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 [email protected].
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.
1. 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. 2006;163:1905-1917.
2. 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. 2000;45:476-481.
3. Lam RW, Hossie H, Solomons K, Yatham LN. Citalopram and bupropion-SR: combining versus switching in patients with treatment-resistant depression. J Clin Psychiatry. 2004;65:337-340.
4. 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. 2006;354:1243-1252.
5. 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.
6. 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. 2011;168:689-701.
7. Sandson NB, Armstrong SC, Cozza KL. An overview of psychotropic drug-drug interactions. Psychosomatics. 2005;46:464-494.
8. 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. 2002;63:181-186.