It is estimated that at least half of persons who begin antidepressant treatment will not respond to monotherapy.1 When a single antidepressant is ineffective, the addition of 1 or more medications to enhance mood and overall antidepressant response is common.2 While it is hoped that such augmentation strategies will be effective, drug augmentation has drawbacks, including increased cost, unclear dosing strategies, and the possibility of drug-drug interactions.3 A review of augmentation strategies by Fava and Rush4 indicates that current evidence is primarily based on open, uncontrolled studies. The review further stated that lithium augmentation is well supported by controlled studies but was more common in the 1980s than today.
Valenstein and associates5 detailed the frequency of antidepressant augmentation strategies used in 244,859 patients with a diagnosis of unipolar depression for whom antidepressants were prescribed in Veterans Affairs mental health settings. Twenty-two percent of patients were receiving an augmenting agent, most commonly a second antidepressant (11%) or a second-generation antipsychotic (7%). Based on this sample, it appears that antidepressant augmentation is common practice. The authors concluded that although lithium augmentation is the most well-supported approach, it is rarely prescribed. It is important to understand whether the most frequent augmentations are supported by scientific evidence. With that in mind, we examined the literature on augmentation strategies for the most frequently prescribed augmentations for unipolar depression as identified by Valenstein and associates.5
We conducted a PubMed search of studies published before January 1, 2007, to find articles containing medications (using the generic name) or class of drug in the title, abstract, or keywords. Only completed original data articles with efficacy data and that studied participants with a diagnosis of depression were included.
We found 22 studies for the most common augmentation strategies. Table 1 displays the most common augmentation classes according to Valenstein and associates5 and the percentage of patients for whom these augmentations were prescribed, as well as the number of studies using these augmentations.
The most commonly prescribed classes of augmentation with a second antidepressant are not well supported. Two of the most frequently prescribed of these combinations—addition of a noradrenergic and specific serotonergic antidepressant (NaSSA) to a norepinephrine-dopamine reuptake inhibitor (NDRI) and addition of an NDRI to a serotonin-norepinephrine reuptake inhibitor (SNRI)—have no published data to support them.
The augmentation of an SSRI with an atypical antipsychotic had the most evidence, with 11 studies, 3 of which used a placebo control. The second-most frequently prescribed antidepressant-antipsychotic augmentation strategy (adding an atypical antipsychotic to an NDRI) has no published data available.
The limited amount of available data is problematic, as is the design or quality of the research. Comparisons vary widely, including studies comparing augmentation strategies with other combination strategies, individual drugs, the augmentation drug by itself, and placebo control groups. Only 6 studies used a placebo control—3 with augmentations with antidepressants and 3 with augmentations with antipsychotics. Of the placebo controls, 5 studies used a placebo augmentation and 1 used a monotherapy placebo group.
Although data from a class of drugs are considered applicable for specific drugs within that class, we examined whether the most frequently prescribed drugs are also the most frequently studied drugs. Table 2 displays the top augmentations and the number of times results of an examination of each combination was published in an article.
Using our search strategy, we were unable to locate any published studies for the most frequently prescribed antidepressant augmentation (bupropion augmented with sertraline), and 4 of the 9 most frequently prescribed antidepressant augmentations do not appear to have any published data. We were unable to locate any published studies on the top 2 antipsychotic augmentations (sertraline augmented with risperidone or with olanzapine), and 7 of the 10 most frequently prescribed antipsychotic augmentations do not appear to have any published data available. With the possible exception of the combination of fluoxetine and olanzapine, no combination appears to have sufficient published data to meet the FDA standard for initial approval of at least 2 positive placebo-controlled studies.
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2. DeBattista C. Augmentation and combination strategies for depression. J Psychopharmacol. 2006;20 (suppl 3):11-18.
3. Antonuccio DO, Burns D, Danton WG. Antidepressants: a triumph of marketing over science? Prevention and Treatment. 2002;5:article 25. Available at: http://www.antidepressantsfacts.com/2002-07-15-Antonuccio-therapy-vs-med.htm. Accessed June 18, 2007.
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