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.