Treatment-Resistant Depression

Treatment-Resistant Depression

Approximately 32 to 35 million adults in the United States have an episode of major depression sometime during their lifetime, and many of them do not respond to initial treatment.1 The results of an analysis undertaken by Fava and Davidson2 suggest that between 29% and 46% of depressed patients fail to respond fully to antidepressant treatment of adequate dose and duration; about 15% of patients fail to respond to multiple treatment trials.3 Fagiolini and Kupfer4 have suggested that patients with treatment-resistant depression (TRD) may represent a biologically unique subtype of depressed patients. Unfortunately, the chances for full recovery diminish the longer a patient remains depressed—a fact that lends a sense of urgency for appropriate therapy.5


Before discussing the effectiveness of individual agents in TRD, it is important to review recent evidence regarding the principles of using these agents to maximize the chance of a response.6-9 Some of the most salient findings from the STAR*D trial on this topic are summarized in Table 1.

The standard strategy for managing patients who are depressed includes an adequate clinical trial; when the response is unsatisfactory, the clinician’s options are:

• Switch to another antidepressant

• Combine a second antidepressant with the first

• Add a second drug that is not approved as an antidepressant

• Start psychotherapy

Click to EnlargeAntidepressants can be grouped into 6 major categories: tricyclic antidepressants (TCAs), SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), serotonin neurotransmitter (5-HT2)-receptor antagonists (eg, nefazodone, trazodone), and novel agents (eg, mirtazapine, bupropion). If a patient fails to respond to one antidepressant class, it makes sense (at least conceptually) to switch to another, although most guidelines acknowledge that 2 failed trials of SSRIs may be justifiable before switching classes.7,8 When examining switching studies, be certain that the reason for switching was a failure to respond to an adequate antidepressant trial rather than a lack of tolerability, as these are fundamentally different issues.


The concept of switching classes of antidepressants is only as valid as the theoretical basis by which the antidepressants are grouped. As noted, some treatment guidelines allow 2 SSRI trials before switching classes. For example, in a study by Thase and colleagues,10 58 patients failed

a trial of fluoxetine; however, there was a 76% response rate to citalopram among completers. Although this study was not blinded, it is interesting that citalopram (which is believed to be the most selective of the SSRIs) was effective when another SSRI was not. It is hoped that as our knowledge of the mechanism of action of antidepressants grows more sophisticated, methods of classifying these agents will evolve to better guide clinicians in switching and combination strategies.

The clinical trial data on switching are surprisingly sparse—a recent meta-analysis identified only 4 randomized controlled trials.11 These trials include data from level 2 of the STAR*D study in which patients who were switched from citalopram to sertraline, venlafaxine XR, or bupropion SR showed remission rates of 27%, 25%, and 26% (respectively) based on the Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR-16).12 The meta-analysis found a modest but statistically significant advantage in switching from SSRIs to non-SSRIs. Of the 5 comparisons, 3 used venlafaxine, which is predominately a serotonergic agent (the serotonin-norepinephrine Ki ratio is 30), although it is classified as an SNRI. This may account for the relative lack of separation. One wonders if duloxetine, with a Ki ratio of 9 and relatively greater noradrenergic potency, might show greater separation.13 However, only one open-label switching study with duloxetine has been published to date.14

In switching antidepressants, 2 pharmacokinetic issues are important:

• Drugs with potent cytochrome P-450 (CYP450) effects—particularly fluoxetine (because of its long half-life)—may produce toxic levels of medications taken concurrently, such as TCAs that are also metabolized by these systems. (This effect is even more of an issue with combinations.)

• Antidepressants that are associated with discontinuation symptoms (eg, paroxetine, venlafaxine, duloxetine) may produce discontinuation syndromes when stopped that can be erroneously attributed to adverse effects of the new drug, particularly if the new drug does not possess a significant degree of serotonin reuptake inhibition.


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