The treatment of unipolar major depression presents a substantial challenge for the clinician. Major depression is a common disorder1 with a high propensity for relapse and recurrence.2 In addition, it is increasingly evident that antidepressant treatment offers moderate benefits and that sequential treatments are invariably required to obtain a satisfactory therapeutic effect.
Recent research findings confirm earlier observations that about 50% of patients with major depression respond to an adequate antidepressant trial, and far fewer, about one third, will achieve full remission.3,4 Moreover, if a patient fails to respond to 2 sequential antidepressant trials, remission rates are alarmingly low, approximately 10% to 15% with yet a third antidepressant.5 Remission is the goal of antidepressant therapy, yet it is estimated that first antidepressant trials (usually with an SSRI) fail in more than one half to two thirds of patients, requiring further therapeutic intervention. There are several options available for such patients; these are outlined in Table 1.
Treatment options after failure to
achieve remission with a first SSRI
|Switch to a second antidepressant|
|Augmentation of the SSRI
|Combination of initial SSRI and a second antidepressant of another class|
|Switch to or add somatic therapies
Rapid transcranial magnetic stimulation
|Addition of specific psychotherapy|
While there is limited clinical trial evidence for the efficacy of these options, few have undergone rigorous randomized, controlled trials. Furthermore, there are few data on the comparable efficacy of these various options. For example, a recent report from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial showed no significant difference in remission rates when either bupropion or buspirone was given to patients who failed to respond to or could not tolerate a trial of the SSRI citalopram.6
Nonetheless, a recent survey of a large Veterans Administration (VA) mental health population found that when an antidepressant produced an incomplete response, a second antidepressant or a second-generation antipsychotic were the most common drugs added to the regimen.7 Given the extremely limited data on the efficacy of both of those options, the findings are surprising and they underscore the need for a critical evaluation of the current clinical approach to treatment-resistant depression.
In the VA study, only one half of one percent of subjects received lithium augmentation despite the general acknowledgement that lithium has the strongest evidence to support its efficacy as an antidepressant augmentation agent.7 This article will focus narrowly on augmentation strategies and their utility as treatment options for refractory depression.
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