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Keyword SearchAugmentation and Combination Strategies in Resistant Depression
J. Craig Nelson, MD
Department of Psychiatry, University of California School of Medicine, San Francisco
Supported by an educational grant from Bristol-Myers Squibb Company and Otsuka America Pharmaceutical, Inc.
A minority of patients with major depressive disorder responds to or achieves remission with initial antidepressant treatment. After having no response or partial response, patients are often switched to another medication or given an additional medication to augment the effects of the current antidepressant. Augmentation strategies involve adding an agent that is not approved by the U.S. Food and Drug Administration (FDA) for use as an antidepressant, while combination strategies involve adding an FDA-approved antidepressant. Augmentation and combination treatments have the potential advantage of maintaining the partial response achieved with the initial antidepressant.
Augmentation Strategies
Two meta-analyses1 found that lithium augmentation is effective, but the majority of included studies were small, used tricyclic antidepressants (TCAs) rather than selective serotonin reuptake inhibitors (SSRIs), and did not clearly define resistant depression. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study2 found that lithium was not well tolerated.
The addition of triiodothyronine (T3)—the preparation of thyroid hormone that is usually employed—to a TCA was reported to hasten clinical response in a sample of patients without treatment resistance significantly more than placebo in 5 of 6 studies included in a meta-analysis and review (p < .002).3 However, another meta-analysis4 of 4 placebo-controlled trials using T3 to augment TCAs in treatment-resistant patients failed to find efficacy. Placebo-controlled trials of T3 augmentation of SSRIs in resistant depression have not been reported, although a STAR*D study5 found that the addition of T3 to citalopram resulted in significantly lower discontinuation rates than lithium augmentation (AV 1).
Although the use of stimulants to augment TCAs or monoamine oxidase inhibitors has a long history, no placebo-controlled studies have been reported. Recently, a controlled trial6 examined extended-release methylphenidate augmentation of SSRI therapy in 60 patients. While response rates appeared to favor methylphenidate (40% vs 23% for placebo), the difference was not significant.
The efficacy of modafinil augmentation was examined in a multicenter, controlled study7 of partial responders to SSRI monotherapy with excessive fatigue and sleepiness. The study found that modafinil-treated patients were more likely to be very much improved and have greater overall improvement on the Clinical Global Impressions-Improvement (CGI-I) scale than placebo-treated patients (AV 2). A subsequent extension study8 reported sustained response in responders and improvement in sleepiness, fatigue, and mood in initial nonresponders.
When added at the beginning of treatment, pindolol augmentation of SSRIs may result in more rapid improvement in patients with depression.9 Conversely, when added later in treatment for refractory depression, pindolol augmentation did not appear to elicit a significant response compared with placebo.10
Low folic acid levels are associated with depression.11 Low folate also predicts reduced response to treatment12 and increased risk of relapse.13 One randomized, double-blind study14 found that adding 500 mcg of folate to fluoxetine therapy enhanced response in women. Men were not responsive to folate, but the dose may have been too low. A meta-analysis15 of omega-3 fatty acid found evidence for efficacy in depression; however, the 10 studies included bipolar samples and monotherapy as well as augmentation trials. A preliminary study16 of antidepressant augmentation with an omega-3 fatty acid in patients with breakthrough unipolar depression showed significant benefits versus placebo augmentation (p < .001).
No existing controlled studies have observed significant results with buspirone or testosterone augmentation. However, methodological problems such as small sample size and lack of established treatment resistance existed. Results of estrogen augmentation trials have been inconsistent and have not clearly shown efficacy; the doses and preparations of estrogen and the patient samples (i.e., premenopausal, perimenopausal, or postmenopausal women) have varied among trials.
