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Comorbidity of Anxiety and Depressive Disorders: Issues in Conceptualization, Assessment, and Treatment

BELZER, KENNETH PhD; SCHNEIER, FRANKLIN R. MD

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Journal of Psychiatric Practice: September 2004 - Volume 10 - Issue 5 - p 296-306
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Abstract

In recent years, comorbidity among psychiatric disorders has received increasing attention in both clinical research and practice. Comorbidity among the anxiety and depressive disorders is particularly common and has significant implications in terms of clinical presentation, assessment, treatment selection and effectiveness, as well as the course of illness, prognosis, and long-term outcome.

It is the principal goal of this review to provide a clinically relevant analysis of some of the more compelling and substantive issues concerning the co-occurrence of anxiety disorders and depressive syndromes. We have attempted to elucidate issues and principles that apply broadly to all of the anxiety disorders currently recognized in the classification system of the Diagnostic and Statistical Manual of Mental Disorders (DSM). 1 However, given the burgeoning empirical literature on each of the specific anxiety disorders, and practical limitations on space, in this review we have focused on two commonly occurring anxiety disorders, social phobia, also known as social anxiety disorder (SAD), and generalized anxiety disorder (GAD) in combination with the principal depressive illnesses, major depressive episode (MDE), major depressive disorder (MDD), and dysthymic disorder (DD).

We have chosen to focus on SAD and GAD for several reasons. Each of these disorders tends to have a chronic and trait-like presentation, with a clear onset not easily discernible. In addition, each of these disorders has particularly high rates of co-occurrence with depressive states and with one another, and each has been receiving increasing clinical and research attention in recent years. Hence, it is anticipated that an examination of issues relevant to SAD and GAD will have broad clinical implications that are relevant for the full spectrum of anxiety and depressive illnesses.

COMORBIDITY AMONG ANXIETY AND DEPRESSIVE DISORDERS: CRITICAL ISSUES

Definition

Feinstein first introduced the term comorbidity in the medical literature in 1970. 2 The term refers to the presence of two or more distinct co-occurring disorders in an individual patient. 3 It was the elimination of earlier restrictive hierarchical exclusionary criteria from the Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised (DSM-III-R) that has enabled clinicians to readily diagnose multiple co-occurring psychiatric disorders. 4 This, in turn, has given rise to the problem of comorbidity in contemporary psychiatric diagnosis.

At a more fundamental and conceptual level, however, comorbidity is largely the product of a nosological system that classifies mental disorders categorically, presupposing discrete diagnostic entities or disease states. Dimensional approaches to diagnosis could conceivably be more capable of addressing the frequent co-occurrence of multiple psychological problems such as anxiety and depression. 3 Nevertheless, no viable and widely accepted alternative dimensional diagnostic system is currently available. Another alternative would merge anxiety and depressive symptoms within a single category. Mixed anxiety-depressive disorder is defined by subsyndromal symptoms of both depression and anxiety in the DSM-IV-TR appendix of disorders for further study. 1 Such developments bring into sharp focus the critical issue as to whether these are indeed distinct disorders that frequently co-occur, or whether they are diverse manifestations of a broader underlying condition such as general negative affectivity. Regardless of how co-occurring symptom complexes are described, clinicians and researchers must continue to grapple with the challenges involved in assessing and treating patients with complex combinations of symptoms.

Prevalence of Anxiety and Depressive Disorders

Representative estimates of the prevalence of DSM-III-R anxiety and depressive disorders in the community can be derived from the National Comorbidity Survey (NCS). Data from this landmark study indicated that lifetime and 12-month prevalences for any anxiety disorder, defined as panic disorder, agoraphobia without panic disorder, social phobia, simple phobia, and GAD were 24.9% and 17.2%, respectively, indicating that anxiety disorders are the most commonly occurring psychiatric illnesses in the non-institutionalized general population of the United States. 5 Notably, these figures do not include obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), acute stress disorder, anxiety disorder due to a general medical condition, or anxiety disorder not otherwise specified, suggesting that the actual lifetime prevalence for the full spectrum of anxiety disorders among the general population is potentially higher.

