Recommendation. Measure symptoms at key decision points. If modest improvement (such as 20% reduction in baseline symptoms) is found at 4 to 6 weeks, continue treating another 4 to 6 weeks, increasing the dosage as tolerated.
Table
Simple system for staging antidepressant resistance
| Stage | Definition |
|---|---|
| I | Failure of at least one adequate trial of one major antidepressant class |
| II | Stage I resistance plus failure of an adequate trial of an antidepressant in a distinctly different class from that used in Stage I |
| III | Stage II resistance plus failure of an adequate trial of a tricyclic antidepressant |
| IV | Stage III resistance plus failure of an adequate trial of a monoamine oxidase inhibitor |
| V | Stage IV resistance plus failure of a course of bilateral electroconvulsive therapy |
| Source: Reprinted with permission from Thase ME, Rush AJ. When at first you don’t succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry 1997;58(suppl 13):24. | |
Treatment options
When initial antidepressant treatment fails to achieve an adequate response—as it does in more than onehalf of major depression cases—the next step is to add a second agent or switch to another agent.
Available evidence14 relies almost exclusively on open, uncontrolled trials, which do not provide definitive answers. Even so, these trials indicate that nonresponse (or nonremission) with one agent does not predict nonresponse/nonremission with another.
Switching strategies. When a selective serotonin reuptake inhibitor (SSRI) is the first treatment, several open trials reveal an approximately 50% response rate to a second SSRI. However, opentrial evidence and retrospective chart review reports also indicate that switching out of class (such as from an SSRI to bupropion) is also approximately 50% effective.15
Some post hoc analyses of acute 8-week trials indicate that the dual-action agent venlafaxine at higher dosages (up to 225 mg/d of venlafaxine XR) is associated with higher remission rates than the more-selective SSRIs.16,17 On the other hand, unpublished data indicate that escitalopram, 10 mg/d, and venlafaxine XR, up to 150 mg/d, did not differ in efficacy among outpatients treated by primary care physicians.18
On the other hand, sertraline and imipramine (a dual-action agent) were equally effective in a 12-week acute-phase trial.19 Furthermore, response and remission rates were similar when nonresponders in each group switched to the other antidepressant.20 This suggests that the dual-action agent (imipramine) was not more effective than the more selective agent (sertraline) in this population.
Well-controlled trials show that monoamine oxidase inhibitors (MAOIs) can be effective when tricyclic antidepressants (TCAs) are not. Switches among the TCAs are associated with a 30% response rate, whereas switching from a TCA to an MAOI typically results in a 50% response rate.21
Controlled prospective comparisons of two or more alternate switch or augment treatments are needed to establish comparative efficacy and tolerability.
Augmentation strategies may include lithium, buspirone, thyroid hormone (T3), stimulants, or atypical antipsychotics. Although head-to-head comparisons are rare, a randomized, controlled trial found that combining olanzapine (mean 50 mg/d), with fluoxetine (mean 15 mg/d) was more effective than each agent used alone.22
Risperidone augmentation is supported by open trials, as is the use of modafinil, other stimulants, and bupropion. An important unanswered question with most augmentation strategies is how long to continue them if they are successful.
Psychotherapy may also play a key role in augmenting medication’s effects. Keller et al23 found in chronically depressed outpatients that 12 weeks of nefazodone, up to 600 mg/d, plus cognitive behavioral analytic system psychotherapy (CBASP) produced higher response and remission rates compared with either treatment alone. A subsequent report24 found that 50% of nefa-zodone and CBASP monotherapy nonresponders did respond when switched to the alternate treatment.
Thus, CBASP may be useful at least in chronic depression to augment medication or as a “switch” to monotherapy if medication alone fails. Interestingly, Nemeroff et al25 found CBASP more effective than nefazodone for patients with chronic major depression who had a childhood history of parental loss or physical, sexual, or emotional abuse.
Antidepressant tachyphylaxis—commonly referred to as “poop-out”—is reported with all antidepressants. That is, even while apparently taking their medications for 6 to 18 months, some patients lose the antidepressant effect, such that some symptoms return or a full relapse/recurrence ensues. Mechanisms of this phenomenon are unknown.
Clinically, some believe that “poop out” is more common with SSRIs than with other antidepressant classes, but no long-term comparative data support or challenge this view. Treatment options include a dosage increase, dosage reduction (especially for long half-life SSRIs such as fluoxetine), or augmentation with the options noted above (such as bupropion, buspirone, etc.).
Benefit of using algorithms
Algorithms (such as the Texas Medication Algorithm Project26 ) have suggested multiple treatment steps for major depression after initial treatment fails, with several options available at each step. Using medication algorithms has been found more effective than treatment-as-usual in outpatients with major depressive disorder.27 No studies have compared different algorithms.