In spite of the tremendous advances made in developing antidepressant treatments and exploring augmentation with second-generation antipsychotics (SGAs), significant obstacles remain for psychiatrists: How should clinicians make use of cutting-edge augmentation studies? How should they use the antipsychotics in their treatment algorithm? How should they think about dosing and side effects?

The first major problem is there have been no great algorithmic studies on adjunctive strategies. In fact, the most useful algorithmic study was the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, from which SGAs were entirely absent. The second problem is that STAR*D showed a clear pattern in which the efficacy of an augmentation agent depended on its placement in the algorithm. Those agents occurring later in the algorithm, such as monoamine oxidase inhibitors (MAOIs), adjunctive triiodothyronine (T3), and adjunctive lithium, appeared to be less effective than adjunctive buspirone, which occurred earlier in the algorithm. This was not the result of a direct comparison. Because of these two problems, it is therefore difficult to determine how to rank the efficacy of SGAs among the agents investigated by the STAR*D study. Among clinical treatment strategies, SGAs might appear toward the end of first-line strategies, perhaps after combinations and stimulants but before buspirone.