that anxiety disorders typically precede the onset of major depression. It is notable that an animal literature has emphasized that after maternal separation, there is first a separation anxiety response, and subsequently a despair response.18 Along these lines, an early neurobiological explanation suggested initial involvement of the GABAergic system in anxiety, with subsequent dysregulation of monoamine neurotransmitters in major depression.19 Ultimately, however, the relevant mechanisms which mediate the temporal sequence from anxiety to depression remain poorly delineated.

Indeed, it is far from clear that anxious depression is characterized by specific neurocircuitry alterations, or by a particular neurochemical or neurogenetic signature. The STAR*D authors conceded that as anxious depression was associated with greater severity of depression, lower socioeconomic status, and higher physical illness burden, anxious depression may not represent a different depression subtype.16 While participants at a recent DSM-5 conference agreed that depression and GAD are different disorders, there was also a view that the relevant neurobiological data in this area are hardly conclusive.20

Clearly, much further psychobiological research is needed. Still, even with future advances, biomarkers will not necessarily be able to carve nature at her joints.21 Nesse and colleagues have emphasized, for example, that there may be many routes by which genetic variations could influence vulnerability to mood and anxiety disorders, including preference for alcohol or for very exciting mates, a tendency to persist in pursuing a life goal even when there is no chance of success, or anxiety that impedes making a needed major life change.22 Thus, we should not be looking only for a few genes specific for, say, co-occurrence of major depression and anxiety, but rather for many genes that influence risk via multiple overlapping pathways.

One useful approach to the psychobiology of anxious depression may be to pay greater attention to the effects of anxiety on key psychological processes in depression. There has been increased attention recently, for example, to disturbances in emotion regulation in several psychiatric disorders, including mood and anxiety disorders.23-25 Anxious depression may be associated with particular kinds of cognitive distortion and with increased avoidance strategies. Such processes may have certain psychobiological correlates; for example, corticolimbic circuitry mediates reappraisal and suppression.23 Furthermore, such processes might then be targeted during treatment.

Along complementary lines, Nesse has argued that there is a need to consider subtypes of disorders based not only on neurocircuitry and genotype findings, but on a deeper understanding of the functions of the underlying motivational systems.26 The profound overlap between anxiety and depression may arise because they are responses to related kinds of danger; a threat that creates anxiety may lead to an actual loss that precipitates depression.27 This kind of evolutionary explanation is important in supplementing proximate explanations (focused on underlying psychobiological mechanisms) with distal explanations (focused on evolved adaptive responses).

Management of depression-anxiety comorbidity

It seems clear that patients with major depression and anxiety symptoms deserve early and robust intervention. Multiple studies with multiple antidepressants have indicated that these agents are efficacious and well tolerated in the treatment of patients with major depression with co-occurring anxiety symptoms.28 Given that anxiety symptoms in depression are an important prognostic indicator, patients with such symptoms need to be evaluated carefully and treated appropriately.

While it is very difficult to demonstrate conclusively that early treatment of anxiety disorders is effective for decreasing the development of subsequent comorbid depression, there are some data which point in this direction.29 It would seem entirely reasonable to encourage the early detection and management of anxiety disorders in order to help prevent the subsequent onset of comorbid major depression, substance use disorders, and other negative outcomes.

An immediate question, however, is whether co-occurrence of depression and anxiety deserves a unique treatment? The presence of unique biological markers would certainly encourage that interventions address the relevant targets. The lack of such markers is consistent with the opinion that no specific pharmacotherapeutic intervention has yet proven distinctively superior in the treatment of anxious depression.28,30 That said, it is noteworthy that there may be a modest advantage for selective serotonin reuptake inhibitors (SSRIs) over bupropion,31 and of agomelatine over SSRIs, in the treatment of anxious depression.32

Work on the management of anxious depression raises the key question of why anxiety is so often overlooked in the management of depression. A key clinical lesson may emerge from a deeper consideration of the experience of depression; we have a tendency to think of depression as a “down,” and to use language consistent with this metaphor (eg, low mood, low energy). This in turn may make it hard to recognize such conditions as bipolar disorder (with its phases of mania) and more agitated depressions (where anxiety plays a key role). This failure to recognize the full spectrum of the experience of depression can have significant negative consequences; in particular, clinicians may underestimate the severity of anxious depression and its clear link with negative outcomes such as suicide.

Perhaps a second clinical lesson emerges from literature which emphasizes the heterogeneity of anxious depression, and the importance of understanding the context of the relevant symptoms. Ghaemi, for example, has emphasized the neglect of the old concept of “neurotic depression,” a form of depression in which there is increased anxiety, often in response to life stressors.33 Similarly, Nesse has emphasized that in such cases a clear understanding of the adaptive value of the relevant emotional responses may be useful.27 Indeed, from a DSM-5 perspective, some forms of anxious depression are perhaps best conceptualized using constructs from the chapter on trauma and stress-related disorders, such as adjustment disorder with mixed anxiety and depression mood,34 rather than as major depression.

On the other hand, the psychobiology of “neurotic depression” may well differ from other forms of depression with anxiety, such as depression with panic attacks or agitated depression. Some psychopathology is best understood using a model of “defect” rather than “defense,” and these kinds of anxious depression may represent maladaptive responses with significant disruptions in the underlying functional systems. Although the neurobiology of agitated depression is poorly understood, there is some evidence that this lies on the bipolar spectrum.35 Thus, some forms of anxious depression should be viewed as indicators of rather serious forms of psychopathology, and clinical interventions should be targeted appropriately.

Conclusion

Anxiety in depression is associated with increased morbidity; anxiety disorders typically precede the development of major depression; and patients with major depression and anxiety respond to efficacious treatments and so deserve early and robust intervention. However, the occurrence of anxiety in depression raises many complex questions. This review emphasizes that both categorical and dimensional approaches to co-occurring depression and anxiety are needed, that anxiety in depression is a heterogeneous construct, and that variants of anxious depression, such as stressor-related depression and agitated depression, likely require quite different approaches. _

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Keywords: anxiety; comorbidity; co-occurrence; depression; diagnostic categories; DSM-5; management; phenomenology; psychobiology