Estimates regarding the prevalence of treatment-resistant depression are available from several sources. Fava and Davidson9 reviewed 36 clinical trials (both open-label and placebo-controlled) of antidepressants for unipolar depression involving more than 3500 patients and reported that between 29% and 46% of patients failed to respond fully following a single antidepressant treatment. Corey-Lisle and colleagues10 reported that symptoms in approximately 22% of patients who received treatment for depression from their primary care physicians remitted following 6 months of treatment; 32% of the patients were partial responders, while 45% were nonresponders. Similarly, Rush and colleagues11 reported an 11% remission rate and a 26.3% response rate in outpatients with depression following 12 months of treatment in 1 of several public-sector community clinics. Finally, Petersen and colleagues7 reported a 50.4% remission rate in outpatients with major depressive disorder (MDD) enrolled in 1 of 2 depression specialty clinics.
Management of treatment-resistant depression
For patients who continue to experience symptoms of depression despite an optimal antidepressant trial, 2 general treatment strategies exist. The first strategy involves switching from one antidepressant to another. The second strategy, termed augmentation, involves adding an antidepressant or nonantidepressant agent to the treatment regimen. Despite the prevalence and consequences of TRD, and despite decades of clinical trials focusing on exploring effective and safe treatments for resistant depression, no gold-standard treatment or treatment consensus among experts has emerged, a fact largely due to the serious lack of positive results in double-blind placebo-controlled studies. In fact, the majority of double-blind augmentation studies conducted that focused on a handful of compounds have yielded discouraging results. Such adjunctive compounds have included (but were not limited to) lithium(Drug information on lithium),12 triiodothyronine,13 pindolol(Drug information on pindolol),14 and TCAs.12 In addition, small placebo-controlled studies that identify promising compounds for use as adjunctive treatment in TRD have often gone unreplicated.15-17
Even less is known regarding the relative efficacy of the various possible switching strategies (ie, from an SSRI to either an SSRI, a serotonin-norepinephrine reuptake inhibitor, a norepinephrine(Drug information on norepinephrine)-dopamine reuptake inhibitor, or vice versa). As a result, more often than not, clinicians' decisions regarding the treatment of resistant depression are guided by anecdotal reports, case series, uncontrolled trials or, at best, small and unreplicated double-blind studies. However, in light of the challenge TRD poses for clinicians and patients alike, identification of novel treatments for resistant depression is urgently needed to help further refine the standard of care for depression. In 2006, there were 2 major areas of interest regarding TRD: the STAR*D trial and the use of atypical antipsychotic agents as an adjunct to standard antidepressant treatment.
STAR*D is a multisite, prospective, randomized, multistep clinical trial of outpatients with nonpsychotic MDD. The study compared various treatment options for those who did not attain a satisfactory response with citalopram(Drug information on citalopram), an SSRI. The study enrolled 2876 adults with MDD (aged 18 to 75 years) from 18 primary care and 23 psychiatric practices. After receiving open-label citalopram (20 to 60 mg/d) for up to 14 weeks, participants without sufficient symptomatic benefit were eligible for randomization to level 2 treatments. Level 2 involved the use of 3 switch (sertraline, bupropion, venlafaxine) and 2 augmentation (bupropion, buspirone(Drug information on buspirone)) pharmacotherapies. Patients who did not experience sufficient symptomatic benefit were then eligible for random assignment to 2 switch (mirtazapine or nortriptyline(Drug information on nortriptyline)) or 2 augmentation (lithium or thyroid hormone) treatments in level 3. Finally, those without sufficient improvement at level 3 were eligible for random assignment to 1 of 2 switch options--tranylcypromine or the combination of mirtazapine(Drug information on mirtazapine) and venlafaxine. Figure 1 presents a summary of the 3 levels.
The primary outcome for the entire STAR*D trial was remission, defined as a 17-item Hamilton Depression Rating Scale (HDRS-17) score of less than 8 at study end point. To date, results have been published for level 1,18 level 2,19,20 and the switch options of level 321 (Figure 2). Overall HDRS-17 remission rates for level 1 were 28%. This result is highly informative, since it demonstrates that remission rates were similar between the STAR*D study sample, a highly generalizable sample with substantial Axis I and Axis III comorbidity, and patients typically enrolled in randomized clinical trials. The difference in remission rates between the level 2 augmentation treatments (bupropion and buspirone) was not statistically significant (29.7% vs 30.1%). However, fewer patients treated with adjunctive bupropion discontinued treatment because of intolerance than patients treated with adjunctive buspirone (12.5% vs 20.6%; P < .009), suggesting that while both treatment approaches appeared to be useful, there was an advantage for bupropion augmentation in terms of tolerability.
There were also no differences in remission rates between the level 2 switch treatments (24.8%, 21.3%, and 17.6% for venlafaxine, bupropion, and sertraline(Drug information on sertraline), respectively), suggesting that all 3 medications were a reasonable choice for patients with SSRI-resistant depression. Finally, there was no statistically significant difference in remission rates between level 3-treatment patients randomized to switch to either mirtazapine or the TCA nortriptyline (12.3% vs 19.8%, respectively). Notable in the level 3 study results were the very low remission rates obtained when patients who had failed to respond to 2 adequate treatments were switched to a third (fewer than 20% in both cases).
Although, to date, the STAR*D trial has failed to identify a treatment strategy that is clearly superior in terms of its overall efficacy and tolerability, the STAR*D database will allow clinicians to examine whether any of these tested treatments are particularly effective among specific subpopulations of patients with MDD (termed "MDD subtypes"), defined either by the presence (or absence) of clinical symptoms, syndromes, comorbid disorders, or genotype. Hypotheses generated from this invaluable database could then be tested prospectively in future randomized, double-blind, placebo-controlled trials.
Augmentation with atypical antipsychotic agents
Atypical antipsychotics are a heterogeneous group, each with a distinct and complex set of receptor affinities involving dopamine(Drug information on dopamine)rgic and serotonergic receptors as well as various effects on noradrenergic, histaminergic, and cholinergic systems. As a result, the receptor-binding profile of the atypical neuroleptics differs substantially from that of the typical antipsychotics. This difference may provide clinical advantages to the atypical antipsychotic agents in therapeutic areas other than schizophrenia.