STAR*D

STAR*D confirmed prior evidence that only about one-third of patients achieve remission with an initial antidepressant.24 Patients who did not achieve remission after a trial of an initial antidepressant had about a 30% chance of achieving remission after switching to another agent. When a patient did not respond to an SSRI (in this case, citalopram), it was shown that the common practice of augmenting with bupropion, and the less common practice of augmenting with buspirone, were both equally effective (30% remission rates), although bupropion was somewhat better tolerated.25 Combination therapy was slightly more effective than switching to a different agent. Patients who switched agents were as likely to respond to another SSRI (sertraline) as they were to agents from other medication classes (bupropion or venlafaxine), with all 3 drugs achieving remission rates between 18% and 24%.26

In patients who did not respond to this second stage of treatment, each successive step was significantly less likely to bring them to remission. This lower rate of remission past the second step of treatment most likely indicates a more refractory underlying disorder; it may also be that after several different treatment steps, the “nonpharmacological” benefits (otherwise known as placebo) such as attention, reassurance, and education, are less likely to be beneficial.27

The augmentation strategy with the best evidence base is the addition of lithium, yet it is the least used.7,28 STAR*D compared lithium with T3 in patients in whom 2 prior levels of treatment had failed and confirmed that lithium can be a useful agent; it helped achieve remission in 16% of patients with refractory depression, although many found it difficult to tolerate. T3 augmentation fared a little better (23% remission rate). This difference was not statistically significant, although T3 was associated with fewer adverse effects.29 These results were similar to those for patients who were switched to either nortriptyline or mirtazapine; the remission rate for both was less than 20%.30

Although STAR*D data suggest that combining medications may be slightly more effective than switching, these differences were not robust. It remains to be answered if and when it is better to add or switch medications in a patient who has not achieved remission after an initial trial of monotherapy. It is not clear how many antidepressants should be tried before polypharmacy is considered or how long a drug combination should be continued. It is also unclear whether certain augmenting agents work dramatically when successful but have lower overall response rates than other agents.31

 

Conclusion

STAR*D showed that although it may be difficult, it is important to achieve full symptom remission in patients with depression; remission has been shown to have a lower rate of relapse than simple treatment response. In those patients for whom more treatment steps were required to achieve remission, relapse rates were higher.32

We should use the available evidence to guide treatment as much as possible, but for now, clinicians can expect to find many situations in which unvalidated trial and error will be a necessary part of the armamentarium. Although polypharmacy may help improve depression in many patients with treatment-refractory symptoms, it should be used with care, and both risks and expenses need to be considered.

Even with sequential monotherapies and polypharmacy, it may be that fewer than 50% of patients achieve a state of sustained remission.26 Each successive treatment failure reduces the likelihood of future success and an attitude of humility and compassion remains a useful element in the treatment of refractory depression.

Drugs Mentioned in This Article
Bupropion (Wellbutrin, Zyban)
Buspirone (BuSpar)
Citalopram (Celexa)
Liothyronine (Cytomel)
Lithium (Eskalith, Lithobid)
Mirtazapine (Remeron)
Nortriptyline (Aventyl, Pamelor)
Trazodone (Desyrel)
Sertraline (Zoloft)
Sildenafil (Viagra)
Venlafaxine (Effexor)
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