The influence of comorbid anxiety disorders on outcome in major depressive disorder



b y D . S . B a l d w i n a n d A . T. V. L o p e s , U n i t e d K i n g d o m

David S. BALDWIN, DM FRCPsych
Antonio T. V. LOPES, MB BS, MRCPsych
Clinical Neuroscience Division
School of Medicine, University of Southampton
Mood and Anxiety Disorders Service
Hampshire Partnership Trust
Southampton, UNITED KINGDOM

Anxiety symptoms are common in patients experiencing major depressive episodes, being reported by approximately 60% of patients, and comorbid anxiety disorders are seen in around 50% of patients with major depressive disorder. 1 One of the early findings of the influential US Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study was that “anxious depression,” defined as a score of 7 or greater on the anxiety- somatization subscale of the Hamilton Rating Scale for Depression,2 was seen in 49% of the patients in primary care, and by 42% of those treated in secondary care.3 Furthermore, a comorbid anxiety disorder was present in approximately half of patients, regardless of the treatment setting.4 This degree of comorbidity is also seen in nonclinical samples: for example, the results of a systematic review of European community studies among people aged 18-65 years found that approximately 30%- 40% of patients with a depressive disorder had a comorbid anxiety disorder, and vice versa.5 The recent European Study of the Epidemiology of Mental Disorders (ESEMeD) also found a high 12-month prevalence of comorbid mood and anxiety disorders (Figure 1).6
There have been few studies of the comorbidity between anxiety and depressive disorders in later life, although a Dutch community study of people aged 55-85 years found that 47.5% of those with a major depressive disorder also met criteria for at least one anxiety disorder, and 26.1% of those with anxiety disorders fulfilled the criteria for major depression. 7 This observation is supported by the findings of studies involving clinical samples of older depressed patients, in whom comorbid anxiety disorders have been found to vary in frequency from between 3%-65%.8-10

Coexisting anxiety symptoms and comorbid anxiety disorders are common in patients with major depressive disorder. This review examines three aspects of the relationship between major depressive disorder and comorbid anxiety disorders: whether the comorbid condition is more severe than “pure” major depression; whether the comorbid condition is associated with worse clinical outcomes than are seen in major depressive disorder alone; and whether the response to antidepressant treatment differs between depressed patients with or without comorbid anxiety disorders. Although not all evidence is consistent, in general terms, the presence of comorbid anxiety disorders in patients with major depressive disorder is associated with greater severity of symptoms and more pronounced impairment. The course of illness is less favorable in patients with the comorbid condition, and relatively fewer depressed patients respond to antidepressant treatment and achieve remission of symptoms if affected by comorbid anxiety disorders. There is a need for randomized placebo-controlled studies specifically in patients with comorbid major depressive disorder and anxiety disorders, in order to determine whether this patient group differs from those with “pure” major depression in its responsiveness to pharmacological or psychological interventions.
Medicographia. 2009;31:126-131. (see French abstract on page 131)

Keywords: major depression; anxiety disorder; comorbid; outcome; response

This review examines three key aspects of the relationship between major depressive disorder and comorbid anxiety disorders. First, whether the comorbid condition is more severe than “pure” major depression; second, whether the comorbid condition is associated with worse clinical outcomes than are seen in major depressive disorder alone; and third, whether the response to antidepressant treatment differs between depressed patients with or without comorbid anxiety disorders.

Greater severity of symptoms and impairment in the comorbid condition

Early studies supported the widespread consensus that patients with comorbid mood and anxiety disorders had more severe symptoms.11-14 Subsequent studies have in general supported this view. For example, a comparison of 276 US primary care depressed patients with or without a lifetime comorbid anxiety disorder demonstrated that the presence of comorbid panic disorder was associated with greater severity of depressive symptoms, more marked impairment in psychosocial functioning, and greater risk of prematurely stopping treatment.15
Similar findings were seen in a more recent naturalistic study of the effects of coexisting anxiety symptoms or comorbid anxiety disorders on symptom severity at baseline and treatment response, in Italian outpatients with major depressive disorder. It was found that the presence of anxiety symptoms and disorders was associated with more frequent suicidal thoughts, greater psychomotor retardation, and greater severity of diurnal variation of symptoms, sexual dysfunction, somatic concerns, and weight loss, when compared with patients with major depressive disorder alone.16
The greater symptom severity associated with the presence of comorbid anxiety disorders is also seen in other age groups: for example, a comparison of the effectiveness of interpersonal psychotherapy versus “treatment as usual” in depressed adolescents (aged 12-18 years) found that comorbidity was associated with both a greater severity of depressive symptoms at baseline, and with lower response rates in both treatment groups.17
The greater symptom severity of the comorbid condition is reflected in a more pronounced degree of impairment of social and occupational functioning. For example, a recent large cross-sectional primary care study performed in Belgium and Luxembourg found that patients with comorbid major depressive disorder and generalized anxiety disorder reported greater impairment of work, and social and family life, than did patients with major depression or generalized anxiety disorder alone.18
Epidemiological studies demonstrate that a number of individuals have multiple comorbid diagnoses, and some of the greater impairment that is associated with comorbid depressive and anxiety disorders may reflect the presence of additional mental health problems. For example, the presence of comorbidity for an anxiety disorder in patients with major depressive disorder has also been associated with greater risk of comorbidity for personality dis- orders: in the aforementioned comparison of US primary care depressed patients, lifetime comorbidity for panic disorder was also associated with the presence of avoidant personality disorder.15

