This study was one of three classic NIMH-sponsored studies of the true of the 21st century, one each in MDD, bipolar illness, and schizophrenia. In the MDD study, called STAR*D, a sequential large randomized clinical trial (RCT) was conducted.
Before STAR*D, there were few RCTs comparing antidepressants to each other, and hardly any looking at outcomes after multiple failed trials.
The STAR*D protocol was as follows: First patients were treated openly with citalopram. If they failed to respond, they were then randomized double-blind to a different monoamine agonist or combination with two monoamine agonists (or other adjunctive agents like buspirone). If they failed this second trial, they were randomized to switching to tricyclic antidepressants (TCAs) or augmentation with lithium or thyroid hormone. If they failed this third trial, they were randomized to a MAOI or the combination of venlfaxine plus mirtazapine.
Response rates are shown in the figure, and further described in By the Numbers. As can be seen, treatment response was good in the first two episodes, but fell by half thereafter. By the fourth monoamine agonist trial, only 15% of subjects respond to any new treatments, even the most potent agents known, the MAOIs.
Figure 1. Summary of the STAR*D protocol's results. The overall cumulative response without later relapse reaches 40% while the overall cumulative long-term response without intolerable side effects is 28%.
Further, even if patients respond, about 40-70% relapse within one year even if they stay on the same agents which led to acute response.
Further if intolerable side effects are included, about 20-30% of patients could not remain on their monoamine agonist treatments due to severe side effects (more with the older agents than with newer ones).
In sum: The good news was that about 60-70% of patients responded eventually for the acute depressive episode, if multiple different agents were used.
The bad news was that this response fell off markedly after the first few trials, and, further, only about one-third stayed well for the long-term, defined as just a year of staying well.
Some researchers and clinicians have interpreted the STAR*D results in a manner similar to what is presented here. The STAR*D researchers themselves adamantly try to interpret their results in as positive a manner as possible.
The case remains, however, that before STAR*D much higher response rates were cited. After STAR*D, such optimism cannot be supported by this scientific evidence.