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Drugs

, Volume 68, Issue 5, pp 653–689 | Cite as

Bupropion

A Review of its Use in the Management of Major Depressive Disorder
  • Sohita Dhillon
  • Lily P. H. Yang
  • Monique P. Curran
Adis Drug Evaluation

Summary

Abstract

Bupropion is presumed to be a dopamine-norepinephrine reuptake inhibitor and is n effective antidepressant. It is available as three oral formulations: (i) bupropion immediate release (IR) [Wellbutrin®] administered three times daily; (ii) bupropion sustained release (SR) [Wellbutrin SR®] administered twice daily; and (iii) bupropion extended/modified release (XR) [Wellbutrin XL®/Wellbutrin XR®] administered once daily. All three formulations are bioequivalent in terms of systemic exposure to bupropion.

Oral three-times-daily bupropion IR was effective and generally well tolerated in the treatment of major depressive disorder (MDD). It was as efficacious and as well tolerated as some tricyclic antidepressants (TCAs) and the selective serotonin reuptake inhibitor (SSRI) fluoxetine. Moreover, it was associated with less somnolence and weight gain than some TCAs. Twice-daily bupropion SR was also efficacious and generally well tolerated in the treatment of MDD. It was as effective as and had a generally similar tolerability profile to some SSRIs, but had the advantage of less somnolence and sexual dysfunction. The efficacy of bupropion XR in terms of primary efficacy measures was established in two of six well designed placebo-controlled studies. Bupropion XR also demonstrated efficacy in terms of some secondary outcomes in five of these studies. Additionally, bupropion XR was similar, in terms of the primary efficacy outcomes, to the SSRI escitalopram in two placebo-controlled trials and to the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine extended release (XR) in two trials (one of which was placebo-controlled), but not in a third placebo-controlled trial where venlafaxine XR was better than bupropion XR. It was generally as well tolerated as escitalopram and venlafaxine XR, but was associated with less sexual dysfunction than escitalopram. Available clinical data suggest that bupropion is an effective and generally well tolerated option in the treatment of MDD, with the newer formulations having the advantage of reduced frequency of daily administration.

Pharmacological Properties

As with all antidepressants, the precise mechanism of action of bupropion in MDD is unknown, although bupropion selectively inhibits dopamine and norepinephrine reuptake. The reuptake inhibition potential of bupropion is greater for dopamine than for norepinephrine. Importantly, bupropion does not affect serotonergic pathways and does not act on postsynaptic histamine, α- or β-adrenergic, dopamine or acetylcholine receptors.

Time to reach maximum plasma concentration (Cmax) varied between bupropion formulations (IR ≈2 h, SR ≈3 h and XR ≈5 h). A decreased number of peak plasma levels were associated with bupropion SR and XR, compared with bupropion IR. However, bioequivalent systemic exposure (as assessed by Cmax and area under the plasma concentration-time curve) was established between all formulations of bupropion and its three pharmacologically active metabolites. Steady state is reached within 8 days. Bupropion is extensively metabolized, mainly by cytochrome P450 (CYP) isoenzymes or via carbonyl reduction. As the active metabolites of bupropion reach higher steady-state concentrations than those of bupropion, these metabolites may be of clinical importance. Bupropion has an elimination half-life (t½) of 20–21 hours and is predominantly (87%) excreted in the urine as metabolites. The t½ of the active metabolites of bupropion are ≈20, ≈33 and ≈37 hours. There is potential for drug-drug interactions between bupropion and drugs that affect CYP2B6 and 2D6 metabolism, drugs that are substrates of these isoenzymes and drugs that affect metabolism in general.

Therapeutic Efficacy

Three-times-daily bupropion IR was effective in the treatment of MDD in a 6-week randomized, double-blind clinical trial in adults with moderate to severe disease, demonstrating greater improvement from baseline in several efficacy measures relative to placebo. Moreover, bupropion IR was as effective as the SSRI fluoxetine, the TCAs nortriptyline, amitriptyline and doxepin, and the atypical antidepressant trazodone in reducing symptoms of depression and anxiety assessed by several efficacy measures in 6- to 13-week trials in adults with MDD.

Similarly, twice-daily bupropion SR was effective in the treatment of MDD in 8-week, randomized, double-blind clinical trials in adults with moderate to severe disease, demonstrating greater improvements from baseline in several efficacy measures relative to placebo. In addition, bupropion SR was effective in preventing relapse in one 52-week relapse-prevention study in a similar patient population. In comparative trials, there were no significant differences between bupropion SR and the SSRIs sertraline or fluoxetine in adults and the SSRI paroxetine in elderly patients with moderate to severe disease in randomized studies of 6- to 16-weeks' duration. Furthermore, bupropion SR was as effective as the SSRI sertraline and the SNRI venlafaxine XR with respect to remission rates (primary efficacy measure) in patients who were switched from citalopram therapy because of a lack of remission of symptoms or because they could not tolerate citalopram in the large, randomized, multicentre STAR*D trial. In the same study, bupropion SR was shown to be as effective as the serotonin receptor agonist buspirone, in terms of remission rates, when used to augment citalopram therapy in a similar patient population. There were some benefits with bupropion SR relative to buspirone therapy as demonstrated by a greater reduction from baseline in self-rated 16-item Quick Inventory of Depressive Symptomology (QIDS-SR-16) score and a lower QIDS-SR-16 score with bupropion compared with buspirone therapy at study end.