Figure 1
Figure 1. Prevalence of pure and comorbid 12-month mood, anxiety, and alcohol use
disorders in the general population. Findings from the European Study of the Epidemiology
of Mental Disorders.
After reference 6: Alonso J, Angermeyer MC, Bernert S, et al. Prevalence of mental disorders in Europe:
results from the European Study of the Epidemiology of Mental Disorders (ESEMeD). Acta Psychiatrica
Scand. 2004;109(suppl 420):21-27. Copyright © 2004, John Wiley & Sons, Inc.

The adverse effects of anxiety disorder comorbidity in patients with unipolar depressive disorder are sometimes also seen in patients with the diagnosis of bipolar disorder, although not all studies have produced consistent findings. An investigation in a consecutive sample of French bipolar inpatients found that those with a lifetime comorbid anxiety disorder (24% of the overall sample) did not differ in terms of disorder severity (assessed by number of hospitalizations, presence of psychosis, substance misuse comorbidity, and suicide attempts), although their response to anticonvulsant drugs was lower than that of the group without comorbid anxiety disorders.19 By contrast, in a longitudinal study of the effects of comorbid anxiety disorders on bipolar disorder patients treated with psychotropic drugs, either alone or in combination with family intervention, comorbidity was associated with greater symptom severity at baseline (even after controlling for depressive symptom severity) and with poorer overall treatment response over 28 months, regardless of the treatment modality.20 The link between bipolar disorder and anxiety disorders is also emphasized by the findings of an investigation of the factors associated with non-response to antidepressant treatment in patients with apparent unipolar depression, which found that the presence of comorbid anxiety disorders was associated with a greater “risk” of unrecognized bipolar disorder.21

Poorer outcome in longitudinal studies in patients with comorbid conditions

The presence of comorbid anxiety disorders with major depression is usually found to be associated with a less favorable long-term outcome. For exam- ple, an early systematic review of the clinical outcome of anxiety and depressive disorders found that patients with comorbid anxiety and depression had generally worse outcomes than patients with either an anxiety disorder alone, or a depressive disorder alone.22
The findings of the United States National Comorbidity Survey indicate that participants were significantly more likely to continue presenting with symptoms of a major depressive if they also fulfilled criteria for comorbid generalized anxiety disorder. Similarly, patients with generalized anxiety disorder and comorbid major depression were more likely to experience continued anxiety symptoms than those without depressive symptoms (Figure 2).23

Figure 2
Figure 2. Persistence of comorbid major depressive
disorder and generalized anxiety disorder (GAD).
MDE, major depressive episode.
After reference 23: Kessler RC, Gruber M, Hettema JM, Hwang I,
Sampson N, Yonkers KA. Co-morbid major depression and generalized
anxiety disorders in the National Comorbidity Survey follow-up.
Psychological Med. 2008;38:365-374. Copyright © 2007, Cambridge
University Press.

In general terms, this adverse effect of comorbidity is manifest through longer persistence of symptoms and with a greater risk of continuing social and occupational impairment. For example, an evaluation of the effects of comorbid post-traumatic stress disorder in female patients with major depressive disorder treated with either antidepressant drugs, cognitive behavior therapy, or through community health referral, found that comorbidity was associated not only with greater severity of depressive and anxiety symptoms at baseline, but also with greater impairment at 1-year follow-up.24 This adverse effect of this pattern of comorbidity on the clinical outcomes supports the earlier findings of a delayed response to treatment of depression in both the acute phase25 and the continuation phase26 of treatment, in depressed patients with comorbid post-traumatic disorder.
The adverse effects of coexisting anxiety symptoms or comorbid anxiety disorder are also seen in older depressed patients. In a study of the effectiveness of antidepressant treatment and interpersonal psychotherapy in patients aged 70 years or older, the presence of greater anxiety symptom severity was associated with a longer duration of symptoms and with higher recurrence rates.27 Similar findings had been seen in an earlier investigation of the course of illness in elderly patients with comorbid major depression and generalized anxiety disorder.28
The adverse effects of comorbidity are also manifest through a greater risk of recurrence of symptoms and possibly through an increased risk of suicide. By way of illustration, long-term follow-up (up to 5 years) of a Finnish nationally representative sample of outpatients with DSM-IV (Diagnostic and Statistical Manual of Mental Disorders – Fourth Edition)–defined major depressive disorder found that the severity of symptoms and the presence of comorbidity, especially for social phobia, predicted both a higher probability of recurrence and a greater number of recurrences.29
While the increased risk of suicide in depression has been known for many years, it remained uncertain as to whether anxiety disorders were also associated with an elevated risk of suicide. However, in recent years, epidemiological studies and a systematic review have demonstrated that anxiety disorders are associated with suicidal thoughts and with attempted, if not completed, suicide.30-32 Moreover, current data indicate that comorbid anxiety disorders amplify the risk of suicide attempts in people with mood disorders.30 As the two greatest risk factors for completed suicide are suicidal thoughts and a recent suicide attempt, it therefore seems reasonable to assume that anxiety disorders carry an increased risk for completed suicide.