In the analysis of specific anxiety disorders, SAD (social phobia) was found to be the third most commonly occurring mental disorder in the NCS (behind major depressive episode and alcohol dependence), with an estimated lifetime prevalence of 13.3%, and 12-month prevalence of 7.4%. 5 Estimates of GAD were considerably lower than those for SAD. However, GAD is still a relatively prevalent disorder, approximately three to four times more common in the general population than panic disorder. 6 Estimates of DSM-III-R GAD from the NCS yielded 12-month and lifetime prevalence rates of 3.1% and 5.1%, respectively. 7 Other epidemiological studies have indicated that GAD is a commonly occurring disorder across cultures, 8–11 and GAD has been found to be the most common anxiety disorder seen in primary care settings. 12

Interestingly, in 2004 Kessler et al. suggested that current prevalence estimates of GAD may underestimate the true rate of clinically significant generalized anxiety in the population. 13 This reflects a bias resulting from arbitrary and overly restrictive diagnostic criteria, which continue to change with each successive version of DSM. Kessler notes that available evidence on diagnostic thresholds for GAD raises questions about whether the requirements for a 6-month minimum duration and a specific number of psycho-physiological symptoms (i.e., three of six) 1 in adults are optimal for capturing all of the people in the general population who suffer from clinically significant chronic or generalized anxiety. A second source of potential bias is the requirement in the DSM system that the anxiety and worry be judged “excessive” to qualify as GAD. Kessler notes, for instance, that no comparable qualification exists for dysphoria in assigning a diagnosis of major depression in DSM-III-R or DSM-IV-TR. 1,4

NCS estimates for individual DSM-III-R depressive disorders were also sizable in magnitude. Specifically, lifetime and 12-month rates of prevalence for a MDE were 17.3% and 10.1%, respectively. For MDD, estimates were 14.9% (lifetime) and 8.6% (12-month); prevalence of DD was estimated to be 6.4% (lifetime) and 2.5% (12-month). 5,14 More recently, data from the National Comorbidity Survey Replication (NCS-R) revealed estimates for lifetime and 12-month prevalence of DSM-IV MDD of 16.2% and 6.6%, respectively. 15

Rates of Comorbidity Among Anxiety and Depressive Disorders

As noted earlier, estimates of comorbidity among the anxiety and depressive disorders are typically quite high. For example, a substantial 59.2% of lifetime and 57.5% of 12-month cases of DSM-IV MDD were comorbid with DSM-IV anxiety disorders in the NCS-R. 15 High rates of MDD were found in persons with SAD in the NCS. Among individuals with lifetime SAD, 29.7% also had a history of MDD. 16 In samples with SAD in anxiety disorder clinics (some of which exclude patients who present with comorbid MDD), rates of lifetime MDD vary widely but commonly exceed 50%. 17–19 Finally, in two primary care samples, 58.3% and 35.8% of cases with SAD had comorbid MDD. 20,21

Similarly, when considering primary cases of MDD, SAD is the most common comorbid anxiety disorder. 22–24 In the NCS, among persons with lifetime MDD, 26.5% also met criteria for lifetime SAD. 16 In clinical samples of depressed patients, rates of SAD have ranged from 15% to more than 25%. 22,23,25

High rates of mood disorders were also found in persons with GAD in the NCS. Among those with lifetime GAD, 62.4% also had a history of MDD, and 39.5% had a history of DD. 7 GAD also appears to have particularly high rates of comorbidity with the depressive disorders in clinical samples. In a sample of 371 patients seeking treatment at a university-based anxiety disorders center, 29% of primary GAD patients presented with a secondary mood disorder (11% MDE and 18% DD). 26 Even higher rates of depression were found by Brawman-Mintzer et al., who reported that 42% of patients with GAD also had a history of a major depressive episode. 27 Rates of secondary DD as high as 50% have also been reported in persons with GAD. 28

Conversely, when considering primary cases of MDD, GAD is also a frequent comorbid condition. In the NCS, 17.2% of respondents with lifetime MDD also met criteria for lifetime GAD. 16 In clinical samples, when a MDE or MDD is the principal diagnosis, rates of comorbid GAD have ranged from 20% to 45%. 26,29,30 Similarly, GAD has consistently been found to be the most common comorbid disorder in patients with DD. For instance, Pini et al. found that 65% of patients with DD had comorbid GAD. This was substantially higher than the number of patients with comorbid MDD (37%). 24

Taken together, these data indicate that the anxiety and depressive disorders are among the most frequently occurring psychiatric illnesses, and that comorbidity of these disorders is quite pervasive in nationally representative community samples and clinical populations.

