Non-random dropout and the relative efficacy of escitalopram and nortriptyline in treating major depressive disorder

Most comparisons of the efficacy of antidepressants have relied on the assumption that missing data are randomly distributed. Dropout rates differ between drugs, suggesting this assumption may not hold true. This paper examines the effect of non-random dropout on a comparison of two antidepressant drugs, escitalopram and nortriptyline, in the treatment of major depressive disorder. The GENDEP study followed adult patients with major depressive disorder over 12 weeks of treatment, and the primary analysis found no difference in efficacy of the two antidepressants under missing at random assumption. By applying the recently developed Muthén-Roy model, we compared the relative efficacy of these two antidepressants taking into account non-random distribution of missing outcomes (NMAR). Individuals who dropped out of the study were those who were not responding to treatment. Based on the best fitting NMAR model, it was found that escitalopram reduced symptom scores by an additional 1.4 points on the Montgomery-åsberg Depression Rating Scale (p = 0.02), equivalent to 5% of baseline depression severity, compared to nortriptyline. We conclude that association between dropout and worsening symptoms led to an overestimate of the effectiveness of treatment, especially with nortriptyline, in the primary analysis. These findings review the primary analysis of GENDEP and suggest that, when non-random dropout is accounted for, escitalopram is more effective than nortriptyline in reducing symptoms of major depression.