Common Augmentation Strategies for Depression: Findings Show Lack of Evidence

Safety was rarely the focus of these studies; most emphasized efficacy issues. We attempted to evaluate the quality of the presentation of the safety data when available. Of the 22 studies, 3 had no safety data, 8 had a safety section, 3 had a comparison with a placebo group, 16 had safety statistics, and 17 had a description of the adverse effects or events (some studies fit more than one of these categories).

It is important to specifically mention the STAR*D study, a large trial that included some augmentations.⁶ The STAR*D was a practical effectiveness trial that had no placebo comparisons. In the trial, patients whose depression had failed to respond to citalopram and who agreed to be randomized to augmentation strategies received either 12 weeks of bupropion or buspirone added to citalopram in phase 2 of the trial. Such augmentation resulted in up to 39% remission, with a subsequent relapse rate of up to 67%.⁷

Subsequent augmentations in the STAR*D study had even lower remission and higher relapse rates. Without a placebo comparison, the interpretation of these results is difficult. It could be argued that any further response was positive among patients who had failed to respond to prior trials. However, one might also consider these results disappointing and conclude that they reflect an unfavorable risk-benefit ratio, given that about 4% of patients experienced a serious adverse event from the first augmentation and that about 13% had to discontinue participation because of intolerance of adverse effects.

In the modern era of evidence-based medicine, augmentation should ideally be guided by existing evidence. Researchers have noted a lack of studies to guide the sequence of augmentation strategies and the identification of patients for whom specific strategies might be most helpful.^8,9 The data summarized here show that more than 40% of the most popular classes of augmentation strategies and more than 55% of the most frequently prescribed combinations of drugs used for augmentation for unipolar depression have no published scientific support. In addition, placebo-controlled comparisons are rare. Statements about safety and efficacy for almost all the most commonly used augmentation strategies appear to be premature. The strategy with the most scientific support (ie, lithium augmentation) is relatively rarely used.

Many of these medications have been available for 2 decades, yet data on the most common augmentation strategies continue to be extremely limited. The recent publication of a major augmentation study on bipolar patients offers some hope that the science of drug augmentation is beginning to evolve.¹⁰ For now, it may be prudent for clinicians and patients to consider the sparse scientific data supporting most augmentation strategies when deciding whether to augment antidepressants. A clinical approach geared to "first do no harm" would suggest that most common augmentation strategies be used judiciously until there are more data to support the practice. It will be important to conduct future scientific studies of efficacy and safety in order to understand the risk of unknown harm for augmentation treatment strategies of unknown benefit.