Order of Onset: Temporal Precedence of Anxiety

When anxiety and mood disorders co-occur, anxiety disorders are more likely to be temporally primary, though temporal primacy need not imply causation. 13 Thus, it is not surprising that examination of the NCS data on MDD revealed that most cases of lifetime MDD were secondary (i.e., occurring in individuals with another primary DSM-III-R disorder), with the most common primary disorders (67.9%) being the anxiety disorders. 14 For example, the onset of SAD preceded the onset of MDD in approximately 70% of comorbid cases in the NCS and the Epidemiological Catchment Area Study. 16,31 Moreover, the risk of onset of MDD within a given year is significantly increased during the year after first onset of an anxiety disorder, with odds ratios ranging from 6.5 for SAD to 62.0 for GAD. 14 Kessler et al. found that the risk for subsequent onset of MDD remains elevated for more than a decade after the first onset of GAD. 14

Course and Functional Impairment

Comorbidity of mood and anxiety disorders is widely understood to be associated with increased severity, persistence, and functional impairment. For instance, depressed patients with anxiety have been reported to be more chronically ill and to respond more poorly to treatment. 32,33 In a recent meta-analysis of naturalistic outcome studies, significantly worse outcomes were found in cases of combined anxiety and depressive disorders than in cases of anxiety disorder or depressive disorder alone. 34 Moreover, some recent clinical trials have suggested that patients with MDD and comorbid mixed anxiety disorders are less likely to respond to selective serotonin reuptake inhibitors (SSRIs) and more likely to drop out of treatment, leading to the impression that MDD that is comorbid with anxiety disorders is generally difficult to treat. 35–37

Impairments in vocational and social functioning, including inability to work, attend school, socialize, or marry, are often substantial in SAD and in MDD. 31,38–41 Among patients with MDD, comorbid SAD has been associated with a history of earlier onset of MDD, 25,42 more major depressive episodes, 16 and an increased risk of suicidality and alcohol dependence. 43 In a prospective community study, young adults with comorbid SAD and depressive disorder who were followed for 4 years were significantly more likely than those with only depressive disorder to experience more intense suicidal ideation, more depressive symptoms, a longer duration of MDD, and greater odds of having attempted suicide during the follow-up period. 44

GAD is characterized by an early onset and predominantly chronic course and is associated with high rates of seeking professional help, increased medication use, substantial impairment in quality of life, and deterioration in emotional well-being. 7,45 The disorder appears to be correlated with stressful life events and, although GAD is marked by a characterological presentation, it is not unusual to see fluctuations in symptomatology corresponding to the presence or absence of life stressors. 46,47 Individuals with GAD are prone to over-utilizing healthcare services, and the disorder is associated with significant social impairment and occupational disability. 48,49

THEORETICAL CONCEPTUALIZATIONS OF COMORBIDITY

There are numerous explanatory models of psychiatric comorbidity, which can parsimoniously be classified into 1) explanations based on sampling and base rates, 2) explanations based on artifacts of diagnostic criteria, 3) explanations based on drawing boundaries in the wrong places, and 4) explanations based on etiological relationships. 3 In terms of enhancing our understanding of psychiatric comorbidity, the most common and promising approaches include epidemiological studies, longitudinal (follow-up) studies, both naturalistic and treatment-oriented, and family and/or genetic studies. 3 Although a comprehensive discussion of this field of investigation is beyond the scope of the present review, some findings specific to the comorbidity between SAD and MDD are considered below.

Family and genetic studies have found mixed results concerning etiological explanations. SAD and MDD do tend to aggregate in families, with an elevated rate of MDD among first-degree relatives of probands with SAD compared with relatives of probands who were not ill (27% versus 15%). The rate of MDD decreased but remained elevated after controlling for the presence or absence of comorbid MDD in probands with SAD, suggesting that shared etiological factors are operating to some extent. 50 One twin study found evidence for shared genetic vulnerability between SAD and MDD (respective heritabilities of 28% and 45%). 43 However, another twin study found a much smaller degree of shared genetic variation between SAD and MDD and some shared environmental factors, consistent with a combination of etiologic explanations. 51

Shared environmental factors may contribute to comorbidity in a variety of ways. A common life event could trigger both disorders. Alternatively, depressed parents might contribute environmentally to the development of both SAD and MDD by being less likely to discourage social avoidance in inhibited children, modeling both depressive and socially unassertive behavior, and being critical of children.