Reduced response rates and less remission of symptoms during treatment

The presence of prominent anxiety symptoms in depressed patients is generally thought to be associated with a lower overall response rate to treatment. For example, an early comparison of the effectiveness of interpersonal psychotherapy or treatment with the tricyclic antidepressant nortriptyline in 157 depressed patients in primary care found that lifetime comorbidity for an anxiety disorder was associated with higher treatment drop-out rates, a delayed recovery in patients with comorbid generalized anxiety disorder, and particularly poor response rates in patients with lifetime panic disorder.33
Subsequently, a comparison of small groups of patients with major depressive disorder that did or did not respond to antidepressant treatment found that comorbid anxiety disorders (and reports of childhood emotional abuse) were significantly more frequent among the nonresponders.34 A much larger randomized trial of stepped collaborative care of 228 depressed patients in a US health maintenance organization found that the presence of comorbid panic disorder was associated with both greater symptom severity at baseline, and with a significantly lower treatment response.35
Furthermore, in a recent investigation of the determinants of non-response in patients with treatment- resistant depression, a comorbid anxiety disorder was the clinical factor most strongly associated with non-response.36
The adverse effects of comorbidity on the response to treatment are seen in a variety of age groups. For example, an evaluation of the effectiveness of cognitive behavioral therapy, systemic behavioral therapy, and nondirective supportive therapy in 101 adolescents (aged 13 to 18 years) fulfilling DSM-III-R criteria for major depression found that the presence of anxiety disorder comorbidity was predictive of symptom persistence.37 At the other end of the age distribution, a longitudinal study in older adults undergoing case management, cognitive behavior therapy, or the combination for treatment of depression found that comorbid anxiety disorders were associated with greater symptom severity at the end of treatment and at follow-up at 6 and 12 months.38
However, not all the evidence for the effect of coexisting anxiety symptoms or comorbid disorders on treatment response is consistent. For example, a comparison of small groups of Australian inpatients with DSM-III-R–defined major depression found that the presence of comorbid anxiety disorders did not affect either treatment choice, or the effectiveness of treatment interventions.39 In addition, a greater severity of coexisting anxiety symptoms at baseline among patients with either chronic major depression or “double depression” (that is, dysthymia plus supervening acute major depression) did not affect overall response rates with either the tricyclic imipramine or the selective serotonin reuptake inhibitor (SSRI) sertraline.40 Furthermore, in both a comparison of the effectiveness of the tricyclic nortriptyline and the SSRI paroxetine in 116 depressed patients aged 60 years or older, and a second comparison of the effectiveness of paroxetine or interpersonal psychotherapy in 125 patients aged 69 years or older, no difference was found in the proportion responding to treatment or in the time to response, between patients with or without anxiety.41
Although outside the scope of this review, it is worth noting that the adverse effects of comorbidity are also seen among patients with primary anxiety disorders. For example, a recent evaluation of clinical outcomes at 1 year following cognitive behavioral therapy in outpatients with panic disorder, with or without agoraphobia, found that the presence of comorbid mood disorders was associated with lower response rates and a reduction in the proportion entering symptomatic remission.42
Comorbidity of major depressive disorder with anxiety disorders has also been associated with a reduced likelihood of achieving symptomatic remission with antidepressant treatments. The findings of STAR*D, sequential treatment of 2876 depressed patients, found that the presence of a comorbid anxiety disorder at baseline was associated with significantly lower rates of achieving symptomatic remission during the initial intervention (with the SSRI, citalopram).43 However, as with studies of overall treatment response, not all evidence is consistent: for example, an evaluation of the effects of comorbid anxiety disorders on response to treatment with the SSRI fluoxetine in 329 patients with DSM-IV– defined major depressive disorder, found no major adverse effects of comorbidity on the likelihood of achieving symptomatic remission.44
Lower response rates and reduced likelihood of achieving symptom remission are factors that may lead to a greater perceived need to utilize antidepressant drugs, and to the concomitant use of two or more antidepressant or other psychotropic drugs, in an attempt to improve outcomes. Data from the recent Canadian Community Health Survey on Mental Health and Well-Being show that the comorbidity of major depressive disorder with anxiety disorders is associated with somewhat higher rates of use of antidepressant drugs than that seen for major depressive disorder alone.45

