As shown in the Figure, continuation of fluoxetine(Drug information on fluoxetine) alone caused no additional benefit as measured by Montgomery-Asberg Depression Rating Scale (MADRS) scores. Olanzapine(Drug information on olanzapine) alone produced only a transient benefit. The combination of olanzapine and fluoxetine, however, was robustly effective by the end of the first week and this was not only sustained through the 8-week trial but also continued through an 8-week extension period.21
More recent research has produced similar findings on a much larger scale. A study at 57 sites in the United States, Canada, France, and the United Kingdom looked at augmentation with risperidone(Drug information on risperidone). This was a 3-phase study. The first phase consisted of screening patients to find those with a Hamilton Rating Scale for Depression (HAM-D) score of greater than 20 and failure of at least one adequate antidepressant trial during the current episode. Qualifying patients were given citalopram(Drug information on citalopram) monotherapy of 20 to 60 mg/d for 4 to 6 weeks. Patients who did not respond were eligible for open-label augmentation with risperidone for 4 weeks. Patients who achieved symptom resolution with this combination were eligible to enter the double-blind continuation phase, which lasted 24 weeks and involved patients either continuing with risperidone and citalopram or with placebo and citalopram.
A small number of patients with de- pression achieved a significant reduction in symptoms with an SSRI alone. However, of the patients with treatment-resistant depression who went on to receive risperidone augmentation, more than 60% achieved greater than a 50% reduction and about 90% achieved at least a 20% reduction in symptoms.22 In this first large-scale continuation trial, the longer-term benefit of continued augmentation with risperidone could only be demonstrated for the most severely ill patients who had treatment-resistant depression.
Looking more closely at another SSRI-atypical antipsychotic combination in patients who have treatment-resistant depression suggests that the matching of augmenting agents to specific patient groups needs to be explored. Dunner and colleagues23 found that patients in whom sertraline(Drug information on sertraline) monotherapy as well as non-SSRI treatment had failed had much larger decreases in depressive symptoms with the combination of ziprasidone(Drug information on ziprasidone) and sertraline than those whose depression was only SSRI-resistant.Psychotherapeutic augmentation
It is important to consider other treatment modalities besides pharmaco-therapy. Psychotherapy should be considered as an augmentation strategy when medication alone does not provide complete remission of symptoms. There are particular symptoms of depression that are targeted by psychotherapy, including hopelessness, anhedonia, low energy, anxiety, negative thoughts and beliefs, interpersonal problems, and medication adherence.24 Cognitive-behavioral therapy (CBT) is one of the best-known, most studied, and most structured formats of psychotherapy. A randomized trial of 156 subjects found that those treated with 8 months of CBT had lower relapse rates at the end of 2 years.25 Another study showed that adding 20 weeks of CBT for patients with incomplete response to antidepressants increased the rate of remission and decreased relapse from 47% with medication alone to 29% with the addition of CBT.26
A type of psychotherapy especially designed to treat chronic, resistant depression is the Cognitive Behavioral Analysis System of Psychotherapy (CBASP). This therapy builds on CBT by including training in interpersonal skills and stress management; these may be significant for persons with longer-term struggles with depression and can hinder recovery if not addressed. A study of 681 patients with chronic depression showed significant response, at least acutely. Of the 519 patients who completed the study, 55% of those treated with nefazodone(Drug information on nefazodone) alone and 52% of those treated with CBASP therapy alone achieved a response. However, 85% of those who received a combination of CBT and CBASP achieved a response.27Augmentation with somatic modalities
Finally, somatic therapies such as electroconvulsive therapy (ECT), vagus nerve stimulation (VNS), repetitive transcranial magnetic stimulation (rTMS), and light therapy can be used in this population. It has been demonstrated that ECT plus medication is superior to medication alone in preventing relapse and recurrence in chronically depressed patients and improving patient survival.28 A complete discussion of VNS is outside the scope of this article, but it is important to include it as an augmentation strategy. VNS is currently approved for the most severely treatment-resistant patients, who would receive it in addition to antidepressant medication. In fact, patients must have failed at least 4 adequate treatment trials for depression. Another option that can be considered is rTMS; however, more research is needed to establish its efficacy in this population.29 Bright-light therapy may also be an effective addition to medication in those patients in whom antidepressant therapy alone fails. A small study found this to be true in 7 of 10 patients.30Conclusions
Our treatment paradigms for treatment-resistant depression are in evolution. We currently have a wide array of options with a limited amount of empiric data to support these strategies. The most compelling data historically are for pharmacologic augmentation with lithium(Drug information on lithium) and thyroid hormone. However, there is an increasing body of data supporting the use of atypical antipsychotic medications and synergistic antidepressant medications. Psychotherapy has proved to be beneficial in treatment-resistant depression and somatic therapies may also prove effective.