Examining Anxious Depression: Differences in Course and Outcomes

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Results of numerous studies indicate that patients with comorbid major depressive disorder and anxiety generally have worse course trajectories and outcomes.
Results of numerous studies indicate that patients with comorbid major depressive disorder and anxiety generally have worse course trajectories and outcomes.

Although anxiety commonly co-occurs with depression, findings on the topic vary across studies because of differing definitions and terms used to describe the concept. For example, various definitions of "anxious depression" have appeared in recent research: major depressive disorder (MDD) with a comorbid anxiety disorder, MDD with anxiety symptoms, and MDD with the anxious distress specifier, as introduced in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). Such variability impedes clear comparisons between observations.

Previous results have linked anxious depression to greater depression severity, reduced treatment response, elevated risk for suicide, and higher risk for cardiovascular disease.1 These findings highlight the importance of elucidating issues pertaining to anxious depression.

To that end, researchers at VU University Medical Center Amsterdam conducted a review of literature exploring the "impact of anxious depression on clinical course trajectories and outcomes, treatment outcomes, and...underlying neurobiological dysregulations."2 When possible, they paid "attention to whether findings [depended] on the various definitions and methods used to classify anxious depression."

Prevalence and Temporal Order

The review revealed high prevalence rates of anxious depression (42%-78%), regardless of the definition and assessment tools used in each study. For example, in a 2015 study of 74,045 adults across 24 countries, at least 46% of participants with lifetime MDD were found to have at least 1 lifetime anxiety disorder.3 In an investigation involving 667 psychiatric outpatients with MDD, the prevalence rate of comorbid generalized anxiety disorder (GAD) was 72%.4 In multiple studies that used the DSM-5 anxious distress specifier, anxious distress was observed in 54% to 78% of patients with MDD.

In addition, several studies have shown that the onset of a first anxiety disorder often preceded the onset of MDD in those with both types of disorders, which suggests that "a temporal priority of anxiety disorders may contribute to the development of depression." In the 2015 study mentioned here, MDD onset followed anxiety onset in 68% of cases, whereas the onset followed MDD onset in 13.5% of cases. In 18.5% of patients, the onset of both disorders was concurrent.3

Effect on Illness Course and Outcomes

Results of numerous studies indicate that patients with comorbid MDD and anxiety generally have worse course trajectories and outcomes, including greater depression severity, lower remission rates, higher readmission rates, greater risk for suicide, lower social and occupational functioning, and increased rates of comorbid health problems including hypertension, asthma, and diabetes.5

In a study published in 2017 in the Journal of Psychiatric Research, comorbid DSM-based anxious distress, but not DSM-IV-based anxiety disorders, was found to predict poor treatment response and more frequent adverse effects in patients with MDD.6 A large review conducted in 2014 (before data regarding the DSM-5 anxious distress specifier were available) reported similar findings for dimensionally defined anxious depression.7 Of note, the 5-item anxious distress specifier has been shown to "adequately predict course and treatment outcomes, making it a potential quick and easy-to-use indicator to select the subgroup of anxious depression patients in need of novel or more intensive treatment and follow-up," according to the present review.

Findings regarding comorbid depression and specific anxiety disorders have been mixed. In 1 study, patients with MDD noted a poorer treatment response in those with comorbid GAD vs panic disorder, whereas other results demonstrate a greater risk for medication-adverse effects in patients with MDD with comorbid panic disorder but not GAD or social anxiety disorder.5,8

Mixed findings were observed for specific comorbid anxiety disorders with respect to treatment response. For instance, a recent naturalistic study across 8 European countries conducted among 1346 patients with MDD showed that those with a comorbid GAD showed poorer treatment response to antidepressant medication compared with those with comorbid panic disorder.5 Another recent study reported a higher likelihood of experiencing antidepressant adverse effects in MDD cases with comorbid panic disorder vs those without, but not in those with comorbid SAD or GAD.8 Research is needed to determine whether patients with anxious depression could benefit from novel treatment strategies.

Neurobiological Differences and Next Steps

A range of studies have observed a distinct neurobiological profile in patients with anxious depression compared with patients with nonanxious depression. Alterations in white blood cell counts suggest altered immune functioning and implicate inflammation as a potential mechanism in anxious depression; dysregulation of the hypothalamic-pituitary-adrenal axis has also been found in such patients.

Other findings have linked anxious depression with more severe cortical thinning in the orbitofrontal and anterior cingulate cortex, insula, and temporal lobes compared with that seen in nonanxious depression.9 Differences in functional connectivity between brain regions has further been demonstrated between the 2 types of patients. "Of note, the [anterior cingulate cortex], insula and other regions structurally and functionally implicated in anxious depression, also play a role in predicting depression course and treatment outcome," the authors explained.10 "Thus, the deficits observed in these regions may be linked to the more severe affective and cognitive symptoms and the more disadvantageous clinical outcomes observed in anxious depression."

Overall, these results show that anxious depression is common and may influence clinical outcomes and the neurobiological profile of patients. Future research in this area should explore which specific features of anxiety underlie these associations. "This may help to identify specific neurobiological targets that can contribute to the improvement of treatments for anxious depressed patients," the authors concluded.

References

  1. Almas A, Forsell Y, Iqbal R, Janszky I, Moller J. Severity of depression, anxious distress and the risk of cardiovascular disease in a Swedish population-based cohort. PLoS One. 2015;10(10):e0140742.
  2. Gaspersz R, Nawijn L, Lamers F, Penninx BWJH. Patients with anxious depression: overview of prevalence, pathophysiology and impact on course and treatment outcome. Curr Opin Psychiatry. 2018;31(1):17-25.
  3. Kessler RC, Sampson NA, Berglund P, et al. Anxious and non-anxious major depressive disorder in the World Health Organization World Mental Health Surveys. Epidemiol Psychiatr Sci. 2015; 24(3):210-226.
  4. Zhou Y, Cao Z, Yang M, et al. Comorbid generalized anxiety disorder and its association with quality of life in patients with major depressive disorder. Sci Rep. 2017; 7:40511.
  5. Dold M, Bartova L, Souery D, et al. Clinical characteristics and treatment outcomes of patients with major depressive disorder and comorbid anxiety disorders: results from a European multicenter study. J Psychiatr Res. 2017;91:1-13.
  6. Gaspersz R, Lamers F, Kent JM, et al. Anxious distress predicts subsequent treatment outcome and side effects in depressed patients starting antidepressant treatment. J Psychiatr Res. 2017;84:41-48.
  7. Ionescu DF, Niciu MJ, Richards EM, Zarate CA Jr. Pharmacologic treatment of dimensional anxious depression: a review. Prim Care Companion CNS Disord. 2014;16(3):PCC.13r01621.
  8. Shankman SA, Gorka SM, Katz AC, et al. Side effects to antidepressant treatment in patients with depression and comorbid panic disorder. J Clin Psychiatry. 2017;78(4):433-440.
  9. Zhao K, Liu H, Yan R, et al. Cortical thickness and subcortical structure volume abnormalities in patients with major depression with and without anxious symptoms. Brain Behav. 2017;7(8):e00754.
  10. Fu CH, Steiner H, Costafreda SG. Predictive neural biomarkers of clinical response in depression: a meta-analysis of functional and structural neuroimaging studies of pharmacological and psychological therapies. Neurobiol Dis. 2013;52:75-83. 
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