The need for studies in patients with comorbid mood and anxiety disorders

The presence of comorbid depressive disorders is usually regarded as an exclusion criterion in randomized placebo-controlled trials of antidepressants in patients with primary anxiety disorders, where proof of efficacy requires the demonstration that anxiety symptoms do not resolve indirectly, mediated by an effect on depression. In addition, depressed patients with comorbid anxiety disorders are often excluded from participating in studies with new antidepressant treatments, perhaps because the presence of significant anxiety symptoms may reduce response rates, and thereby impede the chance to distinguish antidepressant from placebo effects. However, comorbidity is the rule in clinical practice, and it is helpful to know whether a single medication can diminish the severity of both anxiety and depressive symptoms in patients with comorbid conditions. However, there are relatively few studies that have specifically focused on investigation of the treatment response in comorbid patients.
An investigation of the effectiveness of open treatment with the SSRI fluoxetine (20 mg/day) in 123 US outpatients with major depressive disorder and at least one comorbid anxiety disorder, both defined according to DSM-III-R criteria, found that it reduced depressive symptom severity between baseline and study end point: however, patients with depression and comorbid obsessive-compulsive disorder were significantly less likely to respond to treatment than patients with other comorbid anxiety disorders.46 A subsequent open but controlled comparison of paroxetine (20-40 mg/day) with moclobemide (a reversible inhibitor of monoamine oxidase A) at a dosage of 300-600 mg/day in 123 Italian outpatients with DSM-III-R–defined major depressive disorder or dysthymia and comorbid anxiety disorder found no significant difference in overall response between the two antidepressants: however paroxetine was superior to moclobemide in the subgroup of 32 patients with comorbid panic disorder.47
The open design and lack of placebo control in these investigations together prevent definitive conclusions being drawn about the potential efficacy of certain antidepressant treatments in comorbid patients. A randomized double-blind comparatorcontrolled trial of sertraline (50-100 mg/day) and imipramine (100-200 mg/day) in patients with comorbid major depressive disorder and panic disor- der found no differences between treatments in the reduction of depressive and panic symptom severity, treatment outcome being concordant for both diagnoses in approximately 70% of patients.48 Again, the absence of a placebo control hinders definitive conclusions, and there is a persistent need for large multicenter studies in patients with comorbid mood and anxiety disorders, that employ a placebo-controlled design.

Conclusions

Anxiety symptoms are integral to major depressive episodes, and many patients with major depressive disorder will have prominent anxiety symptoms: furthermore, a significant proportion of depressed patients will show either lifetime or concurrent comorbidity for anxiety disorders. In general terms, the presence of comorbid anxiety disorders is associated with a greater severity of symptoms and more pronounced symptom-related disability and impairment, with a less favorable outcome, greater risk of symptom persistence, recurrence, and possibly suicide, and a less satisfactory response to antidepressant treatment. It is also associated with lower rates of recovery and a reduced likelihood of achieving symptomatic remission. There is a clear need for further randomized controlled trials in patients with comorbid mood and anxiety disorders, as this group comprises a probable majority of depressed individuals seen within routine clinical practice settings.

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IMPACT DES TROUBLES ANXIEUX COMORBIDES
SUR LA RÉMISSION DE LA DÉPRESSION
La coexistence de symptômes anxieux et de troubles anxieux comorbides est fréquente chez les patients atteints de troubles dépressifs majeurs (TDM). Cet article étudie trois aspects de la relation entre les TDM et les troubles anxieux comorbides : lorsque l’état comorbide est plus sévère que la dépression majeure « pure » ; lorsque l’évolution clinique de l’état comorbide est plus sévère que celle des TDM isolés ; et lorsque la réponse au traitement antidépresseur diffère entre les patients avec ou sans troubles anxieux comorbides associés. En général, même si les données ne sont pas toutes concordantes, la présence de troubles anxieux comorbides chez les patients atteints de TDM est associée à une plus grande sévérité des symptômes et à une atteinte plus prononcée. L’évolution de la maladie est moins favorable chez les patients atteints de comorbidité et un plus petit nombre d’entre eux répondent au traitement antidépresseur et obtiennent une rémission de leurs symptômes. Des études randomisées contrôlées contre placebo sont nécessaires chez les patients souffrant de TDM et de troubles anxieux comorbides afin de déterminer si ces derniers diffèrent de ceux souffrant de dépression majeure « pure » dans la réponse aux traitements pharmacologiques et psychologiques.