Anxiety disorders are common in depressed patients. Several studies of the full range of Diagnostic and Statistical Manual of Mental

Disorders-defined anxiety disorders in depressed psychiatric outpatients each found that when diagnoses are based on semi-structured diagnostic interviews >40% of the patients had a comorbid anxiety disorder. The recognition of comorbidity is not simply of academic interest, but it has important clinical significance. Epidemiological studies, such as the National Comorbidity Study, have demonstrated that depressed individuals with a history of anxiety disorders are at increased risk for hospitalization, suicide attempt, and greater impairment from the depression. The co-occurrence of anxiety disorders in depressed patients has been associated with a more chronic course of depression in psychiatric patients, primary care patients, and epidemiological samples. Recent research has suggested that clinicians underrecognize anxiety disorder comorbidity in depressed patients. The clinical significance of this underrecognition is highlighted by the finding that patients often want treatment to address their anxiety disorder comorbidity. When anxiety disorders are detected they often influence clinicians' selection of antidepressant medication, though some of clinicians' prescribing biases are not supported by empirical data.

In this monograph, Iwona Chelminski, PhD, reviews the significance of anxiety in patients with depression as well as diagnostic instruments for recognizing this comorbidity. Next, Mark Zimmerman, MD, addresses the factors that affect the clinician's choice of antidepressant, focusing on the influence of comorbid anxiety. Finally, Sidney Zisook, MD, discusses the differential efficacy of antidepressants as well as the role of psychotherapy in patients with comorbid anxiety and depression.

There is considerable symptom overlap and high levels of comorbidity between anxiety disorders and depression. The recognition of this comorbidity has both academic interest and clinical significance. Epidemiological studies have demonstrated that depressed individuals with a history of anxiety disorders are at increased risk for hospitalization, suicide attempt, and greater impairment from the depression. These individuals also tend to have a more chronic course of depression, as observed in psychiatric patients, primary care patients, and epidemiological samples. Van Valkenberg and colleagues reported that depressed patients with anxiety had poorer outcome and greater psychosocial impairment than those without an anxiety disorder. In the National Institute of Mental Health Collaborative Depression Study, the presence of panic attacks predicted a lower rate of recovery during the first 2 years of the follow-up interval. Similarly, Grunhaus found poorer outcome in depressed patients with comorbid panic disorder than in depressed patients without panic. In an 8-month follow-up study, depressed primary care patients with a history of generalized anxiety disorder (GAD) or panic disorder were less likely to have recovered from their depressive episode.

Gaynes and colleagues prospectively followed primary care patients with major depressive disorder (MDD) every 3 months for 1 year after their initial diagnostic evaluation. At baseline, half of the original 85 patients had a coexisting anxiety disorder, the most frequent being social phobia (n=38). Twelve months after intake, 68 of the patients were available for the final interview. Those with a comorbid anxiety disorder were significantly more likely to still be in an episode of depression (82% vs 57%; risk ratio=1.44; 95% CI 1.02-2.04), and they experienced more disability days during the course of the 12 months than the depressed patients without an anxiety disorder (67.1 days vs 27.5 days).

Although there is a wide array of choices of antidepressants, there is little empirical evidence to guide clinicians in their selection. Most reviews of the antidepressant literature, including the American Psychiatric Association's (APA) Practice Guideline for the Treatment of Major Depressive Disorder, conclude that these medications are generally equally effective. Consistent with this, a recent metaanalysis of studies comparing two or more new-generation antidepressants found little evidence that any medication was superior to the others. Although the APA guideline suggests that the choice of antidepressant be based principally on side effects, tolerability, patient preference, and cost, it also reviewed evidence of differential treatment response related to patients' clinical profiles. For patients with nonpsychotic, nonbipolar major depressive disorder (MDD), the guideline indicated that the presence of anxiety symptoms, atypical features, melancholic subtype, symptom severity, and borderline personality disorder may be associated with differential response to antidepressants. Selective serotonin reuptake inhibitors (SSRIs) are recommended for high anxiety, SSRIs and clomipramine for obsessive-compulsive disorder (OCD) symptoms, tricyclic antidepressants (TCAs) for severe depression and melancholia, and SSRIs and monoamine oxidase inhibitors (MAOIs) for atypical depression.

What is most striking in the guideline's review is how limited in scope and utility are the data to guide the outpatient psychiatrist in selecting an antidepressant. Melancholia and severe depression are relatively infrequently encountered in the outpatient setting. The most common comorbidities in depressed outpatients are anxiety disorders, but the guideline simply says that bupropion may be anxiogenic and should be avoided, and that although MAOIs may work well in depressed patients with anxiety, other medications are preferred. It does not discuss the possible influence of specific comorbidities on antidepressant selection.