SAD might contribute causally to the development of comorbid MDD via demoralization, the stress of poor social functioning, and secondary negative life events (e.g., job loss). The lack of social supports that characterizes SAD may contribute to greater severity of MDD symptoms and increased suicidality. Likewise, MDD symptoms such as anhedonia and fatigue may further increase social avoidance behavior, creating a vicious cycle of escalating fear, avoidance, and depression.

There are two possible explanations for the greater than expected comorbidity of SAD and temporally secondary MDD: 1) SAD could be a causal risk factor for MDD; or 2) SAD and MDD could both be the consequences of a common underlying factor. The findings that a) more severe SAD and b) more active, as opposed to remitted, SAD are each more commonly associated with the development of MDD support the hypothesis of a causal relationship. 16,44

It is noteworthy that research by Kendler and colleagues has also shown that there is a shared genetic vulnerability for GAD and MDD. Findings from several large twin studies suggest that liability for GAD and major depression is influenced by the same genetic factors, but development of either disorder is a result of mostly distinctive environmental determinants and experiences. 52–54

ASSESSMENT OF COMORBID ANXIETY AND DEPRESSION

For any patient presenting with a chief complaint of depression, the clinician should routinely inquire about common comorbidity, such as symptoms of anxiety disorders. Careful assessment of anxiety and depression symptoms and their relationship to each other is important for thorough understanding of the patient’s experience, to assess suicidality, to guide choices of medication and therapy treatment, and to anticipate the course of illness. The assessment of anxiety comorbidity in depression should take into consideration both full anxiety disorders and subsyndromal anxiety symptoms.

Assessment should include a longitudinal history, including determining the age of onset and context of onset of each set of symptoms. Did one syndrome clearly emerge first or was onset simultaneous? As noted earlier, SAD and GAD most commonly precede the onset of major depression. Concurrent onset of anxiety and depressive syndromes sometimes occurs in the context of an extreme stressor, with or without a full PTSD syndrome. The temporal course of symptoms and their relationship to each other should be ascertained. Do the syndromes wax and wane concurrently, does one seem to lead to the other, or does each of them seem to have a life of its own? What role do stressors play in the fluctuation or recurrence of each set of symptoms over time?

While the etiologic relationship between anxiety and depressive symptoms can rarely be determined with certainty for an individual, patients often have beliefs about this that can inform the treatment. For example, a mild depression that appears to take the form of demoralization secondary to chronic anxiety symptoms may be more likely to respond to anxiolytic treatment than a depression that seems autonomous. Anxiety that occurs only in the context of a major depressive episode may best be considered an element of depression and, according to the DSM-IV-TR, may not warrant an additional anxiety disorder diagnosis. It is also important to determine the response of each set of symptoms to prior treatments, which may be a valuable predictor of future responses. Family history of disorders and their responses to treatment may also offer clues to the patient’s condition and potential for response to similar treatments.

Any patient who presents with either anxiety or depression should be evaluated for current symptoms of both anxiety disorders and depression. SAD or panic attacks co-occurring with major depression may be a risk factor for suicidal behavior. 31 Comorbid panic disorder or SAD may be associated with bipolar depression. 55 In some patients, particular anxious or depressive symptom clusters may be related to specific functional impairments, and this may be helpful in identifying primary targets for treatment and monitoring response.

MEDICATION TREATMENT OF COMORBID ANXIETY AND DEPRESSION

Initiating Treatment

Most medications useful for patients with comorbid anxiety and depression have been studied primarily in patients with major depression and in patients with noncomorbid anxiety disorders. Because the drug development process is often geared toward obtaining FDA approval for a DSM-defined indication, comorbid disorders that might affect treatment response of the index disorder are typically a cause for exclusion from clinical trials. Drugs with potential efficacy in both depression and anxiety are often labeled “antidepressants” because they are first studied in major depression (the indication with the largest market for the pharmaceutical industry), although most antidepressants have later been shown to have anxiolytic properties. We are left to infer the utility of medications for comorbid depression and anxiety from studies of noncomorbid samples, and from a smaller database of studies in comorbid patients, including studies of patients with subsyndromal anxiety and depression, major depression with subsyndromal anxiety, major depression with mixed anxiety disorders, and major depression with a specific anxiety disorder.

