Treatment-Resistant Unipolar Depression

Treatment-Resistant Unipolar Depression

Definition
Systematic integration of available data on clinical management is hampered by multiple definitions of treatment-resistant depression. It would appear that the first step to optimize treatment outcomes requires only to have patients exposed to adequate doses of antidepressants for adequate periods of time. But the specifics of the recommendation are more complex. What is an adequate dose, and how long is an adequate duration of an antidepressant trial? These issues are discussed in more detail later in this chapter.

Reasonable data correlate response with blood levels of imipramine, desipramine, amitriptyline, and nortriptyline but not the other tricyclic antidepressants (TCAs): clomipramine, trimipramine, protriptyline, doxepin. In the face of nonresponse, it is useful to check blood levels for those antidepressants with established dose-response relationships.

Data for the average patient with moderate depression, however, suggest an overall flat dose-response relationship for the specific selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, sertraline, paroxetine, citalopram, and fluvoxamine), making it difficult to know from randomized clinical trials how and when (if ever) to increase these widely prescribed agents. In contrast, in one study it was found that the majority of patients who did not respond after 8 weeks of fluoxetine at a fixed dose of 20 mg responded when the dosage was increased to 40 mg. Bupropion appears to be equally effective at 150 mg or 300 mg daily. Dose-response relationships are less clear with nefazodone and mirtazapine, whereas a dose-response relationship has been found for venlafaxine. A reasonable range of minimal doses has been recommended in treatment guidelines (Depression Guideline Panel 1993). A comprehensive method to organize a complex treatment history has been proposed and validated. To ensure an adequate trial, patients should at least be exposed to the minimally effective tolerated antidepressant dose.

The definition of adequate duration is more complex than the definition of adequate dosing. Antidepressants have long been known to have a delayed onset of action for many but not all patients. Early onset and late onset but persistent patterns of response have been related to a "true" drug pattern, whereas those who respond to placebo tend to have a more fluctuating pattern during an acute-treatment trial of 6-8 weeks. Data from clinical trials suggest that an adequate trial for most patients is in the range of 4-8 weeks to demonstrate response, although the full benefit may not be realized until 12 weeks of acute treatment, especially for chronic depression.

As patients continue to exhibit an almost complete lack of response during the course of an antidepressant trial, the ultimate probability of response starts to fall. About two-thirds of patients who will have an ultimate response at 6 or 8 weeks will have evidence of response by the fourth week of treatment. One must realize, however, that if 4 weeks is used to declare response or nonresponse to an antidepressant, about one-third of ultimate responders will be misclassified as nonresponders. It might be difficult to persuade patients to continue with an antidepressant that has been ineffective for 8 weeks. It makes sense to require a minimum of 4 weeks of treatment at therapeutic doses to define an adequate trial. Guidelines for individual patients suggest a range of time from 4 to 12 weeks.