Two of six placebo-controlled trials in adult and elderly patients with moderate to severe MDD demonstrated greater improvements from baseline in the 30-item self-rated Inventory of Depressive Symptomology scale or Montgomery-Åsberg Depression Rating Scale (MADRS) total scores (primary efficacy measures) with once-daily bupropion XR relative to placebo. However, in the trial involving elderly patients, although significant reduction from baseline in MADRS total scores in bupropion XR relative to placebo recipients in the last-observation-carried-forward analysis (primary efficacy measure) was not observed, significant improvements from baseline were observed in the protocol-defined observed-case or per-protocol analyses and according to the rank analysis of covariance and robust regression analysis. Benefit with respect to some secondary measures was observed with bupropion XR relative to placebo in five of six placebo-controlled efficacy studies in adults and the elderly.

There were no significant differences between bupropion XR and the SSRI escitalopram in terms of the change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D-17) total score (primary efficacy measure) in patients with moderate to severe disease in placebo-controlled studies of 8 weeks' duration. Similarly, in two 8- and 12-week studies, one of which was placebo-controlled, in patients with similar disease, there were no significant differences between bupropion XR and the SNRI venlafaxine in terms of primary (MADRS total score) or secondary (HAM-D-17 total score) efficacy measures. Additionally, in the 12-week study, more patients achieved remission with bupropion XR than venlafaxine XR therapy. However, in one 8-week placebo-controlled study, venlafaxine XR was better than bupropion XR in terms of MADRS total scores (primary efficacy measure).

Tolerability

All three formulations of bupropion (IR, SR or XR) were generally well tolerated in patients with moderate to severe MDD. Adverse event-related withdrawal rates in pooled analyses were 5–11 % in bupropion IR, SR or XR recipients. Overall, the most common treatment-emergent adverse events reported in bupropion IR, SR or XR versus placebo recipients were headache (20–26% vs 20–23%), dry mouth (16–28% vs 7–18%) and nausea (13–23% vs 8–19%); agitation was another common treatment-emergent adverse event reported in 32% of bupropion IR compared with 22% of placebo recipients. Bupropion SR and XR were also well tolerated in terms of their effects on sexual functioning in patients with MDD.

Most adverse events associated with bupropion SR or XR relative to placebo were mild to moderate in severity. However, there is a dose-dependent risk of seizures (0.4% with bupropion IR 300–450 mg/day; 0.1% with bupropion SR 100–300 mg/day, increasing to 0.4% with bupropion SR 400 mg/day; and 0.1% with bupropion XR ≤450 mg/day) associated with the use of bupropion. Although the effect of bupropion (IR, SR or XR) on suicidality is not clear, it is recommended that patients should be monitored closely. In general, the effects of bupropion (IR, SR or XR) on vital signs (systolic and diastolic blood pressure and heart rate) were small, although some changes (largely an increase in ≤12% of patients) in these parameters with bupropion XR were of potential concern or were sustained (in 3–11% of patients) during therapy.

Although the tolerability profile of bupropion (IR, SR or XR) was generally similar to that of TCAs (nortriptyline, amitriptyline and doxepin), an atypical antidepressant (trazodone), SSRIs (including sertraline, fluoxetine and escitalopram) and an SNRI (venlafaxine XR) in patients with moderate to severe MDD, some adverse events were reported in fewer bupropion than comparator recipients.

Bupropion SR and XR were associated with less sexual dysfunction than SSRIs, such as sertraline and escitalopram. Bupropion XR had a more favourable effect on sexual function than venlafaxine XR in one study, which assessed the parameter as the primary outcome measure, but not in two others where sexual function was assessed as a secondary outcome measure. Bupropion IR and SR were associated with less somnolence relative to some TCAs and SSRIs. On the other hand, the incidence of dry mouth was higher with bupropion IR and SR than with some SSRIs, but lower than that observed with some TCAs. In patients receiving citalopram therapy augmented with bupropion SR or buspirone in the STAR*D trial, discontinuation rates due to intolerance were lower with bupropion SR plus citalopram than with buspirone plus citalopram.

Although bupropion IR, SR and XR were associated with a weight gain of >2.3 kg (>5 lb), the incidence of weight gain was ≈4-fold lower with bupropion IR than with TCAs. Bupropion (IR, SR or XR) was also associated with a weight loss of >2.3 kg (>5 lb). However, the incidence of weight loss with bupropion IR was approximately twice that observed with TCAs. No clinically significant changes in weight were observed in bupropion SR or placebo recipients after 52 weeks of therapy.

Keywords

Major Depressive Disorder Bupropion Escitalopram Immediate Release Primary Efficacy Measure 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  • Sohita Dhillon
    • 1
    • 2
  • Lily P. H. Yang
    • 1
    • 2
  • Monique P. Curran
    • 1
    • 2
  1. 1.Wolters Kluwer Health ¦ AdisMairangi Bay, North Shore, 0754, AucklandNew Zealand
  2. 2.Wolters Kluwer HealthConshohockenUSA

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