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While SSRIs and SNRIs are valuable in the treatment of major depression, partial response or nonresponse occurs in many patients. Research has found that bupropion was the most frequently chosen agent for addition to an SSRI after inadequate response.
This is the third in a series of occasional columns that aim to help clinicians interpret research related to a clinical question. Perhaps more important, the tips and discussion of the issues aim to improve clinicians’ understanding of research methodology and critical appraisal of the literature in general. Your questions, comments, and suggestions are eagerly solicited at firstname.lastname@example.org.
While SSRIs and SNRIs are valuable in the treatment of major depressive disorder (MDD), partial response or nonresponse occurs in many patients.1 In a survey of clinicians, the most frequently chosen agent for addition to an SSRI after inadequate response was bupropion (30%).2 In that survey, bupropion was chosen as the “augmenting” agent by more experienced clinicians; by US rather than Canadian clinicians; and by clinicians from community, individual practice, or group settings rather than from academic settings.
TIP: Many treatment strategies that are widely practiced are not based on scientific evidence. Make it a habit to question treatments that are routinely used. Some of these treatments may in fact turn out to be effective, but some others will be shown to be myths. The history of medicine is full of treatments that were widely used for years before being shown to be myths.
Is the strategy of adding bupropion to an SSRI or SNRI based on reliable scientific studies or mainly on the hypothesis that combining antidepressants with different mechanisms of action may result in greater efficacy than using either one of them alone?
Case reports and open-label studies3 have suggested that augmentation of SSRIs or SNRIs with bupropion may be efficacious.
TIP: When trying to determine whether a treatment is efficacious or not, look for only double-blind, randomized, controlled trials (RCTs). Case reports and uncontrolled studies can only suggest that a treatment may work, but such treatments are frequently disproved. Busy clinicians can save a lot of reading time and avoid confusion by focusing only on RCTs whenever possible.
Before looking for evidence, we should define our questions. Is addition of bupropion to an SSRI or SNRI helpful in patients (1) with minimal or no response to the SSRI or SNRI? (2) with response to the SSRI or SNRI (greater than 50% improvement) but failure to achieve remission? or (3) who are just starting treatment with the SSRI or SNRI, ie, from the outset? (The possibility that bupropion may treat some of the adverse effects of serotonergic antidepressants is beyond the purview of this column.) Importantly, we must distinguish from switching from an SSRI to bupropion (ie, is any perceived benefit from the addition of bupropion to an SSRI better than simply switching to bupropion?).
A systematic search of the MEDLINE and Scopus databases was done (last on December 8, 2011). Many clinicians will be surprised to know that no RCT of the addition of bupropion to an SSRI or SNRI has ever been conducted. This includes a comparison to simply continuing the SSRI or SNRI, switching to bupropion, or other possible comparison strategies. There are, however, other types of studies that shed some tentative light on the issue and a discussion of their limitations may be of general educational value.
The STAR*D study included the addition of bupropion in patients with MDD who did not achieve remission after 12 weeks of treatment with citalopram.4 This strategy was compared with augmentation of citalopram with buspirone. However, in this large sample (N = 565), no statistically significant difference was found in remission (the primary outcome measure) between the two groups.
TIP: If no statistically significant difference is found between two treatments, we cannot conclude that they work equally well or equally poorly. Without a placebo control group, it is not possible to say whether this particular study in this particular set of patients had the ability to detect a meaningful effect or difference. This concept is called “assay sensitivity” and is analogous to a control window in a home pregnancy test that indicates that the test is working correctly. In clinical trials, if one or more of the treatments is superior to placebo, this indicates that the “assay” is working.
However, in the STAR*D study, citalopram plus bupropion was found to be better than citalopram plus buspirone on several secondary outcome measures.4
TIP: Why do researchers differentiate between primary and secondary outcome measures? Because hypothesis testing is based on probability, and the more statistical tests of comparison that are done, the greater the likelihood that one test will be “significant” by chance alone. Secondary outcome measures should either be corrected for multiple comparisons (a simple way for readers to do this is to divide 0.05 by the number of comparisons and use that P value as the cutoff for statistical significance) or be considered tentative and in need of confirmation.
In the STAR*D study, the only difference that met this lower cutoff was number of dropouts because of intolerance (P < .0009) (ie, patients receiving citalopram+buspirone dropped out because of adverse effects more often than those receiving citalproam+bupropion). Notably, the proportion of patients who had a response (50% or greater reduction) on self-rated depression did not differ between the two groups. Thus, we cannot conclude with confidence from this study that the combination of an SSRI and bupropion is efficacious on the basis of either response or remission as the outcome.
