Comorbidity in Generalized Anxiety Disorder

      Comorbidity in generalized anxiety disorder (GAD) is a subject of increasing theoretic and practical importance. Because comorbid disorders are especially common among persons with GAD, some investigators have questioned whether this is an independent disorder or a prodrome, residual, or severity marker for other anxiety or depressive disorders.
      • Brown T.A.
      • Barlow D.H.
      • Liebowitz M.R.
      The empirical basis of generalized anxiety disorder.
      • Kessler R.C.
      • Du Pont R.L.
      • Berglund P.
      • et al.
      Impairment in pure and comorbid generalized anxiety disorder and major depression at 12 months in two national surveys.
      Pure GAD exists in a significant minority of persons, however, so there is a basis for retaining the category. Rates of comorbidity are especially high for other anxiety disorders, such as panic disorder, and depressive disorders, such as dysthymia and major depressive disorder (MDD).
      • Wittchen H.U.
      • Zhao S.
      • Kessler R.C.
      • et al.
      DSM-III-R generalized anxiety disorder in the National Comorbidity Survey.
      Such a pattern suggests that these co-occurring disorders are somehow related to GAD and that understanding these relationships may increase clinicians' knowledge of cause and classification.
      • Maser J.D.
      Generalized anxiety disorder and its comorbidities: Disputes at the boundaries.
      Also, because patients with comorbidity seem to respond less well to treatment and have a worse outcome, treatment planning must take coexisting disorders into account.
      • Brown T.A.
      • Barlow D.H.
      Comorbidity among anxiety disorders: Implications for treatment and DSM-IV.
      This article reviews data concerning these issues, but first, several comments about the definition and meaning of comorbidity are needed.
      Feinstein
      • Feinstein A.R.
      The pre-therapeutic classification of co-morbidity in chronic disease.
      first used the term comorbidity to refer to patients with co-occurring medical illness. Since the removal of hierarchical rules from the DSM-III-R, extensive comorbidity among psychiatric disorders has been documented.
      • Kessler R.C.
      The prevalence of psychiatric comorbidity.
      Among psychiatric patients, half have more than one current diagnosis, and among persons in the general population, half of those with a lifetime disorder have another diagnosis as well.
      • Kessler R.C.
      • McGonagle K.A.
      • Zhao S.
      • et al.
      Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: Results from the National Comorbidity Survey.
      Such comorbidity has research and clinical implications. To begin with, high rates of co-occurrence may mean that diagnostic categories are poorly defined.
      • Blashfield R.K.
      Comorbidity and classification.
      Also, relationships between categories and other variables may be caused by comorbidity which then must be taken into account. Also, extensive comorbidity may provide clues to causal relationships, and, finally, comorbid conditions may influence treatment response and outcome.
      • Kent J.M.
      • Gorman J.M.
      Drug treatment of anxiety disorders with comorbidity.
      The classification system influences rates of comorbidity in several ways. For instance, the splitting rather than lumping of disorders tends to increase rates of comorbidity.
      • Frances A.
      • Widiger T.
      • Fyer M.R.
      The influence of classification methods on comorbidity.
      Thus, dividing anxiety neurosis (DSM-II) into panic disorder and GAD (DSM-III) results in many patients with both disorders. Diagnostic thresholds also influence comorbidity rates. As thresholds are lowered, the prevalence of a disorder increases and the rates of comorbidity decrease. For example, Breslau and Davis
      • Breslau N.
      • Davis G.C.
      DSM-III generalized anxiety disorder: An empirical investigation of more stringent criteria.
      observed that, when stricter criteria were applied, the prevalence of GAD in a sample of women decreased from 45% to 9%, and the prevalence of coexisting depression increased. Eliminating hierarchical exclusionary rules dramatically increases comorbidity.
      • Blashfield R.K.
      Comorbidity and classification.
      In the DSM-III, GAD was a residual category, but in the DSM-III-R, the disorder achieved independent status, making it one of the most prevalent of all disorders.
      There are several reasons why two or more disorders may occur in one individual, and these must be kept in mind in evaluating studies. Klein and Riso identified 11 possible explanations
      From Klein DN, Riso LP: Psychiatric disorders: Problems of boundaries and comorbidity. In Costello CG (ed): Basic Issues in Psychopathology. New York, Guilford, 1994, pp 19–66; with permission.
      *From Klein DN, Riso LP: Psychiatric disorders: Problems of boundaries and comorbidity. In Costello CG (ed): Basic Issues in Psychopathology. New York, Guilford, 1994, pp 19–66; with permission.
      :
      • Explanations based on sampling and base rates
        • 1. Comorbidity due to chance
        • 2. Comorbidity due to sampling bias
        • 3. Comorbidity due to population stratification
      • Explanations based on artifacts of diagnostic criteria
        • 4. Comorbidity due to overlapping criteria
        • 5. Comorbidity due to one disorder encompassing the other
      • Explanations based on drawing boundaries in the wrong places
        • 6. Multiformity
        • 7. Heterogeneity of the comorbid condition
        • 8. The comorbid condition is a third, independent disorder
        • 9. The pure and comorbid conditions are different phases or alternative expressions of the same disorder
      • Explanations based on etiological relationships
        • 10. One disorder is a risk factor for the other
        • 11. The two disorders arise from overlapping etiologic processes
      Several of these explanations are especially relevant to GAD. For instance, symptoms that overlap with dysthymia and MDD, such as worry, poor concentration, and sleep difficulty, contribute to artifactual comorbidity (model 4). Also, GAD may be a secondary manifestation of a more pervasive condition in the context of panic disorder (model 5). According to model 9, pure and comorbid conditions are merely different phases of the same disorder. Evidence that GAD may be a prodromal or residual form of panic disorder in some instances fits this model.
      • Fava G.A.
      • Grandi S.
      • Rafanelli C.
      • et al.
      Prodromal symptoms in panic disorder with agoraphobia: A replication study.
      The final explanatory models are based on causal relationships. Thus, one disorder might be a risk factor for another. Some investigators have suggested, for example, that GAD is a personality vulnerability for other disorders.
      • Brown T.A.
      • Barlow D.H.
      • Liebowitz M.R.
      The empirical basis of generalized anxiety disorder.
      • Sanderson W.C.
      • Wetzler S.
      Chronic anxiety and generalized anxiety disorder: Issues in comorbidity.
      An alternative model views comorbid conditions as having a common cause. For instance, evidence shows that GAD and MDD have a shared genetic diathesis.
      • Kendler K.S.
      • Neale M.C.
      • Kessler R.C.
      • et al.
      Major depression and generalized anxiety disorder: Same genes, (partly) different environments?.
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