Why should clinicians try to disentangle anxiety and depression symptoms, when both syndromes generally respond to selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs)? Among the SSRIs/SNRIs that have been approved for MDD, the quality of data supporting the efficacy of each for various anxiety disorders differs across the anxiety disorders (see Table 1). It therefore seems reasonable to offer patients with comorbid disorders a medication that has established efficacy for each of their syndromes. Although several clinical trials comparing pairs of antidepressants in the treatment of depression with comorbid anxiety have reported differences in efficacy between medications, further study is needed before it can be claimed definitively that any specific SSRI/SNRI is superior in efficacy for depression with comorbid anxiety.

Table 1
Table 1:
Antidepressant efficacy in anxiety disorders

Data from comorbid samples and from depressed patients with subsyndromal anxiety generally support the efficacy of SSRIs/SNRIs and tricyclic antidepressants (TCAs). 56,57 However, some recent clinical trials have suggested that patients with MDD and comorbid mixed anxiety disorders are less likely to respond to SSRIs and more likely to drop out of treatment than those with MDD alone. 35,36 Among other antidepressants, bupropion, sometimes considered “activating,” has appeared to be well tolerated in controlled trials of depression with anxiety. 58 The novel antidepressants mirtazapine and nefazodone also appear useful in patients with depression and anxiety symptoms. Anxiolytics without antidepressant efficacy, such as the benzodiazepines, are not a suitable monotherapy for most patients with comorbid anxiety disorders and major depression.

While it may be tempting to initiate treatment with both an antidepressant and an anxiolytic to maximize and speed response, it is generally preferable to begin with monotherapy with an agent such as an SSRI/SNRI that has potential efficacy for both depressive and anxiety symptoms. This minimizes the risk of adverse effects; in addition, initiating dual therapy has not been shown to be superior. There may, however, be specific cases (e.g., acute debilitating panic attacks), when it is helpful to initiate treatment with a benzodiazepine for rapid symptom relief and then to add an SSRI/SNRI shortly afterward. 59 The benzodiazepine may be tapered off after a few weeks as the antidepressant response develops.

Another consideration in initiating SSRI/SNRI treatment is the dose escalation schedule. It has been reported that patients with comorbid panic disorders sometimes experience “hyperstimulation” symptoms such as nervousness, insomnia, and panic in response to standard starting doses of SSRIs and other antidepressants. Therefore, initiating antidepressant treatment at a lower dose in patients with panic disorder may be useful in improving patient acceptance.

Assessment of response to antidepressants also requires attention to anxiety disorder comorbidity. In a study of patients with MDD and comorbid generalized SAD, a more severe and pervasive form of SAD introduced in DSM-III-R in which fears are related to most social situations, depressive symptoms began to improve before anxiety symptoms. 60 Patients may need to be encouraged to stay the course of treatment even if they fail to see improvement in anxiety symptoms during the initial month of treatment. OCD has also been reported to show a delayed response, and there is some evidence suggesting that higher doses of SSRIs may have superior efficacy in OCD. 61

The clinician may need to tailor his or her medication management style to the individual needs of patients with comorbid anxiety disorders. Patients with panic disorder or GAD, in particular, may tend to worry more about adverse effects. It can be reassuring to emphasize one’s availability to discuss adverse effects as they arise, especially in the early weeks of treatment. Patients with SAD may be reluctant to call with their concerns, and they should be encouraged to maintain communication with the clinician, rather than to flee treatment to avoid what they may experience as a confrontation.

Treatment of Nonresponders and Partial Responders

The most common outcome of a single medication trial in a patient with comorbid anxiety and depression is a partial response. Comorbid diagnoses must again be taken into account at this stage. If response has been partial, and it is judged insufficient, then augmentation with psychotherapy or another medication targeting the remaining symptomatology should be considered. Unfortunately, there is little controlled research to guide decisions about treatment augmentation, and even fewer data in samples with comorbid anxiety and depression.