A recent, small clinical trial from India randomized 60 patients with MDD who had not responded adequately to a 4-week trial of an SSRI to the addition of either bupropion or placebo.5 The study found that add-on bupropion was significantly superior to add-on placebo in reducing the severity of depression. However, a few serious problems with the study design prevent us from drawing confident conclusions.
First, the trial was conducted in a single-blind rather than a double-blind manner, which is not a minor problem. Remember that investigators are likely to have conscious and unconscious biases in favor of the treatment they are evaluating, perhaps even more so than patients. This bias not only can affect investigators’ ratings but also may be inadvertently communicated to the patients. Therefore, double-blind is not an optional feature but rather is crucial to the conduct of scientifically valid research.
Second, it would be more appropriate to set the minimum duration of the trial of the SSRI at 6 (or even 8) weeks before patients are considered to have an inadequate response to the antidepressant.
Third, the SSRI trial was received before patients entered this study. Thus, their adherence and the trajectory of improvement could not have been reliably determined. It is now standard to conduct a prospective trial of the antidepressant; all patients also receive a placebo to determine whether patients have an adequate response to the SSRI.
Fourth, during the 4 weeks of the trial, the dose of the SSRI was increased if needed. This added a potential source of bias that is hard to evaluate.
Recently, the Combining Medications to Enhance Depression Outcomes (CO-MED) study looked at our third issue above.6 This randomized single-blind trial assessed whether the combination of escitalopram and bupropion from the outset in patients with MDD who were not treatment-resistant was superior to escitalopram and placebo. There was no difference in remission rates after 12 weeks of treatment.
How would the single-blind nature of administration of bupropion or matching placebo in this study affect our interpretation of the result?
TIP: For any design feature, ask yourself if it strengthens or weakens the findings of the study. In this case, if the investigator knew which patients were getting a placebo and which were getting bupropion and an unconscious bias operated, wouldn’t the investigator be less likely to rate the patients who were receiving placebo as improved? If so, lack of investigator blinding would make it more likely that in combination with escitalopram, bupropion would be found more efficacious than placebo. Since this was not found, we can conclude that the single-blind actually strengthens the conclusion that bupropion is not more efficacious than placebo when added to escitalopram from the outset.
If, in the future, bupropion augmentation is more convincingly shown to be superior to augmentation with a placebo, the question remains about the mechanism of this augmentation, which, in turn, leads to some important clinical questions:
1. Is the addition of bupropion more efficacious than increasing the dose of the SSRI or SNRI? Bupropion is a moderately potent inhibitor of cytochrome P-450 2D6. Therefore, it may increase the levels of some antidepressants, including duloxetine.7 However, another study did not find plasma levels of paroxetine to be elevated after addition of bupropion.8 Conversely, fluoxetine, fluvoxamine, sertraline, and paroxetine may, at least in theory, increase bupropion levels by inhibiting cytochrome P-450 2B6 isoenzyme.7
2. Is the addition of bupropion more efficacious than switching to bupropion? That is, is the addition of bupropion effective only because bupropion alone is efficacious in these patients-or can we truly refer to the combination as augmentation?
Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report.
Am J Psychiatry.
Mischoulon D, Nierenberg AA, Kizilbash L, et al. Strategies for managing depression refractory to selective serotonin reuptake inhibitor treatment: a survey of clinicians.
Can J Psychiatry
Lam RW, Hossie H, Solomons K, Yatham LN. CitalÂopram and bupropion-SR: combining versus switching in patients with treatment-resistant depression.
J Clin Psychiatry
Trivedi MH, Fava M, Wisniewski SR, et al; STAR*D Study Team. Medication augmentation after the failure of SSRIs for depression.
N Engl J Med
Gulrez G, Badyal DK, Deswal RS, Sharma A. Bupropion as an augmenting agent in patients of depression with partial response.
Basic Clin Pharmacol Toxicol
. 2011 Sep 3; [Epub ahead of print]. doi:10.1111/j.1742-7843.2011.00788.x.
Rush AJ, Trivedi MH, Stewart JW, et al. Combining medications to enhance depression outcomes (CO-MED): acute and long-term outcomes of a single-blind randomized study.
Am J Psychiatry
Sandson NB, Armstrong SC, Cozza KL. An overview of psychotropic drug-drug interactions.
Kennedy SH, McCann SM, Masellis M, et al. Combining bupropion SR with venlafaxine, paroxetine, or fluoxetine: a preliminary report on pharmacokinetic, therapeutic, and sexual dysfunction effects.
J Clin Psychiatry