Anxious Depression and Response to Treatment

In this issue of the Journal, Fava and associates present data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study demonstrating that among 2,876 patients with major depression, those who were more anxious were less likely to respond and remit during citalopram treatment and were more likely to experience adverse events. Considering the magnitude of differences observed in recent placebo-controlled trials in depression and antidepressant comparison studies, the difference in response rates between anxious and nonanxious groups in the STAR*D sample—41.7% and 52.8%, respectively—is appreciable and an important finding.

In Level 2 of STAR*D, 1,292 patients who either had not remitted or were intolerant of citalopram switched to another antidepressant or received augmentation therapy. Again anxious patients were less responsive, and the difference in remission rates between the anxious and nonanxious patients was even greater. Level 2 included five different drug treatment options, but none was superior to any other for the anxious patients.

High levels of anxiety were also associated with significantly greater side effect frequency, intensity, and overall burden. A greater proportion of anxious than nonanxious patients discontinued treatment because of intolerance (19.2% and 14.6%, respectively). Serious adverse events and hospitalizations for general medical conditions were both more common in the anxious patients. Given the size of the STAR*D sample and the inclusion of both psychiatric and primary care sites, these data make a compelling case for the predictive value of anxiety.

The authors defined "anxious depression" according to a cutoff on the anxiety-somatization factor of the Hamilton Depression Rating Scale (HAM-D), and they compared this factor with other descriptors of anxiety. Anxious depression in all definitions was significantly associated with remission, but total score on the anxiety-somatization factor explained the highest proportion of the variance. Anxiety-somatization scores in the sample appeared to be normally distributed.

Clinicians may find the term "nonanxious" misleading. Most depressed patients report some anxiety even if it is not prominent.

Anxious depression is associated with other characteristics, which have been reported previously and in previous STAR*D publications. Anxious depression is associated with greater symptom severity, suicidality, and unemployment, less education, worse functioning, and poor prognosis.

Interest in anxious depression has a long history. In 1959, British psychiatrists West and Dally reported findings suggesting that iproniazid might be especially useful for these patients (1). Subsequently, two groups (2, 3) conducted studies comparing amitriptyline and phenelzine and obtained similar results; both drugs were effective, but phenelzine was slightly more effective for anxiety.

Studies of tricyclic antidepressants have had mixed results. I found 10 reports that included 24 clinical trials. In about one-third of the trials tricyclics were found to be less effective in anxious depression, and in two-thirds no difference was observed in the response of anxious and less anxious patients. For example, in a review of 14 trials with 788 patients and various tricyclics used as comparators, response rates were 62.7% and 62.1%, respectively, in anxious and less anxious patients (4). Anxious depression was defined in terms of various symptoms or based on the presence of panic disorder. Only two of the tricyclic trials were placebo controlled. (For a detailed review, see the data supplement that accompanies the online version of this editorial.)