If depressive symptoms have remitted, but anxiety remains problematic, augmentation with a variety of anxiolytics may be considered. Buspirone is effective for GAD with depressive symptoms and may be useful in augmenting SSRIs in SAD. 62,63 Propranolol taken as needed is commonly helpful in reducing performance anxiety in nongeneralized SAD, where social fears are more circumscribed, occurring in specific social situations (e.g., giving a speech or presentation). Among the anticonvulsants, valproic acid may have efficacy in panic disorder, 64 gabapentin appeared to be efficacious in a controlled trial in SAD, 65 and lamotrigine showed benefit for PTSD in a small controlled trial. 66 Benzodiazepines are efficacious anxiolytics that are used less frequently than in the past due to concerns about the development of dependence and abuse. They remain useful, however, especially in the treatment of panic disorder, SAD, and GAD. 67–69 Because benzodiazepines can sometimes worsen depression, they should be carefully monitored when prescribed for patients with comorbid depression. TCAs have established efficacy in panic disorder and, to a lesser extent, in GAD, but caution must be employed when using them in combination with SSRIs/SNRIs due to pharmacokinetic interactions that can increase TCA levels to toxicity. 67,69 The use of clomipramine in conjunction with SSRIs for OCD has been reported, but again the combination must be carefully monitored to avoid toxicity from elevated clomipramine levels. 70

When anxiety symptoms remit but depression persists, typical antidepressant augmentation strategies may be employed. Thyroid augmentation can sometimes cause symptoms like palpitations that may be particularly disturbing to some anxious patients. Antipsychotics have had mixed results in SAD. 71,72

If the initial trial of an SSRI/SNRI is completely ineffective or the patient is unable to tolerate the medication, another drug in the same class or alternative medications with activity for both anxiety and depression may be considered, such as the novel antidepressants bupropion, nefazodone, or mirtazapine. TCAs are useful for depression accompanied by generalized anxiety or panic disorder, and clomipramine is an alternative for patients with comorbid OCD or panic disorder. The anticonvulsant lamotrigine has antidepressant properties, but its anxiolytic effects have not been well studied. Monoamine oxidase inhibitors (MAOIs) should be considered, particularly for patients who have MDD with atypical features or who have generalized SAD. 73

Psychosocial Treatment of Comorbid Anxiety and Depression

Numerous well-controlled randomized clinical trials (efficacy studies) have yielded evidence that anxiety and depressive disorders are amenable to treatment with psychosocial interventions. Both cognitive-behavioral therapies (CBT) and interpersonal psychotherapy (IPT) have shown significant promise in treating these disorders. However, the majority of controlled studies have typically focused on patients who meet rigid study inclusion criteria. Among other things, this may involve the diagnosis of a specific anxiety or depressive disorder, with restrictions on, or exclusion of, comorbid conditions. Hence, the pursuit of internal validity (i.e., the determination that a particular intervention has efficacy in the treatment of a specific or pure anxiety or depressive disorder) can, to some extent, compromise the external validity or generalizability of the findings to commonly co-occurring disorders that are typically seen in the clinical setting.

Fortunately, individual and/or group psychotherapies designed to address specific anxiety and depressive syndromes have exhibited generalizing effects on comorbid conditions. For instance, meta-analyses of controlled clinical trials of CBT for GAD have consistently shown that these treatments yield clinical improvement in comorbid depressive symptoms. 74–77 Comorbidity often occurs below the full syndrome level. Frequently, panic attacks, worry, social-evaluative anxiety, obsessive-compulsive thoughts and/or behavior, and depression will be present to some extent along with another primary mood or anxiety disorder, but will not meet the requirements for a formal diagnosis. 78 Sanderson and McGinn discussed a symptom-focused CBT approach as an alternative to more traditional disorder-based approaches. 78 This is especially appealing when there is comorbidity not only at the syndrome level, but also at the symptom level. Among its advantages, a symptom-focused approach provides a flexible framework that allows the clinician to tailor the treatment to the “symptom configuration” and individual needs of each patient, thus maximizing treatment effectiveness. 78

An example of the application of such an approach might involve a patient who presents with GAD, but who also experiences significant social-evaluative fears, and, as a consequence of social withdrawal and isolation, becomes increasingly depressed. The symptom-focused approach would address the tension and arousal of generalized anxiety by teaching the patient self-monitoring and applied relaxation skills. 79 Cognitive restructuring techniques would be used to modify various “automatic thoughts” and “core beliefs,” as well as maladaptive appraisals and attribution styles, which function to generate chronic worry, social anxiety, and depressive rumination. 79–81 The patient would also engage in behavioral exposure to anxiety-provoking social situations and receive social skills training if interpersonal skill deficits are present. 81 Finally, to address the inactivity, passivity, and anhedonia accompanying the depression, a CBT therapist would assist the patient in planning therapeutic activities, including scheduling of pleasant events and/or behavioral activation (i.e., implementing procedures focused on increasing patient activity and access to positive reinforcers). 80,82 The specific treatment elements would be chosen sequentially based on the severity of symptoms (e.g., depression may need to be addressed before other symptoms in order to facilitate the patient’s engagement in therapy). An earlier treatment strategy in the sequence may or may not have generalizing therapeutic effects on less severe symptoms that will be addressed later in the sequence. 78

Depending upon various clinical parameters, such as the nature of onset (whether acute or insidious), the severity of the initial presentation, chronicity, and prior treatment attempts and response, psychosocial treatments including CBT and IPT have the potential to serve as first-line interventions for comorbid anxiety and depressive disorders. These treatments may be more attractive to patients who have reservations about medication and the potentially aversive side-effect profiles associated with some psychotropics. Also, the social support of a more intensive ongoing psychotherapeutic relationship may be intrinsically appealing.

The fact remains, however, that anxiety and depressive disorders are often difficult illnesses to address and are frequently refractory to treatment. Co-occurrence of these disorders only serves to exacerbate the difficulties inherent in treating anxiety and depressive states. Some evidence indicates that the presence of comorbid depression in patients with anxiety disorders, including SAD and panic disorder, is a risk factor for poorer outcome with CBT. 83,84 Furthermore, in cases in which severe depression and/or suicidality are present, it is advisable to initiate pharmacotherapy immediately, concomitant with psychotherapy. Some evidence suggests, however, that concurrent medication may reduce the durability of CBT in treatment of panic disorder. 85 Sequencing of pharmacotherapy and psychotherapy may also represent a viable strategy in the anxiety disorders.

SUMMARY AND RECOMMENDATIONS

Comorbidity between anxiety and depressive disorders is substantial and pervasive in both the general population and in patients presenting to primary care and the mental health specialty sector. In fact, comorbidity among these disorders may represent the rule rather than the exception, especially within clinical samples. The following recommendations are worthy of consideration.

Improved efforts toward screening and detection of anxiety, depression, and their comorbidity in primary care settings are necessary. For example, GAD, a disorder highly comorbid with depression, other anxiety syndromes, and somatic illnesses, is the anxiety disorder most commonly seen in primary care. These patients are recognized among physicians as being a problem population of “high healthcare utilizers” and “high complainers” in clinical practice. Yet, because fewer than 20% of patients with GAD present in primary care with psychological complaints, GAD remains a poorly recognized disorder by primary care providers. 12,49 Improved screening and early detection of mixed anxiety and depressive states at the primary care level will have significant implications for illness course, management, and treatment response, as well as broader consequences for general patterns of healthcare utilization.

Another critical issue for future research, and one that has substantive implications for the treatment of patients with comorbidity, is the exploration of optimal integration and/or sequencing of pharmacotherapy and psychosocial therapy. In this regard, it is noteworthy that results of a recent meta-analysis indicated that combined pharmacotherapy and psychotherapy were associated with a small but consistent improvement in treatment outcome for major depression. 86 In their 2004 analysis of the literature, Friedman et al. concluded that the addition of psychotherapy to antidepressant medication may be particularly effective with chronic or severely depressed patients. 86 Moreover, the addition of CBT to pharmacotherapy may be effective in relapse prevention, especially among individuals who discontinue pharmacotherapy, although some evidence to the contrary has been reported. 85 Such findings warrant further investigation in combining treatments for anxiety disorders.

A closely related issue is the need to increase the external validity of clinical trials by designing studies that include specific comorbid samples. In order to address the clinical realities of comorbidity at the symptom and syndrome level, patient samples recruited for efficacy studies should more accurately reflect the composition of populations who present to primary care and mental health service providers. Additional study of specific comorbid samples will help diminish the existing “disconnect” between research and practice.

Finally, we are now in the early stages of a new generation of large multi-center controlled clinical trials that are attempting to evaluate the comparative and combined efficacy of medication and psychosocial therapy for both MDD and a number of specific anxiety disorders. 85,87 Research of this nature is likely to have significant implications for the pervasive comorbidity among the anxiety and depressive disorders, which will in turn translate into new standards of practice. However, until findings from such research are conclusive and widely disseminated, exigencies of clinical practice will necessitate that clinicians go beyond the current data, relying in part upon accumulated experience and clinical acumen when confronted by the complexities of comorbid anxiety and depression.

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Keywords:

comorbidity; anxiety disorders; social anxiety disorder; generalized anxiety disorder; major depression; assessment; treatment

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